Sample records for cblc-type methylmalonic aciduria

  1. N-carbamylglutamate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria. (United States)

    Filippi, Luca; Gozzini, Elena; Fiorini, Patrizio; Malvagia, Sabrina; la Marca, Giancarlo; Donati, Maria Alice


    In propionic aciduria and methylmalonic aciduria, hyperammonemia as a symptom of metabolic decompensation is one of the major clinical problems. Hyperammonemia is a true neonatal emergency with high mortality and neurological complications in most survivors. It requires a rapid and vigorous treatment in order to normalize the ammonia concentration as fast as possible. We report on two full-term neonates, one with propionic aciduria and the other with methylmalonic aciduria, whose plasma ammonia concentrations responded dramatically to oral N-carbamylglutamate. N-carbamylglutamate, added to the classic treatment, quickly normalized plasma ammonia levels in both patients and avoided the need of hemodialysis or peritoneal dialysis. A particularly sudden fall of ammonia was obtained in one patient through beginning N-carbamylglutamate treatment precociously.

  2. Prenatal diagnosis of methylmalonic aciduria by measuring methylmalonic acid in dried amniotic fluid on filter paper using gas chromatography-mass spectrometry. (United States)

    Inoue, Yoshito; Ohse, Morimasa


    Methylmalonic aciduria is a common inherited metabolic disorder. Methylmalonic acid (MMA), a key indicator of methylmalonic aciduria, increases in the amniotic fluid of affected fetuses. For prenatal diagnosis, the MMA in amniotic fluid can be measured by stable-isotope dilution gas chromatography-mass spectrometry. Here, we quantified the MMA in cell-free amniotic fluid samples that had been dried on filter paper and transported at ambient temperatures, and compared the results with data obtained from the original amniotic fluid. Our results indicated that the filter paper method was reproducible and accurate enough to be applied to clinical analysis. We also used the filter paper method to screen at-risk fetuses and obtained a clear diagnosis in each case. We conclude that our method enables the prenatal diagnosis of methylmalonic aciduria using practical procedures and a simplified method for transporting the samples.

  3. Neurodegeneration and chronic renal failure in methylmalonic aciduria--a pathophysiological approach. (United States)

    Morath, M A; Okun, J G; Müller, I B; Sauer, S W; Hörster, F; Hoffmann, G F; Kölker, S


    In the last decades the survival of patients with methylmalonic aciduria has been improved. However, the overall outcome of affected patients remains disappointing. The disease course is often complicated by acute life-threatening metabolic crises, which can result in multiple organ failure or even death, resembling primary defects of mitochondrial energy metabolism. Biochemical abnormalities during metabolic derangement, such as metabolic acidosis, ketonaemia/ketonuria, lactic acidosis, hypoglycaemia and hyperammonaemia, suggest mitochondrial dysfunction. In addition, long-term complications such as chronic renal failure and neurological disease are frequently found. Neuropathophysiological studies have focused on various effects caused by accumulation of putatively toxic organic acids, the so-called 'toxic metabolite' hypothesis. In previous studies, methylmalonate (MMA) has been considered as the major neurotoxin in methylmalonic aciduria, whereas more recent studies have highlighted a synergistic inhibition of mitochondrial energy metabolism (pyruvate dehydrogenase complex, tricarboxylic acid cycle, respiratory chain, mitochondrial salvage pathway of deoxyribonucleoside triphosphate (dNTP)) induced by propionyl-CoA, 2-methylcitrate and MMA as the key pathomechanism of inherited disorders of propionate metabolism. Intracerebral accumulation of toxic metabolites ('trapping' hypothesis') is considered a biochemical risk factor for neurodegeneration. Secondary effects of mitochondrial dysfunction, such as oxidative stress and impaired mtDNA homeostasis, contribute to pathogenesis of these disorders. The underlying pathomechanisms of chronic renal insufficiency in methylmalonic acidurias are not yet understood. We hypothesize that renal and cerebral pathomechanisms share some similarities, such as an involvement of dicarboxylic acid transport. This review aims to give a comprehensive overview on recent pathomechanistic concepts for methylmalonic acidurias.

  4. Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model

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    Buck, Nicole E., E-mail: [Metabolic Research, Murdoch Childrens Research Institute, The University of Melbourne, Department of Paediatrics, Royal Children' s Hospital, Flemington Road, Parkville, VIC 3052 (Australia); Pennell, Samuel D.; Wood, Leonie R. [Metabolic Research, Murdoch Childrens Research Institute, The University of Melbourne, Department of Paediatrics, Royal Children' s Hospital, Flemington Road, Parkville, VIC 3052 (Australia); Pitt, James J. [Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children' s Hospital, Parkville (Australia); Allen, Katrina J. [Gastro and Food Allergy, Murdoch Childrens Research Institute, Parkville (Australia); Peters, Heidi L. [Metabolic Research, Murdoch Childrens Research Institute, The University of Melbourne, Department of Paediatrics, Royal Children' s Hospital, Flemington Road, Parkville, VIC 3052 (Australia)


    Highlights: Black-Right-Pointing-Pointer Fetal cells were transplanted into a methylmalonic acid mouse model. Black-Right-Pointing-Pointer Cell engraftment was detected in liver, spleen and bone marrow. Black-Right-Pointing-Pointer Biochemical disease correction was measured in blood samples. Black-Right-Pointing-Pointer A double dose of 5 million cells (1 week apart) proved more effective. Black-Right-Pointing-Pointer Higher levels of engraftment may be required for greater disease correction. -- Abstract: Methylmalonic aciduria is a rare disorder caused by an inborn error of organic acid metabolism. Current treatment options are limited and generally focus on disease management. We aimed to investigate the use of fetal progenitor cells to treat this disorder using a mouse model with an intermediate form of methylmalonic aciduria. Fetal liver cells were isolated from healthy fetuses at embryonic day 15-17 and intravenously transplanted into sub-lethally irradiated mice. Liver donor cell engraftment was determined by PCR. Disease correction was monitored by urine and blood methylmalonic acid concentration and weight change. Initial studies indicated that pre-transplantation sub-lethal irradiation followed by transplantation with 5 million cells were suitable. We found that a double dose of 5 million cells (1 week apart) provided a more effective treatment. Donor cell liver engraftment of up to 5% was measured. Disease correction, as defined by a decrease in blood methylmalonic acid concentration, was effected in methylmalonic acid mice transplanted with a double dose of cells and who showed donor cell liver engraftment. Mean plasma methylmalonic acid concentration decreased from 810 {+-} 156 (sham transplanted) to 338 {+-} 157 {mu}mol/L (double dose of 5 million cells) while mean blood C3 carnitine concentration decreased from 20.5 {+-} 4 (sham transplanted) to 5.3 {+-} 1.9 {mu}mol/L (double dose of 5 million cells). In conclusion, higher levels of engraftment may

  5. N-carbamylglutamate enhances ammonia detoxification in a patient with decompensated methylmalonic aciduria. (United States)

    Gebhardt, Boris; Vlaho, Stefan; Fischer, Doris; Sewell, Adrian; Böhles, Hansjosef


    In patients with methylmalonic aciduria (MMA), the accumulating metabolite propiony-CoA results in an inhibition of the urea circle via the decreased synthesis of N-acetylglutamate, an essential activator of carbamylphosphat synthetase (CPS). This results in one of the major clinical problems which is hyperammonaemia. In a patient with decompensated MMA, the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA-induced hyperammonaemia. Oral carbamylgutamate administration resulted in an impressive increase in ammonia detoxification compared to peritoneal dialysis. Safe, fast and easy to administer, carbamylglutamate improves the acute therapy of decompensated MMA by increasing ammonia detoxification and avoiding hyperammonaemia.

  6. A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria

    DEFF Research Database (Denmark)

    Østergaard, Elsebet; Schwartz, Marianne; Batbayli, Mustafa;


    Mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria is associated with mutations in SUCLA2, the gene encoding a beta subunit of succinate-CoA ligase, where 17 patients have been reported. Mutations in SUCLG1, encoding the alpha subunit of the enzyme, have been reported...

  7. Prenatal diagnosis of methylmalonic aciduria by analysis of organic acids and total homocysteine in amniotic fluid

    Institute of Scientific and Technical Information of China (English)


    Background Methylmalonic aciduria (MMA )is the most frequent disease of organic aciduria in China.Various biochemical strategies are followed for the prenatal diagnosis of MMA.However,since fetuses affected by MMA have decreased excretion of methylmalonic acid,the difficulties of prenatal biochemical diagnosis are obvious.Gas chromatography mass spectrometry (GC/MS) and tandem mass spectrometry (ESI/MS/MS) have allowed us to identify the disease in affected fetuses.The aim of this study was to determine the value of analysis of organic acids and total homocysteine in amniotic fluid in prenatal diagnosis of MMA.Methods The clinical diagnoses and outcomes of nine probands with MMA and the prenatal diagnoses based on biochemical analysis of nine fetuses at risk for MMA were investigated.Amniotic fluid samples from pregnancies at risk for MMA and metabolically normal pregnancies were obtained at 16-24 weeks of gestation.Methylmalonic acid and methylcitric acid were measured by GC/MS,propionylcarnitine was analyzed by ESI/MS/MS,and total homocysteine was determined by fluorescence polarization immunoassay.Results In two pregnancies,high levels of methylmalonic acid,methylcitric acid,propionylcarnitine,and total homocysteine indicated combined MMA and homocysteinemia in the fetuses.One of the mothers continued pregnancy and received cobalamin supplement as prenatal treatment,and the other terminated her pregnancy.In one pregnancy,significantly elevated levels of methylmalonic acid,methylcitric acid,and propionylcarnitine,and normal level of total homocysteine was found indicating isolated MMA in the fetus;abortion was performed on this case.In the other six pregnancies,all the levels of the above mentioned metabolites were normal suggesting that the fetuses were not affected by MMA. The diagnoses were confirmed after delivery by testing urinary organic acids and plasma total homocysteine.Conclusions The metabolic abnormalities of MMA occur early in gestation.The level of

  8. Clinical experience with N-carbamylglutamate in a single-centre cohort of patients with propionic and methylmalonic aciduria


    Alberto Burlina; Chiara Cazzorla; Elisa Zanonato; Emanuela Viggiano; Ilaria Fasan; Giulia Polo


    Background: The effect of long-term N-carbamylglutamate (NCG) treatment on the rate and severity of decompensations due to propionic aciduria (PA) and methylmalonic aciduria (MMA) is unknown. This paper presents clinical experience from a single-centre cohort of patients with PA and MMA who received continuous long-term treatment with NCG. Methods: The effect of oral NCG treatment (initial dose: 50 mg/kg/day) was investigated in patients with PA or MMA who were experiencing frequent progre...

  9. Methylmalonic aciduria (cblF): case report and response to therapy. (United States)

    Waggoner, D J; Ueda, K; Mantia, C; Dowton, S B


    Methylmalonic acidemia can be secondary to a deficiency of methylmalonyl CoA mutase or to a defect of cobalamin metabolism that is classified by complementation group. We report on a new patient with cblF complementation group that is associated with an elevation of both methylmalonic acid and homocysteine, and her outcome in response to routine therapy and a dietary restriction.

  10. Crystal Structure And Mutagenisis of the Metallochaperone MeaB: Insight Into the Causes of the Methylmalonic Aciduria

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    Hubbard, P.A.; Padovani, D.; Labunska, T.; Mahlstedt, S.A.; Banerjee, R.; Drennan, C.L.


    MeaB is an auxiliary protein that plays a crucial role in the protection and assembly of the B{sub 12}-dependent enzyme methylmalonyl-CoA mutase. Impairments in the human homologue of MeaB, MMAA, lead to methylmalonic aciduria, an inborn error of metabolism. To explore the role of this metallochaperone, its structure was solved in the nucleotide-free form, as well as in the presence of product, GDP. MeaB is a homodimer, with each subunit containing a central {alpha}/{beta}-core G domain that is typical of the GTPase family, as well as a-helical extensions at the N and C termini that are not found in other metalloenzyme chaperone GTPases. The C-terminal extension appears to be essential for nucleotide-independent dimerization, and the N-terminal region is implicated in protein-protein interaction with its partner protein, methylmalonyl-CoA mutase. The structure of MeaB confirms that it is a member of the G3E family of P-loop GTPases, which contains other putative metallochaperones HypB, CooC, and UreG. Interestingly, the so-called switch regions, responsible for signal transduction following GTP hydrolysis, are found at the dimer interface of MeaB instead of being positioned at the surface of the protein where its partner protein methylmalonyl-CoA mutase should bind. This observation suggests a large conformation change of MeaB must occur between the GDP- and GTP-bound forms of this protein. Because of their high sequence homology, the missense mutations in MMAA that result in methylmalonic aciduria have been mapped onto MeaB and, in conjunction with mutagenesis data, provide possible explanations for the pathology of this disease.

  11. N-Carbamylglutamate Is an Effective Treatment for Acute Neonatal Hyperammonaemia in a Patient with Methylmalonic Aciduria. (United States)

    Yap, Sufin; Leong, Huey Yin; Abdul Aziz, Fadzlina; Hassim, Haszlin; Sthaneshwar, Pavai; Teh, Ser Huy; Abdullah, Ili Syazwana; Ngu, Lock Hock; Mohamed, Zulqarnain


    N-carbamylglutamate (NCG) has been used in combination with ammonia scavengers (sodium benzoate, sodium phenylbutyrate) and dialysis to treat hyperammonaemia in methylmalonic aciduria (MMA). The sole use of NCG for acute neonatal hyperammonaemia secondary to MMA is demonstrated in a neonate presenting at day 9 with encephalopathy, severe metabolic acidosis, hyperammonaemia (1,089 μmol/l), ketonuria and urinary methylmalonic acids. Emergency treatment included discontinuing protein feeds, providing high calories, carnitine and hydroxocobalamin. NCG 200 mg given at 0 and 90 min decreased plasma ammonia dramatically from 1,089 to 567 µmol/l at 90 min and further to 236 µmol/l at 6 h. Normalisation of ammonia was achieved at 12 h with two further doses of NCG 100 mg. This allowed for early re-institution of feeds at 14 h, followed by metabolic stabilization and recovery. Due to the effectiveness of NCG in this case, the use of the more invasive conventional ammonia-lowering therapeutic options could be avoided.

  12. Refractory focal epilepsy in a patient with methylmalonic aciduria: case report on positive and long-lasting effect of rufinamide. (United States)

    von Stülpnagel, C; Leichsenring, M; Müller, A; Staudt, M; Kluger, G


    We report on a 5-year-old boy with methylmalonic aciduria, an autosomal recessive inborn error of metabolism leading to accumulation of methylmalonic-CoA and thereby causing intoxication with leading symptoms of hyperammonaemia and metabolic acidosis. Hyperammonemia itself causes brain oedema. In our patient, this led to a vast metabolic stroke of the left hemisphere and subsequent pharmacoresistant epilepsy. Guided by his main seizures--drop attacks--the orphan drug rufinamide (RUF) was introduced as "off-label use" and led to freedom of drop attacks and tonic-clonic seizures over a period of 14 months as well as normalisation of the electroencephalogramm. Only once during an episode of fever and diarrhoea with reduced level of RUF did some provoked seizures with focal complex semiology for the time period of infection occur. In the 16 months follow-up, the patient also improved in his development, showing a more stable gait with the hemiparesis and understanding more complex sentences.

  13. Resolution of cor pulmonale after medical management in a patient with cblC-type methylmalonic aciduria and homocystinuria: a case report. (United States)

    Profitlich, Laurie; Kirmse, Brian; Wasserstein, Melissa P; Diaz, George; Srivastava, Shubhika


    We describe a 3-year-old Hispanic male with cblC-type methylmalonic aciduria and homocystinuria who presented to the emergency department with progressive tachypnea, vomiting, and edema secondary to pulmonary embolism and cor pulmonale. With aggressive medical management, there was complete resolution of right heart failure and pulmonary hypertension after 3 months. Pulmonary embolism is rare in the pediatric population. Children with cblC-type methylmalonic aciduria and homocystinuria may be at increased risk for thrombus formation and pulmonary embolism due to chronic hyperhomocystinemia, a risk factor for thrombus formation in the adult population. Aspirin therapy may be indicated in children with inborn errors of metabolism that predispose to hyperhomocystinemia.

  14. Renal thrombotic microangiopathy in patients with cblC defect : review of an under-recognized entity

    NARCIS (Netherlands)

    Beck, Bodo B; van Spronsen, FrancJan; Diepstra, Arjan; Berger, Rolf M F; Kömhoff, Martin


    Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is the most common genetic type of functional cobalamin (vitamin B12) deficiency. This metabolic disease is characterized by marked heterogeneity of neurocognitive disease (microcephaly, seizures, developmental delay, ataxia, hypoto

  15. Combined methylmalonic aciduria and homocysteinemia with hydrocephalus as an early presentation: a case report%以脑积水起病的甲基丙二酸尿症合并同型半胱氨酸血症1例报道

    Institute of Scientific and Technical Information of China (English)

    刘黎黎; 侯新琳; 周丛乐; 杨艳玲


    A case of combined methylmalonic aciduria and homocysteinemia presenting with hydrocephalus as an early manifestation was reported for its rarity to see and to discuss the relationship between metabolic diseases and hydrocephalus by literature review. The case was an infant with seizures and hydrocephalus as an early manifestation of the disease, combined with macrocyticanemia, development retardation and visual hearing function lesions. The EEG showed hypsarrhythmia and the MRI showed hydrocephalus. Plasma homocysteinemia level increased (143.06 umol/L) and urine methylmalonic aciduria was 1483 times beyond normal. Based on gene analysis results and increased methylmalonic aciduria and homocysteinemia levels, combined methylmalonic aciduria and homocysteinemia was confirmed, presenting CblC defect ( gene mutations homozygous for c. 609G > A). After treatment by venous injection of vitamin B12, oral folic acid and betaine, seizures were controlled and development was progressive with ventricle retraction. It was concluded that hydrocephalus can be the early presentation in children with combined methylmalonic aciduria and homocysteinemia. Doctors should carry out metabolic disease screening for patients with hydrocephalus, especially when the cause of hydrocephalus is uncertain.%甲基丙二酸尿症合并同型半胱氨酸血症极少以脑积水起病.本文报道1例以脑积水起病的该病病例,并进行文献复习,探讨该类有机酸代谢病与脑积水的关系.该患儿以抽搐、脑积水起病,存在大细胞性贫血,发育评估落后,视听功能损伤,脑电图高峰失律,头颅磁共振及超声证实脑积水.血同型半胱氨酸升高,为143.06μmol/L,尿代谢筛查甲基丙二酸浓度为正常值的1483倍,基因检测确诊甲基丙二酸尿症合并同型半胱氨酸血症,为位于lp34.1的c.609G>A纯合突变,属于CblC型维生素B12合成酶缺陷.确诊后加用静脉维生素B12、口服叶酸、甜菜碱后,患儿抽搐缓

  16. Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins.

    NARCIS (Netherlands)

    Schwab, M.A.; Sauer, S.W.; Okun, J.G.; Nijtmans, L.G.J.; Rodenburg, R.J.T.; Heuvel, L.P.W.J. van den; Drose, S.; Brandt, U.; Hoffmann, G.F.; Laak, H.J. ter; Kolker, S.; Smeitink, J.A.M.


    Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternat

  17. A Methylmalonic Acidemia Case Presenting with Acrodermatitis Enteropathica

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    hesaneh izadyar


    Full Text Available We encountered a patient with methylmalonic aciduria associated with skin lesions resembling acrodermatitis enteropathica. This child was being fed with a low-protein diet when the skin disorder developed. A deficiency in plasma levels isoleucine, was confirmed. Supplementation of a high-caloric, protein-rich diet led to a prompt improvement of skin lesions. We assume that in our patient the skin lesions were the result of malnutrition, rather than being primarily associated with the underlying metabolic disease. To our knowledge, few reports are so far available concerning methylmalonic aciduria complicated by skin eruptions.

  18. Peripheral nervous impairment in a patient with methylmalonic aciduria combined with hyperhomocysteinemia%以周围神经损伤为主要表现的甲基丙二酸尿症合并同型半胱氨酸血症1例

    Institute of Scientific and Technical Information of China (English)

    季涛云; 张月华; 李飞天; 秦炯; 杨艳玲


    甲基丙二酸尿症合并同型半胱氨酸血症可以导致多系统损伤,以中枢神经损伤为主,周围神经损伤较少见.本文拟就1例以周围神经损伤为主要表现的甲基丙二酸尿症合并同型半胱氨酸血症患者进行研究.患儿为10岁男童,主因“双下肢无力1个月”就诊,既往轻度智力运动发育落后,轻度学习困难.3岁时曾有蛋白尿,经治疗后好转.8岁6个月时曾有抽搐,应用丙戊酸钠治疗后发作控制.体格检查显示双侧膝腱反射减弱,双侧跟腱反射未引出,浅深感觉未见异常,双侧巴氏征(+),肌电图检查证实为周围神经损伤.尿液甲基丙二酸及血清同型半胱氨酸显著升高,符合甲基丙二酸尿症合并同型半胱氨酸血症诊断,MMACHC基因分析显示患者存在两个致病杂合突变(c.365A>T和c.609G >A),证实为cblC缺陷.针对原发病,给予维生素B12、亚叶酸钙、左卡尼汀及甜菜碱治疗,患者病情逐步改善,半年后随访患儿无力症状消失,运动功能恢复,智力发育亦显著进步,可正常就读.本例患者提示,周围神经损伤也是甲基丙二酸尿症合并同型半胱氨酸血症的合并症之一,对不明原因周围神经疾病,尤其是伴有多系统受累的患者,应尽早行尿液有机酸分析及血清总同型半胱氨酸测定,以明确诊断,正确治疗,改善预后.%Methylmalonic aciduria combined homocysteinemia can cause multisystemic damages, mainly involving central nervous system, while the peripheral nerves are rarely impaired. A 10-year-old boy complained of weakness of both lower extremities for 1 month. His past history showed mildly delay of intelligence as well as motor development. He had proteinuria when he was 3 years old and was diagnosed as epilepsy, which was controlled by sodium valproate when he was 8 years 6 months old. His physical examination showed attenuated bilateral knee jerk reflex, while the bilateral achilles tendon reflex was absent

  19. MMACHC gene mutation analysis in the prenatal diagnosis of methylmalonic aciduria with homocystinuria%甲基丙二酸血症结合同型半胱氨酸血症家系MMACHC 基因突变分析及在产前诊断中的应用

    Institute of Scientific and Technical Information of China (English)

    蔡奥捷; 宗亚楠; 刘宁; 魏振玲; 白莹; 赵振华; 孔祥东


    Objective To analyse MMACHC mutations for 45 pedigrees with combined methylmalonic aciduria and homocyctinuria by Sanger sequencing, and to discuss the utility of prenatal genetic diagnosis for these pedigrees.Method Peripheral blood was collected from 45 probands and their parents from 2012-2015 in Genetic Counselling Clinic of the First Affiliated Hospital of Zhengzhou University, and the DNA were extracted from the blood.Then the coding sequence of MMACHC gene was amplified by PCR, and the PCR products were further sequenced to detect mutations for each pedigree.For 12 families, chorionic villus sampling was performed on the pregnant women to make prenatal genetic diagnosis.Result There were 14 distinct mutations detected in the 45 pedigrees, and the most frequent mutations are c.609G>A(W203X),c.658-660delAAG(K220del)and c.80A>G (Q27A).Two of those mutations have not been reported before:one is a splicing site mutation c.81+1G>A;while the other is a missense mutation c.665A>G,p.Y222C.Most mutations were found in exon 4.Among the 12 pedigrees who received prenatal diagnosis, 2 fetuses were normal, 7 fetuses were carriers of heterozygous mutation, and the other 3 fetuses were patients with compound heterozygous mutation or homozygous mutation.The couples whose fetuses were normal or carriers continued the gestation, while the couples whose fetuses were patients decided to terminate the pregnancy.After delivery, the outcome of the fetuses was the same as the prenatal diagnose results.Conclusion Two novel mutations of MMACHC were identified and prenatal genetic diagnosis helps to avoid the delivery of combined methylmalonic aciduria and homocyctinuria patients.%目的:利用Sanger测序对45例甲基丙二酸血症结合同型半胱氨酸血症家系MMACHC基因的突变进行分析,并探讨其对甲基丙二酸血症结合同型半胱氨酸血症生育史家系再次生育前行产前诊断的可能性。方法采集2012至2015年来自郑州大学第一附

  20. Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia?

    Directory of Open Access Journals (Sweden)

    Guffon Nathalie


    Full Text Available Abstract Background Hyperammonemia in patients with methylmalonic aciduria (MMA and propionic aciduria (PA is caused by accumulation of propionyl-CoA which decreases the synthesis of N-acetyl-glutamate, the natural activator of carbamyl phosphate synthetase 1. A treatment approach with carglumic acid, the structural analogue of N-acetyl-glutamate, has been proposed to decrease high ammonia levels encountered in MMA and PA crises. Case presentation We described two patients (one with MMA and one with PA with hyperammonemia at diagnosis. Carglumic acid, when associated with standard treatment of organic acidurias, may be helpful in normalizing the ammonia level. Conclusion Even though the usual treatment which decreases toxic metabolites remains the standard, carglumic acid could be helpful in lowering plasma ammonia levels over 400 micromol/L more rapidly.

  1. Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia? (United States)

    Levrat, Virginie; Forest, Isabelle; Fouilhoux, Alain; Acquaviva, Cécile; Vianey-Saban, Christine; Guffon, Nathalie


    Background Hyperammonemia in patients with methylmalonic aciduria (MMA) and propionic aciduria (PA) is caused by accumulation of propionyl-CoA which decreases the synthesis of N-acetyl-glutamate, the natural activator of carbamyl phosphate synthetase 1. A treatment approach with carglumic acid, the structural analogue of N-acetyl-glutamate, has been proposed to decrease high ammonia levels encountered in MMA and PA crises. Case presentation We described two patients (one with MMA and one with PA) with hyperammonemia at diagnosis. Carglumic acid, when associated with standard treatment of organic acidurias, may be helpful in normalizing the ammonia level. Conclusion Even though the usual treatment which decreases toxic metabolites remains the standard, carglumic acid could be helpful in lowering plasma ammonia levels over 400 micromol/L more rapidly. PMID:18234091

  2. Impact of age at onset and newborn screening on outcome in organic acidurias

    DEFF Research Database (Denmark)

    Heringer, Jana; Valayannopoulos, Vassili; Lund, Allan M;


    analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO). RESULTS: Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group......BACKGROUND AND AIM: To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation. METHODS: Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients...... with methylmalonic (MMA, n = 164), propionic (PA, n = 144) and isovaleric aciduria (IVA, n = 83), and glutaric aciduria type 1 (GA1, n = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some...

  3. Methylmalonic acidemia mimicking diabetic ketoacidosis in an infant. (United States)

    Guven, A; Cebeci, N; Dursun, A; Aktekin, Eh; Baumgartner, Mr; Fowler, B


    Methylmalonic acidemia (MMA) is an inherited organic acidemia usually present with recurrent episodes of acute illness. A typical episode is ushered in with ketonuria and vomiting, followed by acidosis, dehydration, and lethargy, leading, in the absence of aggressive treatment, to coma and death. We report an infant with MMA presented with diabetes symptoms. A 13-month-old girl complained of polydipsia, diuresis, and loss of weight. She had clinical signs of diabetic ketoacidosis such as dehydration, deep sighing respiration, smell of ketones, lethargy, and vomiting. Laboratory analysis showed hyperglycemia with acidosis and ketonuria. She was treated with parenteral fluid, electrolyte, and insulin infusion. Two days after her discharge, after having a meal rich in protein, she was brought unconscious with hepatomegaly, severe acidosis, ketonuria, and mild hyperammonemia. The absence of hyperglycemia and the presence of neurologic findings suggested organic acidemia. MMA was diagnosed because of methylmalonic aciduria and elevated C3 carnitine esters. Cranial magnetic resonance imaging (MRI) showed increased uptake of radiocontrast material in the basal ganglia bilaterally. A homozygous mutation in exon 4 of the MMAA gene was found in mutation analysis and confirmed the diagnosis of cblA-deficient MMA. Neurologic regression was improved with treatment of low-protein diet, vitamin B12, and l-carnitine. In patients born to consanguineous parents who admit during infancy with severe acidosis refractory to treatment, organic acidemias should be kept in mind, even they have high blood glucose. The definitive diagnosis is important because it may allow a specific treatment and a favorable evolution to prevent the sequelae.

  4. Diagnosis and management of glutaric aciduria type I - revised recommendations

    NARCIS (Netherlands)

    Koelker, Stefan; Christensen, Ernst; Leonard, James V.; Greenberg, Cheryl R.; Boneh, Avihu; Burlina, Alberto B.; Burlina, Alessandro P.; Dixon, Marjorie; Duran, Marinus; Garcia Cazorla, Angels; Goodman, Stephen I.; Koeller, David M.; Kyllerman, Marten; Muehlhausen, Chris; Mueler, Edith; Okun, Juergen G.; Wilcken, Bridget; Hoffmann, Georg F.; Burgard, Peter


    Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises pre

  5. Physicians' use of plasma methylmalonic acid as a diagnostic tool

    DEFF Research Database (Denmark)

    Hvas, A M; Vestergaard, H; Gerdes, Lars Ulrik;


    : This lack of response to an increased plasma methylmalonic acid raises an important question. Is the clinical response inadequate, or is the connection between an increased level of plasma methylmalonic acid and signs of clinical significant cobalamin deficiency less clear?......OBJECTIVES: To investigate physicians' reasons for requesting plasma methylmalonic acid and their reactions to an increased concentration of plasma methylmalonic acid. DESIGN: Study of medical records. SETTING: Three somatic district hospitals in Denmark. SUBJECTS: Medical records of 198 patients...... with a plasma methylmalonic acid measurement above the reference interval. Information on diagnostic decisions was available for 177 patients. MAIN OUTCOME MEASURES: Reasons for requesting plasma methylmalonic acid and the reactions to the finding of elevated plasma methylmalonic acid. RESULTS: An explicit...

  6. Methylmalonic acid values in healthy Dutch children.

    NARCIS (Netherlands)

    Hogeveen, M.; Beynum, I van; Rooij, A. van; Kluijtmans, L.; Heijer, M. den; Blom, H.


    BACKGROUND: Plasma methylmalonic acid (MMA) is a specific marker for functional cobalamin deficiency. This deficiency can give rise to non-specific but serious symptoms in childhood such as developmental delay, convulsions and failure to thrive and may even lead to irreversible neurological damage.

  7. Clinical experience with N-carbamylglutamate in a single-centre cohort of patients with propionic and methylmalonic aciduria

    Directory of Open Access Journals (Sweden)

    Alberto Burlina


    Conclusion: These observations suggest that, in addition to short-term benefits for the acute treatment of hyperammonaemia, NCG may be effective and well tolerated as a long-term treatment in patients with severe PA and MMA, and that further prospective studies are warranted.

  8. Isolation and Expression of a cDNA Encoding Methylmalonic Aciduria Type A Protein from Euglena gracilis Z

    Directory of Open Access Journals (Sweden)

    Fumio Watanabe


    Full Text Available In animals, cobalamin (Cbl is a cofactor for methionine synthase and methylmalonyl-CoA mutase (MCM, which utilizes methylcobalamin and 5′-deoxyadenosylcobalamin (AdoCbl, respectively. The cblA complementation class of inborn errors of Cbl metabolism in humans is one of three known disorders that affect AdoCbl synthesis. The gene responsible for cblA has been identified in humans (MMAA as well as its homolog (meaB in Methylobacterium extorquens. Recently, it has been reported that human MMAA plays an important role in the protection and reactivation of MCM in vitro. However, the physiological function of MMAA is largely unknown. In the present study, we isolated the cDNA encoding MMAA from Euglena gracilis Z, a photosynthetic flagellate. The deduced amino acid sequence of the cDNA shows 79%, 79%, 79% and 80% similarity to human, mouse, Danio rerio MMAAs and M. extorquens MeaB, respectively. The level of the MCM transcript was higher in Cbl-deficient cultures of E. gracilis than in those supplemented with Cbl. In contrast, no significant differences were observed in the levels of the MMAA transcript under the same two conditions. No significant difference in MCM activity was observed between Escherichia coli that expressed either MCM together with MMAA or expressed MCM alone.

  9. Short-term outcome of propionic aciduria treated at presentation with N-carbamylglutamate: a retrospective review of four patients. (United States)

    Lévesque, Sébastien; Lambert, Marie; Karalis, Aspasia; Melancon, Serge; Russell, Laura; Braverman, Nancy


    N-carbamylglutamate (NCG) has been reported to decrease ammonia levels in patients with propionic aciduria (PA) and methylmalonic aciduria (MMA), but reports on clinical outcomes remain scant. Here, we report a retrospective series of four patients with neonatal PA treated with NCG at presentation. Patients presented between 2 and 9 days of age and peak plasma ammonia ranged from 524 to 1,572 μM. Patients received bolus (30-200 mg/kg) and sustaining (115-300 mg/kg per day) doses of NCG in addition to a standard treatment regimen that included ammonia scavenger drugs. Ammonia levels decreased significantly in three of the four cases within 2 h after administration of NCG and fell below 100 μM in all within 12-29 h. Two patients received NCG (bolus 200 mg/kg) while ammonia was above 500 μM (740 and 1,572) and their levels fell below 500 μM by 4 and 8 h post-treatment, respectively. Outcomes of these NGC-treated patients were not improved over previously reported PA patients who did not receive NCG: two died during the initial episode and one after his third metabolic decompensation at 46 days. The survivor is now 3 years old and has a well-controlled seizure disorder and a mild developmental delay mostly in language. We conclude that despite a trial of NCG and a rapid fall in plasma ammonia, the short-term outcome of these patients was not improved.


    Institute of Scientific and Technical Information of China (English)


    Objective To follow up study on α-ketoadipic aciduria , which is a rare inborn error of metabolism of L-ly sine, hydroxy-L-lysine, and L-tryptophan. Methods The case with α-ketoadipic aciduria was investigated clinically and metabolites were detected by using gas chromatography-mass spectrometry techniques during a period of 15 years (9months~ 15years). Results The case had growth retardation at the onset but later grew normally. The urinary metabolites showed persisent abnormality compatible with α-ketoadipic aciduria. The concentrations of α-ketoadipate , α-aminoadipate and α-hy droxyadipate were 33mmol/mol creatinine, 92~266mmol/mol creatinine and 17~28mmol/mol creatinine , respectively. Glutarate also increased in their urine. Conclusion The study suggested the clinical course of a-ketoadipic aciduria is benign and the clinical manifestations are various. The follow-up study on this case with α-ketoadipic aciduria must be continued.

  11. L-2-hydroxyglutaric aciduria: A case report

    Directory of Open Access Journals (Sweden)

    Jović Nebojša J.


    Full Text Available Introduction. L-2-Hydroxyglutaric aciduria (L-2-HGA is an autosomal recessive neurometabolic disease with a slowly progressive course and characterized by increased levels of hydroxyglutaric acid in urine, cerebrospinal fluid and plasma. In this condition clinical features mainly consist of mental deterioration, ataxia and motor deficits. Case Outline. The patient is a 16-year-old girl, the first and only child of healthy, non-consanguineous parents of Serbian origin. At the age of 4 years her walk became unsteady and ataxic. Other signs of cerebellar involvement were soon observed. Head circumference was above two standard deviations (55 cm. Mild mental retardation was revealed by formal intelligence testing (IQ 60. MR examination of the brain showed confluent subcortical white matter lesions spread centripetally, and atrophy of the cerebellar vermis with involvement of dentate nuclei, without deep white matter abnormalities. Laboratory investigation revealed increased amounts and a very large peak of HGA in urine and plasma. Enantiomeric analysis confirmed the L-configuration (>90% establishing the diagnosis of L-2-HGA. The first epileptic seizure, partial with secondary generalization, occurred at age of 8 years. Favorable seizure control was achieved. A slow progression of neurological impairment was noted. Therapeutic trials with oral coenzyme Q10 and with oral riboflavin showed no biochemical and clinical effects. Recently, the diagnosis was proven by the presence of a mutation in the L-2-HGA gene. Conclusion. To our knowledge, this is the first report of L-2-HGA in Serbia. L-2-HGA must be considered in the differential diagnosis based on specific findings in cranial MRI.

  12. Refractory seizures associated with an organic aciduria in a dog. (United States)

    Platt, Simon; McGrotty, Yvonne L; Abramson, Carley J; Jakobs, Cornelis


    A 6-month-old, female Cavalier King Charles spaniel exhibited seizures that were difficult to control with standard anticonvulsants over a 12-month period. The diagnosis of an organic aciduria with excessive excretion of hexanoylglycine was determined when the dog was 20 months old. Recurrent and cluster seizures were eventually controlled with the addition of levetiracetam to potassium bromide and phenobarbital.

  13. Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

    DEFF Research Database (Denmark)

    Kranendijk, Martijn; Struys, Eduard A; Gibson, K Michael;


    We performed molecular, enzyme, and metabolic studies in 50 patients with D-2-hydroxyglutaric aciduria (D-2-HGA) who accumulated D-2-hydroxyglutarate (D-2-HG) in physiological fluids. Presumed pathogenic mutations were detected in 24 of 50 patients in the D-2-hydroxyglutarate dehydrogenase (D2HGD...

  14. Clinical and neuropathological picture of ethylmalonic aciduria - diagnostic dilemma. (United States)

    Jamroz, Ewa; Paprocka, Justyna; Adamek, Dariusz; Pytel, Justyna; Szczechowska, Katarzyna; Grabska, Natalia; Malec, Michalina; Głuszkiewicz, Ewa; Daab, Michał; Wodołażski, Anatolij


    Increased ethylmalonic acid (EMA) in urine is a non-specific finding, and is observed in a number of inborn errors of metabolism, as well as in individuals who carry one of two common polymorphisms identified in the SCAD coding region. The authors present an 8-month-old girl with a suspicion of neuroinfection, although the clinical presentation led to diagnosis of ethylmalonic aciduria. From the neuropathological point of view the most remarkable changes were observed in the brain cortex, which was diffusely damaged practically in all regions of the brain. Of note, the most severe destruction was observed in the deepest regions of the sulci. The cortex of the affected regions showed no normal stratification and its structure was almost totally replaced by a form of "granulation tissue" with a markedly increased number of capillaries. To the authors' knowledge this is the first clinical report of ethylmalonic aciduria with brain autopsy findings.

  15. Antioxidant dysfunction: potential risk for neurotoxicity in ethylmalonic aciduria

    DEFF Research Database (Denmark)

    Pedersen, Christina B; Zolkipli, Zarazuela; Vang, Søren;


    likely due to decreased ACADS gene expression and/or elimination of misfolded SCAD protein. Analysis of the mitochondrial proteome in patient fibroblasts identified a number of differentially expressed protein candidates, including reduced expression of the antioxidant superoxide dismutase 2 (SOD2......). Additionally, patient fibroblasts demonstrated significantly higher sensitivity to oxidative stress than control fibroblasts. We propose that reduced mitochondrial antioxidant capacity is a potential risk factor for ACADS c.625G>A-associated ethylmalonic aciduria and that mitochondrial dysfunction contributes...

  16. Maleic Acid--but Not Structurally Related Methylmalonic Acid--Interrupts Energy Metabolism by Impaired Calcium Homeostasis.

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    Ali Tunç Tuncel

    Full Text Available Maleic acid (MA has been shown to induce Fanconi syndrome via disturbance of renal energy homeostasis, though the underlying pathomechanism is still under debate. Our study aimed to examine the pathomechanism underlying maleic acid-induced nephrotoxicity. Methylmalonic acid (MMA is structurally similar to MA and accumulates in patients affected with methymalonic aciduria, a defect in the degradation of branched-chain amino acids, odd-chain fatty acids and cholesterol, which is associated with the development of tubulointerstitial nephritis resulting in chronic renal failure. We therefore used MMA application as a control experiment in our study and stressed hPTECs with MA and MMA to further validate the specificity of our findings. MMA did not show any toxic effects on proximal tubule cells, whereas maleic acid induced concentration-dependent and time-dependent cell death shown by increased lactate dehydrogenase release as well as ethidium homodimer and calcein acetoxymethyl ester staining. The toxic effect of MA was blocked by administration of single amino acids, in particular L-alanine and L-glutamate. MA application further resulted in severe impairment of cellular energy homeostasis on the level of glycolysis, respiratory chain, and citric acid cycle resulting in ATP depletion. As underlying mechanism we could identify disturbance of calcium homeostasis. MA toxicity was critically dependent on calcium levels in culture medium and blocked by the extra- and intracellular calcium chelators EGTA and BAPTA-AM respectively. Moreover, MA-induced cell death was associated with activation of calcium-dependent calpain proteases. In summary, our study shows a comprehensive pathomechanistic concept for MA-induced dysfunction and damage of human proximal tubule cells.

  17. Glutaric aciduria type 1: neuroimaging features with clinical correlation

    Energy Technology Data Exchange (ETDEWEB)

    Mohammad, Shaimaa Abdelsattar; Ahmed, Khaled A. [Ain-Shams University, Department of Radiodiagnosis, Faculty of Medicine, Cairo (Egypt); Abdelkhalek, Heba Salah; Zaki, Osama K. [Ain-Shams University, Medical Genetics Unit, Pediatric Department, Faculty of Medicine, Cairo (Egypt)


    Glutaric aciduria type 1 is a rare neurometabolic disease with high morbidity. To describe the MR imaging abnormalities in glutaric aciduria type 1 and to identify any association between the clinical and imaging features. MRI scans of 29 children (mean age: 16.9 months) with confirmed diagnosis of glutaric aciduria type 1 were retrospectively reviewed. Gray matter and white matter scores were calculated based on a previously published pattern-recognition approach of assessing leukoencephalopathies. Hippocampal formation and opercular topography were assessed in relation to the known embryological basis. MRI scores were correlated with morbidity score. The most consistent MRI abnormality was widened operculum with dilatation of the subarachnoid spaces surrounding underdeveloped frontotemporal lobes. Incomplete hippocampal inversion was also seen. The globus pallidus was the most frequently involved gray matter structure (86%). In addition to the central tegmental tract, white matter abnormalities preferentially involved the central and periventricular regions. The morbidity score correlated with the gray matter abnormality score (P = 0.004). Patients with dystonia had higher gray matter and morbidity scores. Morbidity is significantly correlated with abnormality of gray matter, rather than white matter, whether secondary to acute encephalopathic crisis or insidious onset disease. (orig.)

  18. D-glyceric aciduria is caused by genetic deficiency of D-glycerate kinase (GLYCTK)

    DEFF Research Database (Denmark)

    Sass, Jörn Oliver; Fischer, Kathleen; Wang, Raymond;


    D-glyceric aciduria is a rare inborn error of serine and fructose metabolism that was first described in 1974. Most affected individuals have presented with neurological symptoms. The molecular basis of D-glyceric aciduria is largely unknown; possible causes that have been discussed are deficienc...

  19. The marker of cobalamin deficiency, plasma methylmalonic acid, correlates to plasma creatinine

    DEFF Research Database (Denmark)

    Hvas, A M; Juul, S; Gerdes, Lars Ulrik;


    OBJECTIVE: To examine the relationship between the two diagnostic tests, plasma methylmalonic acid and plasma cobalamins, and their association with plasma creatinine, age and sex. DESIGN: Cross-sectional study of simultaneous laboratory measurements. SETTING: County of Aarhus, Denmark. SUBJECTS......: Records on 1689 patients who had their first plasma methylmalonic acid measurement during 1995 and 1996, and who had a simultaneous measurement of plasma cobalamins. Plasma creatinine values measured within a week of measurements of plasma methylmalonic acid and plasma cobalamins were available for 1255...... of the patients. MAIN OUTCOME MEASURES: Predictors of variation in plasma methylmalonic acid; plasma cobalamins, plasma creatinine, age and sex. RESULTS: Plasma methylmalonic acid was positively correlated with plasma creatinine, even for plasma creatinine within the normal range. These associations remained...

  20. N-carbamylglutamate protects patients with decompensated propionic aciduria from hyperammonaemia. (United States)

    Gebhardt, B; Dittrich, S; Parbel, S; Vlaho, S; Matsika, O; Bohles, H


    In patients with propionic aciduria, the accumulating metabolite propionyl-CoA causes a disturbance of the urea cycle via the inhibition of N-acetylglutamate synthesis. Lack of this allosteric activator results in an inhibition of carbamoylphosphate synthase (CPS). This finally leads to hyperammonaemia. In two patients with decompensated propionic aciduria the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA associated hyperammonaemia. Oral carbamyl glutamate administration resulted in a significant increase in ammonia detoxification and could avoid further dialysis therapy. Safe, fast and easy to administer, carbamyl glutamate improves the acute therapy of decompensated propionic aciduria by increasing ammonia detoxification and avoiding hyperammonaemia.

  1. Methylmalonic Acidemia: Diagnosis and Neuroimaging Findings of This Neurometabolic Disorder (An Iranian Pediatric Case Series

    Directory of Open Access Journals (Sweden)

    Parvaneh KARIMZADEH


    Full Text Available How To Cite This Article: Karimzadeh P, Jafari N, Jabbehdari S, Taghdiri MM, Nemati H, Saket S, Alaee MR, Ghofrani M, Tonakebni SH. Methylmalonic Acidemia: Diagnosis and Neuroimaging Findings of This Neurometabolic Disorder (An Iranian Pediatric Case Series. Iran J Child Neurol. 2013 Summer; 7(3: 63-66. ObjectiveMethylmalonic acidemia is one of the inborn errors of metabolism resulting in the accumulation of acylcarnitine in blood and increased urinary methylmalonic acid excretion. This disorder can have symptoms, such as neurological and gastrointestinal manifestations, lethargy, and anorexia.Materials & MethodsThe patients who were diagnosed as methylmalonic acidemia in the Neurology Department of Mofid Children’s Hospital in Tehran, Iran, between 2002 and 2012 were included in our study. The disorder was confirmed by clinical findings, neuroimaging findings, and neurometabolic and geneticassessment in reference laboratory in Germany. We assessed the age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of 20 patients with methylmalonic acidemia.ResultsEighty percent of the patients were offspring of consanguineous marriages. Half of the patients had Failure to thrive (FTT due to anorexia; 85% had history of developmental delay or regression, and 20% had refractory seizure, which all of them were controlled. The patients with methylmalonic acidemia were followed for approximately 5 years and the follow-up showedthat the patients with early diagnosis had a more favorable clinical response in growth index, refractory seizure, anorexia, and neurodevelopmental delay. Neuroimaging findings included brain atrophy, basal ganglia involvement (often in putamen, and periventricular leukomalacia.ConclusionAccording to the results of this study, we suggest that early assessment and diagnosis have an important role in the prevention of disease progression and clinical signs.References:1. Trinh BC

  2. Adult methylmalonic acidemia presented as neuromyelitis optica: one case report

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    Sheng-de LI


    Full Text Available A 26-year-old male was admitted to our department, complaining of cognitive impairment, urine incontinence for 3 months, blurred vision for one month and numbness of bilateral lower limbs for 20 days. Presumed as “depression” and “viral encephalitis”, antidepressant and dexamethasone had been given but had no response. Neurological examination demonstrated impaired orientation to time and place; hearing impairment of right ear; normal muscle force in upper limbs, proximal lower muscle force was 2 and distal was 0; normal tendon reflex in both upper limbs; diminished tendon reflex in both lower limbs; left palmomental reflex (+; bilateral Babinski sign (+. Below T10: diminished superficial, deep sensation and cortical sensory. Cranial MRI on admission revealed widened sulci in bilateral cleft and frontal, temporal and insular lobes, indicating brain atrophy. Spinal MRI revealed high-intensity signals of C3-7 level and T1-12 level. The patient was diagnosed as “neuromyelitis optica (NMO” at first, but cognitive impairment is really rare in NMO. It finally turned out to be “inherited metabolic diseases” with the negative results of aquaporin 4 (AQP4, NMO-IgG, GM1, voltage-gated potassium channel (VGKC from serum and cerebrospinal fluid (CSF. The elevated level of plasm homocysteine [30.79 mmol/L (5-20 mmol/L] and urine methylmalonic acid [0.40 mmol/L (0.001 mmol/L] ascertained the diagnosis of methylmalonic acidemia. The patient was given oral treatment of folate 5 mg (3 times a day, 13 days and levocarnitine 1 g (3 times a day, 8 days and intramuscular injection of mecobalamine 1mg (once a day, 4 days or 0.50 mg (once a day, 8 days and adenosylcobalamine 0.50 mg (once a day, 8 days. Sixteen days on discharge, the patient’s neurological examination revealed no obvious recovery of vision; lower muscle force: about Ⅳ, right sensory level: T12-L1, and left sensory level lowered to L3. Reexamination of MRI revealed brain atrophy

  3. Early Liver Transplantation for Neonatal-Onset Methylmalonic Acidemia. (United States)

    Spada, Marco; Calvo, Pier Luigi; Brunati, Andrea; Peruzzi, Licia; Dell'Olio, Dominic; Romagnoli, Renato; Porta, Francesco


    With conventional dietary treatment, the clinical course of methylmalonic acidemia due to cobalamin-unresponsive methylmalonyl-CoA mutase (MCM) deficiency is characterized by the persistent risk of recurrent life-threatening decompensation episodes with metabolic acidosis, hyperammonemia, and coma. Liver transplant has been proposed as an alternative treatment and anecdotally attempted in the last 2 decades with inconsistent results. Most criticisms of this approach have been directed at the continuing risk of neurologic and renal damage after transplant. Here, we report the perioperative and postoperative clinical and biochemical outcomes of 2 patients with severe MCM deficiency who underwent early liver transplant. In both cases, liver transplant allowed prevention of decompensation episodes, normalization of dietary protein intake, and a marked improvement of quality of life. No serious complications have been observed at 12 years' and 2 years' follow-up, respectively, except for mild kidney function impairment in the older patient. On the basis of our experience, we strongly suggest that liver transplant should be offered as a therapeutic option for children with cobalamin-unresponsive MCM deficiency at an early stage of the disease.

  4. Damage of blood system in patients with organic aciduria%有机酸尿症的血液系统损害临床分析

    Institute of Scientific and Technical Information of China (English)

    彭晓音; 刘嵘; 王立文; 李尔珍; 师晓东; 朱彦丽; 陈倩; 王昕


    目的 探讨有机酸尿症中血液系统损害的临床特点.方法回顾性分析36 例有机酸尿症患儿的临床特点、实验室检查结果及血液系统异常情况.结果 36 例患儿中出现血液系统异常19 例(52.8%),其中贫血(Hb<100 g/L)8 例(22.2%),血常规提示两系(贫血、中性粒细胞缺乏)减少8 例(22.2%),三系减少2 例(5.6%),单纯血小板减少1 例(2.8%).血液系统损害可先于、同时或晚于神经系统受累.36 例患儿中甲基丙二酸尿症31 例,其中19 例为维生素B12 有效型,11 例(61.1%)有血液系统异常;而12 例维生素B12 无效型中仅1 例(7.7%)有血液系统异常,两者差异有统计学意义(P=0.003).结论对于不明原因或治疗效果不好的血液系统疾病患儿要注意神经系统体征检查,及时完善尿有机酸分析,避免漏诊.%Objective To investigate the haematological abnormalities in organic aciduria. Methods The clinical features, laboratory investigation and hematological abnormalities from 36 children with organic aciduria were retrospectively analyzed. Results Nineteen (52.8%) of the 36 patients had haematological abnormalities. Bight (22.2%) of them were anemia (Hb<100 g/L); eight patients (22.2%) were observed with bieytopenia (anemia, neutropenia); while 2 (5.6%) with pancytope-nia; and 1 (2.8%) with thrombocytopenia. Haematological abnormalities may occur prior to, at the same time or later than the involvement of the nervous system. Thirty-one of 36 patients were diagnosed as methylmalonic aciduria (MMA). Nineteen of MMA patients showed vitamin 12 response, eleven (61.1%) of them were with hematological abnormalities. Twelve of MMA patients were not vitamin 12 responsive and only one (7.7%) of them showed hematological abnormalities. Significant difference was observed between these two groups (P=0.003). Conclusions For patients with, unexplained blood diseases or ineffective treatment outcome, neurological signs need to be examined. Timely

  5. Severe infantile hypotonia with ethylmalonic aciduria: case report. (United States)

    Okuyaz, Cetin; Ezgü, Fatih Süheyl; Biberoglu, Gürsel; Zeviani, Massimo; Tiranti, Valeria; Yilgör, Esat


    An 8-month-old girl was admitted to an outpatient clinic with significant hypotonia and weakness. Organic acid analysis in urine revealed a significant increase in ethylmalonic acid. A deoxyribonucleic analysis revealed the presence of a 625G>A (G-to-A substitution at nucleotide 625) variant short-chain acyl-coenzyme A dehydrogenase gene polymorphism. With the clinical, biochemical and molecular findings, short-chain acyl-coenzyme A dehydrogenase deficiency was suspected. Because 625G>A and 511C>T (C-to-T substitution at nucleotide 511) genetic variations are also present in 14% of the general population, these are considered to be genetic sensitivity variations rather than causing a disease themselves and to result in possible short-chain acyl-coenzyme A dehydrogenase deficiency in the presence of environmental factors such as fever and hunger as well as cellular, biochemical, and other genetic factors. It was stressed that severe infantile hypotonia could also be the only manifestation of ethylmalonic aciduria spectrum disorders.

  6. L-2-Hydroxyglutaric Aciduria is a Diagnostic Indicator of Leukodystrophy: A Case Report

    Directory of Open Access Journals (Sweden)

    Mahmoud Reza ASHRAFI


    Full Text Available How to Cite this Article: Ashrafi MR, Nikkhah A, Houshmand M, Aryani O. L-2-Hydroxyglutaric Aciduria is a Diagnostic Indicator of Leukodystrophy: A CaseReport Iranian Journal of Child Neurology 2011;5(4:37-38. L-2-Hydroxyglutaric aciduria is a rare autosomal recessive inherited neurometabolic disorder.It is characterized by slow progressive neurological dysfunction with cerebellar ataxia, pyramidal and extrapyramidal signs, intellectual decline, and seizures. Herein, we report a case of a 7-year-old boy from Tehran whose symptoms and signs indicated leukoencephalopathy with macrocephaly and motor delay. References 1. Barth PG, Hoffmann GF, Jaeken J, Lehnert W, Hanefeld F, van Gennip AH, et al. L-2-hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol 1992;32(1:66-71. 2. Duran M, Kamerling JP, Bakker HD, Van Gennip AH, Wadman S. L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J Inherit Metab Dis 1980;3(4:109-12. 3. Haliloglu G, Jobard F, Oguz KK, Anlar B, Akalan N, Coskun T, et al. L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings. Neuropediatrics  2008;39(2:119-22. 4. De Klerk JB, Huijmans JG, Stroink H, Robben SG, Jakobs C, Duran M. L-2-hydroxyglutaric aciduria: clinical heterogeneity versus biochemical homogeneity in a sibship. Neuropediatrics 1997;28(6:314-7. 5. Fenichel GM. Clinical pediatric neurology: a signs and symptoms approach. Saunders:Elsevier, 2009. 6. Diogo L, Fineza I, Canha J, Borges L, Cardoso ML, Vilarinho L. Macrocephaly as the presenting feature of L-2-hydroxyglutaric aciduria in a 5-month-old boy. J Inherit Metab Dis 1996;19(3:369-70. 7. Rzem R, Van Schaftingen E, Veiga-da-Cunha M. The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. Biochimie 2006;88(1:113-6. 8. Shafeghati Y, Vakili G, Entezari A. L-2-hydroxyglutaric aciduria: A report of six cases and Review of the Literature

  7. Vitamin B12 Deficiency Stimulates Osteoclastogenesis via Increased Homocysteine and Methylmalonic Acid

    NARCIS (Netherlands)

    Vaes, B.L.T.; Lute, C.; Blom, H.J.; Bravenboer, N.; Vries, de T.J.; Everts, V.; Dhonukshe-Rutten, R.A.M.; Müller, M.R.; Groot, de C.P.G.M.; Steegenga, W.T.


    The risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B12 deficiency is especially prevalent in the elderly and causes increased homocysteine (Hcy) and methylmalonic acid (MMA) levels. These three factors have been recognized as risk factors for reduced bone

  8. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1

    DEFF Research Database (Denmark)

    Kölker, Stefan; Cazorla, Angeles Garcia; Valayannopoulos, Vassili;


    BACKGROUND: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. AIMS/METHODS: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. RESULTS: We registere...

  9. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2

    DEFF Research Database (Denmark)

    Kölker, Stefan; Valayannopoulos, Vassili; Burlina, Alberto B;


    BACKGROUND: The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. AIMS: To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. RESULTS: Acquired microcephaly and movement disorde...

  10. OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria

    DEFF Research Database (Denmark)

    Huizing, Marjan; Dorward, Heidi; Ly, Lien


    3-Methylglutaconic aciduria type III (3-MGCA type III), caused by recessive mutations in the 2-exon gene OPA3, is characterized by early-onset bilateral optic atrophy, later-onset extrapyramidal dysfunction, and increased urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid. Her...

  11. Trichloroethylene-induced formic aciduria: effect of dose, sex and strain of rat. (United States)

    Yaqoob, Noreen; Evans, Andrew R; Lock, Edward A


    The industrial solvent trichloroethylene (TCE) has been reported to increase the excretion of formic acid in the urine of male Fischer 344 (F-344) rats following large oral doses. We have examined the dose-response relationship for formic aciduria in male and female Fischer 344 rats, the effect of some known metabolites of TCE and examined the response in male Wistar rats to help understand its relevance to renal toxicity. We report that doses of TCE as low as 8 mg/kg for 3 days to both male and female F344 rats produced formic aciduria. The formic aciduria was time-dependent being more marked after 3 doses compared to one dose in male F344 rats and to a lesser extent in female F344 rats. TCE administration to male Wistar rats produced less formic aciduria than in male F344 rats, indicating a strain difference in response. As TCE is primarily metabolised by cytochrome P450 2E1, Wistar rats were administered inducers of cytochrome P450 2E1 followed by TCE, this increased formic acid excretion to a concentration similar to that observed in male F344 rats, indicating a role for P450. Administration of the major metabolites of TCE, trichloroethanol and trichloroacetic acid to male F344 rats also produced a marked and sustained formic aciduria, while the metabolite of TCE formed via glutathione conjugation had no effect on formic acid excretion. The mechanism whereby this response occurs is currently not understood, but the formic acid excreted is not a metabolite of TCE, but appears to be due to interference with the metabolic utilisation of formate by a down stream metabolite of TCE. Over the three days of the studies no histopathological evidence of kidney toxicity was observed in F344 rats given TCE, indicating that the perturbation of formate metabolism does not lead to acute renal injury.

  12. Nutrient-dense foods and exercise in frail elderly: effects on B vitamins, homocysteine, methylmalonic acid, and neuropsychological functioning

    NARCIS (Netherlands)

    Jong, de N.; Chin A Paw, M.J.M.; Groot, de C.P.G.M.; Rutten, R.A.M.; Swinkels, D.W.; Kok, F.J.; Staveren, van W.A.


    Frail elders are at risk of suboptimal micronutrient status, functional decline, and neurologic disorders. The influence of oral multimicronutrients in physiologic doses and of moderately intense physical exercise on homocysteine (Hcy), methylmalonic acid (MMA), and neurologic functioning have not y

  13. A Prospective Study on Serum Methylmalonic Acid and Homocysteine in Pregnant Women


    Choi, Rihwa; Choi, Sunkyu; Lim, Yaeji; Cho, Yoon Young; Kim, Hye Jeong; Kim, Sun Wook; Chung, Jae Hoon; Oh, Soo-young; Lee,Soo-Youn


    This study aimed to investigate serum methylmalonic acid (MMA) and homocysteine levels and to assess their effects on pregnancy and neonatal outcomes. Serum MMA and homocysteine levels in 278 pregnant Korean women, determined by liquid chromatography–tandem mass spectrometry in each trimester, were compared with those of previous studies in other ethnic groups. We investigated the association between MMA and homocysteine status with pregnancy and neonatal events: gestational diabetes, preecla...

  14. Propionic and Methylmalonic Acidemia: Antisense Therapeutics for Intronic Variations Causing Aberrantly Spliced Messenger RNA


    Rincón, A. ; Aguado, C. ; Desviat, L. R. ; Sánchez-Alcudia, R. ; Ugarte, M. ; Pérez, B. 


    We describe the use of antisense morpholino oligonucleotides (AMOs) to restore normal splicing caused by intronic molecular defects identified in methylmalonic acidemia (MMA) and propionic acidemia (PA). The three new point mutations described in deep intronic regions increase the splicing scores of pseudoexons or generate consensus binding motifs for splicing factors, such as SRp40, which favor the intronic inclusions in MUT (r.1957ins76), PCCA (r.1284ins84), or PCCB (r.654ins72) messenger R...

  15. A Case of Glutaric Aciduria Type I with a Novel Mutation

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    Nilgun Uyduran Unal


    Full Text Available Glutaric aciduria type I is an autosomal recessive inherited disorder caused by the deficiency of glutaryl CoA dehydrogenase. The incidence of the disease is 1/100.000. Glutaryl CoA dehydrogenase gene is located on locus 19p13.2. More than 200 mutations have been described for this gene. Most common mutation in the population is C1240T. Clinical symptoms included neurological regression complications such as loss of sucking and swallowing reflexes choreoathetosis, seizures, rigidity and opisthotonos. In treatment high-carbohydrate, low-protein diet and carnitine is given. We would like to report this interesting case in order to present a new mutation for glutaric aciduria type I. [Cukurova Med J 2013; 38(4.000: 809-812

  16. Hyperkalemia after acute metabolic decompensation in two children with vitamin B12-unresponsive methylmalonic acidemia and normal renal function. (United States)

    Pela, I; Gasperini, S; Pasquini, E; Donati, M A


    The patients affected by vitamin B12-unresponsive methylmalonic acidemia (MMA) on the long run develop chronic renal disease with interstitial nephropathy and progressive renal insufficiency. The mechanism of nephrotoxicity in vitamin B12-unresponsive MMA is not yet known. Chronic hyporeninemic hypoaldosteronism has been found in many cases of methylmalonic acidemia, hyperkalemia and renal tubular acidosis type 4. We report 2 patients affected by B12-unresponsive methylmalonic acidemia diagnosed at the age of 23 months and 5 years, respectively, with normal glomerular filtration and function. They showed hyporeninemic hypoaldosteronism and significant hyperkalemia requiring sodium potassium exchange resin (Kayexalate) therapy after an episode of metabolic decompensation leading to diagnosis of MMA. In both children, hyporeninemic hypoaldosteronism and hyperkalemia disappeared after 6 months of good metabolic control.

  17. Imaging of the brain, including diffusion-weighted imaging in methylmalonic acidemia

    Energy Technology Data Exchange (ETDEWEB)

    Michel, Steven J.; Given, Curtis A. [Department of Diagnostic Radiology, University of Kentucky Chandler Medical Center, Room HX-311C, 800 Rose Street, Lexington, KY 40536 (United States); Robertson, William C. [Department of Pediatric Neurology, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536 (United States)


    Methylmalonic acidemia (MMA) is a multifactorial autosomal recessive inborn error of organic acid metabolism, often presenting with neurologic findings. We report the imaging findings in a case of a child with classic neurological and laboratory findings for MMA. Imaging studies demonstrated abnormalities within the basal ganglia, particularly the globi pallidi (GP). Diffusion-weighted abnormalities seen in patients with MMA during an acute episode of metabolic acidosis and at follow-up are discussed. The authors are aware of only one prior report of serial examinations demonstrating resolution of restricted diffusion in the GP. The biochemical and pathophysiologic basis of the imaging findings of MMA are explained. (orig.)

  18. CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria

    DEFF Research Database (Denmark)

    Saunders, Carol; Smith, Laurie; Wibrand, Flemming;


    of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent......3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form...

  19. OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria

    DEFF Research Database (Denmark)

    Huizing, Marjan; Dorward, Heidi; Ly, Lien;


    3-Methylglutaconic aciduria type III (3-MGCA type III), caused by recessive mutations in the 2-exon gene OPA3, is characterized by early-onset bilateral optic atrophy, later-onset extrapyramidal dysfunction, and increased urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid. Her...... we report the identification of a novel third OPA3 coding exon, the apparent product of a segmental duplication event, resulting in two gene transcripts, OPA3A and OPA3B. OPA3A deficiency (as in optic atrophy type 3) causes up-regulation of OPA3B. OPA3 protein function remains unknown...

  20. Striatal necrosis in type 1 glutaric aciduria: Different stages in two siblings

    Directory of Open Access Journals (Sweden)

    Anitha Sen


    Full Text Available Two siblings born of a consanguineous marriage with history of neurologic deterioration were imaged. Imaging features are classical of glutaric aciduria type 1 (GA-1, acute (striatal necrosis stage in younger sibling, and chronic stage in older sibling. GA-1 is an autosomal recessive disease with typical imaging features. Greater awareness about this condition among clinicians and radiologists is essential for early diagnosis and prevention of its catastrophic consequences. Striatal necrosis with stroke-like signal intensity on imaging correlates with clinical stage of patients.


    Directory of Open Access Journals (Sweden)

    Hedieh SANEIFARD


    Full Text Available Organic acidemias are the group of metabolic disorders which define by high anion gap metabolic acidosis, hypo or hyperglycemia & hyperammonemia.Because of the severity of disease in children and its fatality in severe form of disease and also need for life long treatment, prenatal diagnosis is an important diagnostic tool.Three approaches to prenatal diagnosis may be possible, including measurement of analytes in amniotic fluid or use of cells obtained by Choronic Villus sampling (CVS or amniocentesis to either assay enzyme activity or extract DNA for molecular genetic testing.Biochemical genetic testing: Prenatal diagnosis for pregnancies at increased risk for propionic acidemia, methylmalonic acidemia, biotin-unresponsive3-methylcrotonyl-CoA carboxylase deficiency, glutaric acidemia type 1, ketothiolase deficiency, methylmalonic aciduria and homocystinuria, cblC type, and isovaleric acidemia is possible by analysis of amniotic fluid if highly accurate quantitative methods are used to measure the appropriate analytes. Amniocentesis is usually performed at approximately 15 to 18 weeks gestation.Prenatal diagnosis for pregnancies at increased risk for MSUD is possible by measurement of enzyme activity in fetal cells obtained by chorionic villous sampling(CVS at approximately ten to 12 weeks gestation or amniocentesis usually performed at approximately 15 to 18 weeks gestation.(If cells from CVS are used, extreme care must be taken to assure that they are fetal rather than maternal cells.Molecular genetic testing:Prenatal diagnosis for pregnancies at increased risk for all disorders is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks of gestation or chorionic villous sampling (CVS at approximately ten to 12 weeks of gestation. Both disease-causing allels of an affected family member must be identified before prenatal testing.Preimplantation genetic diagnosis (PGD

  2. A simple high-throughput method for the determination of plasma methylmalonic acid by liquid chromatography-tandem mass spectrometry.

    NARCIS (Netherlands)

    Blom, H.J.; Rooij, A. van; Hogeveen, M.


    BACKGROUND: Cobalamin (Cbl) deficiency is a common clinical phenomenon, in particular among the elderly and possibly also among infants. Methylmalonic acid (MMA) is the most sensitive and specific marker of intracellular Cbl status, but its application is hindered by limited methods available for ac

  3. Novel cases of D-2-hydroxyglutaric aciduria with IDH1 or IDH2 mosaic mutations identified by amplicon deep sequencing

    DEFF Research Database (Denmark)

    Nota, Benjamin; Hamilton, Eline M; Sie, Daoud


    Mosaic IDH1 mutations are described as the cause of metaphyseal chondromatosis with increased urinary excretion of D-2-hydroxyglutarate (MC-HGA), and mutations in IDH2 as the cause of D-2-hydroxyglutaric aciduria (D-2HGA) type II. Mosaicism for IDH2 mutations has not previously been reported as a...

  4. A mouse model of L-2-hydroxyglutaric aciduria, a disorder of metabolite repair.

    Directory of Open Access Journals (Sweden)

    Rim Rzem

    Full Text Available The purpose of the present work was to progress in our understanding of the pathophysiology of L-2-hydroxyglutaric aciduria, due to a defect in L-2-hydroxyglutarate dehydrogenase, by creating and studying a mouse model of this disease. L-2-hydroxyglutarate dehydrogenase-deficient mice (l2hgdh-/- accumulated L-2-hydroxyglutarate in tissues, most particularly in brain and testis, where the concentration reached ≈ 3.5 μmol/g. Male mice showed a 30% higher excretion of L-2-hydroxyglutarate compared to female mice, supporting that this dicarboxylic acid is partially made in males by lactate dehydrogenase C, a poorly specific form of this enzyme exclusively expressed in testes. Involvement of mitochondrial malate dehydrogenase in the formation of L-2-hydroxyglutarate was supported by the commensurate decrease in the formation of this dicarboxylic acid when down-regulating this enzyme in mouse l2hgdh-/- embryonic fibroblasts. The concentration of lysine and arginine was markedly increased in the brain of l2hgdh-/- adult mice. Saccharopine was depleted and glutamine was decreased by ≈ 40%. Lysine-α-ketoglutarate reductase, which converts lysine to saccharopine, was inhibited by L-2-hydroxyglutarate with a Ki of ≈ 0.8 mM. As low but significant activities of the bifunctional enzyme lysine-α-ketoglutarate reductase/saccharopine dehydrogenase were found in brain, these findings suggest that the classical lysine degradation pathway also operates in brain and is inhibited by the high concentrations of L-2-hydroxyglutarate found in l2hgdh-/- mice. Pathological analysis of the brain showed significant spongiosis. The vacuolar lesions mostly affected oligodendrocytes and myelin sheats, as in other dicarboxylic acidurias, suggesting that the pathophysiology of this model of leukodystrophy may involve irreversible pumping of a dicarboxylate in oligodendrocytes. Neurobehavioral testing indicated that the mice mostly suffered from a deficit in learning

  5. Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

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    Stephan Klopries


    Full Text Available Polyketides are biosynthesized through consecutive decarboxylative Claisen condensations between a carboxylic acid and differently substituted malonic acid thioesters, both tethered to the giant polyketide synthase enzymes. Individual malonic acid derivatives are typically required to be activated as coenzyme A-thioesters prior to their enzyme-catalyzed transfer onto the polyketide synthase. Control over the selection of malonic acid building blocks promises great potential for the experimental alteration of polyketide structure and bioactivity. One requirement for this endeavor is the supplementation of the bacterial polyketide fermentation system with tailored synthetic thioester-activated malonates. The membrane permeable N-acetylcysteamine has been proposed as a coenzyme A-mimic for this purpose. Here, the incorporation efficiency into different polyketides of N-acetylcysteamine activated methylmalonate is studied and quantified, showing a surprisingly high and transferable activity of these polyketide synthase substrate analogues in vivo.

  6. Methylmalonic acid quantification in low serum volumes by UPLC-MS/MS. (United States)

    Pedersen, Theresa L; Keyes, William R; Shahab-Ferdows, Setareh; Allen, Lindsay H; Newman, John W


    Methylmalonic acid (MMA) is a metabolic intermediate transformed to succinic acid (SA) by a vitamin B(12)-dependent catalytic step, and is broadly used as a clinical biomarker of functional vitamin B12 status. However, reported methods use between 100 and 1000 μL of serum or plasma making them sub-optimal for sample-limited studies, including those with neonates and infants. LC-MS/MS based protocols to measure MMA as n-butyl esters in the presence of tri-deuterated MMA (MMA-d(3)) were modified for use with 25 μL of human serum by scaling down sample processing volumes and analysis by UPLC-MS/MS. Plasma-based calibration solutions were found to be unnecessary, and chromatographic resolution and peak shape of SA and MMA was optimized in cyclohexyl-urido-3-dodecanoic acid (CUDA) was included as internal standard allowing direct assessment of MMA recovery. Sample concentrations in the low normal range produced a signal:noise of >100:1. MMA intra- and inter-assay variability was under 10%. MMA-d(3) surrogate recovery averaged 93±14%. MMA stability exceeded three years in frozen samples and was unaffected by up to five freeze/thaw cycles. In conclusion, we report that methylmalonic acid can be measured with 25 μL of serum using water based standards. The assay signal:noise per concentration indicates that the method could perform as implemented with as little as 5 μL of serum. The reported method is applicable for studies of functional B12 status in sample limited experiments including investigations of nutritional status in neonates and in studies where low normal MMA levels are expected.

  7. Acute renal failure potentiates methylmalonate-induced oxidative stress in brain and kidney of rats. (United States)

    Schuck, P F; Alves, L; Pettenuzzo, L F; Felisberto, F; Rodrigues, L B; Freitas, B W; Petronilho, F; Dal-Pizzol, F; Streck, E L; Ferreira, G C


    Tissue methylmalonic acid (MMA) accumulation is the biochemical hallmark of methylmalonic acidemia. The disease is clinically characterized by progressive neurological deterioration and kidney failure, whose pathophysiology is still unclear. In the present work we investigated the effects of acute MMA administration on various parameters of oxidative stress in cerebral cortex and kidney of young rats, as well as the influence of acute renal failure on MMA-elicited effects on these parameters. Acute renal failure was induced by gentamicin, an aminoglycoside antibiotic whose utilization over prolonged periods causes nephrotoxicity. The administration of gentamicin alone increased carbonyl content and inhibited superoxide dismutase (SOD) activity in cerebral cortex, as well as increased thiobarbituric acid-reactive substances (TBA-RS) and sulfhydryl levels and diminished glutathione peroxidase activity in kidney. On the other hand, MMA administration increased TBA-RS levels in cerebral cortex and decreased SOD activity in kidney. Furthermore, the simultaneous administration of MMA and gentamicin to the rats provoked an augment in TBA-RS levels and superoxide generation in cerebral cortex and in TBA-RS, carbonyl and sulfhydryl levels in kidney, while diminished SOD activity in both studied tissues. Finally, nitrate/nitrite content, reduced glutathione levels, 2',7'-dihydrodichlorofluorescein oxidation and catalase activity were not affected by this animal treatment in either tissue. In conclusion, our present data are in line with the hypothesis that MMA acts as a toxin in brain and kidney of rats and suggest that renal injury potentiates the toxicity of MMA on oxidative stress parameters in brain and peripheral tissues.

  8. Methylmalonic acidemia (United States)

    ... that avoids substances called isoleucine, threonine, methionine, and valine. Liver or kidney transplantation (or both) have been ... Rezvani I, Rosenblatt DS. Valine, leucine, isoleucine, and related ... RM, Behrman RE, St. Geme III JW, Schor NF, Stanton BF, eds. ...

  9. Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.

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    Paris Jafari

    Full Text Available Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i 3-OHGA causes the death of astrocytes, (ii deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I.

  10. Estudio de pacientes con aciduria glutárica tipo II, mediante la incubación de fibroblastos con ácidos palmítico y mirístico tritiados = Study of patients with type II glutaric aciduria by incubation of fibroblasts with tritiated palmitic and myristic acids

    Directory of Open Access Journals (Sweden)

    Osorio Orozco, José Henry


    Full Text Available Introducción: la aciduria glutárica tipo II, o deficiencia múltiple de acil-CoA deshidrogenasas, es un trastorno causado por deficiencia de la flavoproteína de transferencia de electrones, de su oxidorreductasa o de ambas; se trata de una enfermedad metabólica autosómica recesiva, caracterizada por acidosis, hipoglicemia, aciduria orgánica, olor a pies sudados y malformaciones en cerebro y riñones.Objetivo: analizar las tasas de oxidación de sustratos tritiados por fibroblastos de pacientes con aciduria glutárica tipo II.Materiales y métodos: se incubaron fibroblastos de dos pacientes con aciduria glutárica tipo II y de 20 controles en presencia de ácidos palmítico y mirístico tritiados.Resultados: se encontró muy deprimida (16%-18% la oxidación de los sustratos tritiados por los fibroblastos procedentes de pacientes con aciduria glutárica tipo II en comparación con los controles.Conclusión: la prueba estudiada permite la confirmación in vitro del diagnóstico de aciduria glutárica tipo II.

  11. Pregnancy in a methylmalonic acidemia patient with kidney transplantation: a case report. (United States)

    Lubrano, R; Bellelli, E; Gentile, I; Paoli, S; Carducci, C; Carducci, C; Santagata, S; Pérez, B; Ugarte, M; Labriola, D; Elli, M


    Presently pregnancy is no more exceptional in women with metabolic diseases. However, it still poses significant medical problems both before and after childbirth. The challenge is even greater if the mother has undergone organ transplantation, because of her metabolic disease. We report on a case of pregnancy in a patient 29-year-old with methylmalonic acidemia cblA type (OMIM 251100) who received a renal transplantation at the age of 17 for end-stage renal disease (ESRD) caused by her primary disease. During pregnancy neither metabolic crises nor renal function changes were observed in the mother, with the only exception of a mild increase of her systemic blood pressure. To the fetus pregnancy was uneventful and during the first 30 months after birth the baby's neuropsychomotor development was normal and there were no episodes of metabolic derangement. This is evidence that methylmalonicacidemia cblA, even when treated with renal transplantation for inherent ESRD, is no contraindication to pregnancy. It is even possible that a functioning transplanted kidney contributes to improve metabolic parameters.

  12. A Prospective Study on Serum Methylmalonic Acid and Homocysteine in Pregnant Women. (United States)

    Choi, Rihwa; Choi, Sunkyu; Lim, Yaeji; Cho, Yoon Young; Kim, Hye Jeong; Kim, Sun Wook; Chung, Jae Hoon; Oh, Soo-Young; Lee, Soo-Youn


    This study aimed to investigate serum methylmalonic acid (MMA) and homocysteine levels and to assess their effects on pregnancy and neonatal outcomes. Serum MMA and homocysteine levels in 278 pregnant Korean women, determined by liquid chromatography-tandem mass spectrometry in each trimester, were compared with those of previous studies in other ethnic groups. We investigated the association between MMA and homocysteine status with pregnancy and neonatal events: gestational diabetes, preeclampsia, gestational age at delivery, preterm birth, small for gestational age, neonatal birth weight, and congenital abnormalities. The median (range) MMA level was 0.142 (0.063-0.446) µmol/L and homocysteine level was 10.6 (4.4-38.0) µmol/L in pregnant women. MMA levels were significantly higher in the third trimester than during other trimesters (p homocysteine levels were not. No significant association was observed between MMA or homocysteine levels and any of the maternal or neonatal outcomes examined. Future studies are needed to assess the associations among maternal serum concentrations of MMA and homocysteine, and maternal and neonatal outcomes.

  13. A Prospective Study on Serum Methylmalonic Acid and Homocysteine in Pregnant Women

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    Rihwa Choi


    Full Text Available This study aimed to investigate serum methylmalonic acid (MMA and homocysteine levels and to assess their effects on pregnancy and neonatal outcomes. Serum MMA and homocysteine levels in 278 pregnant Korean women, determined by liquid chromatography–tandem mass spectrometry in each trimester, were compared with those of previous studies in other ethnic groups. We investigated the association between MMA and homocysteine status with pregnancy and neonatal events: gestational diabetes, preeclampsia, gestational age at delivery, preterm birth, small for gestational age, neonatal birth weight, and congenital abnormalities. The median (range MMA level was 0.142 (0.063–0.446 µmol/L and homocysteine level was 10.6 (4.4–38.0 µmol/L in pregnant women. MMA levels were significantly higher in the third trimester than during other trimesters (p < 0.05, while homocysteine levels were not. No significant association was observed between MMA or homocysteine levels and any of the maternal or neonatal outcomes examined. Future studies are needed to assess the associations among maternal serum concentrations of MMA and homocysteine, and maternal and neonatal outcomes.

  14. Vitamin B(12) deficiency stimulates osteoclastogenesis via increased homocysteine and methylmalonic acid. (United States)

    Vaes, Bart L T; Lute, Carolien; Blom, Henk J; Bravenboer, Nathalie; de Vries, Teun J; Everts, Vincent; Dhonukshe-Rutten, Rosalie A; Müller, Michael; de Groot, Lisette C P G M; Steegenga, Wilma T


    The risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B(12) deficiency is especially prevalent in the elderly and causes increased homocysteine (Hcy) and methylmalonic acid (MMA) levels. These three factors have been recognized as risk factors for reduced bone mineral density and increased fracture risk, though mechanistic evidence is still lacking. In the present study, we investigated the influence of B(12), Hcy, and MMA on differentiation and activity of bone cells. B(12) deficiency did not affect the onset of osteoblast differentiation, maturation, matrix mineralization, or adipocyte differentiation from human mesenchymal stem cells (hMSCs). B(12) deficiency caused an increase in the secretion of Hcy and MMA into the culture medium by osteoblasts, but Hcy and MMA appeared to have no effect on hMSC osteoblast differentiation. We further studied the effect of B(12), Hcy, and MMA on the formation of multinucleated tartrate-resistant acid phosphatase-positive osteoclasts from mouse bone marrow. We observed that B(12) did not show an effect on osteoclastogenesis. However, Hcy as well as MMA were found to induce osteoclastogenesis in a dose-dependent manner. On the basis of these results, we conclude that B(12) deficiency may lead to decreased bone mass by increased osteoclast formation due to increased MMA and Hcy levels.

  15. Vitamin B12, folate, homocysteine and urinary methylmalonic acid levels in infants. (United States)

    Karademir, F; Suleymanoglu, S; Ersen, A; Aydinoz, S; Gultepe, M; Meral, C; Ozkaya, H; Gocmen, I


    Serum vitamin B12 and folate, and their functional markers, plasma homocysteine and urinary methylmalonate (uMMA) were measured in 204 healthy, term infants at birth, and at 2 and 6 months. Compared with infants receiving formula food, those fed mother's milk had lower vitamin B12 and folate at 2 and 6 months. In infants receiving mother's milk, vitamin B12 levels were similar at birth (238 pg/ml) and 2 months (243 pg/ml), whereas with formula milk the level was significantly higher at 2 months (558 pg/ml) than at birth (257 pg/ml). Vitamin B12 was negatively correlated with homocysteine at birth and 6 months. The level of uMMA (mmol/mol creatinine) was higher at 2 (mother's milk, 25.5; formula, 23.97) and 6 months (19.77; 15) than at birth (11.97; 10.88), and was not correlated with vitamin B12 levels. Homocysteine may be a reliable marker of vitamin B12 status in neonates and infants; however, uMMA is not suitable as a marker of vitamin B12 status.

  16. Fractional anisotropy for assessment of white matter tracts injury in methylmalonic acidemia

    Institute of Scientific and Technical Information of China (English)

    GAO Yu; GUAN Wen-ye; WANG Jiang; ZHANG Yu-zhen; LI Yu-hua; HAN Lian-shu


    Background Methylmalonic acidemia (MMA) is a multifactorial autosomal recessive inborn error of organic acid metabolism, often presenting with neurological symptoms. As neurological disorders are often related to white matter injury, diffusion tensor imaging (DTI) is an excellent tool for assessment of white matter injury and possibly for diagnosing this disorder.Methods We retrospectively analyzed DTI images of 12 patients with MMA (7 males, 5 females, age range: 7-12 months, mean age: 9.25±1.70 months) with negative MRI findings. And another 12 age-matched and gender-matched infants were enrolled as control subjects. Fractional anisotropy (FA) of different white matter tracts of the brain was measured in both groups.Results For patients with negative MRI findings, compared with healthy infants, a statistically significant reduction in DTI FA value of the frontal white matter, temporal white matter, and occipital white matter was observed (P<0.01).Conclusions In addition to conventional T1W and T2W MR Image, Brain DTI presents a useful, sensitive and complementary tool for the assessment of brain damage in patients with MMA.

  17. Interaction of glutaric aciduria type 1-related glutaryl-CoA dehydrogenase with mitochondrial matrix proteins.

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    Jessica Schmiesing

    Full Text Available Glutaric aciduria type 1 (GA1 is an inherited neurometabolic disorder caused by mutations in the GCDH gene encoding glutaryl-CoA dehydrogenase (GCDH, which forms homo- and heteromeric complexes in the mitochondrial matrix. GA1 patients are prone to the development of encephalopathic crises which lead to an irreversible disabling dystonic movement disorder. The clinical and biochemical manifestations of GA1 vary considerably and lack correlations to the genotype. Using an affinity chromatography approach we report here for the first time on the identification of mitochondrial proteins interacting directly with GCDH. Among others, dihydrolipoamide S-succinyltransferase (DLST involved in the formation of glutaryl-CoA, and the β-subunit of the electron transfer flavoprotein (ETFB serving as electron acceptor, were identified as GCDH binding partners. We have adapted the yellow fluorescent protein-based fragment complementation assay and visualized the oligomerization of GCDH as well as its direct interaction with DLST and ETFB in mitochondria of living cells. These data suggest that GCDH is a constituent of multimeric mitochondrial dehydrogenase complexes, and the characterization of their interrelated functions may provide new insights into the regulation of lysine oxidation and the pathophysiology of GA1.

  18. Clinical and Mutational Analysis of the GCDH Gene in Malaysian Patients with Glutaric Aciduria Type 1 (United States)

    Yakob, Yusnita; Abdul Azize, Nor Azimah; Md Yunus, Zabedah; Huey Yin, Leong; Mohd Khalid, Mohd Khairul Nizam; Lock Hock, Ngu


    Glutaric aciduria type 1 (GA1) is an autosomal recessive metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase enzyme encoded by the GCDH gene. In this study, we presented the clinical and molecular findings of seven GA1 patients in Malaysia. All the patients were symptomatic from infancy and diagnosed clinically from large excretion of glutaric and 3-hydroxyglutaric acids. Bidirectional sequencing of the GCDH gene revealed ten mutations, three of which were novel (Gln76Pro, Glu131Val, and Gly390Trp). The spectrum of mutations included eight missense mutations, a nonsense mutation, and a splice site mutation. Two mutations (Gln76Pro and Arg386Gln) were homozygous in two patients with parental consanguinity. All mutations were predicted to be disease causing by MutationTaster2. In conclusion, this is the first report of both clinical and molecular aspects of GA1 in Malaysian patients. Despite the lack of genotype and phenotype correlation, early diagnosis and timely treatment remained the most important determinant of patient outcome. PMID:27672653

  19. Current concepts in organic acidurias: understanding intra- and extracerebral disease manifestation. (United States)

    Kölker, Stefan; Burgard, Peter; Sauer, Sven W; Okun, Jürgen G


    This review focuses on the pathophysiology of organic acidurias (OADs), in particular, OADs caused by deficient amino acid metabolism. OADs are termed classical if patients present with acute metabolic decompensation and multiorgan dysfunction or cerebral if patients predominantly present with neurological symptoms but without metabolic crises. In both groups, however, the brain is the major target. The high energy demand of the brain, the gate-keeping function of the blood-brain barrier, a high lipid content, vulnerable neuronal subpopulations, and glutamatergic neurotransmission all make the brain particularly vulnerable against mitochondrial dysfunction, oxidative stress, and excitotoxicity. In fact, toxic metabolites in OADs are thought to cause secondary impairment of energy metabolism; some of these toxic metabolites are trapped in the brain. In contrast to cerebral OADs, patients with classical OADs have an increased risk of multiorgan dysfunction. The lack of the anaplerotic propionate pathway, synergistic inhibition of energy metabolism by toxic metabolites, and multiple oxidative phosphorylation (OXPHOS) deficiency may best explain the involvement of organs with a high energy demand. Intriguingly, late-onset organ dysfunction may manifest even under metabolically stable conditions. This might be explained by chronic mitochondrial DNA depletion, increased production of reactive oxygen species, and altered gene expression due to histone modification. In conclusion, pathomechanisms underlying the acute disease manifestation in OADs, with a particular focus on the brain, are partially understood. More work is required to predict the risk and to elucidate the mechanism of late-onset organ dysfunction, extracerebral disease manifestation, and tumorigenesis.

  20. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. (United States)

    Boy, Nikolas; Mühlhausen, Chris; Maier, Esther M; Heringer, Jana; Assmann, Birgit; Burgard, Peter; Dixon, Marjorie; Fleissner, Sandra; Greenberg, Cheryl R; Harting, Inga; Hoffmann, Georg F; Karall, Daniela; Koeller, David M; Krawinkel, Michael B; Okun, Jürgen G; Opladen, Thomas; Posset, Roland; Sahm, Katja; Zschocke, Johannes; Kölker, Stefan


    Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.

  1. Mechanistic effects of amino acids and glucose in a novel glutaric aciduria type 1 cell model.

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    Xi Fu

    Full Text Available Acute neurological crises involving striatal degeneration induced by a deficiency of glutaryl-CoA dehydrogenase (GCDH and the accumulation of glutaric (GA and 3-hydroxyglutaric acid (3-OHGA are considered to be the most striking features of glutaric aciduria type I (GA1. In the present study, we investigated the mechanisms of apoptosis and energy metabolism impairment in our novel GA1 neuronal model. We also explored the effects of appropriate amounts of amino acids (2 mM arginine, 2 mM homoarginine, 0.45 g/L tyrosine and 10 mM leucine and 2 g/L glucose on these cells. Our results revealed that the novel GA1 neuronal model effectively simulates the hypermetabolic state of GA1. We found that leucine, tyrosine, arginine, homoarginine or glucose treatment of the GA1 model cells reduced the gene expression of caspase-3, caspase-8, caspase-9, bax, fos, and jun and restored the intracellular NADH and ATP levels. Tyrosine, arginine or homoarginine treatment in particular showed anti-apoptotic effects; increased α-ketoglutarate dehydrogenase complex (OGDC, fumarase (FH, and citrate synthase (CS expression; and relieved the observed impairment in energy metabolism. To the best of our knowledge, this study is the first to investigate the protective mechanisms of amino acids and glucose in GA1 at the cellular level from the point of view of apoptosis and energy metabolism. Our data support the results of previous studies, indicating that supplementation of arginine and homoarginine as a dietary control strategy can have a therapeutic effect on GA1. All of these findings facilitate the understanding of cell apoptosis and energy metabolism impairment in GA1 and reveal new therapeutic perspectives for this disease.

  2. Mechanistic effects of amino acids and glucose in a novel glutaric aciduria type 1 cell model. (United States)

    Fu, Xi; Gao, Hongjie; Tian, Fengyan; Gao, Jinzhi; Lou, Liping; Liang, Yan; Ning, Qin; Luo, Xiaoping


    Acute neurological crises involving striatal degeneration induced by a deficiency of glutaryl-CoA dehydrogenase (GCDH) and the accumulation of glutaric (GA) and 3-hydroxyglutaric acid (3-OHGA) are considered to be the most striking features of glutaric aciduria type I (GA1). In the present study, we investigated the mechanisms of apoptosis and energy metabolism impairment in our novel GA1 neuronal model. We also explored the effects of appropriate amounts of amino acids (2 mM arginine, 2 mM homoarginine, 0.45 g/L tyrosine and 10 mM leucine) and 2 g/L glucose on these cells. Our results revealed that the novel GA1 neuronal model effectively simulates the hypermetabolic state of GA1. We found that leucine, tyrosine, arginine, homoarginine or glucose treatment of the GA1 model cells reduced the gene expression of caspase-3, caspase-8, caspase-9, bax, fos, and jun and restored the intracellular NADH and ATP levels. Tyrosine, arginine or homoarginine treatment in particular showed anti-apoptotic effects; increased α-ketoglutarate dehydrogenase complex (OGDC), fumarase (FH), and citrate synthase (CS) expression; and relieved the observed impairment in energy metabolism. To the best of our knowledge, this study is the first to investigate the protective mechanisms of amino acids and glucose in GA1 at the cellular level from the point of view of apoptosis and energy metabolism. Our data support the results of previous studies, indicating that supplementation of arginine and homoarginine as a dietary control strategy can have a therapeutic effect on GA1. All of these findings facilitate the understanding of cell apoptosis and energy metabolism impairment in GA1 and reveal new therapeutic perspectives for this disease.

  3. Response to Quinlivan: Post-fortification, folate intake in vitamin B12 deficiency is positively related to homocysteine and methylmalonic acid (United States)

    With cross-sectional data, causes and effects are difficult to distinguish, and Quinlivan suggests that high circulating concentrations of homcysteine (Hcy), methylmalonic acid (MMA), and folate observed among vitamin B12-deficient survey participants all resulted from a lack of vitamin B12 (1). How...

  4. A L2HGDH initiator methionine codon mutation in a Yorkshire terrier with L-2-hydroxyglutaric aciduria

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    Farias Fabiana HG


    Full Text Available Abstract Background L-2-hydroxyglutaric aciduria is a metabolic repair deficiency characterized by elevated levels of L-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid. Neurological signs associated with the disease in humans and dogs include seizures, ataxia and dementia. Case presentation Here we describe an 8 month old Yorkshire terrier that presented with episodes of hyperactivity and aggressive behavior. Between episodes, the dog’s behavior and neurologic examinations were normal. A T2 weighted MRI of the brain showed diffuse grey matter hyperintensity and a urine metabolite screen showed elevated 2-hydroxyglutaric acid. We sequenced all 10 exons and intron-exon borders of L2HGDH from the affected dog and identified a homozygous A to G transition in the initiator methionine codon. The first inframe methionine is at p.M183 which is past the mitochondrial targeting domain of the protein. Initiation of translation at p.M183 would encode an N-terminal truncated protein unlikely to be functional. Conclusions We have identified a mutation in the initiation codon of L2HGDH that is likely to result in a non-functional gene. The Yorkshire terrier could serve as an animal model to understand the pathogenesis of L-2-hydroxyglutaric aciduria and to evaluate potential therapies.

  5. 甲基丙二酸血症16例%Methylmalonic Acidemia in 16 Children

    Institute of Scientific and Technical Information of China (English)

    殷星; 贾天明; 张晓莉; 杜开先; 李小丽; 刘涛; 袁艳


    Objective To explore the clinical characteristics and treatment of methylmalonic acidemia( MMA). Methods Sixteen patients with MMA were confirmed by gas chromatography - mass spectrometry ( GC/MS). Results The patients' age of onset ranged from 5 days to 2 years. The main clinical manifestations were poor feeding and vomiting(6 cases) .developmental retardation or retardation(6 cases), weak reaction(5 cases) ,convulsion(1 case). The laboratory findings showed metabolic acidosis in 8 cases,hyperammonemia in 1 case. Some abnormalities were noted by the brain CT or MRI in 11 cases. Two patients had abnormal findings in visual evoked potentials. Two patients were abnormal among 3 patients who received auditory brainstem response examination. There was remarkable elevation of urinary methylmalonic acid concentration in all the patients. Of the 8 cases without therapy ,2 patients died before the diagnosis was made ,6 cases died at home after giving up therapy. Seven cases received therapy of vitamin Bl2 and supplementation of L - carnitine with restricted - protein diet. The follow - up of 6 cases for a period ranging from 2 months to 2 years showed progress though developmental retardation could be found,only 1 case obviously fell behind the normal. One case was not to have follow - up due to short treatment time. One case failed to have follow - up. Conclusions The clinical manifestations of MMA are nonspecific, which include week reaction, developmental retardation or degradation, convulsion, poor feeding and vomiting,muscular dystonia,metabolic acidosis,hyperammonemia,abnormal signal in basal ganglia in the cranial MRI. GC/MS can be used to confirm the diagnosis. Early diagnosis and early treatment is the key to improve the prognosis.%目的 探讨甲基丙二酸血症的临床特征及治疗.方法 对本院通过气相色谱-质谱法尿有机酸分析确诊甲基丙二酸血症的患儿16例进行临床特征及诊疗分析.结果 本院16例

  6. Trichloroethylene and trichloroethanol-induced formic aciduria and renal injury in male F-344 rats following 12 weeks exposure. (United States)

    Yaqoob, Noreen; Evans, Andrew; Foster, John R; Lock, Edward A


    Trichloroethylene (TCE) is widely used as a cleaning and decreasing agent and has been shown to cause liver tumours in rodents and a small incidence of renal tubule tumours in male rats. The basis for the renal tubule injury is believed to be related to metabolism of TCE via glutathione conjugation to yield the cysteine conjugate that can be activated by the enzyme cysteine conjugate β-lyase in the kidney. More recently TCE and its major metabolite trichloroethanol (TCE-OH) have been shown to cause formic aciduria which can cause renal injury after chronic exposure in rats. In this study we have compared the renal toxicity of TCE and TCE-OH in rats to try and ascertain whether the glutathione pathway or formic aciduria can account for the toxicity. Male rats were given TCE (500mg/kg/day) or TCE-OH at (100mg/kg/day) for 12 weeks and the extent of renal injury measured at several time points using biomarkers of nephrotoxicity and prior to termination assessing renal tubule cell proliferation. The extent of formic aciduria was also determined at several time points, while renal pathology and plasma urea and creatinine were determined at the end of the study. TCE produced a very mild increase in biomarkers of renal injury, total protein, and glucose over the first two weeks of exposure and increased Kim-1 and NAG in urine after 1 and 5 weeks exposure, while TCE-OH did not produce a consistent increase in these biomarkers in urine. However, both chemicals produced a marked and sustained increase in the excretion of formic acid in urine to a very similar extent. The activity of methionine synthase in the liver of TCE and TCE-OH treated rats was inhibited by about 50% indicative of a block in folate synthesis. Both renal pathology and renal tubule cell proliferation were reduced after TCE and TCE-OH treatment compared to controls. Our findings do not clearly identify the pathway which is responsible for the renal toxicity of TCE but do provide some support for metabolism

  7. Investigation of the cerebral energy status in patients with glutaric aciduria type I by 31P magnetic resonance spectroscopy. (United States)

    Möller, H E; Koch, H G; Weglage, J; Freudenberg, F; Ullrich, K


    In vivo phosphorus magnetic resonance spectroscopy (MRS) was used to investigate markers of the cerebral energy status in two patients with glutaric aciduria type I (GA-I). Besides an increased concentration of phosphomonoesters in one patient, no other significant alterations from controls were found. This might indicate increased resynthesis of dendritic processes secondary to preceding metabolic crises. In contrast to previous cell-culture studies, no cerebral depletion of phosphocreatine (PCr) was observed. In conclusion, a severe global and permanent depletion of cerebral energy supplies must be ruled out. The benefit of a permanent creatine substitution to stabilize mitochondrial energy metabolism seems thus questionable. However, as MRS was performed during stable clinical conditions, the possibility of a PCr decrease during acute metabolic crises cannot be assessed.

  8. Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families

    Energy Technology Data Exchange (ETDEWEB)

    Suchi, Mariko; Mizuno, Haruo; Tsuboi, Takashi [Nagoya City Univ. Medical School (Japan)] [and others


    Uridine monophosphate (UMP) synthase is a bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, orotate phosphoribosyltransferase (OPRT) and orotidine-5{prime}-monophosphate decarboxylase (ODC). Loss of either enzymatic activity results in hereditary orotic aciduria, a rare autosomal recessive disorder characterized by retarded growth, anemia, and excessive urinary excretion of orotic acid. We have isolated the UMP synthase chromosomal gene from a {lambda}EMBL-3 human genomic library and report a single-copy gene spanning {approximately}15 kb. The UMP synthase genomic structure encodes six exons ranging in size from 115 bp to 672 bp, and all splicing junctions adhere to the canonical GT/AG rule. Cognate promoter elements implicated in glucocorticoid- and cAMP-mediated regulation as well as in liver-, myeloid-, and lymphocyte-specific expression are located within the 5{prime} flanking sequence. Molecular investigation of UMP synthase deficiency in a Japanese orotic aciduria patient revealed mutations R96G (A- to-G transition; nt 286) and G429R (G-to-C transversion; nt 1285) in one allele and V109G (T-to-G transversion; nt 326) in the other allele. Expression of human UMP synthase cDNAs containing these mutations in pyrimidine auxotrophic Escherichia coli and in recombinant baculovirus-infected Sf21 cells demonstrates impaired activity presumably associated with the urinary orotic acid substrate accumulations observed in vivo. We further establish the identity of two polymorphisms, G213A ({nu} = .26) and 440 Gpoly ({nu} = .27) located in exons 3 and 6, respectively, which did not significantly compromise either OPRT or ODC function. 76 refs., 5 figs., 7 tabs.

  9. Anesthetic management of comprehensive dental restoration in a child with glutaric aciduria type 1 using volatile sevoflurane. (United States)

    Teng, Wei-Nung; Lin, Su-Man; Niu, Dau-Ming; Kuo, Yi-Min; Chan, Kwok-Hon; Sung, Chun-Sung


    Glutaric aciduria type 1 (GA1) is a rare, inherited mitochondrial disorder that results from deficiency of mitochondrial glutaryl-CoA dehydrogenase. Most patients develop neurological dysfunction early in life, which leads to severe disabilities. We present a 37-month-old girl with GA1 manifested as macrocephaly and hypotonia who received comprehensive dental restoration surgery under general anesthesia with sevoflurane. She was placed on specialized fluid management during a preoperative fasting period and anesthesia was administered without complications. All the physiological parameters, including glucose and lactate blood levels and arterial blood gas were carefully monitored and maintained within normal range perioperatively. Strategies for anesthetic management should include prevention of pulmonary aspiration, dehydration, hyperthermia and catabolic state, adequate analgesia to minimize surgical stress, and avoidance of prolonged neuromuscular blockade. We administered general anesthesia with sevoflurane uneventfully, which was well tolerated by our patient with GA1. Additionally, communication with a pediatric geneticist and surgeons should be undertaken to formulate a comprehensive anesthetic strategy in these patients.

  10. Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria. (United States)

    Menao, Sebastián; López-Viñas, Eduardo; Mir, Cecilia; Puisac, Beatriz; Gratacós, Esther; Arnedo, María; Carrasco, Patricia; Moreno, Susana; Ramos, Mónica; Gil, María Concepción; Pié, Angeles; Ribes, Antonia; Pérez-Cerda, Celia; Ugarte, Magdalena; Clayton, Peter T; Korman, Stanley H; Serra, Dolors; Asins, Guillermina; Ramos, Feliciano J; Gómez-Puertas, Paulino; Hegardt, Fausto G; Casals, Nuria; Pié, Juan


    3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder that affects ketogenesis and L-leucine catabolism. The clinical acute symptoms include vomiting, convulsions, metabolic acidosis, hypoketotic hypoglycaemia and lethargy. To date, 33 mutations in 100 patients have been reported in the HMGCL gene. In this study 10 new mutations in 24 patients are described. They include: 5 missense mutations: c.109G>A, c.425C>T, c.521G>A, c.575T>C and c.598A>T, 2 nonsense mutations: c.242G>A and c.559G>T, one small deletion: c.853delC, and 2 mutations in intron regions: c.497+4A>G and c.750+1G>A. Two prevalent mutations were detected, 109G>T (E37X) in 38% of disease alleles analyzed and c.504_505delCT in 10% of them. Although patients are mainly of European origin (71%) and mostly Spanish (54%), the group is ethnically diverse and includes, for the first time, patients from Pakistan, Palestine and Ecuador. We also present a simple, efficient method to express the enzyme and we analyze the possible functional effects of missense mutations. The finding that all identified missense mutations cause a >95% decrease in the enzyme activity, indicates that the disease appears only in very severe genotypes."

  11. Chronic postnatal administration of methylmalonic acid provokes a decrease of myelin content and ganglioside N-acetylneuraminic acid concentration in cerebrum of young rats

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    Brusque A.M.


    Full Text Available Levels of methylmalonic acid (MMA comparable to those of human methylmalonic acidemia were achieved in blood (2-2.5 mmol/l and brain (1.35 µmol/g of rats by administering buffered MMA, pH 7.4, subcutaneously twice a day from the 5th to the 28th day of life. MMA doses ranged from 0.76 to 1.67 µmol/g as a function of animal age. Control rats were treated with saline in the same volumes. The animals were sacrificed by decapitation on the 28th day of age. Blood was taken and the brain was rapidly removed. Medulla, pons, the olfactory lobes and cerebellum were discarded and the rest of the brain ("cerebrum" was isolated. Body and "cerebrum" weight were measured, as well as the cholesterol and triglyceride concentrations in blood and the content of myelin, total lipids, and the concentrations of the lipid fractions (cholesterol, glycerolipids, phospholipids and ganglioside N-acetylneuraminic acid (ganglioside-NANA in the "cerebrum". Chronic MMA administration had no effect on body or "cerebrum" weight, suggesting that the metabolites per se neither affect the appetite of the rats nor cause malnutrition. In contrast, MMA caused a significant reduction of plasma triglycerides, but not of plasma cholesterol levels. A significant diminution of myelin content and of ganglioside-NANA concentration was also observed in the "cerebrum". We propose that the reduction of myelin content and ganglioside-NANA caused by MMA may be related to the delayed myelination/cerebral atrophy and neurological dysfunction found in methylmalonic acidemic children.

  12. Enfermedad de la orina con olor a jarabe de Arce (MSUD y aciduria metilmalónica. Presentación neonatal

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    Bermúdez M.


    Full Text Available La identificación de un error innato del metabolismo (EIM en el recién nacido requiere de unarápida sospecha clínica por parte del pediatra y posterior puesta en marcha de una adecuada metodología diagnóstica. Entre estas urgencias neonatales se deben considerar la producida porla enfermedad de orina con olor a jarabe de arce y la aciduria metilmalónica. Estos (EIM se debena deficiencias en las enzimas o coenzimas que intervienen en el catabolismo de los aminoácidos:La MSUD es el resultado de la deficiencia en el catabolismo de los aminoácidos de cadenaramificada leucina isoleucina, valina y se produce un aumento de estos a.a. y de sus cetácidos ensangre y en orina. En la aciduria metilmalónica se altera el catabolismo de la isoleucina, valinametionina treonina, colesterol y se produce acumulación del ácido metilmalónico.

  13. Development and implementation of a novel assay for L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) in cell lysates: L-2-HGDH deficiency in 15 patients with L-2-hydroxyglutaric aciduria

    DEFF Research Database (Denmark)

    Kranendijk, M; Salomons, G S; Gibson, K M


    L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by mutations in the gene encoding L-2-hydroxyglutarate dehydrogenase. An assay to evaluate L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) activity in fibroblast, lymphoblast and/or lymphoc...

  14. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. (United States)

    Kühne, T; Bubl, R; Baumgartner, R


    We present a 9-month-old exclusively breast-fed baby of a strict vegetarian mother who had excluded all animal proteins from her diet. The patient's symptoms included dystrophy, weakness, muscular atrophy, loss of tendon reflexes, psychomotor regression and haematological abnormalities. Biochemical investigations revealed severe methylmalonic aciduria and homocystinuria in the patient, slight methylmalonic aciduria in the mother and low concentrations of serum vitamin B12 in both patient and mother.

  15. Organic acidemia/aciduria and therapy%有机酸血(尿)症及其临床处理

    Institute of Scientific and Technical Information of China (English)

    肖昕; 郝虎


    The organic acidemia/aciduria is one of the most common inherited metabolic disorders in clinic,more than 50 species have been found until now.The illness is believed to be caused by gene mutation,leading to the reduction or loss of enzyme activity and the accumulation of carboxylic acid and its metabolites.The manifestations of increased blood organic acids include refractory metabolic acidosis,paroxysmal vomiting,feeding difficulties,hypotonia,convulsions and disturbance of consciousness.Most of the organic acidemia begins in neonatal period or infancy,accompanied by progressive neurological damages at most of the time.There are little specific clinical features can be found in this kind of diseases,therefore,early diagnosis and treatment must be initiated in order to decrease risk of neurological induries and damages or acute deaths.So application of the gas chromatography-mass spectrometry and tandem mass spectrometry is important to the early diagnosis,helpful for improving the outcomes and reducing child mortality.%有机酸血(尿)症是临床最常见的一类遗传代谢病,目前已经发现约50余种,多数在新生儿期或婴幼儿期发病.临床上多表现为顽固性代谢性酸中毒、发作性呕吐、喂养困难、肌张力低下、惊厥和意识障碍等.由于本类疾病临床没有特异性,若不能早期诊断和治疗,易出现猝死或不可逆转的神经系统损伤.利用气相色谱-质谱联用技术和(或)串联质谱技术对疑似有机酸血(尿)症患儿进行早期生化诊断是改善患儿预后和挽救患儿生命的关键.

  16. Population prevalence, attributable risk, and attributable risk percentage for high methylmalonic acid concentrations in the post-folic acid fortification period in the US

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    Ganji Vijay


    Full Text Available Abstract Background Serum methylmalonic acid (MMA is regarded as a sensitive marker of vitamin B-12 status. Elevated circulating MMA is linked to neurological abnormalities. Contribution of age, supplement use, kidney dysfunction, and vitamin B-12 deficiency to high serum MMA in post-folic acid fortification period is unknown. Methods We investigated prevalence, population attributable risk (PAR, and PAR% for high MMA concentrations in the US. Data from 3 cross-sectional National Health and Nutrition Examination Surveys conducted in post-folic acid fortification period were used (n = 18569. Results Likelihood of having high serum MMA for white relative to black was 2.5 (P P P P P Conclusions Old age is the strongest determinant of PAR for high MMA. About 5 cases of high serum MMA/1000 people would be reduced if vitamin B-12 deficiency (

  17. Clinical features andMUT gene mutation spectrum in Chinese patients with isolated methylmalonic acidemia:identifi cation of ten novel allelic variants

    Institute of Scientific and Technical Information of China (English)

    Lian-Shu Han; Zhuo Huang; Feng Han; Jun Ye; Wen-Juan Qiu; Hui-Wen Zhang; Yu Wang; Zhu-Wen Gong; Xue-Fan Gu


    Background: This study aims to studyMUT gene mutation spectrum in Chinese patients with isolated methylmalonic academia (MMA) and their clinical features for the potential genotype-phenotype correlation. Methods: Forty-three patients were diagnosed with isolated MMA by elevated blood propionylcarnitine, propionylcarnitine to acetylcarnitine ratio, and urine methylmalonate without hyperhomocysteinemia. The MUT gene was amplifi ed by polymerase chain reaction and directly sequenced. Those patients with at least one variant allele were included. The novel missense mutations were assessed by bioinformatic analysis and screened against alleles sequenced from 50 control participants. Results: Among the 43 patients, 38 had typical clinical presentations, and the majority (30/38) experienced early-onset MMA. Eight patients died and seven were lost to follow-up. Twenty patients had poor outcomes and eight showed normal development. The 43 identifi edMUT gene mutations had at least one variant allele, whereas 35 had two mutant alleles. Of the 33 mutations reported before, eight recurrent mutations were identified in 32 patients, and c.729_730insTT (p.D244Lfs*39) was the most common (12/78) in the mutant alleles. Of the 10 novel mutations, six were missense mutations and four were premature termination codon mutations. The six novel missense mutations seemed to be pathogenic. Conclusions: A total of 10 novelMUT mutations were detected in the Chinese population. c.729_730insTT (p.D244Lfs*39) was the most frequent mutation. A genotype-phenotype correlation could not be found, but the genotypic characterization indicated the need of genetic counseling for MMA patients and early prenatal diagnoses for high-risk families.

  18. 3-羟基丁酸尿症伴小脑性共济失调病例报告%A Case Report of 3-Hydroxybutyric Aciduria with Cerebellar Ataxia

    Institute of Scientific and Technical Information of China (English)

    陈晓鹏; 曹韦; 周小平; 蒋雨平


    Aim To report a case of 3-hydroxybutyric aciduria with cerebellar ataxia. Methods A case of 3-hydroxybutyric aciduria with cerebellar ataxia as initial manifestations was collectedand and reviewed. Results The case was a adult femalepatient,who was examined and found signs of cerebellar ataxia and high levels of 3-hydroxybutyric acid, acetylacetate, 2-keto-3-methypentanoate, 2-keto-isocaproate in acid. Conclusion The patient was diagnosed 3-hydroxybutyric aciduria with cerebellar ataxia.%目的:报告3-羟基丁酸尿症伴小脑性共济失调的病例。方法收集以共济失调为首发症状的3-羟基丁酸尿症患者的临床资料,结合文献复习进行分析。结果3-羟基丁酸尿症患者经临床体检发现有小脑共济失调的体征和尿中3-羟基丁酸、乙酰乙酸、2-酮-3-甲基戊酸、2-酮-异己酸显著升高。结论发现1例3-羟基丁酸尿症伴小脑性共济失调病例。

  19. Blood Concentrations of Homocysteine and Methylmalonic Acid among Demented and Non-Demented Swedish Elderly with and without Home Care Services and Vitamin B12 Prescriptions

    Directory of Open Access Journals (Sweden)

    Nils-Olof Hagnelius


    Full Text Available Background and Aims: Total plasma homocysteine (tHcy has been suggested as a risk factor of dementia. Our aim was to investigate potential differences in tHcy status in relation to the prescription of vitamin B12 and dementia diagnosis. We examined whether vitamin B12 prescriptions, a family history of dementia, or the need for home care service might be associated with tHcy values. Methods: A cross-sectional monocenter study comprising 926 consecutive subjects attending our Memory Care Unit was conducted. Results: Demented subjects being prescribed vitamin B12 had higher serum vitamin B12 (p = 0.025 but also higher tHcy (p 12 prescriptions. tHcy levels were significantly higher in non-demented subjects receiving home care service (p = 0.007. This group also had lower serum albumin (dementia: p 12 prescriptions (dementia with/without vitamin B12 prescription: p = 0.561; non-dementia with/without vitamin B12 prescription: p = 0.710. Conclusion: Despite vitamin B12 prescriptions, demented subjects had higher tHcy and methylmalonate values. The elevated metabolite values could not be explained by differences in renal function. Thus, elderly subjects on vitamin B12 prescription appear to have unmet nutritional needs.

  20. Nutritional Supplementation with Chlorella pyrenoidosa Lowers Serum Methylmalonic Acid in Vegans and Vegetarians with a Suspected Vitamin B₁₂ Deficiency. (United States)

    Merchant, Randall Edward; Phillips, Todd W; Udani, Jay


    Since vitamin B12 occurs in substantial amounts only in foods derived from animals, vegetarians and particularly vegans are at risk of developing deficiencies of this essential vitamin. The chlorella used for this study is a commercially available whole-food supplement, which is believed to contain the physiologically active form of the vitamin. This exploratory open-label study was performed to determine if adding 9 g of Chlorella pyrenoidosa daily could help mitigate a vitamin B12 deficiency in vegetarians and vegans. Seventeen vegan or vegetarian adults (26-57 years of age) with a known vitamin B12 deficiency, as evidenced by a baseline serum methylmalonic acid (MMA) level above 270 nmol/L at screening, but who otherwise appeared healthy were enrolled in the study. Each participant added 9 g of C. pyrenoidosa to their daily diet for 60 ± 5 days and their serum MMA, vitamin B12, homocysteine (Hcy) levels as well as mean corpuscular volume (MCV), hemoglobin (Hgb), and hematocrit (Hct) were measured at 30 and 60 days from baseline. After 30 and 60 days, the serum MMA level fell significantly (P vegans to get the vitamin B12 they need.

  1. 1 Cases of 2-Methyl 3-Hydroxybutyric Aciduria%2-甲基3-羟基丁酸尿症1例

    Institute of Scientific and Technical Information of China (English)

    潘桂梅; 宁伟伟; 张娜


    2-methyl 3- hydroxybutyric aciduria is a rare disease, incidence of a disease is low, but is often associated with severe acidosis fatal, it should be early diagnosis, timely treatment of the primary disease, when the infant vomiting, seizures ketosis, severe metabolic acidosis found clinical y, we should consider the possible metabolic diseases as screening, early diagnosis of metabolic disease with hematuria.%2-甲基3-羟基丁酸尿症为罕见病,发病率低,但常并发致死性的严重酸中毒,故应尽早明确病因、及时治疗原发病,当临床上发现婴幼儿有呕吐、发作性酮症、严重代谢性酸中毒时,应考虑代谢性疾病可能,尽早行血尿代谢病筛查以明确诊断。

  2. High-Throughput Analysis of Methylmalonic Acid in Serum, Plasma, and Urine by LC-MS/MS. Method for Analyzing Isomers Without Chromatographic Separation. (United States)

    Kushnir, Mark M; Nelson, Gordon J; Frank, Elizabeth L; Rockwood, Alan L


    Measurement of methylmalonic acid (MMA) plays an important role in the diagnosis of vitamin B12 deficiency. Vitamin B12 is an essential cofactor for the enzymatic carbon rearrangement of methylmalonyl-CoA (MMA-CoA) to succinyl-CoA (SA-CoA), and the lack of vitamin B12 leads to elevated concentrations of MMA. Presence of succinic acid (SA) complicates the analysis because mass spectra of MMA and SA are indistinguishable, when analyzed in negative ion mode and the peaks are difficult to resolve chromatographically. We developed a method for the selective analysis of MMA that exploits the significant difference in fragmentation patterns of di-butyl derivatives of the isomers MMA and SA in a tandem mass spectrometer when analyzed in positive ion mode. Tandem mass spectra of di-butyl derivatives of MMA and SA are very distinct; this allows selective analysis of MMA in the presence of SA. The instrumental analysis is performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in positive ion mode, which is, in combination with selective extraction of acidic compounds, is highly selective for organic acids with multiple carboxyl groups (dicarboxylic, tricarboxylic, etc.). In this method organic acids with a single carboxyl group are virtually undetectable in the mass spectrometer; the only organic acid, other than MMA, that is detected by this method is its isomer, SA. Quantitative measurement of MMA in this method is performed using a deconvolution algorithm, which mathematically resolves the signal corresponding to MMA and does not require chromatographic resolution of the MMA and SA peaks. Because of its high selectivity, the method utilizes isocratic chromatographic separation; reconditioning and re-equilibration of the chromatographic column between injections is unnecessary. The above features of the method allow high-throughput analysis of MMA with analysis cycle time of 1 min.

  3. Methylmalonic acid quantified in dried blood spots provides a precise, valid, and stable measure of functional vitamin B-12 status in healthy women. (United States)

    Schroder, Theresa H; Quay, Teo A W; Lamers, Yvonne


    Methylmalonic acid (MMA) is a sensitive and specific functional biomarker of vitamin B-12 status, commonly assessed in plasma or serum. Dried blood spots (DBSs) allow simpler and more cost-efficient blood sampling than plasma. To facilitate convenient testing for vitamin B-12 deficiency in large-scale surveys and in population groups from remote areas, we developed a method for MMA quantification in DBSs and tested its applicability as well as the long-term stability of MMA in DBSs at various temperatures. MMA was extracted from an 8-mm DBS punch with water:methanol (95:5, v:v) and methyl-d3-malonic acid as the internal standard. After sample cleanup by ultrafiltration and hexane extraction, MMA was quantified by using reversed-phase LC-tandem mass spectrometry. Extraction conditions were optimized to maximize the detection signal and achieve DBS extract concentrations above the lowest limit of quantification (signal-to-noise ratio ≥ 10) of 10 nmol/L. Recovery was between 93% and 96%. Intra- and interassay variation (CV%) for DBS MMA was 0.49% and 2.3%, respectively. Calibrators showed linearity (R(2) = 0.998) between 10 and 10,000 nmol/L. In 94 healthy women, MMA concentrations in DBS extract (min-max: 10.2-80.5 nmol/L) and plasma (min-max: 68-950 nmol/L) were correlated (ρ = 0.90) (P < 0.001). MMA concentrations in DBSs were stable at room temperature for 1 wk, in the refrigerator for 8 wk, and at -80°C for at least 1 y. This simple and robust method allows quantification of MMA in DBSs of healthy individuals. The linear relation between plasma and DBS MMA suggests that DBS MMA could predict plasma MMA, the current reference indicator for functional vitamin B-12 deficiency. With the advantages of minimally invasive specimen collection and no need for laborious blood processing steps, this method has the potential to be a reliable, convenient, and field-applicable alternative for assessment of vitamin B-12 status.

  4. Clinical analysis of methylmalonic acidemia in 95 children%儿童甲基丙二酸血症95例临床分析

    Institute of Scientific and Technical Information of China (English)

    李启亮; 宋文琪


    Objective To accumulate knowledge of methylmalonic acidemia (MMA) screening by studying the clinical characteristics and laboratory characteristics of the disease.Methods The clinical manifestations and the results of laboratory tests of 95 cases of MMA were analyzed.Results The age of onset was from 1 day to 12 years.Six cases had the episodes of vomiting,lethargy in 14 cases and recurrent difficuhy with feeding in 4 cases,seizures in 24 cases,mental retardation and movement disorders in 18 cases,dysarthria in 3 cases,debilitation and BLE edemas in 10 cases,jaundice in 7 cases,complaints of precordium in 6 cases,anaemia in 3 cases.The laboratory tests showed that the counts of white blood cells(WBC)were increased in 26 cases and the counts of red blood cells (RBC)were decreased in 26 cases.The results of urine routine tests were abnormal in 37 cases.The results of renal function tests were abnormal in 18 cases.The results of hepatic function tests were abnormal in 17 cases.The results of myocardial enzyme were abnormal in 40 cases.The results of blood gas test were abnormal in 1 1 cases.The levels of glucose were decreased in 6 cases.The levels of lactic acid were increased in 62 cases.The levels of blood ammonia were increased in 50 cases.Remarkable elevation of urinary methymalonic concentration was confirmed in 97% patients by gas chromatography-mass spectrometry (GC-MS).Remarkable elevation of C3,C3/C0 and C3/C2 concentrations was confirmed in 89% patients by liquid chromatography-tandem mass spectrometry (LC-MS/MS).Conclusion The main clinical features of MMA include lethargy,seizure,vomiting,developmental retardation or regradation,hyperarmnonemia and hyperlactacidemia.Urine organic acids analysis by GS-MS and dry blood spots (amino acids and acylcarnitine) analysis by LC-MS/MS are very important to the diagnosis of MMA.%目的 探讨甲基丙二酸血症(methylmalonic acidemia,MMA)的临床和实验室特征,为筛查MMA积累经验.方法 对2006年6

  5. Clinical analysis of methylmalonic acidmia in 26 cases and literatare review%甲基丙二酸血症26例临床分析并文献复习

    Institute of Scientific and Technical Information of China (English)

    穆静; 杨燕


    Objective To explore the clinical characteristics and treatment of methylmalonic acidemia(MMA) in order to improve our understanding of it.Methods We analyzed the clinical manifestations,laboratory examinations and treatments of 26 cases of methylmalonic acidemia in children.Results Twenty-four cases were involved in nervous system.Nine patients were involved in renal system.Eight cases of hematological involved.Liver enzyme elevated in 2 cases as well as the cardiac system were involved in 3 cases.One case was with pneumonia onset.The laboratory findings showed metabolic acidosis in 12 cases,hyperhomocysteinemia in 8 cases and remarkable elevation of urinary methylmalonic acid concentration in all cases.Some abnormalities in globus pallidus and cerebral white matter as well as diffuse cerebral atrophy were noted by the brain CT and MRI in 15 cases.Sixteen children have received therapy of vitamin B12,and supplementation of L-carnitine with restricted-protein diet.The follow-up for a period ranging from 3 months to 1.5 years( mean 8.5 months) of 15 cases with medical therapy showed a favorable outcome of nervous system improvement in 12 cases,however,2 patients died from severe metabolic acidosis.8 patients with renal involvement were normal in urine routine and renal function.Conclusion Methylmalonic acidemia has different clinical features,so early urine organic acids analysis by GC/MS method is essential Long-term and reasonable treatment after diagnosis is an effective way to improve the prognosis.%目的 探讨甲基丙二酸血症的临床特征和治疗方法.方法 对26例甲基丙二酸血症患儿的临床表现、辅助检查及诊疗情况进行分析.结果 26例患儿中主要临床表现:24例神经系统受累,9例肾脏受累,8例血液系统受累,2例肝脏受累,3例心脏受累,1例肺部受累.气相色谱-质谱法尿有机酸分析显示26例患儿尿甲基丙二酸浓度均明显高于正常.12例失代偿性代谢性酸中毒,8例血同

  6. Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1

    DEFF Research Database (Denmark)

    Carrozzo, Rosalba; Verrigni, Daniela; Rasmussen, Magnhild


    deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently......BACKGROUND: The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings...

  7. Cyanocobalamin Injection (United States)

    ... used to treat inherited conditions that decrease the absorption of vitamin B12 from the intestine. Cyanocobalamin injection is also sometimes used to treat methylmalonic aciduria (an inherited disease in which the body cannot break down protein) and is sometimes given to unborn babies to ...

  8. 戊二酸尿症1型28例的临床与实验室特征%Clinical and laboratory studies on 28 patients with glutaric aciduria type 1

    Institute of Scientific and Technical Information of China (English)

    王峤; 丁圆; 刘玉鹏; 李溪远; 吴桐菲; 宋金青; 王玉洁; 杨艳玲


    Objective To investigate the clinical,biochemical and genetic profiles of 28 Chinese patients with glutaric aciduria type 1.Method Twenty-eight patients with glutaric aciduria type 1 seen in the Department of Pediatrics,Peking University First Hospital from July 2003 to October 2013 were studied.The data of clinical course,laboratory examinations,cranial MRI and GCDH gene mutations of the patients were analyzed.Result (1) Three cases were detected by newborn screening,and the other patients were diagnosed at the age of 2 months to 17 years.(2) 22 patients (79%) were infant onset cases with psychomotor retardation,dystonia,seizures,athetosis,recurrent vomiting,drowsiness or feeding difficulty.Only two of the 22 patients with infant onset got normal intelligence and movement after treatment.Twenty of them were improved slowly with delayed development,dystonia and other neurological problems.Three patients (11%) had late onset.They had motor regression,headache and seizure at the age of 8,9 and 17 years,respectively.Rapid improvement was observed after treatment.(3) Cranial MRI has been checked in 23 patients ; 22 of them showed characteristic widening of the Sylvian fissure,abnormalities of the basal ganglia,leukoencephalopathy and brain atrophy.Thirty-five mutations in GCDH gene of the patients were identified; c.148T > C (p.W50R)was the most common mutation with the frequency of 7.7% ; 6 mutations (c.628A > G,c.700C >T,c.731G > T,c.963G > C,c.1031C > T and c.1109T > C) were novel.Conclusion Glutaric aciduria type 1 usually induced neurological deterioration resulting in severe psychomotor retardation and dystonia.Most of our patients were clinically diagnosed.Patients with early onset usually remained having neurological damage.Phenotype and genotype correlation has not been found in the patients.Neonatal screening for organic acidurias should be expanded in China.%目的 分析戊二酸尿症1型患者的临床、生

  9. Development and implementation of a novel assay for L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) in cell lysates: L-2-HGDH deficiency in 15 patients with L-2-hydroxyglutaric aciduria. (United States)

    Kranendijk, M; Salomons, G S; Gibson, K M; Aktuglu-Zeybek, C; Bekri, S; Christensen, E; Clarke, J; Hahn, A; Korman, S H; Mejaski-Bosnjak, V; Superti-Furga, A; Vianey-Saban, C; van der Knaap, M S; Jakobs, C; Struys, E A


    L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by mutations in the gene encoding L-2-hydroxyglutarate dehydrogenase. An assay to evaluate L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) activity in fibroblast, lymphoblast and/or lymphocyte lysates has hitherto been unavailable. We developed an L-2-HGDH enzyme assay in cell lysates based on the conversion of stable-isotope-labelled L-2-hydroxyglutarate to 2-ketoglutarate, which is converted into L-glutamate in situ. The formation of stable isotope labelled L-glutamate is therefore a direct measure of L-2-HGDH activity, and this product is detected by liquid chromatography-tandem mass spectrometry. A deficiency of L-2-HGDH activity was detected in cell lysates from 15 out of 15 L-2-HGA patients. Therefore, this specific assay confirmed the diagnosis unambiguously affirming the relationship between molecular and biochemical observations. Residual activity was detected in cells derived from one L-2-HGA patient. The L-2-HGDH assay will be valuable for examining in vitro riboflavin/FAD therapy to rescue L-2-HGDH activity.

  10. Therapy of metabolic disorders with intravenous (IV) access ports and long term intravenous L-carnitine therapy. (United States)

    Winter, S; Birek, L; Walker, T; Phalin-Roque, J; Chandler, M J; Field, C; Zorn, E


    With the expansion of newborn screening to include many organic acidurias and fatty acid oxidation defects, effective therapies of these disorders will be needed. Currently severe disorders such as methylmalonic and propionic aciduria. conventional therapy with diet and oral L-camitine often prove ineffective in preventing failure to thrive and recurrent metabolic decompensations. L-carnitine provides a natural pathway for removal of the toxic metabolites in these disorders and is life saving therapy but, with poor oral absorption (25%), it is difficult to supply adequate carnitine to meet the metabolic needs of these patients. Long term intravenous L-carnitine therapy, administered through a subcutaneous venous access port in 5 patients with organic acidurias [propionic aciduria (2), methylmalonic aciduria (2), 3 methylglutaconic aciduria(1)] resulted in improved growth, lower frequency of metabolic decompensations and increased tolerance of natural protein in the diet. An added benefit was the ability to initiate fluid. electrolytes, and antibiotics during metabolic decompensations at home thus averting hospitalizations.

  11. 3例非典型异戊酸尿症患儿临床及基因型研究%Clinical and genetic features of three patients with non-classical isovaleric aciduria

    Institute of Scientific and Technical Information of China (English)

    李溪远; 秦亚萍; 杨艳玲; 华瑛; 丁圆; 吴桐菲; 宋金青; 刘玉鹏; 王峤; 张尧; 李梦秋


    Objective To explore the clinical, therapeutic and genetic features of IVD gene in late-onset non-classical isovaleric aciduria. Methods One boy and two girls presented with intractable vomiting were admitted. Urine organic acids and blood acylcarnitines proifles were analyzed. Isovaleric aciduria was diagnosed and conifrmed by IVD gene analysis. The patients were treated with leucine-restricted diet and the supplements of L-carnitine and glycine. Results Three patients had recurrent vomiting, drowsiness, odor of sweaty feet and metabolic acidosis from the age of 1 to 2 years. All of them had normal intelligence and leukopenia. One had oligocythemia. The blood isovalerylcarnitines (4.6 to 8.2μmol/L) and urine isovalerylglycines (36.1 to 1783.56 mmol/mmol creatinine) were elevated. Six mutations were found in their IVD gene. Four mutations (c.157C>T, c.214G>A, c.1183C>G and c.1208A>G) were reported. Two (c.1039G>A and c.1076A>G) were novel. The patients completely recovered after treatment with protein-restricted diet and the supplements of L-carnitine and glycine. Currently, they were aged 19 months to 14 years with normal physical and psychomotor development. Conclusions The clinical features of late-onset non-classical isovaleric aciduria are complex. It is onset in infants and young children and characteristic of recurrent vomiting and metabolic acidosis, which can be diagnosed by the blood acylcarnitine spectrum, urine organic acid analysis, and conifrmed by genetic analysis. L-carnitine supplement and diet intervention has signiifcant effects.%目的:探讨迟发型非典型异戊酸尿症患儿的临床、治疗及IVD基因突变特点。方法3例非典型异戊酸尿症患儿,经尿液有机酸、血液酯酰肉碱谱分析发现异戊酸尿症,并经IVD基因突变检测确诊。患儿给予左卡尼汀、甘氨酸补充治疗及限亮氨酸饮食干预并进行随访。结果3例患儿于1~2岁间发病,有不明原因呕吐、嗜睡,伴汗

  12. Mutation screening and prenatal diagnosis of methylmalonic academia in a Chinese pedigree by Ion Torrent semiconductor sequencing%应用Ion Torrent测序技术检测一个甲基丙二酸血症家系的致病突变暨产前诊断

    Institute of Scientific and Technical Information of China (English)

    李璃; 马定远; 孙云; 张菁菁; 王玉国; 蒋涛; 许争峰


    Objective To identify pathogenic mutations in a Chinese pedigree affected with methylmalonic academia for genetic counseling and prenatal diagnosis.Methods Molecular analysis of the MUT,MMACHC,MMAA and MMAB genes was performed for the proband with methylmalonic academia by Ion Torrent semiconductor sequencing.Candidate mutations were validated by Sanger sequencing.The couple was offered prenatal diagnosis via analyzing of the fetal DNA through amniocentesis.Results The proband was found to be compound heterozygous for c.609G>A (p.Trp203X) and c.658_660del AAG (p.Lys220del) mutations,which were inherited respectively from each of his parents.Prenatal diagnosis showed that the fetus has inherited two wild-type parental alleles.Conclusion The targeted Ion Torrent PGM sequencing has detected pathogenic mutations in the Chinese pedigree affected with methylmalonic academia,which has provided molecular evidence for clinical diagnosis,genetic counseling and prenatal diagnosis for the family.%目的 对一个甲基丙二酸血症家系进行基因检测,以明确致病突变,为家系成员再生育提供遗传咨询和产前诊断.方法 应用Ion Torrent半导体测序技术,对甲基丙二酸血症患儿MUT、MMACHC、MMAA和MMAB基因同时进行检测,筛选致病突变位点,并用Sanger测序法进行验证,同时对患儿双亲进行基因检测.患儿母亲再次妊娠时进行产前基因检测,以明确胎儿受累情况.结果 患儿MMACHC基因编码区存在c.609G>A(p.Trp203X)杂合无义突变、c.658_660del AAG(p.Lys220del)杂合缺失突变.患儿母亲携带c.658 660del AAG突变,父亲携带c.609G>A突变.产前基因检测结果显示胎儿未遗传父母携带的MMACHC致病突变.结论 应用Ion Torrent半导体测序技术快速筛查到一个甲基丙二酸血症家系的致病突变,可为临床诊断及遗传咨询提供准确的依据.

  13. 神经干细胞治疗甲基丙二酸血症继发脑损伤4例临床观察%Clinical observation of neural stem cells in treatment of 4 patients with methylmalonic acidemia secondary to brain injury

    Institute of Scientific and Technical Information of China (English)

    杨辉; 屈素清; 刘卫鹏; 杜侃; 杨印祥; 栾佐


    Objective To observe the neural stem cell therapeutic effect with methylmalonic acidemia(MMA) secondary to brain injury.Methods From April 2008 to October 2010, 4 patients with methylmalonic acidemia secondary to brain injury admitted to our hospital .All the patients re-ceived the neural stem cell transplantation via ventricle puncture positioned by MRI , and all the pa-tients were given a follow-up at 1 month and 6 month after the transplantation with Gesell scales assessment .Results Three of the four patients got improvements in motor and fine skills , visual and intellectual reactions after the transplantation within 1 month.In the following 6 months the conti-nuing improvements could be observed after the transplantation among the 3 patients.Cell therapy did not appear irreversible adverse events .Conclusion Neural stem cell therapy is safe and reliable , it can improve the clinical manifestations in children with methylmalonic academia secondary to brain injury in a short time .The efficacy can sustain to 6 months after the transplantation .On the basis of the treatment for the cause , the neural stem cell transplantation provides a new method of treatment for methylmalonic acidemia secondary to brain injury .But the long-term effect needs a further follow-up observation .%目的:观察神经干细胞治疗甲基丙二酸血症继发脑损伤儿童的临床疗效。方法2008年4月-2010年10月在我院治疗的甲基丙二酸血症继发脑损伤儿童4例,所有患儿均在磁共振头皮定位下行侧脑室穿刺神经干细胞移植。移植后1个月对患儿综合评估,并随访至移植后6个月,对患儿行Gesell发育量表评估。结果4例中,3例在移植后1个月内出现大运动、精细动作、视听反应及智力反应等方面的进步;跟踪随访至移植后6个月,3例均持续出现不同程度进步。细胞治疗均未出现不可逆不良事件。结论神经干细胞治疗安全可靠,能在短时间改善

  14. Changes of vitamin B12 and methylmalonic acid levels in diabetic patients treated with metformin%维生素B12与甲基丙二酸水平在糖尿病二甲双胍治疗中的变化

    Institute of Scientific and Technical Information of China (English)

    孙爱丽; 刘元涛; 倪一虹; 孙福敦; 庄向华; 李晓博; 姜冬青; 潘喆; 娄能俊


    为观察在二甲双胍治疗糖尿病时对维生素B12的影响,探讨甲基丙二酸对诊断维生素B12缺乏的价值,本研究选取126例2型糖尿病患者进行研究,发现应用二甲双胍可导致糖尿病患者血清维生素B12水平降低[(501.62±219.98对762.86±360.92)ng/L,P<0.01];尿甲基丙二酸对维生素B12早期缺乏的诊断价值较高,其敏感性、特异性为81.25%、83.75%.%The aim of the study was to investigate the influence of metformin on serum vitamin B12 in patients with type 2 diabetes mellitus,and to determine the value of methylmalonic acid in the diagnosis of vitamin B12 deficiency.126 type 2 diabetic patients were recruited.The results showed that metformin lowered serum vitamin B12 level in these patients [(501.62 ± 219.98 vs 762.86 ± 360.92) ng/L,P<0.01].Urinary methylmalonic acid may be a candidate biochemical indicator for early diagnosis of vitamin B12 deficiency in the diabetic patients,with high sensitivity (81.25%) and specificity (83.75%).

  15. Genetics Home Reference: 2-hydroxyglutaric aciduria (United States)

    ... Errami A, Gissen P, Gradowska W, Hobson E, Islam L, Korman SH, Kurczynski T, Maranda B, Meli ... Site Map Customer Support Selection Criteria for Links Copyright Privacy Accessibility FOIA Viewers & Players U.S. ...

  16. LC-MS/MS方法检测血中甲基丙二酸含量及应用分析%Analysis of blood methylmalonic acid with a liquid chromatography-tandem mass spectrometry method and its application

    Institute of Scientific and Technical Information of China (English)

    崔学峰; 倪君君; 相婷; 高慧媛; 李玮; 吴立军


    for the diagnosis and screening of methylmalonic academia in the clinic. Methods MMA was extracted from 205 serum samples from healthy controls and 146 serum samples from patients with liquidliquid extraction method with MTBE as the extraction solvent. The supernatant was transferred to a tube and dried with nitrogen gas. Then the residual was derived with HCI-BuOH mixed agent to give a product, which was analyzed directly by LC-MS-MS system with a gradient elution, selective reaction monitor, a Discovery C18 column (50 mm × 2. 1 mm ,5 μm) as the isolation column and a mobile phase consisting of methanol and water (0. 1% formic acid, V/V), respectively. The concentration of MMA was detected with the isotope internal standard method. The stand curve was employed with a series of calibrators. The recovery was estimated with the 3 serum samples with the concentrations of 2, 25, 80 μg/L respectively. The accuracy,precision and stability were also tested with quality control samples. Moreover, the range of concentrations in healthy people were detected to investigate the influence of hemolysis on the detection results. Thirteen samples were randomly tested according to the digital chart. The testing results were compared with the results provided by Medical Diagnositic institution (MDI) in Germany. The paired t-test was applied to statistical analysis. Results The linear range of this method was 2-100 μg/L, and the correlation coefficient (R2 ) was more than 0. 995. The retention time of MMA derivative was 10. 5 min. Succinic acid and MMA were not found to interfere with each other. The within-run RSD was less than 6. 4%, and the between-run RSD was less than 5.0%. The recovery rates were from 96. 42% to 103. 33%. The limit of quantification was 1 μg/L.The accuracies of the method were form 94. 2% to 108. 2%. The samples were stable for 6 h at room temperature and stable for 70 d even keep at - 20 ℃. The samples were stable after 10 freeze-thaw cycles. The

  17. Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases* (United States)

    Yamada, Kazuhiro; Gherasim, Carmen; Banerjee, Ruma; Koutmos, Markos


    In mammals, B12 (or cobalamin) is an essential cofactor required by methionine synthase and methylmalonyl-CoA mutase. A complex intracellular pathway supports the assimilation of cobalamin into its active cofactor forms and delivery to its target enzymes. MMADHC (the methylmalonic aciduria and homocystinuria type D protein), commonly referred to as CblD, is a key chaperone involved in intracellular cobalamin trafficking, and mutations in CblD cause methylmalonic aciduria and/or homocystinuria. Herein, we report the first crystal structure of the globular C-terminal domain of human CblD, which is sufficient for its interaction with MMADHC (the methylmalonic aciduria and homocystinuria type C protein), or CblC, and for supporting the cytoplasmic cobalamin trafficking pathway. CblD contains an α+β fold that is structurally reminiscent of the nitro-FMN reductase superfamily. Two of the closest structural relatives of CblD are CblC, a multifunctional enzyme important for cobalamin trafficking, and the activation domain of methionine synthase. CblD, CblC, and the activation domain of methionine synthase share several distinguishing features and, together with two recently described corrinoid-dependent reductive dehalogenases, constitute a new subclass within the nitro-FMN reductase superfamily. We demonstrate that CblD enhances oxidation of cob(II)alamin bound to CblC and that disease-causing mutations in CblD impair the kinetics of this reaction. The striking structural similarity of CblD to CblC, believed to be contiguous in the cobalamin trafficking pathway, suggests the co-option of molecular mimicry as a strategy for achieving its function. PMID:26364851

  18. Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases. (United States)

    Yamada, Kazuhiro; Gherasim, Carmen; Banerjee, Ruma; Koutmos, Markos


    In mammals, B12 (or cobalamin) is an essential cofactor required by methionine synthase and methylmalonyl-CoA mutase. A complex intracellular pathway supports the assimilation of cobalamin into its active cofactor forms and delivery to its target enzymes. MMADHC (the methylmalonic aciduria and homocystinuria type D protein), commonly referred to as CblD, is a key chaperone involved in intracellular cobalamin trafficking, and mutations in CblD cause methylmalonic aciduria and/or homocystinuria. Herein, we report the first crystal structure of the globular C-terminal domain of human CblD, which is sufficient for its interaction with MMADHC (the methylmalonic aciduria and homocystinuria type C protein), or CblC, and for supporting the cytoplasmic cobalamin trafficking pathway. CblD contains an α+β fold that is structurally reminiscent of the nitro-FMN reductase superfamily. Two of the closest structural relatives of CblD are CblC, a multifunctional enzyme important for cobalamin trafficking, and the activation domain of methionine synthase. CblD, CblC, and the activation domain of methionine synthase share several distinguishing features and, together with two recently described corrinoid-dependent reductive dehalogenases, constitute a new subclass within the nitro-FMN reductase superfamily. We demonstrate that CblD enhances oxidation of cob(II)alamin bound to CblC and that disease-causing mutations in CblD impair the kinetics of this reaction. The striking structural similarity of CblD to CblC, believed to be contiguous in the cobalamin trafficking pathway, suggests the co-option of molecular mimicry as a strategy for achieving its function.


    Directory of Open Access Journals (Sweden)

    Massoud HOUSHMAND


    Full Text Available Glutaric Acidemia, Type I (GA I, was first described in 1975. The disease is caused by a genetic deficiency of the enzyme, Glutaryl-CoA Dehydrogenase (GCD, which leads to the buildup of Glutaric acid in the tissues and its excretion in the urine of affected patients. GCD is involved in the catabolism of the amino acids, Lysine, Hydroxylysine, and Tryptophan. Over 200 cases of GA I have been reported in the medical literature. GA I is one of the most common organic acidemias and has an estimated incidence of about 1 in 50,000 live births.Because of the initial slow progression of clinical symptoms, GA I is frequently undiagnosed until an acute metabolic crisis occurs. A total of 25 unrelated patients suspected to GA1 were investigated in our study. Genomic DNA was extracted from peripheral blood cells of the 25 probands whom were biochemically and/or clinically and/or neuro-radiologically suspected to GA1. 15 of them had elevated glutaric acid in the urine organic acid test.PCR and direct sequencing of all 11 exons and their flanking region of the GCDH gene were examined.Some of them were investigated for known mutation in the other their family members. Fifteen patients had homozygous mutations and 10 patients were normal for GCDH gene. Our Results Showed:• 60% Known mutation were found in our 15 patients• 80% can be detected by 4 exons sequencing so for molecular investigatins exon 6, 7, 8, 10 are good choice for beginning of analysis• 33% was mutation in exon 7, so because of the cost of genetic diagnosis we suggest that investigation begin with this exon.• Pro 348 Leu was most detected 20%.• 40% are new mutations wich will be investigated for phenotype Genotype Correlations.


    Directory of Open Access Journals (Sweden)

    Parvaneh KARIMZADEH


    Full Text Available This condition is due to deficiency in electron transport flavoprotein or electron transport fluvoprotein dehydrogenase.The clinical presentation is characteristic of fatty acid oxidation disorders. This disorder is poor prognostic and death in infancy is common.The central nervous system involving causes neurodevelopmental delay, hypotonia, and head lag. Different type of seizures such as infantile spasm and generalized tonic clonic seizure begin in infancy and become refractory to antiepileptic drugs. Also episodes of status epilepticus are frequent. Neurological exam shows manifestation of upper motor neuron disease including exaggerated deep tendon reflex, ankle clonus and positive Babinski sign.Infectious disease and Intercurrent illnesses may lead to neurological deterioration and coma or death in the first few years of life. Also hemorrhagic episodes, for example, petechiae, ecchymose, hematuria and blood in stool associated with infectious disease is common manifestation.The hematologic investigations show no evidence of abnormalities in clotting and platelet function.The facial features of these patients resemble to each other and are mildly dismorphic. Sometimes the nasal bridge is depressed.Neuroimaging evaluation revealed delayed myelination and frontotemporal atrophy with high T2 intensity in basal ganglia.Acute catabolic state with crises of lactic academia and hypoglycemia are frequent but lactate and pyruvate can remain high between attacks.During attacks lactate level as high as 17 mmol/l and acidosis is more severe with PH values of 7.05 to 7.10.The major metabolic abnormality is high excretion of ethylmalonic acid in the urine.This disorder is transmitted in an autosomal recessive trait and boys and girls have been reported in same family.Ethyl malonicaciduria is lethal during infancy or first few years of life. Treatment with carnitine, vitamin C, vitamin D and riboflavin did not show dramatic effect. Diet with restricted methionine is helpful for decrease excretion of ethylmalonic acid in the urine and decrease the level of serum lactate and pyruvate.Case presentation A 2-year-old boy was referred to author’ clinic for evaluation of neurodevelopmental delay.He was the product of first pregnancy of consanguineous parents born by cesarean section.He had rolling and creeping but did not have the ability of sitting, standing and walking. He could not speak. He had a history of admission for bloody stool after 20 days of birth but hematologic evaluation did not confirm abnormal evidence.Neurological exam showed cerebral hypotonia (hypotonicity with no weight bearing and exaggerated deep tendon reflex. MRI revealed abnormal signal intensity in periventricular white matter and basal ganglia.Routine lab exam and venous blood Gas, ammonia and high performance liquid chromatography were in normal limits. Serum lactate level was mildly elevated.Urine organic acid showed high ethlymalonic acid 2125 mmol/molcreatinine (normal<17, therefore the diagnosis of ethyl malonicacidurai was confirmed. 

  1. IDH2 mutations in patients with D-2-hydroxyglutaric aciduria.

    NARCIS (Netherlands)

    Kranendijk, M.; Struys, E.A.; Schaftingen, E. van; Gibson, K.M.; Kanhai, W.A.; Knaap, M.S. van der; Amiel, J.; Buist, N.R.; Das, A.M.; Klerk, J.B. De; Feigenbaum, A.S.; Grange, D.K.; Hofstede, F.C.; Holme, E.; Kirk, E.P.; Korman, S.H.; Morava, E.; Morris, A.; Smeitink, J.A.M.; Sukhai, R.N.; Vallance, H.; Jakobs, C.; Salomons, G.S.


    Heterozygous somatic mutations in the genes encoding isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) were recently discovered in human neoplastic disorders. These mutations disable the enzymes' normal ability to convert isocitrate to 2-ketoglutarate (2-KG) and confer on the enzymes a new function:

  2. Mutation analysis of methylmalonyl CoA mutase gene exon 2 in Egyptian families: Identification of 25 novel allelic variants

    Directory of Open Access Journals (Sweden)

    Dina A. Ghoraba


    Full Text Available Methylmalonic aciduria (MMA is an autosomal recessive disorder of methylmalonate and cobalamin (cbl; vitamin B12 metabolism. It is an inborn error of organic acid metabolism which commonly results from a defect in the gene encoding the methylmalonyl-CoA mutase (MCM apoenzyme. Here we report the results of mutation study of exon 2 of the methylmalonyl CoA mutase (MUT gene, coding MCM residues from 1 to 128, in ten unrelated Egyptian families affected with methylmalonic aciduria. Patients were presented with a wide-anion gap metabolic acidosis. The diagnosis has established by the measurement of C3 (propionylcarnitine and C3:C2 (propionylcarnitine/acetylcarnitine in blood by using liquid chromatography–tandem mass spectrometry (LC/MS–MS and was confirmed by the detection of an abnormally elevated level of methylmalonic acid in urine by using gas chromatography–mass spectrometry (GC/MS and isocratic cation exchange high-performance liquid-chromatography (HPLC. Direct sequencing of gDNA of the MUT gene exon 2 has revealed a total of 26 allelic variants: ten of which were intronic, eight were located upstream to the exon 2 coding region, four were novel modifications predicted to affect the splicing region, three were novel mutations within the coding region: c.15G>A (p.K5K, c.165C>A (p.N55K and c.7del (p.R3EfsX14, as well as the previously reported mutation c.323G>A (p.R108H.

  3. Cinical treatment of 3-hydroxy-3-methylglutaric aciduria and a novel mutation on 3-hydroxy-3-methylglutaryl-coenzyme A lyase gene%3-羟基-3-甲基戊二酸尿症患儿的临床诊治及3-羟基-3-甲基戊二酰裂解酶基因新突变分析

    Institute of Scientific and Technical Information of China (English)

    艾力克木·阿不都玩克; 古力米热·布然江; 李溪远; 杨艳玲


    产前诊断亦至关重要。%Objective To investigate the clinical manifestations and biochemical characteristics of 3-hydroxy-3-methylglutaric aciduria,and discuss results of 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HMGCL)gene mutation.Methods The clinical data of a boy with 3-hydroxy-3-methylglutaric aciduria who was treated at Peking University First Hospital on December 7th 2014 was collected into this study. The admission examination, auxiliary examination, diagnosis and treatment, genedetection and follow-up of this boy were retrospectively analyzed.The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Peking University First Hospital. Informed consents were obtained from patient′s parents.Results The boy complained of unexplained diarrhea,vomiting,repeated hematemesis,fever 2 d and coma 3 h.The admission examination and auxiliary examination results showed increased white blood cell count,liver damage,electrolyte imbalance,low blood sugar,blood clotting abnormalities,low-protein,high ammonia,metabolic acidosis.Cranial MRI result showed that abnormal signal could be found in bilateral lateral ventricle and double fronto-temporal parietal cortex. The final diagnosis of the boy was 3-hydroxy-3- methylglutaric aciduria.By limiting protein intake,intravenous infusion of glucose and L-carnitine treatment,the symptom alleviated gradually.Genetic analysis results showed that exon region of HMGCL was found two heterozygous mutation point:c.509G> T and c.348 + 1 G> C,where c.509G> T was heterozygous mutation from the mother,c.348 + 1 G > C emerged in child homozygous mutation,the mutation site of c.348 + 1G> C splice site mutation caused amino acid changes p.Cys170Phe,splicing (cysteine phenylalanine,shear mutation).After discharge,the six months follow-up results showed as follow. Psychomotor developed slightly behind the health children,but no significant setback.The boy lived in good general condition,and biochemical

  4. Crystal structures of Mycobacterial MeaB and MMAA-like GTPases. (United States)

    Edwards, Thomas E; Baugh, Loren; Bullen, Jameson; Baydo, Ruth O; Witte, Pam; Thompkins, Kaitlin; Phan, Isabelle Q H; Abendroth, Jan; Clifton, Matthew C; Sankaran, Banumathi; Van Voorhis, Wesley C; Myler, Peter J; Staker, Bart L; Grundner, Christoph; Lorimer, Donald D


    The methylmalonyl Co-A mutase-associated GTPase MeaB from Methylobacterium extorquens is involved in glyoxylate regulation and required for growth. In humans, mutations in the homolog methylmalonic aciduria associated protein (MMAA) cause methylmalonic aciduria, which is often fatal. The central role of MeaB from bacteria to humans suggests that MeaB is also important in other, pathogenic bacteria such as Mycobacterium tuberculosis. However, the identity of the mycobacterial MeaB homolog is presently unclear. Here, we identify the M. tuberculosis protein Rv1496 and its homologs in M. smegmatis and M. thermoresistibile as MeaB. The crystal structures of all three homologs are highly similar to MeaB and MMAA structures and reveal a characteristic three-domain homodimer with GDP bound in the G domain active site. A structure of Rv1496 obtained from a crystal grown in the presence of GTP exhibited electron density for GDP, suggesting GTPase activity. These structures identify the mycobacterial MeaB and provide a structural framework for therapeutic targeting of M. tuberculosis MeaB.

  5. Hutchinson-Gilford progeria syndrome caused by an LMNA mutation: a case report. (United States)

    Chu, Yan; Xu, Zi-Gang; Xu, Zhe; Ma, Lin


    Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year-old boy who was born at full term but presented with scleroderma-like appearance at 1 month of age and gradually developed clinical manifestations of progeria. He had characteristic facial features of prominent eyes, scalp, and leg veins; loss of scalp hair, eyebrows, and eyelashes; stunted growth; scleroderma-like changes of the skin; and a premature aged appearance. Metabolic investigations showed transient methylmalonic aciduria, and genetic testing of the peripheral blood identified the c.1824C>T heterozygous LMNA mutation. The present case is reported because of its rarity.

  6. Methylmalonic Acid in Amniotic Fluid and Maternal Urine as a Marker for Neural Tube Defects

    Institute of Scientific and Technical Information of China (English)

    罗小平; 张炼; 魏虹; 刘皖君; 王慕逖; 宁琴


    To evaluate the implication of methymalonic acid (MMA) in the early diagnosis of neural tube defects (NTD), a quantitative assay for MMA was established by using gas chromatographymass spectrometry with stable isotope of MMA as an internal standard. Amniotic fluid and maternal urine MMA concentration, maternal serum folate, red blood cell folate and vitamin B12 levels were measured in the middle term of NTD-affected and normal pregnancies. Amniotic fluid and maternal urine MMA concentrations in the middle term of NTD affected pregnancies (1.4 ± 0.9 μmol/L, and 22.1 ± 12.6 nmol/μmol creatinine) were significantly higher than that of normal pregnancies (1.0±0.4μ mol/L, and 2.5± 1.1 nmol/μmol creatinine). There was no significant difference between normal and NTD pregnancies for serum folate, red blood cell folate and vitamin B12 levels.The results suggested that MMAs in amniotic fluid and maternal urine are sensitive markers for early diagnosis of NTD. Vitamin B12 is an active cofactor involved in the remethylation of homocycteine and its deficiency is an independent risk factor for NTD. MMA is a specific and sensitive marker for intracellular vitamin B12 deficiency. This study suggests that it is necessary to monitor the vitamin B12 deficiency and advocates vitamin B12 supplementation with folate prevention program.

  7. Acute Illness Protocol for Organic Acidemias: Methylmalonic Acidemia and Propionic Acidemia. (United States)

    Aldubayan, Saud H; Rodan, Lance H; Berry, Gerard T; Levy, Harvey L


    Inborn errors of metabolism (IEM) are genetic disorders that disrupt enzyme activity, cellular transport, or energy production. They are individually rare, but collectively have an incidence of 1:1000. Most patients with IEMs are followed by a physician with expertise in Biochemical Genetics (Metabolism), but may present outside of this setting. Because IEMs can present acutely with life-threatening crises that require specific interventions, it is critical for the emergency medicine physicians, pediatricians, internists, and critical care physicians as well as biochemical geneticists to be familiar with the initial assessment and management of patients with these disorders. Appropriate early care can be lifesaving. This protocol is not designed to replace the expert consultation of a biochemical geneticist but rather to improve early care and increase the level of comfort of the acute care physician with initial management of organic acidemias until specialty consultation is obtained.

  8. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

    DEFF Research Database (Denmark)

    Baumgartner, Matthias R; Hörster, Friederike; Dionisi-Vici, Carlo


    and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under......:100'000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA...


    Directory of Open Access Journals (Sweden)

    M. Kadivar R. Moradian


    Full Text Available Abstract- The syndrome of diabetes mellitus, sensorineural deafness and megaloblastic anemia dose not result from thiamine deficiency. The previous reported patients had no sign of beriberi, had normal nutrition, and had no evidence of malabsorption. The features of this syndrome with apparent inheritance of autosomal recessive trait may define this puzzling syndrome as a true thiamine dependency state. The first Iranian patient was described by Vossough et al. in 1995. We found nine new cases with diagnostic criteria of thiamine responsive megaloblastic anemia during eight years of our study. In two patients, presentation of diabetes and anemia was concomitant. All of them were deaf with sensorineural hearing loss which was detected in infancy up to two years of age. The presence of congenital valvular heart disease was eliminated by normal echocardiography, but cardiomyopathy was discovered in two. Nonspecific amino-aciduria was discovered in three but urinary screening tests for hereditary orotic aciduria were negative. Ox-Phos biochemistry of muscle mitochondria which demonstrates severe defect in complexes I, III, IV in diabetes mellitus associated with deafness, were done but was unremarkable in our patients. Urinary methylmalonic acid and methyl malonyl carnitine by GS/MS and TMS was done in our patients and showed abnormal results in six patients. Thiamine gene, SLC 19A2, was detected in four patients.

  10. Identification and quantitation of urinary dicarboxylic acids as their dicyclohexyl esters in disease states by gas chromatography mass spectrometry. (United States)

    Norman, E J; Berry, H K; Denton, M D


    Clinical studies were conducted by gas chromatography mass spectrometry selected ion monitoring of urinary dicarboxylic acids as dicyclohexyl esters. The dicyclohexyl esters of the dicarboxylic acids give characteristic electron impact mass spectra suitable for selected ion monitoring. The mass spectra exhibit a prominent acid + 1H ion and an (acid + 1H)-H2O ion for use as quantitating and confirming ions. The cyclohexyl esters are stable for days at room temperature and have excellent chromatographic properties. Dicarboxylic acid quantitation is performed within one hour using only 50 microliter of unpurified urine. A rapid method specifically for methylmalonic acid quantitation is described which has assisted physicians in the diagnosis of pernicious anemia and methylmalonic aciduria. This procedure is applicable for screening urinary organic acids for detection of inborn errors of metabolism. The detection of a child with elevated medium length dicarboxylic acids in the terminal urine specimen is reported. This condition, previously described as an inborn error, is attributed to a terminal event. Finally, an increase in urinary succinic acid paralleling putrescine levels is described during a response to cancer chemotherapy.

  11. The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, Costeff syndrome. (United States)

    Sofer, S; Schweiger, A; Blumkin, L; Yahalom, G; Anikster, Y; Lev, D; Ben-Zeev, B; Lerman-Sagie, T; Hassin-Baer, S


    Costeff syndrome is a rare genetic neuro-ophthalmological syndrome consisting of early-onset bilateral optic atrophy along with a progressive complex motor disorder with elevated levels of urinary 3-methylglutaconic acid and 3-methylglutaric acid. While borderline to mild cognitive deficits have been considered to be common in patients with this syndrome, a comprehensive cognitive assessment has never been performed. The aim of the current study was to explore the cognitive profile associated with Costeff syndrome. Sixteen adult patients diagnosed with Costeff syndrome were administered a neuropsychological test battery that was composed of standardized verbal tests adapted for the blind. General intelligence ranged from average to borderline, with a group mean consistent with intact general cognitive functioning (VIQmean  = 85, z = -1) in the low-average range of the general population. The auditory immediate and delayed memory indexes were in the average range and were significantly higher than the general cognitive functioning, whereas the working memory index was significantly lower than the general cognitive functioning. Adult patients with Costeff syndrome have intact global cognition and learning abilities and strong auditory memory performance. © 2015 Wiley Periodicals, Inc.

  12. 2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA dehydrogenase deficiency

    DEFF Research Database (Denmark)

    Korman, Stanley H; Andresen, Brage S; Zeharia, Avraham


    -mass spectrometry for urine organic acids, quantification of 2-MBG, and chiral determination of 2-methylbutyric acid. Blood-spot acylcarnitines were measured by electrospray-tandem mass spectrometry. Mutations in the ACADSB gene encoding SBCAD were identified by direct sequencing. RESULTS: SBCADD was confirmed...... of urine acylglycines is problematic. Excretion of 2-ethylhydracrylic acid (2-EHA), an intermediate formed in the normally minor R-pathway of L-isoleucine oxidation, has not previously been described in SBCADD. METHODS: Samples from four patients with 2-MBG excretion were analyzed by gas chromatography...... in each patient by demonstration of different ACADSB gene mutations. In multiple urine samples, organic acid analysis revealed a prominent 2-EHA peak usually exceeding the size of the 2-MBG peak. Approximately 40-46% of total 2-methylbutyric acid conjugates were in the form of the R-isomer, indicating...

  13. Diagnosis and management of glutaric aciduria type I--revised recommendations

    DEFF Research Database (Denmark)

    Kölker, Stefan; Christensen, Ernst; Leonard, James V


    is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine...... supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia...

  14. Adenoviral-mediated correction of methylmalonyl-CoA mutase deficiency in murine fibroblasts and human hepatocytes

    Directory of Open Access Journals (Sweden)

    Korson Mark


    Full Text Available Abstract Background Methylmalonic acidemia (MMA, a common organic aciduria, is caused by deficiency of the mitochondrial localized, 5'deoxyadenosylcobalamin dependent enzyme, methylmalonyl-CoA mutase (MUT. Liver transplantation in the absence of gross hepatic dysfunction provides supportive therapy and metabolic stability in severely affected patients, which invites the concept of using cell and gene delivery as future treatments for this condition. Methods To assess the effectiveness of gene delivery to restore the defective metabolism in this disorder, adenoviral correction experiments were performed using murine Mut embryonic fibroblasts and primary human methylmalonyl-CoA mutase deficient hepatocytes derived from a patient who harbored two early truncating mutations, E224X and R228X, in the MUT gene. Enzymatic and expression studies were used to assess the extent of functional correction. Results Primary hepatocytes, isolated from the native liver after removal subsequent to a combined liver-kidney transplantation procedure, or Mut murine fibroblasts were infected with a second generation recombinant adenoviral vector that expressed the murine methylmalonyl-CoA mutase as well as eGFP from distinct promoters. After transduction, [1-14C] propionate macromolecular incorporation studies and Western analysis demonstrated complete correction of the enzymatic defect in both cell types. Viral reconstitution of enzymatic expression in the human methylmalonyl-CoA mutase deficient hepatocytes exceeded that seen in fibroblasts or control hepatocytes. Conclusion These experiments provide proof of principle for viral correction in methylmalonic acidemia and suggest that hepatocyte-directed gene delivery will be an effective therapeutic treatment strategy in both murine models and in human patients. Primary hepatocytes from a liver that was unsuitable for transplantation provided an important resource for these studies.

  15. Ethylmalonic aciduria is associated with an amino acid variant of short chain acyl-coenzyme A dehydrogenase

    DEFF Research Database (Denmark)

    Corydon, M J; Gregersen, N; Lehnert, W


    metabolized by propionyl-CoA carboxylase to EMA. We have recently detected a guanine to adenine polymorphism in the SCAD gene at position 625 in the SCAD cDNA, which changes glycine 209 to serine (G209S). The variant allele (A625) is present in homozygous and in heterozygous form in 7 and 34.8% of the general...

  16. Structural Characterization of a Human-Type Corrinoid Adenosyltransferase Confirms That Coenzyme B[subscript 12] Is Synthesized through a Four-Coordinate Intermediate

    Energy Technology Data Exchange (ETDEWEB)

    St. Maurice, Martin; Mera, Paola; Park, Kiyoung; Brunold, Thomas C.; Escalante-Semerena, Jorge C.; Rayment, Ivan (UW)


    ATP:cob(I)alamin adenosyltransferases (ACAs) catalyze the transfer of the 5{prime}-deoxyadenosyl moiety from ATP to the upper axial ligand position of cobalamin in the synthesis of coenzyme B{sub 12}. For the ACA-catalyzed reaction to proceed, cob(II)alamin must be reduced to cob(I)alamin in the enzyme active site. This reduction is facilitated through the generation of a four-coordinate cob(II)alamin intermediate on the enzyme. We have determined the high-resolution crystal structure of a human-type ACA from Lactobacillus reuteri with a four-coordinate cob(II)alamin bound in the enzyme active site and with the product, adenosylcobalamin, partially occupied in the active site. The assembled structures represent snapshots of the steps in the ACA-catalyzed formation of the cobalt-carbon bond of coenzyme B{sub 12}. The structures define the corrinoid binding site and provide visual evidence for a base-off, four-coordinate cob(II)alamin intermediate. The complete structural description of ACA-mediated catalysis reveals the molecular features of four-coordinate cob(II)alamin stabilization and provides additional insights into the molecular basis for dysfunction in human patients suffering from methylmalonic aciduria.

  17. Cobalamin C deficiency in an adolescent with altered mental status and anorexia. (United States)

    Rahmandar, Maria H; Bawcom, Amanda; Romano, Mary E; Hamid, Rizwan


    Although cobalamin (cbl) C deficiency is the most common inherited disorder of vitamin B12 metabolism, the late-onset form of the disease can be difficult to recognize because it has a broad phenotypic spectrum. In this report, we describe an adolescent female exposed to unknown illicit substances and sexual abuse who presented with psychosis, anorexia, seizures, and ataxia. The patient's diagnosis was delayed until a metabolic workup was initiated, revealing hyperhomocysteinemia, low normal plasma methionine, and methylmalonic aciduria. Ultimately, cblC deficiency was confirmed when molecular testing showed compound heterozygosity for mutations (c.271dupA and c.482G>A) in the MMACHC gene. This diagnosis led to appropriate treatment with hydroxocobalamin, betaine, and folate, which resulted in improvement of her clinical symptoms and laboratory values. This patient demonstrates a previously unrecognized presentation of late-onset cblC deficiency. Although neuropsychiatric symptoms are common in late-onset disease, seizures and cerebellar involvement are not. Furthermore, anorexia has not been previously described in these patients. This case emphasizes that inborn errors of metabolism should be part of the differential diagnosis for a teenager presenting with altered mental status, especially when the diagnosis is challenging or neurologic symptoms are unexplained. Correct diagnosis of this condition is important because treatment is available and can result in clinical improvement.(1.)

  18. Structural Basis of Multifunctionality in a Vitamin B[subscript 12]-processing Enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Koutmos, Markos; Gherasim, Carmen; Smith, Janet L.; Banerjee, Ruma (Michigan)


    An early step in the intracellular processing of vitamin B{sub 12} involves CblC, which exhibits dual reactivity, catalyzing the reductive decyanation of cyanocobalamin (vitamin B{sub 12}), and the dealkylation of alkylcobalamins (e.g. methylcobalamin; MeCbl). Insights into how the CblC scaffold supports this chemical dichotomy have been unavailable despite it being the most common locus of patient mutations associated with inherited cobalamin disorders that manifest in both severe homocystinuria and methylmalonic aciduria. Herein, we report structures of human CblC, with and without bound MeCbl, which provide novel biochemical insights into its mechanism of action. Our results reveal that CblC is the most divergent member of the NADPH-dependent flavin reductase family and can use FMN or FAD as a prosthetic group to catalyze reductive decyanation. Furthermore, CblC is the first example of an enzyme with glutathione transferase activity that has a sequence and structure unrelated to the GST superfamily. CblC thus represents an example of evolutionary adaptation of a common structural platform to perform diverse chemistries. The CblC structure allows us to rationalize the biochemical basis of a number of pathological mutations associated with severe clinical phenotypes.

  19. A new chemical diagnostic method for inborn errors of metabolism by mass spectrometry-rapid, practical, and simultaneous urinary metabolites analysis. (United States)

    Matsumoto, I; Kuhara, T


    -two target metabolic diseases are: methylmalonic acidemia; propionic acidemia; isovaleric acidemia; maple syrup urine disease; β-ketothiolase deficiency; galactosemia; phenylketonuria; hyperphenylalaninemia; homocystinuria; alkaptonuria; multiple carboxylase deficiency; nonketotic hyperglycinemia; lysinuria; cystinuria; tyrosinemia; glutaric aciduria type I; β-hydroxy-β-methylglutaric acidemia; β-methylcrotonylglycinuria; α-aminoadipic-α-ketoadipic aciduria; ornitine transcarbamylase deficiency (four urea cycle disorders can be screened); glutaric aciduria type II; and neuroblastoma. Neuroblastoma is not an IEM, and is examined at ca. 6 months of age. The twenty-two target diseases will be reconsidered during the pilot study. An accurate chemical diagnosis and hence early treatment of not only organic acidemias but also amino acidemias, and sugar-, polyol-, and nucleic acid base-accumulating metabolic disorders can be made at a very early stage of life. This procedure is also applicable to metabolic profiling of other body fluids that are potentially informative for the study and characterization of a wide range of inherited and acquired metabolic disorders. © 1997 John Wiley & Sons, Inc.

  20. AB152. Inborn errors of metabolism spectrum in symptomatic children of north India: 5-year prospective data from tertiary care centre (United States)

    Kumar, Somesh; Lomash, Avinash; Varughese, Bijo; Bidhan, Sourabh; Khalil, Sumaira; Polipalli, Sunil K.; Kapoor, Seema


    Background Children with high suspicion of IEM is a more effective screening strategy in a resource limited country like India. We present a prospective analysis of symptomatic children with red flag signs suggestive of IEM referred for analysis by LCMSMS. This study investigated the spectrum of IEM in symptomatic children over a period of 5 years (1st June 2010 to May 31st 2015). Methods A total of 3,250 symptomatic children for IEM were screened. Dried blood spots were collected and processed by MS/MS (API-2000 & 3200 Qtrap), using a non derivatized kit, analysed by R-4 Stork algorithm. Results A total of 3,250 children, 1,803 boys (56.34%), 1,397 girls (43.66%) with a median age of 20.8 months (range, 0.04-148.2 months) were screened. The 125 were diagnosed with an inborn error of metabolism, with a detection rate of 3.90%. Of these, 78 (62.40%) were males and 47 (38.60%) were females with a median age of 6.55 months. Clinical variation among the patients were unexplained encephalopathy, seizures, convulsions, delayed milestones with global developmental delay, persistent metabolic acidosis with increase anion GAP. The commonest group was amino acid disorders affecting 61 (48.8%) with phenylketonuria (n=5), hyperphenylalaninemia (n=4), maple syrup urine disease (n=8), hypermethioninemia (n=3), hyperglycemia (n=14), tyrosinemia (n=5), classic neonatal onset citrullinemia (n=4), 3 with hyperornithinemia, 10 with rasied alanine (as a secondary indicator), 3 with argininemia and 2 with remethylation defect. Organic acidemias 37 (29.60%) were methylmalonic academia (n=15), malonic aciduria (n=3), propionic aciduria (n=5), glutaric academia type I (n=5) and with 3-Methyl crotonyl-CoA carboxylase deficiency (n=9). Fatty acids disorders were seen in 27 (21.60%) children with medium-chain acyl-CoA dehydrogenase deficiency being the commonest (n=5), and very-long chain acyl-CoA dehydrogenase deficiency (n=2), carnitine palmitoyl-transferase Ia deficiency (n=12), carnitine


    Directory of Open Access Journals (Sweden)

    Mahmoud Reza ASHRAFI


    maple syrup urine disease (MSUD, and abnormalities of the globus pallidus in methylmalonic acidemia. Macrocephaly is common in GA I.• Some differential agnosis of MRI findings in organic academia is consist of: HIE, mucopolysacaridosis, middle fossa arachnoid cyst, leighdisease, hexachlorophene toxicity in neonates, myelin splitting disorders.• Some organic aciduria such as L-2-Hydroxyglutaricaciduria may suggest leukodystrophy in MRI.

  2. Diagnosis of glutaric aciduria type 1 by measuring 3-hydroxyglutaric acid in dried urine spots by liquid chromatography tandem mass spectrometry

    DEFF Research Database (Denmark)

    Al-Dirbashi, Osama Y; Kölker, Stefan; Ng, Dione;


    on stable isotope dilution gas chromatography mass spectrometry (GC-MS) and require extensive sample preparation. Here we describe a simple liquid chromatography tandem MS (LC-MS/MS) method to quantify this important metabolite in dried urine spots (DUS). This method is based on derivatization with 4-[2-(N...... for 45 min, and 5 μl of the reaction solution was analyzed by LC-MS/MS. Reference ranges obtained were in excellent agreement with the literature. The method was applied retrospectively for the analysis of DUS samples from established low- and high-excreter GA1 patients as well as controls (n = 100......). Comparison of results obtained versus those obtained by GC-MS was satisfactory (n = 14). In populations with a high risk of GA1, this approach will be useful as a primary screening method for high- or low-excreter variants. In these populations, however, DUS analysis should not be implemented before...

  3. General (medium-chain) acyl-CoA dehydrogenase deficiency (non-ketotic dicarboxylic aciduria): quantitative urinary excretion pattern of 23 biologically significant organic acids in three cases. (United States)

    Gregersen, N; Kølvraa, S; Rasmussen, K; Mortensen, P B; Divry, P; David, M; Hobolth, N


    Urinary analysis of the pattern of 23 organic acid metabolites derived from fatty acids in three patients with general (medium-chain) acyl-CoA dehydrogenase deficiency was performed. Although there exist quantitative differences in the excreted amounts of the different metabolites in the three patients the qualitative picture was the same. The excretion of adipic, suberic and sebacic acids was substantial, whereas that of dodecanedioic acid was within or just above control limit. The monounsaturated C6-C10-dicarboxylic acid excretion was only marginally or not increased. 5-OH-hexanoic acid and hexanoylglycine were excreted in excessive amounts, whereas 7-OH-octanoic acid, 9-OH-decanoic acid, octanoylglycine and decanoylglycine were excreted in limited amounts. The excreted amounts of 6-OH-hexanoic, 8-OH-octanoic and 10-OH-decanoic acids were not or only marginally elevated compared to controls. In one of the patients the excretion of ethylmalonic and methylsuccinic acids was enhanced, whereas the excretion of these two acids in the two other patients was comparable to that in controls. The urinary excretion of hexanoic, octanoic, decanoic and dodecanoic acids was just a little above the control limit, whereas the esterified hexanoic and octanoic acids were excreted in appreciable amounts. It is argued that the microsomal omega- and omega-1-oxidation systems are involved in the dicarboxylic and omega-1-OH-monocarboxylic acids formation at C10 and C12 level and that the C8-C6-dicarboxylic and omega-1-OH-monocarboxylic acids are formed from higher chained acids by beta-oxidation in both mitochondria and peroxisomes.

  4. Proteomic and biochemical studies of lysine malonylation suggest its malonic aciduria-associated regulatory role in mitochondrial function and fatty acid oxidation

    NARCIS (Netherlands)

    Colak, G.; Pougovkina, O.; Dai, L.; Tan, M.; Brinke, te H.; Huang, H.; Wanders, R.J.; Locasale, J.W.; Lombard, D.B.; Boer, de V.C.J.; Zhao, Y.


    The protein substrates of sirtuin 5-regulated lysine malonylation (Kmal) remain unknown, hindering its functional analysis. In this study, we carried out proteomic screening, which identified 4042 Kmal sites on 1426 proteins in mouse liver and 4943 Kmal sites on 1822 proteins in human fibroblasts. I

  5. Analysis of inherited metabolic disease in Beijing by gas chromatography-mass spectrometry%气相色谱-质谱法检测遗传代谢性疾病高危患儿

    Institute of Scientific and Technical Information of China (English)

    彭薇; 张万巧; 封志纯


    Objective To learn the incidence of the inherited metabolic diseases in Beijing. Methods Urine samples were analyzed by gas chromatography-mass spectrometry(GC-MS)for inherited metabolic diseases in high risky infants in Beijing . Results Urine samples from 411 high risky infants were analyzed by gas chromatography-mass spectrometry. 269 cases (65.5%) were detected to have metabolic abnormalities, including 19 cases (4.6%) diagnosed of inherited metabolic diseases in which there were 15 cases of methylmalonic academia and 1 case each of propionic academia, hyperphenylalaninemia, urea cycle abnormality and pyroglutamic aciduria. There were 22 suspected cases (5.4%) of inherited metabolic diseases including 13 cases of lactic acidosis, 5 cases of primary glycerol aciduria, 4 cases of fatty acid metabolic disorders including 1 case each of Citrin defects, tyrosinemia, galactosemia 3-methylcrotonoyl coenzyme A carboxylase deifciency and maple syrup urine disease. There were also 228 cases (55.5%) of metabolic abnormalities, such as increasing urine levels of lactic acid, sucrose,lactose, galactose, N-acetyl tyrosine, succinic acid, dicarboxylic acid and abnormal serine/threonine ratio. Conclusions Methylmalonic academia might be the most common inherited metabolic diseases in high risky infants in Beijing. For infants with clinical manifestations but unclear etiology, GC-MS should be performed. MS-MS and gene analysis could be combined if necessary.%目的:了解北京地区遗传性代谢性疾病(IMD)的发病情况。方法利用气相色谱-质谱法(GC-MS)对IMD高危儿进行尿液化学分析。结果411例IMD高危儿中检测出代谢异常269例(65.5%),其中确诊IMD 19例(4.6%),包括甲基丙二酸血症15例,丙酸血症、高苯丙氨酸血症、尿素循环异常和焦谷氨酸尿症各1例;疑似IMD 22例(5.4%),包括乳酸血症13例,原发性甘油尿症5例,脂肪酸代谢异常4例,Citrin缺陷症、酪氨

  6. Urease Inhibitor Drug Treatment for Urea Cycle Disorders (United States)


    Ornithine Transcarbamylase Deficiency; Argininosuccinate Synthetase Deficiency (Citrullinemia); Argininosuccinic Acid Lyase Deficiency (Argininosuccinic Aciduria); Carbamyl-Phosphate Synthase I Deficiency

  7. 3-Methylglutaconic aciduria—lessons from 50 genes and 977 patients

    DEFF Research Database (Denmark)

    Wortmann, Saskia B; Kluijtmans, Leo A J; Rodenburg, Richard J;


    Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin...... with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders...

  8. The syndrome of deafness-dystonia: clinical and genetic heterogeneity. (United States)

    Kojovic, Maja; Pareés, Isabel; Lampreia, Tania; Pienczk-Reclawowicz, Karolina; Xiromerisiou, Georgia; Rubio-Agusti, Ignacio; Kramberger, Milica; Carecchio, Miryam; Alazami, Anas M; Brancati, Francesco; Slawek, Jaroslaw; Pirtosek, Zvezdan; Valente, Enza Maria; Alkuraya, Fowzan S; Edwards, Mark J; Bhatia, Kailash P


    The syndrome of deafness-dystonia is rare and refers to the association of hearing impairment and dystonia when these are dominant features of a disease. Known genetic causes include Mohr-Tranebjaerg syndrome, Woodhouse-Sakati syndrome, and mitochondrial disorders, but the cause frequently remains unidentified. The aim of the current study was to better characterize etiological and clinical aspects of deafness-dystonia syndrome. We evaluated 20 patients with deafness-dystonia syndrome who were seen during the period between 1994 and 2011. The cause was identified in only 7 patients and included methylmalonic aciduria, meningoencephalitis, perinatal hypoxic-ischemic injury, large genomic deletion on chromosome 7q21, translocase of inner mitochondrial membrane 8 homolog A (TIMM8A) mutation (Mohr-Tranebjaerg syndrome), and chromosome 2 open reading frame 37 (C2orf37) mutation (Woodhouse-Sakati syndrome). The age of onset and clinical characteristics in these patients varied, depending on the etiology. In 13 patients, the cause remained unexplained despite extensive work-up. In the group of patients who had unknown etiology, a family history for deafness and/or dystonia was present the majority of patients, suggesting a strong genetic component. Sensory-neural deafness always preceded dystonia. Two clinical patterns of deafness-dystonia syndrome were observed: patients who had an onset in childhood had generalized dystonia (10 of 13 patients) with frequent bulbar involvement, whereas patients who had a dystonia onset in adulthood had segmental dystonia (3 of 13 patients) with the invariable presence of laryngeal dystonia. Deafness-dystonia syndrome is etiologically and clinically heterogeneous, and most patients have an unknown cause. The different age at onset and variable family history suggest a heterogeneous genetic background, possibly including currently unidentified genetic conditions.

  9. A Study on the Humoral and Complement Immune System of Patients with Organic Acidemia. (United States)

    Alizadeh Najjarbashi, Faegheh; Mesdaghi, Mehrnaz; Alaei, Mohammadreza; Shakiba, Marjan; Jami, Aliakbar; Ghadimi, Farah


    Patients with organic acidemia are prone to different infections, which lead to acidosis episodes. Some studies have evaluated the status of immune system in acidotic phase in these patients, but to the best of our knowledge no study has evaluated the immune system in non-acidotic phase of the disease. In this study, thirty-one patients with organic acidemia were enrolled. For evaluation of humoral immunity, serum IgA, IgG, IgE, IgM, isohemaggltuinin titer, anti tetanus and anti diphtheria IgG were measured. For screening of complement deficiencies, serum C3, C4, and CH50 were assessed. Eleven patients had Maple Syrup Urine Disease (MSUD), 10 had methylmalonic acidemia, 5 had isovaleric acidemia, 4 had glutaric aciduria, and 1 had propionic acidemia. Serum IgM level was less than normal in 2 patients. Serum isohemagglutinin titer was less than 1:8 in 2 other patients. IgA, IgE, and IgG were within normal range for all patients. Anti tetanus and anti diphtheria IgG levels were low in two patients with MSUD. No significant relationship was found between any of the measured parameters and history of recurrent admissions, recurrent infections and the type of their diseases. Five patients had high C3 level, 4 had high C4 level, and 5 had high CH50 percentage. Totally, 10 patients had high complement level, but no remarkable connection was noted between the type of the disease and complement level. Minor insignificant deficiencies in humoral immunity in non-acidotic phase of organic acidemia were found. Some components of complement system showed increase in some patients, which might be due to decreased pH in extracellular fluid.

  10. Screening of Inherited Metabolic Disorders in Infants with Infantile Spasms. (United States)

    Liu, Xiao-Ming; Li, Rui; Chen, Sheng-Zhi; Sang, Yan; Chen, Jiao; Fan, Cong-Hai


    The objective of this study is to explore the incidence of inherited metabolic disorders (IMD) in infants with infantile spasms (IS), with an attempt to improve the early diagnosis and etiological and symptomatic treatment. Urine and blood samples were collected from 60 IS patients and analyzed for the quantification of amino acids, organic acids, and fatty acids by gas chromatography-mass spectrometry and tandem mass spectrum. Routine urine tests, hepatic function tests, blood biochemistry, brain imaging, as well as examinations of the brain stem auditory/visual evoked potentials were also examined. In addition to antiepileptic therapy, etiological and symptomatic treatments were also conducted in infants with confirmed IMD and the follow-up lasted for 6 months in these pediatric patients. Metabolic disorders were found in 28 (46.67 %) of 60 IS infants, among them 13 (21.67 %) were confirmed to be with IMD. Twelve of these 13 IS patients with definite IMD diagnoses (92.31 %) experienced varying degrees of delayed development of intelligence and motor function, 8 patients (61.54 %) had abnormal cranial CT or MRI findings, 11 patients (84.61 %) had abnormal brain stem evoked potentials, 4 patients (30.77 %) had abnormal hepatic functions, 3 patients (23.07 %) had abnormal blood biochemistry, 2 patients (15.38 %) had positive (+ to ++) results for routine urine ketones, and 2 patients (15.38 %) had skin lesions. After treatment in children who were diagnosed IMD, the well controlled epileptic seizures and the satisfactory developments in mental and motor were found in 4 cases of methylmalonic acidemia, 2 cases of classical phenylketonuria, and one case of biotin deficiency disease, glutaric acidemia type I, and 4-hydroxybutyric aciduria in each. IMD is a key biological cause in IS. Early screening for IMD is warranted in IS infants to facilitate the improvement for the prognosis and an early etiological treatment.


    Directory of Open Access Journals (Sweden)



    Full Text Available BA C KGRO U N D: Inborn errors of metabolism (IEM comprises of a diverse group of heterogeneous disorders manifesting in paediatric population. Cases of Inborn errors of metabolism, individually are rare but collectively are common. The timing of presentation dep ends on significant accumulation of toxic metabolites or on the deficiency of substrate. These disorders manifest by subtle neurologic or psychiatric features often go undiagnosed until adulthood. OBJ E C TI V E S : The objectives of the present study was to carry out preliminary screening on urine samples from pediatric population with either metabolic or neurological manifestations for inborn errors of metabolism and to know the prevalence of aminoaciduria in tertia ry care setup for early diagnosis and detection. METH O DS: The present study is a cross sectional time bound study carried out at Niloufer Institute of Child Health, Osmania Medical College, Hyderabad, from August 2013 to July 2014. A total of 119 samples w ere analyzed from suspected cases of IEM. Samples were analyzed for all physical and chemical parameters and positive cases reported by these investigations were referred for confirmation by TMS, HPLC, and GCMS . RE S UL T S : Among 119 children analyzed, 29 wer e given presumptive diagnosis of IEM based on screening tests, urinary aminoacidogram by TLC and clinical correlation. Analysis of the data showed that maximum were in the neonatal age group. Out of these 29 positive cases, 17 were generalized aminoaciduri as, 2 were branched chain aminoaciduria, another 2 were methylmalonic aciduria, and one cases each of other aminoacidurias. CO N C LU S IO N : Early recognition of IEM by screening tests in combination with strong clinical suspicion will help the clinicians to in itiate prompt early treatment to prevent lethal neurological complications and developmental delay. These simple screening tests are highly cost effective and will reduce the economic burden of the

  12. Oxidative stress parameters in urine from patients with disorders of propionate metabolism: a beneficial effect of L:-carnitine supplementation. (United States)

    Ribas, Graziela S; Biancini, Giovana B; Mescka, Caroline; Wayhs, Carlos Y; Sitta, Angela; Wajner, Moacir; Vargas, Carmen R


    Propionic (PA) and methylmalonic (MMA) acidurias are inherited disorders caused by deficiency of propionyl-CoA carboxylase and methylmalonyl-CoA mutase, respectively. Affected patients present acute metabolic crises in the neonatal period and long-term neurological deficits. Treatments of these diseases include a protein restricted diet and L: -carnitine supplementation. L: -Carnitine is widely used in the therapy of these diseases to prevent secondary L: -carnitine deficiency and promote detoxification, and several recent in vitro and in vivo studies have reported antioxidant and antiperoxidative effects of this compound. In this study, we evaluated the oxidative stress parameters, isoprostane and di-tyrosine levels, and the antioxidant capacity, in urine from patients with PA and MMA at the diagnosis, and during treatment with L: -carnitine and protein-restricted diet. We verified a significant increase of isoprostanes and di-tyrosine, as well as a significant reduction of the antioxidant capacity in urine from these patients at diagnosis, as compared to controls. Furthermore, treated patients presented a marked reduction of isoprostanes and di-tyrosine levels in relation to untreated patients. In addition, patients with higher levels of protein and lipid oxidative damage, determined by di-tyrosine and isoprostanes levels, also presented lower urinary concentrations of total and free L: -carnitine. In conclusion, the present results indicate that treatment with low protein diet and L: -carnitine significantly reduces urinary biomarkers of protein and lipid oxidative damage in patients with disorders of propionate metabolism and that L: -carnitine supplementation may be specially involved in this protection.

  13. 遗传性代谢病高危婴幼儿4710例尿素酶预处理-气相色谱-质谱技术筛查分析%Screening analysis of 4 710 cases of inherited metabolic diseases in high - risk infants using urease pretreat-ment-gas chromatography-mass spectrometry

    Institute of Scientific and Technical Information of China (English)

    郝虎; 李思涛; 欧阳学军; 方素珍; 兰和魁; 张春花; 石聪聪; 肖昕


    Objective To detect the incidence of inherited metabolic diseases(IMD)and disorders of metabo-lism in 4 710 high - risk infants,as well as providing basis of clinical diagnosis and treatment by using urease pretreat-ment - gas chromatography - mass spectrometry(UP - GC - MS). Methods Samples were collected from high - risk infants with IMD,after removing urea,putting in internal standard,removing protein,vacuum drying and bis (trimethyl - silyl)trifluoroacetamide / trimethyl - chlorosilane derivativing,UP - GC - MS was used to analyze compo-sitions such as organic acids,amino acids,carbohydrates,pyridoxines,purines and pyrimidines,then metabolic analysis was proceeded to refer to the normal detection value of the healthy children,finally a metabolic diagnosis was made ba-sing on the clinical data such as the high - risk clinical manifestations and general biochemical tests and other special examinations. Results In the 4 710 cases,there were 98 cases of IMD(2. 1% ),326 cases of suspected IMD(6. 9% ), 2 610 cases of metabolic disorders(55. 4% ). There were 98 cases of IMD,including 57 cases of methylmalonic aciduria,12 cases of propionic acidemia,7 cases of glutaric aciduria,5 cases of hyperphenylalaninemia,maple syrup u-rine disease and multiple carboxylase defects each,4 cases of isovaleric acidemia and 3 cases of 4 - hydroxy butyric acid urine disease. Conclusions UP - GC - MS is a effective way to diagnose IMD and metabolic disorders of infants. Common IMD in Guangdong Province include methylmalonic aciduria,propionic academia,glutaric aciduria,hyperphe-nylalaninemia,maple syrup urine disease and multiple carboxylase defects. The results of the tests can provide effective guidance for diagnosis and treatment of suspected infants.%目的:通过尿素酶预处理-气相色谱-质谱法(UP-GC-MS)检测4710例高危婴幼儿遗传性代谢病(IMD)及代谢紊乱的发病率,为临床诊断和治疗提供依据。方法对高危婴幼儿

  14. 甲基丙二酸血症合并癫痫27例临床特点及预后分析%Electroclinical features and prognosis of epilepsy in children with methylmalonic academia

    Institute of Scientific and Technical Information of China (English)

    赵英; 张月华; 杨艳玲; 马秀伟; 刘晓燕; 杨志仙; 包新华; 秦炯; 吴希如


    目的 总结甲基丙二酸血症(MMA)合并癫痫的临床特点及预后.方法 对1997年1月至2009年12月北京大学第一医院儿科住院确诊的27例MMA合并癫痫发作患儿的临床资料、辅助检查结果、随访资料进行分析.结果 27例患儿除癫痫发作外,合并其他神经系统受损表现包括:智力运动发育落后或倒退22例、发作性嗜睡10例、肌张力增高8例、肌张力减低8例、反复呕吐4例、震颤和共济失调各2例、姿势异常1例.癫痫首次发作年龄为生后8d至11岁,发作类型包括部分性发作21例、全面强直阵挛发作5例、强直发作3例、肌阵孪发作3例,痉挛发作2例;5例忠儿同时有2~3种发作类型.脑电图(EEG)检查有22例异常,包括:背景节律慢17例,局灶或多灶性痫样放电16例、广泛性痫样放电4例、高度失律2例和爆发抑制1例.头颅MRI检查24例显示脑萎缩14例,脑白质异常信号12例,胼胝体发育不良2例,双侧基底节病变2例和小脑萎缩1例.维生素B12有效型较维生素B12无效型患儿预后好.结论 癫痫是MMA的常见症状,部分性发作较其他发作类型更常见.对不明原因的癫痫惠儿若伴其他神经系统症状,应进行尿有机酸分析,早期明确病因诊断,改善预后.%Objective To summarize the clinical features and prognosis of epilepsy in children with MMA. Methods From Jan. 1997 to Dec. 2009 in Department of Pediatrics, Peking University First Hospital, the medical records of hospitalized MMA patients complicated with epilepsy were retrospectively reviewed. The clinical manifestations,laboratory examination results, and treatment modalities were analyzed. Results From 63 pediatric inpatients diagnosed with MMA, 27 children (42.9%) complicated with epilepsy were enrolled in this study. These 27 patients were also accompanied with other neurological manifestations, including mental retardation or regression (n = 22), lethargy (n =10) ,increased muscle tone (n = 8) ,muscle hypotonia (n = 8) ,recurrent vomiting (n = 4) ,tremor (n = 2), ataxia (n =2), and abnormal posture (n = 1 ).The onset age of seizure ranged from 8 days to 11 years. The seizure types included partial seizure (n = 21 ), generalized tonic-clonic seizure (n = 5 ), tonic seizure (n = 3 ), myoclonie seizure (n = 3 ), and epileptic spasm (n = 2). Five patients had 2 or 3 seizure types. Nine patients (33.3%) had a history of status epilepticus.EEG showed slow background activity in 17 patients, focal or multifocal discharges in 16 patients, generalized discharges in 4 patients, hypsarrathmia in 2 patients, and suppression-burst pattern in 1 patient. Cranial MRI showed cerebral atrophy (n = 14), white matter changes (n = 12), agenesis of corpus callosum (n = 2), abnormal signal in basal ganglia (n = 2), and cerebellar atrophy (n = 1 ). Twenty-one patients were MMA combined with homocysteinemia. Seventeen patients were confirmed with cobalamin C disease and one with partial mutase deficiency (mut-). Vitamin B 12-responsive patients hada better outcome compared with vitamin B 12-unresponsive patients. Conclusion Epilepsy is a common manifestation of patients with MMA.Partial seizures is more common than other seizure types. Urine organic acid analysis should be performed for children with unknown cause of epilepsy combined with other neurological manifestations, so as to promptly identify the etiology and improve the prognosis.

  15. 56例儿童甲基丙二酸血症的脑改变影像学特点%Brain imaging characters in 56 children with methylmalonic academia

    Institute of Scientific and Technical Information of China (English)

    刘玥; 阴捷; 彭芸; 段晓岷; 刘志敏; 尹光恒


    目的 探讨甲基丙二酸血症(MMA)患儿颅脑CT和MRI特点及其相关病理生理学机制.方法 对56例MMA患儿的常规CT和MRI图像进行回顾性分析,男41例,女15例,年龄6天~9岁,平均年龄11.6月,30例行MR检查,17例行CT检查,9例行CT和MR检查.收集每例患儿的临床资料.全部病例均经尿有机酸分析确诊.结果 常见的影像学表现是大脑半球皮层萎缩(34例),脑室扩张(18例),侧脑室旁白质异常(18例),皮层下白质异常(18例),脑白质髓鞘化延迟(14例),胼胝体纤细(9例),小脑萎缩(5例),基底节区异常(5例),颅内主要动脉僵直并分支减少(7例).11例MMA患儿在急性代谢性酸中毒时,弥散加权像出现异常信号.2例脑影像学表现正常.结论 MMA的中枢神经系统影像学表现是非特异的,但影像学表现和临床资料相结合,可以提示MMA,有助于及时诊断、治疗和评估预后.%Objective To recognize the CT and MR brain sectional imaging characters in children with MMA and to discuss related pathophysiological mechanisms. Methods We retrospectively analyzed CT and MRI of 56 patients images with MMA (41 males, 15 females, age range:6 days to 9 years, mean age 11. 6 months). Brain imaging studies (30 MR, 17 CT and 9 CT+MRI studies) from 56 children were reviewed and reported by two neuroradiologists. The clinical data were collected for each patient. Results The most common findings were cortical atrophy (34 studies), ventricular dilation (18), periventricular white matter abnormality (18), subcortical white matter abnormality (18), myelination delay (14), thinning of the corpus callosum (9), cerebellar atrophy (5), basal ganglionic abnormalities (5), and increased arterial stiffness and few branches (7). Diffusion-weighted abnormalities were seen in 11 patients with MMA during an acute episode of metabolic acidosis. The brain images in 2 patients were normal. Conclusion Radiological findings of MMA are nonspecific. A combination of common clinical and radiological findings should raise the suspicion of MMA and help physician diagnose and evaluate the prognosis.

  16. Lab Tracker and Copper Calculator (United States)

    ... insomnia Psychiatric: Depression; neuroses; personality changes; psychosis Other symptoms: Renal abnormalities: amino-aciduria and nephrolithiasis; skeletal abnormalities: premature osteoporosis and arthritis; cardiomyopathy, dysrhythmias; pancreatitis; hypoparathyroidism; menstrual irregularities: ...

  17. Kayser-Fleischer Rings (United States)

    ... insomnia Psychiatric: Depression; neuroses; personality changes; psychosis Other symptoms: Renal abnormalities: amino-aciduria and nephrolithiasis; skeletal abnormalities: premature osteoporosis and arthritis; cardiomyopathy, dysrhythmias; pancreatitis; hypoparathyroidism; menstrual irregularities: ...

  18. How Is Wilson Disease Diagnosed? (United States)

    ... insomnia Psychiatric: Depression; neuroses; personality changes; psychosis Other symptoms: Renal abnormalities: amino-aciduria and nephrolithiasis; skeletal abnormalities: premature osteoporosis and arthritis; cardiomyopathy, dysrhythmias; pancreatitis; hypoparathyroidism; menstrual irregularities: ...

  19. Fatty acid desaturase 1 polymorphisms are associated with coronary heart disease in a Chinese population

    Institute of Scientific and Technical Information of China (English)

    LIU Si-jun; HU Zhi-bin; WANG Hui; SHEN Hong-bing; ZHI Hong; CHEN Pei-zhan; CHEN Wei; LU Feng; MA Gen-shan; DAI Jun-cheng; SHEN Chong; LIU Nai-feng


    Background A recent genome-wide association study in Caucasians revealed that three loci (rs174547 in fatty acid desaturase 1 (FADS1),rs2338104 near mevalonate kinase/methylmalonic aciduria,cobalamin deficiency,cblB type (MVK/MMAB) and rs10468017 near hepatic lipase (LIPC)) influence the plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG).However,there are few reports on the associations between these polymorphisms and plasma lipid concentrations in Chinese individuals.This study aimed to evaluate the associations between these three polymorphisms with HDL-C and TG concentrations,as well as coronary heart disease (CHD) susceptibility in Chinese individuals.Methods We conducted a population-based case-control study in Chinese individuals to evaluate the associations between these three polymorphisms and HDL-C and TG concentrations,and also evaluated their associations with susceptibility to CHD.Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism assays and TaqMan genotyping assays.Results We found significant differences in TG and HDL-C concentrations among the TT,TC and CC genotypes of FADS1 rs174547 (P=0.017 and 0.003,respectively,multiple linear regression).The CC variant of rs174547 was significantly associated with hyperlipidemia compared with the TT variant (adjusted odds ratio (OR) =1.71,95% confidence intervals (CI):1.16-2.54).The FADS1 rs174547 CC variant was also associated with significantly increased CHD risk compared with the TT and TC variant (adjusted OR=1.53,95% CI:1.01-2.31),and the effect was more evident among nonsmokers and females.The polymorphisms rs2338104 and rs10468017 did not significantly influence HDL-C or TG concentrations in this Chinese population.Conclusion rs174547 in FADS1 may contribute to the susceptibility of CHD by altering HDL-C and TG levels in Chinese individuals.

  20. Glutaric aciduria type Ⅱ resembling Rett syndrome in a case%临床表现为Rett综合征的戊二酸尿症Ⅱ型一例

    Institute of Scientific and Technical Information of China (English)

    王红梅; 邹丽萍; 吕俊兰; 王旭



  1. Folate and MMA predict cognitive impairment in elderly stroke survivors: A cross sectional study. (United States)

    Pascoe, Michaela C; Linden, Thomas


    Elderly stroke survivors are at risk of malnutrition and long-term cognitive impairment. Vitamin B-related metabolites, folate and methylmalonic acid, have been implicated in cognitive function. We conducted a study exploring the relationship between blood folate, methylmalonic acid and post-stroke cognitive impairment. This is a cross sectional study of elderly Swedish patients (n=149) 20 months post-stroke, assessed using the Mini Mental State Examination, serum blood levels of methylmalonic acid and red blood cell levels of folate. Linear modeling indicated that low levels of blood folate and elevated methylmalonic acid significantly contributed to cognitive impairment in stroke survivors. Half of the stroke survivors were shown to have folate deficiency at 20 months after stroke. Folate deficiency is common long term after stroke and both low folate and elevated methylmalonic acid appear to be associated with long term cognitive impairment, in elderly Swedish stroke survivors.

  2. Selected Abstracts of the 8th International Workshop on Neonatology; Cagliari (Italy; October 24-27, 2012

    Directory of Open Access Journals (Sweden)

    --- Various Authors


    Full Text Available Selected Abstracts of the 8th International Workshop on Neonatology • SYSTEMS MEDICINE IN PERINATOLOGY AND PEDIATRICS TAILORED BIOMARKERS, DRUGS AND TREATMENTS • Cagliari (Italy • October 24th-27th 2012The Workshop has been organized on behalf of Union of European Neonatal and Perinatal Societies, Union of Mediterranean Neonatal Societies, Italian Society of Neonatology, UNICEF, and under the High Patronage of the President of the Italian Republic. ABS 1. Urinary metabolomics as a new strategy to discriminate response to ibuprofen therapy in preterm neonates with patent ductus arteriosus • M. Castell Miñana et al.; Valencia (Spain ABS 2. A metabolomic approach to identify preterm neonates born of mothers with chorioamnionitis: preliminary data • L. Pugni et al.; Milan, Cagliari (Italy ABS 3. Urinary metabolomics in twins at birth • L. Paladini et al.; Lecce, Rome, Cagliari (Italy ABS 4. From prenatal diagnosis to neonatology: risk and protective factors in the development of mother-preterm child relationship • E. Boni et al.; Pavia (Italy ABS 5. Prolonged refrigerated storage of human milk: effects on nutritive and non-nutritive characteristics • P. Di Nicola et al.; Turin (Italy ABS 6. Use of donor human milk in nicu: is donor milk competing with breastfeeding or supporting it? • P. Di Nicola et al.; Turin (Italy ABS 7. Prenatal diagnosis of methymalonic aciduria and homocistinuria Cbl-C type using dna analysis • A. Zappu et al.; Cagliari (Italy ABS 8. Human breast milk vs formula milk. Is 1H-nmr metabolomics able to help to find the right formula? • A. Noto et al.; Cagliari (Italy ABS 9. A 1H-NMR study of Crisponi syndrome: can metabolomics help to describe the disorder? • M. Lussu et al.; Cagliari (Italy ABS 10. Nestin immunoreactivity in the developing human kidney • Y. Gibo et al.; Matsumoto (Japan, Rome, Cagliari (Italy ABS 11. A non-invasive approach to characterize epileptic children born elbw compared to

  3. An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study

    DEFF Research Database (Denmark)

    Steenweg, Marjan E; Jakobs, Cornelis; Errami, Abdellatif;


    L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of ...

  4. On-demand anakinra treatment is effective in mevalonate kinase deficiency

    NARCIS (Netherlands)

    Bodar, E.J.; Kuijk, L.M.; Drenth, J.P.H.; Meer, J.W. van der; Simon, A.; Frenkel, J.


    BACKGROUND: Mevalonate kinase deficiency (MKD) is a hereditary autoinflammatory syndrome marked by recurrent attacks of fever and inflammation. Severe enzyme deficiency results in mevalonic aciduria (MA) and milder deficiency in hyperimmunoglobulin D syndrome (HIDS). Treatment remains a challenge. O

  5. Barth Syndrome

    DEFF Research Database (Denmark)

    Saric, Ana; Andreau, Karine; Armand, Anne-Sophie


    Mutations in the gene encoding the enzyme tafazzin, TAZ, cause Barth syndrome (BTHS). Individuals with this X-linked multisystem disorder present cardiomyopathy (CM) (often dilated), skeletal muscle weakness, neutropenia, growth retardation, and 3-methylglutaconic aciduria. Biopsies of the heart,...

  6. MRI finding of ethylmalonic encephalopathy: case report

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Yong; Lee, Shi Kyung; Han, Chun Hwan; Rho, Eun Jin [Kangnam General Hospital Public Corporation, Seoul (Korea, Republic of)


    Ethylmalonic encephalopathy is a rare syndrom characterized by developmental delay, acrocyanosis, petechiae, chronic diarrhea, and ethylmalonic, lactic, and methylsuccinic aciduria. We report the MRI finding of ethylmalonic encephalopathy including previously unreported intracranial hematoma.

  7. Selective screening of inborn errors of metabolism by using the tandem mass spectrometry:pilot study of 552 children at high risk%串联质谱技术选择性筛查遗传代谢病高危患儿552例初步分析

    Institute of Scientific and Technical Information of China (English)

    娄燕; 尹娜; 陈凤琴; 程亚颖; 徐丽瑾; 戴方; 宋晓涛


    目的 应用串联质谱(tandem mass spectrometry,MS/MS)技术进行遗传代谢病(IEM)高危儿筛查,初步了解我国IEM的发病种类和阳性率,为其有效防治提供科学依据.方法 利用MS/MS技术对在河北省石家庄市8所省、市级医院就医的552例可疑IEM患儿的血液样本进行IEM筛查.结果 发现阳性患儿64例,阳性率为11.6%.其中甲基丙二酸血症或丙酸血症33例,苯丙酮尿症2例,肉碱棕桐酞转移酶缺乏I型3例,长链酞基辅酶A脱氢酶缺乏症1例,中链酸基辅酶A脱氢酶缺乏症2例,枫糖尿症6例,短链酸基辅酶A脱氢酶缺乏症2例,戊二酸血症I型2例,异戊酸血症2例,同型肤氨酸尿症2例,肉碱缺乏症4例,酪氨酸血症1例,精氨酸境拍酸尿症1例,瓜氨酸血症2例,精氨酸血症1例.结论 MS/MS技术是筛查诊断IEM的有效工具.%Objective To study the application of tandem mass spectrometry (MS/MS) in the selective screening of inborn errors of metabolism (IEM) in high risk children and to understand the positive rate and types of IEM.Methods MS/MS was used to examine 552 blood samples from high risk cases of IEM who came from 8 hospitals in Shijiazhuang,Hebei Province.Results Sixty-four children ( 11.6% ) were confirmed with IEM by the MS/MS, including 33 cases of methylmalonic acidemia or propionic acidemias, 2 cases of phenylketonuria, 3 cases of carnitine palmotoyl transferase Ⅰ deficiency, 1 case of long-chain acyl-CoA dehydrogenase deficiency, 2 cases of medium-chain acyl-CoA dehydrogenase deficiency, 6 cases of maple syrup urine disease, 2 cases of short-chain acyl-CoA dehydrogenase deficiency, 2 cases of glutaric acidemia type Ⅰ, 2 cases of isovaleric acidemia, 2 cases of homocystinuria, 4 cases of carnitine deficiency, 1 case of tyrosinemia, 1 case of argininosuccinic aciduria, 2 cases of citrullinemia and 1 case of argininemia.Conclusions MS/MS can be used to screen and classify IEM.

  8. Vitamin B12 and Folate Test (United States)

    ... AACC products and services. Advertising & Sponsorship: Policy | Opportunities Vitamin B12 and Folate Share this page: Was this ... as: Cobalamin; Folic Acid; RBC Folate Formal name: Vitamin B12; Folate Related tests: Complete Blood Count , Methylmalonic ...

  9. 尿素酶预处理-气相色谱-质谱技术筛查遗传性代谢病高危儿%Screening of Inherited Metabolic Disorders in High-Risk Infants Using Urease Pretreatment-Gas Chromatography-Mass Spectrometry

    Institute of Scientific and Technical Information of China (English)

    高平明; 郝虎; 李思涛; 刘冰清; 刘梦娴; 李雯丽; 肖昕


    Objective To detect the incidence of inherited metabolic disorders(IMD) and disorders of metabolism in high - risk infants, and to provide basis for clinical diagnosis by using urease pretreatment - gas chromatography - mass spectrometry (UP - GC - MS). Methods Urine samples from high - risk infants of IMD were collected, and they were decomposed with urease, and heptadecanoic acid was added as an internal standard, protein was denaturated with ethanol and precipitate was removed by centrifugation, evaporation was performed to dryness, the residue was trimethylsilylly derivatized with bis (trimethylsilyl) trifluoroaeetamide/trimethyl - chlorosilane. GC - MS was used to analyze compositions such as organic acids, amino acids, carbohydrates, pyridoxines, purines and pyrimidines. Results Eight hundred and ninety cases of metabolic disorders were found in 1 330 high - risk infants(66. 9% ) including 21 diagnosed cases( 1. 6% ) of inherited metabolic disorders (which included 8 cases of methylmalonic aciduria,3 cases of hyperphenylalaninemia,2 cases of abnormal urea cycle, galactosemia, maple syrup urine disease,isovaleric acidemia and propionic academia,respectively). There were 49 suspected cases (3.7%) of IMD,including tyrosinemia(23 cases) ,abnormal urea cycle(8 cases),fatty acid metabolic disorders(12 cases) and Citrin defects(6 cases).In particular,4 cases of the above were diagnosed accurately by tandem mass spectrometry (MS - MS) and genetic analysis. There were 40 cases (3. 0% ) of non - inherited metabolic disorders (28 cases of lactic acidosis and 12 cases of glycerol aciduria). There were also 780 cases of metabolic disorders(58. 6% ) ,such as increasing urine levels of galactose,4 - hydroxy phenyl lactic acid,N - acetyl tyrosine,lactic acid,lactose, succinic acid, ketodicarboxylic, and abnormal serine/threonine ratio. Conclusions UP - GC - MS is an effective method to diagnose IMD and disorders of metabolism in pediatrics. If necessary, MS - MS and/or gene

  10. Comparación entre el abordaje de henderson – hasselbalch y stewart para la interpretación de la alcalosis metabólica hipocloremica y aciduria paradójica en el modelo experimental de ovinos con pérdida de flujo abomasal


    Martinez Rodriguez, David Alexander


    La presente investigación evaluó el modelo de Diferencia de Iones Fuertes para la interpretación de la alcalosis metabólica hipoclorémica usando el modelo experimental de ovinos con pérdida masiva de flujo abomasal. Se encontró que existe una alta correlación entre el pH plasmático medido y calculada a partir del SID efectivo, que el electrolito que más se ve afectado en este tipo de desorden es el Cl- con una marcada disminución en su concentración que se ve reflejado en un marcado aumento e...

  11. Mevalonate kinase deficiency and neuroinflammation: balance between apoptosis and pyroptosis. (United States)

    Tricarico, Paola Maura; Marcuzzi, Annalisa; Piscianz, Elisa; Monasta, Lorenzo; Crovella, Sergio; Kleiner, Giulio


    Mevalonic aciduria, a rare autosomal recessive disease, represents the most severe form of the periodic fever, known as Mevalonate Kinase Deficiency. This disease is caused by the mutation of the MVK gene, which codes for the enzyme mevalonate kinase, along the cholesterol pathway. Mevalonic aciduria patients show recurrent fever episodes with associated inflammatory symptoms, severe neurologic impairments, or death, in early childhood. The typical neurodegeneration occurring in mevalonic aciduria is linked both to the intrinsic apoptosis pathway (caspase-3 and -9), which is triggered by mitochondrial damage, and to pyroptosis (caspase-1). These cell death mechanisms seem to be also related to the assembly of the inflammasome, which may, in turn, activate pro-inflammatory cytokines and chemokines. Thus, this particular molecular platform may play a crucial role in neuroinflammation mechanisms. Nowadays, a specific therapy is still lacking and the pathogenic mechanisms involving neuroinflammation and neuronal dysfunction have not yet been completely understood, making mevalonic aciduria an orphan drug disease. This review aims to analyze the relationship among neuroinflammation, mitochondrial damage, programmed cell death, and neurodegeneration. Targeting inflammation and degeneration in the central nervous system might help identify promising treatment approaches for mevalonic aciduria or other diseases in which these mechanisms are involved.

  12. Mevalonate Kinase Deficiency and Neuroinflammation: Balance between Apoptosis and Pyroptosis

    Directory of Open Access Journals (Sweden)

    Paola Maura Tricarico


    Full Text Available Mevalonic aciduria, a rare autosomal recessive disease, represents the most severe form of the periodic fever, known as Mevalonate Kinase Deficiency. This disease is caused by the mutation of the MVK gene, which codes for the enzyme mevalonate kinase, along the cholesterol pathway. Mevalonic aciduria patients show recurrent fever episodes with associated inflammatory symptoms, severe neurologic impairments, or death, in early childhood. The typical neurodegeneration occurring in mevalonic aciduria is linked both to the intrinsic apoptosis pathway (caspase-3 and -9, which is triggered by mitochondrial damage, and to pyroptosis (caspase-1. These cell death mechanisms seem to be also related to the assembly of the inflammasome, which may, in turn, activate pro-inflammatory cytokines and chemokines. Thus, this particular molecular platform may play a crucial role in neuroinflammation mechanisms. Nowadays, a specific therapy is still lacking and the pathogenic mechanisms involving neuroinflammation and neuronal dysfunction have not yet been completely understood, making mevalonic aciduria an orphan drug disease. This review aims to analyze the relationship among neuroinflammation, mitochondrial damage, programmed cell death, and neurodegeneration. Targeting inflammation and degeneration in the central nervous system might help identify promising treatment approaches for mevalonic aciduria or other diseases in which these mechanisms are involved.

  13. The effects of various inhibitors on the regulation of orotic acid excretion in sparse-fur mutant mice (spf/Y) deficient in ornithine transcarbamylase. (United States)

    Nelson, J; Qureshi, I A; Vasudevan, S; Sarma, D S


    Experiments were conducted to determine whether the excessive orotic aciduria, induced in sparse-fur male mice (spf/Y) deficient in ornithine transcarbamylase (OTC), may be regulated by some inhibitors, such as acivicin (0.014 mmol/100 g body weight, i.p.), N-(phosphonoacetyl)-L-aspartate (PALA, 2.5 mg/100 g body weight, i.p.), adenine (3 g/kg diet) and cycloheximide (0.35 mmol/kg body weight, i.p.). We also administered ornithine (1 mmol/100 g body weight, i.p.), a substrate of the urea cycle, to alleviate the metabolic deficiency of arginine in spf/Y mice which may also be responsible for excessive orotic aciduria. The orotic aciduria remained insensitive to acivicin, indicating mitochondria as the source of carbamyl phosphate. However, orotate excretion was significantly decreased by PALA (P handle excess mitochondrial carbamyl phosphate and orotic acid.

  14. Excretion of amino acids by humans during space flight (United States)

    Stein, T. P.; Schluter, M. D.


    We measured the urine amino acid distribution patterns before, during and after space flight on the Space Shuttle. The urine samples were collected on two separate flights of the space shuttle. The first flight lasted 9.5 days and the second flight 15 days. Urine was collected continuously on 8 subjects for the period beginning 10 d before launch to 6 d after landing. Results: In contrast to the earlier Skylab missions where a pronounced amino aciduria was found, on shuttle the urinary amino acids showed little change with spaceflight except for a marked decrease in all of the amino acids on FD (flight day) 1 (pvaline on FD3 and FD4 (p<0.05). Conclusions: (i) Amino aciduria is not an inevitable consequence of space flight. (ii) The occurrence of amino aciduria, like muscle protein breakdown is a mission specific effect rather than part of the general human response to microgravity.

  15. Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency. (United States)

    Korman, Stanley H; Waterham, Hans R; Gutman, Alisa; Jakobs, Cornelis; Wanders, Ronald J A


    Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The urine organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/- hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C>A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid. This C12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic acids by mitochondria after their initial shortening by beta-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of urine organic acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorder.

  16. Pilot Experience with an External Quality Assurance Scheme for Acylcarnitines in Plasma/Serum

    NARCIS (Netherlands)

    Sala, P Ruiz; Ruijter, G; Acquaviva, C; Chabli, A; de Sain-van der Velden, M G M; Garcia-Villoria, J; Heiner-Fokkema, M R; Jeannesson-Thivisol, E; Leckstrom, K; Franzson, L; Lynes, G; Olesen, J; Onkenhout, W; Petrou, P; Drousiotou, A; Ribes, A; Vianey-Saban, C; Merinero, B


    The analysis of acylcarnitines (AC) in plasma/serum is established as a useful test for the biochemical diagnosis and the monitoring of treatment of organic acidurias and fatty acid oxidation defects. External quality assurance (EQA) for qualitative and quantitative AC is offered by ERNDIM and CDC i

  17. Disease: H01225 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D-2-hydroxyglutarate in body fluids. MeSH: C535306 OMIM: 613657 600721 PMID:15609246 Struys EA, Salomon... RN, Vallance H, Jakobs C, Salomons GS IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330:336 (2010) ...

  18. Transient Fanconi syndrome in Quarter horses. (United States)

    Ohmes, Cameon M; Davis, Elizabeth G; Beard, Laurie A; Vander Werf, Karie A; Bianco, Alex W; Giger, Urs


    Two Quarter horses with weight loss had glucosuria, euglycemia, and a mild metabolic acidosis suggesting a proximal renal tubular defect. Further testing revealed transient generalized aminoaciduria, lactic aciduria, and glucosuria, indicating Fanconi syndrome. Both horses recovered with supportive therapy. This is the first report of acquired Fanconi syndrome in horses.

  19. Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.

    NARCIS (Netherlands)

    Wortmann, S.B.; Vaz, F.M.; Gardeitchik, T.; Vissers, L.E.L.M.; Renkema, G.H.; Schuurs-Hoeijmakers, J.H.M.; Kulik, W.; Lammens, M.M.Y.; Christin, C.; Kluijtmans, L.A.J.; Rodenburg, R.J.T.; Nijtmans, L.G.J.; Grunewald, A.; Klein, C.; Gerhold, J.M.; Kozicz, T.L.; Hasselt, P.M. van; Harakalova, M.; Kloosterman, W.; Baric, I.; Pronicka, E.; Ucar, S.K.; Naess, K.; Singhal, K.K.; Krumina, Z.; Gilissen, C.F.H.A.; Bokhoven, J.H.L.M. van; Veltman, J.A.; Smeitink, J.A.M.; Lefeber, D.J.; Spelbrink, J.N.; Wevers, R.A.; Morava, E.; Brouwer, A.P.M. de


    Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endo

  20. Eyes on MEGDEL: Distinctive Basal Ganglia Involvement in Dystonia Deafness Syndrome

    NARCIS (Netherlands)

    Wortmann, S.B.; Hasselt, P.M. van; Baric, I.; Burlina, A.; Darin, N.; Horster, F.; Coker, M.; Ucar, S. Kalkan; Krumina, Z.; Naess, K.; Ngu, L.H.; Pronicka, E.; Riordan, G.; Santer, R.; Wassmer, E.; Zschocke, J.; Schiff, M.; Meirleir, L. de; Alowain, M.A.; Smeitink, J.A.M.; Morava, E.; Kozicz, L.T.; Wevers, R.A.; Wolf, N.I.; Willemsen, M.A.


    Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #61473

  1. Study of clinic etiologies about newborn infants with high risk of inborn error of metabolism%高危新生儿遗传代谢病临床病因学分析

    Institute of Scientific and Technical Information of China (English)

    庄太凤; 马建荣; 温春玲; 邢继伟; 张巍; 杨艳玲


    Objective To investigate the clinic etiologies about newborn infants with high risk of inborn error of metabolism ( IEM) in NICU. Methods We did a urine organic acid analysis about 100 newhom infants with high risk of IEM by GC/MS. At the same time . blood routine , liver and renal function , blood lactic acid, blood pyruvic acid , β-hydroxyhutyric acid ,blood ammonia and serum homocysteine were determined. There were 24 patients diagnosed IEM by analysis results among the 100 cases. After 1 or 2 courses of treatment to the 24 patients , we did follow-up examination. Results There were 12 cases confirmed with IEM in the 24 patients ,including 2 patients with propionic acidemia ( PA) ,2 with tyrosinemia,2 with homocystinemia , 1 with methylmalonic aciduria ( MMA) ,1 with glutaric acidosis type Ⅱ ( GAⅡ) ,1 with congenital lactose intolerance,1 with hypermethioninemia ,1 with β-ketothiolase deficiency and 1 with ornithine carbamoyltransferase deficiency ( OCTD). Those diseases were autosomal recessive inheritance . There were different clinical features in 12 IEM cases ,including 3 patients with blood vessel pathological changes ( microthrombus engendered and encephalon parenchyma haemo -rrhage),2 with eclampsia ,2 with recurred metabolic acidosis ,1 with sudden death,1 with recurred hypoglycemia,1 with obstinated diarrhoea ,1 with jaundice correlated with inheritance and 1 with severe pneumonia. In the crises of the 12 IEM patients , 100% patients showed hyperammonemia, 83% metabolic acidosis and pyruvemia , 67% nephridium impaired , 50% with liver impaired ,42% with blood impaired. Conclusions The newbom infants with high risk of IEM had complicated etiologies . The neonates' IEM spectrum were amplification by new technique ( eg. GC/MS ). The amplification of IEM spectrum would show more etiologies of newborn and help diagnosis and treatment .%目的 初步研究新生儿重症监护室(NICU)先天性遗传代谢病(IEM)高危新

  2. 遗传学新技术在发育迟缓患儿病因诊断中的应用价值%The application of new genetic technology in the children with developmental delay and mental retardation

    Institute of Scientific and Technical Information of China (English)

    黎芳; 宇亚芬; 麻宏伟


    /180), forty-nine percent (24/49)of the cases were diagnosed by chromosomal karyotype analysis icluding 15 cases of Down’s syndrome and 9 cases of other chromosome abnormality,iffty-one percent (25/49) of the cases were diagnosed by new genetic technology including 14 cases of chromosome microdeletion syndromes, 6 cases of inherited metabolic diseases and 5 cases caused by gene mutation. Three cases of Prader-Willi syndrome ,two cases of Angelman syndrome ,22q13 deletion syndrome and Smith—Magenis syndrome and one cases of cat cry syndrome, 22q11 deletion syndrome and 1p36 deletion syndrome were included in the fourteen cases of chromosome microdeletion syndromes.Three cases of methylmalonic acid , one cases of maple syrup urine disease, tyrosinemia and glutaric aciduria were included in the six inherited metabolic diseases.Three cases of fragile X syndrome and two cases of Cornelia de Lange syndrome were diagnosed by gene mutation analysis. Conclusions New genetic technology improved the level of diagnosis in the child care department,children with normal chromosome examination cannot be excluded chromosome microdeletion syndrome and inherited metabolic diseases.The chromosomal karyotype analysis, MLPA ,genetic mutation analysis, MS-MS and GC-MS play complementary role in clinical applications,and cannot be replaced by each other.The genetic testing technology should be selected based on special faces and clinical characteristics .

  3. Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status, and recommendations for revised cut-points (United States)

    Background: We propose a novel approach to diagnose B12 status by combining four blood markers: total B12 (B12), holo-transcobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). Combined B12 status is expressed as cB12=log10[(holoTC•B12)/(MMA•Hcy)]–(reference, age function). Her...

  4. Homocysteine as a potential biochemical marker for depression in elderly stroke survivors

    Directory of Open Access Journals (Sweden)

    Michaela C. Pascoe


    Full Text Available Background: Elderly stroke survivors have been reported to be at risk of malnutrition and depression. Vitamin B-related metabolites such as methylmalonic acid and homocysteine have been implicated in depression. Objective: We conducted a study exploring the relationship between homocysteine and post-stroke depression. Design: Three methodologies were used: Observational cohort study of elderly Swedish patients (n=149 1.5 years post-stroke, assessed using Diagnostic and Statistical Manual of Mental Disorders, Montgomery Åsberg Depression Rating Scale and serum blood levels of methylmalonic acid and homocysteine. Results: Homocysteine significantly correlated with depressive symptomatology in stroke survivors (β = 0.18*. Individuals with abnormal levels of methylmalonic acid and homocysteine were almost twice more likely to show depressive symptomatology than those with normal levels (depressive symptoms 22%; no depressive symptoms 12%. Comparison of methylmalonic acid and homocysteine levels with literature data showed fewer stroke survivors had vitamin deficiency than did reference individuals (normal range 66%; elevated 34%. Conclusions: Homocysteine is significantly associated with depressive symptomatology in elderly Swedish stroke survivors.

  5. Milde vitamine B12 deficiëntie en het cognitief functioneren van ouderen : de effectiviteit van orale supplementen

    NARCIS (Netherlands)

    Eussen, S.J.P.M.


    Cobalamin deficiency is common in older people and has been recognised as a possible cause for several clinical manifestations such as anaemia and cognitive impairment. Markers for cobalamin deficiency include increased concentrations of plasma total homocysteine (tHcy) and methylmalonic acid (MMA),

  6. Succinyl-CoA Ligase Deficiency: A Mitochondrial Hepatoencephalomyopathy

    NARCIS (Netherlands)

    J.L.K. van Hove; M.S. Saenz; J.A. Thomas; R.C. Gallagher; M.A. Lovell; L.Z. Fenton; S. Shanske; S.M. Myers; R.J.A. Wanders; J. Ruiter; M. Turkenburg; H.R. Waterham


    This patient presented on the first day of life with pronounced lactic acidosis with an elevated lactate/pyruvate ratio. Urine organic acids showed Krebs cycle metabolites and mildly elevated methylmalonate and methylcitrate. The acylcarnitine profile showed elevated propionylcarnitine and succinylc

  7. Serum vitamin B-12 concentrations within reference values do not exclude functional vitamin B-12 deficiency in PKU patients of various ages

    NARCIS (Netherlands)

    Vugteveen, Inge; Hoeksma, Marieke; Monsen, Anne-Lise Bjorke; Heiner-Fokkema, Rebecca; Reijngoud, Dirk-Jan; van Rijn, Margreet; van Spronsen, Francjan J.


    Homocysteine (Hcy) and in particular methylmalonic acid (MMA) are considered reliable parameters for vitamin B-12 status in healthy individuals. Phenylketonuria (PKU) patients are at risk for functional vitamin B-12 deficiency based on their diet. Objective: The aim of this study was to investigate

  8. Combined indicator of vitamin B 12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points (United States)

    Background: A novel approach to determine vitamin B 12 status is to combine four blood markers: total B 12 (B 12 ), holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). This combined indicator of B 12 status is expressed as cB 12 = log 10 [(holoTC · B 12 )/ (MMA · Hcy...

  9. Propionic acidemia associated with visual hallucinations. (United States)

    Shuaib, Taghreed; Al-Hashmi, Nadia; Ghaziuddin, Mohammad; Megdad, Eman; Abebe, Dejene; Al-Saif, Amr; Doubi, Alaa; Aldhalaan, Hesham; Abouzied, Mohei Eldin; Al-Owain, Mohammed


    Propionic acidemia, an autosomal recessive disorder, is a common form of organic aciduria resulting from the deficiency of propionyl-CoA carboxylase. It is characterized by frequent and potentially lethal episodes of metabolic acidosis often accompanied by hyperammonemia. A wide range of brain abnormalities have been reported in propionic acidemia. We report recurrent visual hallucinations in 2 children with propionic acidemia. Four visual hallucination events were observed in the 2 patients. Three episodes were preceded by an intercurrent illness, and 2 were associated with mild metabolic decompensation. The 2 events in one patient were associated with a seizure disorder with abnormal electroencephalogram. Brain magnetic resonance imaging showed abnormal basal ganglia and faint temporo-occipital swelling bilaterally. This is probably the first report of visual hallucinations in propionic acidemia and should alert the treating clinicians to look for visual hallucinations in patients with organic acidurias, especially in an unusually anxious child.

  10. [MVK gene abnormality and new approach to treatment of hyper IgD syndrome and periodic fever syndrome]. (United States)

    Naruto, Takuya


    Hyper IgD and periodic fever syndrome (HIDS; OMIM 260920) is one of the hereditary autoinflammatory syndromes characterized by recurrent episodes of fever and inflammation.. HIDS is an autosomal recessive disorder characterized by recurrent fever attacks in early childhood. HIDS caused by mevalonate kinase (MK) mutations, also that is the gene of mevalonic aciduria (OMIM 251170). During febrile episodes, urinary mevalonate concentrations were found to be significantly elevated in patients. Diagnosis of HIDS was retrieving gene or measurement of the enzyme activity in peripheral blood lymphocyte in general. This of HIDS is an activity decline of MK, and a complete deficiency of MK becomes a mevalonic aciduria with a nervous symptom. The relation between the fever and inflammation of mevalonate or isoprenoid products are uncertain. The therapy attempt with statins, which is inhibited the next enzyme after HMG-CoA reductase, or inhibit the proinflammatory cytokines.

  11. Cobalamin status during normal pregnancy and postpartum: a longitudinal study comprising 406 danish women

    DEFF Research Database (Denmark)

    Milman, N; Byg, KE; Bergholt, T;


    OBJECTIVES: To assess cobalamin (vitamin B(12)) status during normal pregnancy and postpartum in a longitudinal setting. METHODS: This study was performed in 1995-1996. It comprised 406 healthy, pregnant Danish Caucasian women, living in Copenhagen County. Cobalamin status, i.e. plasma (P......-) cobalamin, P-methylmalonic acid and P-homocysteine was measured at 18, 32 and 39 wk gestation and 8 wk postpartum during lactation. RESULTS: P-cobalamin showed a gradual, significant decline during pregnancy (P ... and 8 wk postpartum median values were 225, 172, 161 and 319 pmol/L, respectively. P-methylmalonic displayed a gradual, significant increase during pregnancy as well as postpartum (P homocysteine demonstrated...

  12. N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia. (United States)

    Kasapkara, Cigdem Seher; Ezgu, Fatih Suheyl; Okur, Ilyas; Tumer, Leyla; Biberoglu, Gursel; Hasanoglu, Alev


    Hyperammonemia occurs mainly in patients with branched-chain organic acidemias such as propionic, methylmalonic, and isovaleric acidemias. Its pathophysiological process is mainly via the competitive inhibition of N-acetylglutamate synthetase. Oral carglumic acid (N-carbamylglutamate) administration can correct hyperammonemia in neonates with propionic and methylmalonic acidemias, thus avoiding dialysis therapy. Isovaleric acidemia is an autosomal recessive disease of leucine metabolism due to deficiency of isovaleryl-CoA dehydrogenase. For the first time, we report a neonate with isovaleric acidemia, whose plasma ammonia concentration dropped dramatically after one oral load of carglumic acid. This experience suggests that carglumic acid could be considered for acute hyperammonemia resulting from isovaleric acidemia. However, trials with more patients are needed.

  13. An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study

    DEFF Research Database (Denmark)

    Steenweg, Marjan E; Jakobs, Cornelis; Errami, Abdellatif;


    L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of ...... variants ( Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype-genotype relationship....

  14. A case of ethylmalonic encephalopathy with atypical clinical and biochemical presentation. (United States)

    Di Rocco, Maja; Caruso, Ubaldo; Briem, Egill; Rossi, Andrea; Allegri, Anna E M; Buzzi, Davide; Tiranti, Valeria


    A child is reported presenting with a clinical picture suggestive of genetic connective tissue disorders (vascular fragility, articular hyperlaxity, delayed motor development, and normal cognitive development), an absence of pathological ethylmalonic acid excretion during inter-critical phases and a homozygous R163W mutation in the ETHE1 gene. This case suggests that ethylmalonic aciduria is not a constant biochemical marker of ethylmalonic encephalopathy and that its normal excretion outside of metabolic decompensation episodes does not exclude this metabolic disease.

  15. N-carbamylglutamate Markedly Enhances Ureagenesis in N-acetylglutamate Deficiency and Propionic Acidemia as Measured by Isotopic Incorporation and Blood Biomarkers


    Tuchman, Mendel; Caldovic, Ljubica; Daikhin, Yevgeny; Horyn, Oksana; Nissim, Ilana; Nissim, Itzhak; Korson, Mark; Burton, Barbara; Yudkoff, Marc


    N-acetylglutamate (NAG) is an endogenous essential cofactor for conversion of ammonia to urea in the liver. Deficiency of NAG causes hyperammonemia and occurs because of inherited deficiency of its producing enzyme, NAG synthase (NAGS), or interference with its function by short fatty acid derivatives. N-carbamylglutamate (NCG) can ameliorate hyperammonemia from NAGS deficiency and propionic and methylmalonic acidemia. We developed a stable isotope 13C tracer method to measure ureagenesis and...

  16. Nutritional vitamin B12 deficiency in a breast-fed infant of a vegan-diet mother. (United States)

    Sklar, R


    A 7-month-old male presented with lethargy and failure to thrive. The child was exclusively breast-fed from birth by a mother who was a strict vegetarian. Laboratory data revealed macrocytic anemia and methylmalonic acid in the urine, consistent with vitamin B12 deficient anemia. The patient responded well to supplementation with B12 alone and was developmentally normal by 11 months of age. This study emphasizes the need for assuring maternal dietary adequacy during pregnancy and after birth.

  17. N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy. (United States)

    Elpeleg, Orly; Shaag, Avraham; Ben-Shalom, Efrat; Schmid, Tal; Bachmann, Claude


    Carbamylphosphate synthase is the first enzymatic reaction of the urea cycle. Its activator, N-acetylglutamate, is synthesized from acetyl-CoA and glutamate in a reaction catalyzed by N-acetylglutamate synthase (NAGS). We have identified the putative human NAGS gene and report the first mutation in this gene in a family with carbamylglutamate responsive hyperammonemia and normal activity of the urea cycle enzymes. Mutation analysis has a higher diagnostic specificity than the enzymatic assay in NAGS deficiency. A therapeutic trial with carbamylglutamate is recommended whenever hyperammonemia without an organic aciduria, increased orotate excretion, or diagnostic amino acidemia/uria is detected.

  18. Infant with cardiomyopathy: When to suspect inborn errors of metabolism?

    Institute of Scientific and Technical Information of China (English)

    Stephanie; L; Byers; Can; Ficicioglu


    Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of “red flags” which should prompt additional evaluation.

  19. Angelman syndrome and isovaleric acidemia: What is the link?

    Directory of Open Access Journals (Sweden)

    Alix Lambrecht


    Full Text Available We report a toddler affected with Angelman syndrome and isovaleric acidemia (IVA. Such association was due to paternal uniparental isodisomy (UPD of chromosome 15 in which the proband inherited two paternal copies of an IVA gene point mutation. As both diseases may have severe impact on neurodevelopment, adequate treatment of IVA should be discussed. In our patient however, the variant identified likely causes asymptomatic organic aciduria. Such findings emphasize that paternal UPD 15 can rarely lead to co-occurrence of Angelman syndrome and potentially treatable inborn errors of metabolism.

  20. Precocious Degenerative Arthropathy And Bluish Patches On Ears : Ochronosis And Alkaptonuria

    Directory of Open Access Journals (Sweden)

    Mahajan Vikram K


    Full Text Available Alkaptonuria is a rare, autosomal recessive disorder of phenylalanin/tyrosine metabolism due to congenital deficiency of the enzyme homogentisic acid oxidase. The diagnosis is clinical and the triad of homogentisic aciduria, ochronosis and precocious degenerative arthritis is characteristic. Its diagnosis in infancy and early therapeutic intervention help delaying its complications. These patients may remain undiagnosed until the darkening of urine soaked diapers is noticed or the early degenerative arthropathy develops. This paper describes two cases of alkaptonuria presenting late in life; one of them had associated hyperthyroidism.

  1. Structural organization of the human short-chain acyl-CoA dehydrogenase gene

    DEFF Research Database (Denmark)

    Corydon, M J; Andresen, B S; Bross, P


    of ethylmalonic acid (EMA). To define the genetic basis of SCAD deficiency and ethylmalonic aciduria in patients, we have determined the sequence of the complete coding portion of the human SCAD gene (ACADS) and all of the intron-exon boundaries. The SCAD gene is approximately 13 kb in length and consists of 10......, 990T, 1260C) constitutes an allelic variant with a frequency of 22% in the general Danish population. Using fluorescence in-situ hybridization, we confirm the localization of the human SCAD gene to the distal part of Chromosome (Chr) 12 and suggest that the SCAD gene is a single-copy gene...

  2. [Uricosuric agent]. (United States)

    Ohno, Iwao


    Urate lowering treatment is indicated in patients with recurrent acute attacks, tophi, gouty arthropathy, radiographic changes of gout, multiple joint involvement, or associated uric acid nephrolithiasis. Uricosuric agents like benzbromarone and probenecid are very useful to treat hyperuricemia as well as allopurinol (xanthine oxidase inhibitor). Uricosuric agents act the urate lowering effect through blocking the URAT1, an urate transporter, in brush border of renal proximal tubular cells. In order to avoid the nephrotoxicity and urolithiasis due to increasing of urinary urate excretion by using uricosuric agents, the proper urinary tract management (enough urine volume and correction of aciduria) should be performed.

  3. A case of asymptomatic pancytopenia with clinical features of hemolysis as a presentation of pernicious anemia

    Directory of Open Access Journals (Sweden)

    Venkateswara K. Kollipara


    Full Text Available Pernicious anemia is an autoimmune disease with a variety of clinical presentations. We describe a case of pernicious anemia presenting with pancytopenia with hemolytic features. Further workup revealed very low vitamin B12 levels and elevated methylmalonic acid. It is important for a general internist to identify pernicious anemia as one of the cause of pancytopenia and hemolytic anemia to avoid extensive workup. Pernicious anemia can present strictly with hematological abnormalities without neurological problems or vice versa as in our case.

  4. Identification of hepatic biomarkers for physiological imbalance of dairy cows in early and mid lactation using proteomic technology

    DEFF Research Database (Denmark)

    Moyes, Kasey; Bendixen, Emøke; Codrea, Marius Cosmin;


    either the greatest (PI) or least (normal; N) degree of PI and were used for isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative profiling in liver using liquid chromatography-tandem mass spectrometry. We identified pyruvate carboxylase and isocitrate dehydrogenase...... as potential hepatic biomarkers for PI for cows during early lactation and alcohol dehydrogenase-4 and methylmalonate-semialdehyde dehydrogenase for cows in mid lactation. This preliminary study identified new biomarkers in liver for PI and provided a better understanding of the differences in coping...

  5. Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome. (United States)

    Wortmann, Saskia B; van Hasselt, Peter M; Barić, Ivo; Burlina, Alberto; Darin, Niklas; Hörster, Friederike; Coker, Mahmut; Ucar, Sema Kalkan; Krumina, Zita; Naess, Karin; Ngu, Lock H; Pronicka, Ewa; Riordan, Gilian; Santer, Rene; Wassmer, Evangeline; Zschocke, Johannes; Schiff, Manuel; de Meirleir, Linda; Alowain, Mohammed A; Smeitink, Jan A M; Morava, Eva; Kozicz, Tamas; Wevers, Ron A; Wolf, Nicole I; Willemsen, Michel A


    Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This "eye" was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings.

  6. Mutations underlying 3-Hydroxy-3-Methylglutaryl CoA Lyase deficiency in the Saudi population

    Directory of Open Access Journals (Sweden)

    Rashed Mohammed S


    Full Text Available Abstract Background 3-Hydroxy-3-Methylglutaric aciduria (3HMG, McKusick: 246450 is an autosomal recessive branched chain organic aciduria caused by deficiency of the enzyme 3-Hydroxy-3-Methylglutaryl CoA lyase (HL, HMGCL, EC HL is encoded by HMGCL gene and many mutations have been reported. 3HMG is commonly observed in Saudi Arabia. Methods We utilized Whole Genome Amplification (WGA, PCR and direct sequencing to identify mutations underlying 3HMG in the Saudi population. Two patients from two unrelated families and thirty-four 3HMG positive dried blood spots (DBS were included. Results We detected the common missense mutation R41Q in 89% of the tested alleles (64 alleles. 2 alleles carried the frame shift mutation F305fs (-2 and the last two alleles had a novel splice site donor IVS6+1G>A mutation which was confirmed by its absence in more than 100 chromosomes from the normal population. All mutations were present in a homozygous state, reflecting extensive consanguinity. The high frequency of R41Q is consistent with a founder effect. Together the three mutations described account for >94% of the pathogenic mutations underlying 3HMG in Saudi Arabia. Conclusion Our study provides the most extensive genotype analysis on 3HMG patients from Saudi Arabia. Our findings have direct implications on rapid molecular diagnosis, prenatal and pre-implantation diagnosis and population based prevention programs directed towards 3HMG.

  7. Biochemical abnormalities in Pearson syndrome. (United States)

    Crippa, Beatrice Letizia; Leon, Eyby; Calhoun, Amy; Lowichik, Amy; Pasquali, Marzia; Longo, Nicola


    Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders.


    Directory of Open Access Journals (Sweden)

    Marjan SHAKIBA


    Full Text Available Organic acid occur as physiologic intermediates in variety of intracellular metabolic pathways, such as catabolism of aminoacid, mitochondrial β oxidation of fatty acids, tricarboxilic acid cycle, and cholestrol and fatty acid biosynthesis. The classical organic aciduria represent the pursuit of abnormalities of aminoacid degradation beyond deamination Their diagnostic hallmark is an accumulation of characteristic organic acids.The clinical features result from toxicity of the accumulating methabolites.Treatment involved 1. protein restriction 2. supplementation of aminoacids with unimpaired metabolism as well as trace elements and 3. specific measures for detoxification if indicated. Diagnostic tests consist of CBC, FBS, Bun, Cr, uric organic acid, TG, Cholestrol Ca, P, ALP, VBG, Na, K, Cl, U/A(PH, SG, Ketone, Ammonia, lactate, pyrovate, Ketone body CPK, Aldolase, SGOT, SGPT, BIL, PT, PTT, Plasma aminoacid HPLC, Homocysteine, Urine aminoacid and carbohydrate chromatography, Acyl carnitine profile, urine organic acids and for next steps tissue specimen and enzyme activity and gene study.clinical chemical indices of organid aciduria is Metabolic acidosis, Increased anion gap, Hyperglycemia and hypoglycemia, Ketosis and Ketonuria, Lactic acidosis, Hyperammonemia, Hyperuricemia, Hypertriglyceridemia, increase of transaminase Granulocytopenia, thrombocytopenia and Anemia. Acylcarnitine profile and urine organic acids are two for important tests for differentiation of types oforganic academia.

  9. Vitamin Status among Breastfed Infants in Bhaktapur, Nepal

    Directory of Open Access Journals (Sweden)

    Manjeswori Ulak


    Full Text Available Vitamin deficiencies are known to be common among infants residing in low- and middle-income countries but relatively few studies have assessed several biochemical parameters simultaneously. The objective of the study was to describe the status of vitamins (A, D, E, B6, B12 and folate in breastfed infants. We measured the plasma concentrations of trans retinol, 25 hydroxy vitamin D, α-tocopherol, pyridoxal 5′-phosphate, cobalamin, folate, methylmalonic acid, homocysteine, hemoglobin and C-reactive protein from 467 randomly selected infants. One in five (22% was deficient in at least one vitamin. Mean (SD plasma folate concentration was 73 (35 nmol/L, and no infant in the sample was folate deficient. Vitamin B6 deficiency and vitamin B12 deficiency was found in 22% and 17% of the infants, respectively. Elevated plasma methylmalonic acid or total homocysteine concentration was found in 82% and 62% of infants, respectively. Fifteen percent of infants were vitamin A deficient and 65% were marginally deficient in vitamin A. Fewer than 5% of infants had low plasma vitamin D concentration or vitamin E concentration (α-tocopherol <9.3 µmol/L. Our results illustrate the importance of continued supplementation campaigns and support the expansion of food fortification and dietary diversification programs that target children and women in Nepal.

  10. Characterization of corrinoid compounds from a Japanese black tea (Batabata-cha) fermented by bacteria. (United States)

    Kittaka-Katsura, Hiromi; Ebara, Syuhei; Watanabe, Fumio; Nakano, Yoshihisa


    A Japanese fermented black tea (Batabata-cha) contained a considerable amount of vitamin B(12) (456 +/- 39 ng per 100 g dry tea leaves and 2.0 +/- 0.3 ng per 100 mL of tea drink). A corrinoid compound was partially purified and characterized from the tea leaves. The patterns of the purified compound by the silica gel 60 thin-layer chromatography and C18 reversed phased high-performance liquid chromatography were identical to those of authentic vitamin B(12). When 20 week old vitamin B(12) deficient rats, which excreted substantial amounts (about 250 mg/day) of methylmalonic acid in urine as an index of vitamin B(12) deficiency, were fed the tea drink (50 mL/day, 1 ng of vitamin B(12)) for 6 weeks, urinary methylmalonic acid excretion (169 +/- 29 mg/day) of the tea drink-supplemented 26 week old rats decreased significantly relative to that (250 +/- 32 mg/day) of the deficient rats. The results indicate that the vitamin B(12) found in the fermented black tea is bioavailable in mammals.

  11. Vitamin Status among Breastfed Infants in Bhaktapur, Nepal. (United States)

    Ulak, Manjeswori; Chandyo, Ram K; Thorne-Lyman, Andrew L; Henjum, Sigrun; Ueland, Per M; Midttun, Øivind; Shrestha, Prakash S; Fawzi, Wafaie W; Graybill, Lauren; Strand, Tor A


    Vitamin deficiencies are known to be common among infants residing in low- and middle-income countries but relatively few studies have assessed several biochemical parameters simultaneously. The objective of the study was to describe the status of vitamins (A, D, E, B₆, B12 and folate) in breastfed infants. We measured the plasma concentrations of trans retinol, 25 hydroxy vitamin D, α-tocopherol, pyridoxal 5'-phosphate, cobalamin, folate, methylmalonic acid, homocysteine, hemoglobin and C-reactive protein from 467 randomly selected infants. One in five (22%) was deficient in at least one vitamin. Mean (SD) plasma folate concentration was 73 (35) nmol/L, and no infant in the sample was folate deficient. Vitamin B₆ deficiency and vitamin B12 deficiency was found in 22% and 17% of the infants, respectively. Elevated plasma methylmalonic acid or total homocysteine concentration was found in 82% and 62% of infants, respectively. Fifteen percent of infants were vitamin A deficient and 65% were marginally deficient in vitamin A. Fewer than 5% of infants had low plasma vitamin D concentration or vitamin E concentration (α-tocopherol <9.3 µmol/L). Our results illustrate the importance of continued supplementation campaigns and support the expansion of food fortification and dietary diversification programs that target children and women in Nepal.

  12. Experimental vitamin B12 deficiency in a human subject: a longitudinal investigation of the performance of the holotranscobalamin (HoloTC, Active-B12) immunoassay. (United States)

    Golding, Paul Henry


    Based on Victor Herbert's model for sequential stages in the development of vitamin B12 deficiency, the holotranscobalamin (HoloTC) immunoassay has controversially been promoted as a more specific and sensitive replacement for the total vitamin B12 test, for the diagnosis of deficiency. There have been no longitudinal studies, by means of experimental cobalamin deficiency, because ethical considerations prevent such risky studies on patients or healthy human volunteers. The objective was to provide a detailed record of the response of HoloTC, compared to total vitamin B12 and metabolites, to the development of experimental vitamin B12 deficiency in an initially replete human subject. This 54 year old male, with a vitamin B12 deficiency possibly caused by a defect in the intracellular cobalamin metabolism, ensured an initially replete condition by means of oral doses of cyanocobalamin supplements at 1000 μg/day for 12 weeks. The subject then depleted himself of vitamin B12, by withholding treatment and using a low-cobalamin diet, until significant metabolic disturbances were observed. The responses of serum total vitamin B12 and HoloTC and the two metabolites, plasma methylmalonic acid and homocysteine, were monitored by weekly blood tests. HoloTC was not significantly more sensitive than either total serum vitamin B12 or total homocysteine, and was much less sensitive than methylmalonic acid. HoloTC decreased from an initial concentration of >128 pmol/L to a minimum of 33 pmol/L on day 742, the only day on which it fell below the lower limit of the reference interval. Total vitamin B12 decreased from an initial concentration of 606 pmol/L to a minimum of 171 pmol/L on day 728. Total homocysteine increased from an initial concentration of 8.4 μmol/L to a maximum of 14.2 μmol/L on day 609. Methylmalonic acid unexpectedly contained four distinct peaks; initially at 0.17 μmol/L, it first exceeded the upper limit of the reference interval on day 386

  13. 2-Methylcitric acid impairs glutamate metabolism and induces permeability transition in brain mitochondria. (United States)

    Amaral, Alexandre Umpierrez; Cecatto, Cristiane; Castilho, Roger Frigério; Wajner, Moacir


    Accumulation of 2-methylcitric acid (2MCA) is observed in methylmalonic and propionic acidemias, which are clinically characterized by severe neurological symptoms. The exact pathogenetic mechanisms of brain abnormalities in these diseases are poorly established and very little has been reported on the role of 2MCA. In the present work we found that 2MCA markedly inhibited ADP-stimulated and uncoupled respiration in mitochondria supported by glutamate, with a less significant inhibition in pyruvate plus malate respiring mitochondria. However, no alterations occurred when α-ketoglutarate or succinate was used as respiratory substrates, suggesting a defect on glutamate oxidative metabolism. It was also observed that 2MCA decreased ATP formation in glutamate plus malate or pyruvate plus malate-supported mitochondria. Furthermore, 2MCA inhibited glutamate dehydrogenase activity at concentrations as low as 0.5 mM. Kinetic studies revealed that this inhibitory effect was competitive in relation to glutamate. In contrast, assays of osmotic swelling in non-respiring mitochondria suggested that 2MCA did not significantly impair mitochondrial glutamate transport. Finally, 2MCA provoked a significant decrease in mitochondrial membrane potential and induced swelling in Ca(2+)-loaded mitochondria supported by different substrates. These effects were totally prevented by cyclosporine A plus ADP or ruthenium red, indicating induction of mitochondrial permeability transition. Taken together, our data strongly indicate that 2MCA behaves as a potent inhibitor of glutamate oxidation by inhibiting glutamate dehydrogenase activity and as a permeability transition inducer, disturbing mitochondrial energy homeostasis. We presume that 2MCA-induced mitochondrial deleterious effects may contribute to the pathogenesis of brain damage in patients affected by methylmalonic and propionic acidemias. We propose that brain glutamate oxidation is disturbed by 2-methylcitric acid (2MCA), which

  14. Aminoacidopatias de interesse neurológico

    Directory of Open Access Journals (Sweden)

    Aron J. Diament


    Full Text Available As aminoácidopatias constituem o grupo mais numeroso dos erros inatos do metabolismo, sendo crescente seu número em vista das inúmeras cadeias metabólicas envolvendo os aminoácidos na economia humana. É apresentada uma classificação atualizada das principais aminoacidopatias que determinam sintomatologia neurológica e/ou mental. São revistos os principais métodos de diagnóstico, apontando-se as falhas de algumas metodologias. São abordadas algumas particularidades da fenilcetonúria, leucinose e acidemia propiônica, principalmente no que concerne à variação genética. Finalmente, são apresentadas duas aminoacidopatias recentemente descritas: a aciduria piroglutâmica e a deficiência da beta-metil-crotonil-CoA-carboxilase.

  15. Effect of a 5-mo nutritional intervention on nutritional status and quality of life for patient with 3-hydroxyisobutyryl-coenzyme A hydrolase deficiency: A case report. (United States)

    Li, Chun-Wei; Yu, Kang; Xu, Yan; Sun, Xia-Yuan; Li, Rong-Rong; Wang, Fang


    3-Hydroxy-isobutyryl-coenzyme A (CoA) hydrolase (HBICH) deficiency is a rare cerebral organic aciduria caused by disturbance of valine catabolism that leads to the accumulation of toxic metabolites, methacrylyl-CoA. The major feature exhibited by a patient with HBICH deficiency includes multiple congenital malformations and abnormal neurologic findings. However, the pathophysiology of this disease remains unknown. The major treatment for HBICH deficiency involves a low-protein diet, especially restricting valine, supplemented with micronutrients and carnitine. To our knowledge, only four patients with HBICH deficiency have been reported. These patients were boys and presented with different clinical, biochemical, and genetic features than our patient. In this report, we described what was to our knowledge the first genetically confirmed girl with HBICH deficiency in China. A 5-mo nutritional intervention was given to the patient by a nutritional support team. On this regimen, the patient's symptoms were alleviated and her quality of life was improved.

  16. Diminished exercise capacity and mitochondrial bc1 complex deficiency in tafazzin-knockdown mice.

    Directory of Open Access Journals (Sweden)

    Corey ePowers


    Full Text Available The phospholipid, cardiolipin, is essential for maintaining mitochondrial structure and optimal function. Cardiolipin-deficiency in humans, Barth syndrome, is characterized by exercise intolerance, dilated cardiomyopathy, neutropenia and 3-methyl-glutaconic aciduria. The causative gene is the mitochondrial acyl-transferase, tafazzin that is essential for remodeling acyl chains of cardiolipin. We sought to determine metabolic rates in tafazzin-deficient mice during resting and exercise, and investigate the impact of cardiolipin deficiency on mitochondrial respiratory chain activities. Tafazzin knockdown in mice markedly impaired oxygen consumption rates during an exercise, without any significant effect on resting metabolic rates. CL-deficiency resulted in significant reduction of mitochondrial respiratory reserve capacity in neonatal cardiomyocytes that is likely to be caused by diminished activity of complex-III, which requires CL for its assembly and optimal activity. Our results may provide mechanistic insights of Barth syndrome pathogenesis.

  17. Neurometabolic diseases of childhood

    Energy Technology Data Exchange (ETDEWEB)

    Patay, Zoltan [St. Jude Children' s Research Hospital, Section of Neuroradiology, Division of Radiology, Department of Radiological Sciences, Memphis, TN (United States); Blaser, Susan I. [The Hospital for Sick Children, Division of Neuroradiology, Department of Diagnostic Imaging, Toronto (Canada); Poretti, Andrea; Huisman, Thierry A.G.M. [Charlotte R. Bloomberg Children' s Center, Pediatric Radiology and Pediatric Neuroradiology, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Baltimore, MD (United States)


    Metabolic diseases affecting the pediatric brain are complex conditions, the underlying mechanisms leading to structural damage are diverse and the diagnostic imaging manifestations are often non-specific; hence early, sensitive and specific diagnosis can be challenging for the radiologist. However, misdiagnosis or a delayed diagnosis can result in a devastating, irreversible injury to the developing brain. Based upon the inborn error, neurometabolic diseases can be subdivided in various groups depending on the predominantly involved tissue (e.g., white matter in leukodystrophies or leukoencephalopathies), the involved metabolic processes (e.g., organic acidurias and aminoacidopathies) and primary age of the child at presentation (e.g., neurometabolic disorders of the newborn). This manuscript summarizes these topics. (orig.)

  18. Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice.

    Directory of Open Access Journals (Sweden)


    Full Text Available Medium-chain acyl-CoA dehydrogenase (MCAD deficiency is the most common inherited disorder of mitochondrial fatty acid beta-oxidation in humans. To better understand the pathogenesis of this disease, we developed a mouse model for MCAD deficiency (MCAD by gene targeting in embryonic stem (ES cells. The MCAD mice developed an organic aciduria and fatty liver, and showed profound cold intolerance at 4 degrees C with prior fasting. The sporadic cardiac lesions seen in MCAD mice have not been reported in human MCAD patients. There was significant neonatal mortality of MCAD pups demonstrating similarities to patterns of clinical episodes and mortality in MCAD-deficient patients. The MCAD-deficient mouse reproduced important aspects of human MCAD deficiency and is a valuable model for further analysis of the roles of fatty acid oxidation and pathogenesis of human diseases involving fatty acid oxidation.

  19. Perioperative management of patient with alkaptonuria and associated multiple comorbidities

    Directory of Open Access Journals (Sweden)

    Ravindra Pandey


    Full Text Available Alkaptonuria is a rare inherited genetic disorder of tyrosine metabolism characterized by a triad of homogentisic aciduria, ochronosis, and arthritis. The most common clinical manifestations of ochronosis involve the musculoskeletal, respiratory, airway, cardiovascular, genitourinary, cutaneous, and ocular systems. We report the perioperative anesthetic management of a 56-year-old alkaptonuric patient, with multiple comorbidities scheduled, for revision total hip replacement. A review of her medical history revealed alkaptonuria, hypothyroidism, rheumatoid arthritis, hypertension, diabetes mellitus, and Pott′s spine with disc prolapse. We want to highlight the need of thorough preoperative evaluation in patients of alkaptonuria, as it is associated with multiple comorbidities. The systemic involvement should determine the anesthetic plan. Caution should be exercised during positioning to prevent injury to the joints and the spine.

  20. Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl-L-cysteine. (United States)

    Gomez-Ospina, Natalia; Scott, Anna I; Oh, Gia J; Potter, Donald; Goel, Veena V; Destino, Lauren; Baugh, Nancy; Enns, Gregory M; Niemi, Anna-Kaisa; Cowan, Tina M


    Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known. Herein we describe clinical and laboratory findings in two fraternal twins with hawkinsinuria who presented with failure to thrive and metabolic acidosis. Close clinical follow-up and laboratory testing revealed previously unrecognized hypoglycemia, hypophosphatemia, combined hyperlipidemia, and anemia, along with the characteristic urinary metabolites, including massive pyroglutamic aciduria. Treatment with N-acetyl-L-cysteine (NAC) restored normal growth and normalized or improved most biochemical parameters. The dramatic response to NAC therapy supports the idea that glutathione depletion plays a key role in the pathogenesis of hawkinsinuria.

  1. [Floppy baby with macrocytic anemia and vegan mother]. (United States)

    Schlapbach, L J; Schütz, B; Nuoffer, J M; Brekenfeld, C; Müller, G; Fluri, S


    We report the case of a 7 month-old girl that presented with acute anemia, generalized muscular hypotonia and failure to thrive. Laboratory evaluation revealed cobalamin deficiency, due to a vegan diet of the mother. The clinical triad of an acquired floppy baby syndrome with megaloblastic anemia and failure to thrive is pathognomic for infantile cobalamin deficiency. Neurological abnormalities are often irreversible and may be associated with delayed myelinization in the MRI. A normal cobalamin level in maternal serum and absence of anemia do not exclude subclinical deficiency. If cobalamin deficiency is suspected, e.g. in pregnant women on vegan diet, urinary methylmalonic acid excretion and plasma homocysteine levels should be determined and cobalamin substitution should be started at an early stage to avoid potentially irreversible damage of the fetus.

  2. Impact of Pre-Pregnancy BMI on B Vitamin and Inflammatory Status in Early Pregnancy: An Observational Cohort Study (United States)

    Bjørke-Monsen, Anne-Lise; Ulvik, Arve; Nilsen, Roy M.; Midttun, Øivind; Roth, Christine; Magnus, Per; Stoltenberg, Camilla; Vollset, Stein Emil; Reichborn-Kjennerud, Ted; Ueland, Per Magne


    Maternal nutrition and inflammation have been suggested as mediators in the development of various adverse pregnancy outcomes associated with maternal obesity. We have investigated the relation between pre-pregnancy BMI, B vitamin status, and inflammatory markers in a group of healthy pregnant women. Cobalamin, folate, pyridoxal 5′-phosphate, and riboflavin; and the metabolic markers homocysteine, methylmalonic acid, and 3-hydroxykynurenine/xanthurenic acid ratio (HK/XA); and markers of cellular inflammation, neopterin and kynurenine/tryptophan ratio (KTR) were determined in pregnancy week 18 and related to pre-pregnancy body mass index (BMI), in 2797 women from the Norwegian Mother and Child Cohort Study (MoBa). Pre-pregnancy BMI was inversely related to folate, cobalamin, pyridoxal 5′-phosphate (PLP), and riboflavin (p pregnant. PMID:27916904

  3. Laughing Gas in a Pediatric Emergency Department-Fun for All Participants: Vitamin B12 Status Among Medical Staff Working With Nitrous Oxide. (United States)

    Staubli, Georg; Baumgartner, Matthias; Sass, Jörn Oliver; Hersberger, Martin


    The efficiency of nitrous oxide in an equimolar mixture with oxygen or in concentrations up to 70% is approved for short painful procedures. Evaluation of the vitamin B12 levels in anesthetic staff applying nitrous oxide showed reduced vitamin B12 plasma levels. This study examines the vitamin B12 status of medical staff working with nitrous oxide in a pediatric emergency department (ED). Medical staff of the ED at the University Children's Hospital Zurich participated. The vitamin B12 status was evaluated by measuring homocysteine, methylmalonic acid, vitamin B12, blood count, and the MTHFR C677T genotype. As a control group, medical personnel working in the "nitrous oxide-free" pediatric intensive care unit were recruited.

  4. Reaction of 4-(7)-aminobenzimidazole with ethyl 2-alkylmalonates in 1, 2, 4-trichlorobenzene

    Energy Technology Data Exchange (ETDEWEB)

    Valle-Aguilera, Lucia E.; Gonzalez-Chavez, Marco M. [Universidad Autonoma de San Luis Potosi, San Luis Potosi (Mexico); Martinez, Roberto [Universidad Nacional Autonoma de Mexico, Mexico, D.F. (Mexico)


    The reaction of 4-(7)-aminobenzimidazole (2) with ethyl malonate or ethyl 2-allylmalonate, using 1, 2, 4-trichlorobenzene as the reaction solvent produces benzodiazepin-4, 6-diones and acetamidobenzimidazoles. However, reaction of (2) with ethyl 2-methylmalonate as well as the 2-butyl and 2-propyl derivatives, produced unknown dihydroxyquinolines in addition to benzodiazepin-4, 6-diones and acetamidobenzimidazoles. [Spanish] La reaccion del 4-(7)-aminobencimidazol (2) con malonato de etilo o 2-alilmalonato de etilo, utilizando el 1, 2, 4-triclorobenceno como disolvente, produce benzodiazepin-4,6-dionas y acetamido bencimidazoles. Sin embargo, la reaccion de (2) con el 2-metilmalonato de etilo, o con derivados de 2-propilo o 2-butilo, produce, ademas de compuestos similares a los anteriores, un tercer compuesto identificado como una dihidroxiquinolina.

  5. Vitamin B12 deficiency with intrinsic factor antibodies in an infant with poor growth and developmental delay. (United States)

    McNeil, Kathleen; Chowdhury, Dhiman; Penney, Lynette; Rashid, Mohsin


    Vitamin B12 deficiency is very rare in infants and may lead to serious hematological and neurodevelopmental abnormalities. The present article describes a case involving a seven-month-old boy with severe vitamin B12 deficiency, likely caused by juvenile pernicious anemia, an entity rarely described. The child presented with feeding intolerance, poor growth and developmental delay. He was noted to have macrocytic anemia, a markedly low serum vitamin B12 level, and elevated homocysteine and methylmalonic acid levels. Antibodies to intrinsic factor were positive. The mother was healthy, with normal vitamin B12 status. Therapy with vitamin B12 supplements led to excellent recovery of symptoms. Vitamin B12 deficiency should be considered in children presenting with failure to thrive, especially when compounded with neurological symptoms. Early diagnosis and adequate treatment is essential to avoid serious complications.

  6. Radiolabeled Apoptosis Imaging Agents for Early Detection of Response to Therapy

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    Kazuma Ogawa


    Full Text Available Since apoptosis plays an important role in maintaining homeostasis and is associated with responses to therapy, molecular imaging of apoptotic cells could be useful for early detection of therapeutic effects, particularly in oncology. Radiolabeled annexin V compounds are the hallmark in apoptosis imaging in vivo. These compounds are reviewed from the genesis of apoptosis (cell death imaging agents up to recent years. They have some disadvantages, including slow clearance and immunogenicity, because they are protein-based imaging agents. For this reason, several studies have been conducted in recent years to develop low molecule apoptosis imaging agents. In this review, radiolabeled phosphatidylserine targeted peptides, radiolabeled bis(zinc(II-dipicolylamine complex, radiolabeled 5-fluoropentyl-2-methyl-malonic acid (ML-10, caspase-3 activity imaging agents, radiolabeled duramycin, and radiolabeled phosphonium cation are reviewed as promising low-molecular-weight apoptosis imaging agents.

  7. Determination of thermodynamic parameters for enolization reaction of malonic and metylmalonic acids by using quartz crystal microbalance

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    Minoru Yoshimoto


    Full Text Available We investigated the process of a bromination reaction of malonic acid and methylmalonic acid in the Belousov-Zhabotinsky reaction by using a quartz crystal microbalance (QCM. The process involves an enolization reaction as a rate-determining step. We found that, in the step, the variation of Br2 concentration induced an exactly quantitative shift of a resonant frequency of the QCM, based on the change of the surface mass on the QCM and the solution viscosity and density. This new finding enabled us to estimate the reaction rate constants and the thermodynamic parameters of the enolization reaction due to a QCM measurement. The values measured by the QCM were in good agreement with those measured by a UV-spectrophotometer. As a result, we succeeded to develop a new measurement method of a nonlinear chemical reaction.

  8. Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin

    DEFF Research Database (Denmark)

    Clarke, Robert; Sherliker, Paul; Hin, Harold


    BACKGROUND: Impaired vitamin B(12) function and decreased vitamin B(12) status have been associated with neurological and cognitive impairment. Current assays analyze total vitamin B(12) concentration, only a small percentage of which is metabolically active. Concentrations of this active component......, carried on holotranscobalamin (holoTC), may be of greater relevance than total vitamin B(12). METHODS: We compared the utility of serum holoTC with conventional vitamin B(12) for detection of vitamin B(12) deficiency in a population-based study of older people, using increased methylmalonic acid (MMA......) concentrations as a marker of metabolic vitamin B(12) deficiency in the overall population (n = 2403) and in subsets with normal (n = 1651) and abnormal (n = 752) renal function. RESULTS: Among all participants, 6% had definite (MMA >0.75 micromol/L) and 16% had probable (MMA >0.45 micromol/L) metabolic vitamin...

  9. Vision Changes after Space Flight Are Related to Alterations in Folate-Dependent One-Carbon Metabolism (United States)

    Smith, Scott M.; Gibson, C. Robert; Mader, Thomas H.; Ericson, Karen; Ploutz-Snyder, Robert; Heer, Martina; Zwart, Sara R.


    About 20% of astronauts on International Space Station missions have developed measurable ophthalmic changes after flight. This study was conducted to determine whether the folate-dependent 1-carbon pathway is altered in these individuals. Data were modeled to evaluate differences between individuals with ophthalmic changes (n=5) and those without them (n=15). We also correlated mean preflight serum concentrations of the 1-carbon metabolites with changes in measured refraction after flight. Serum homocysteine (HCy), cystathionine, 2-methylcitric acid, and methylmalonic acid concentrations were 25%-45% higher (Prefraction, and preflight serum concentrations of 2-methylcitric acid tended to be associated (P=0.06) with ophthalmic changes. The biochemical differences observed in those with vision issues strongly suggests impairment of the folate-dependent 1-carbon transfer pathway. Impairment of this pathway, by polymorphisms, diet or other means, may interact with components of the microgravity environment to influence these pathophysiologic changes. This study was funded by the NASA Human Research Program.

  10. Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin. (United States)

    Tein, Ingrid; Elpeleg, Orly; Ben-Zeev, Bruria; Korman, Stanley H; Lossos, Alexander; Lev, Dorit; Lerman-Sagie, Tally; Leshinsky-Silver, Esther; Vockley, Jerry; Berry, Gerard T; Lamhonwah, Anne-Marie; Matern, Dietrich; Roe, Charles R; Gregersen, Niels


    We report 10 children (7 male, 3 female), 3 homozygous for c.319C>T mutation and 7 heterozygous for c.319C>T on one allele and c.625G>A variant on the other in the short-chain acyl-CoA dehydrogenase (SCAD) gene (ACADS). All were of Ashkenazi Jewish origin in which group we found a c.319C>T heterozygote frequency of 1:15 suggesting the presence of a founder mutation or selective advantage. Phenotype was variable with onset from birth to early childhood. Features included hypotonia (8/10), developmental delay (8/10), myopathy (4/10) with multicore changes in two and lipid storage in one, facial weakness (3/10), lethargy (5/10), feeding difficulties (4/10) and congenital abnormalities (3/7). One female with multiminicore myopathy had progressive external ophthalmoplegia, ptosis and cardiomyopathy with pneumonia and respiratory failure. Two brothers presented with psychosis, pyramidal signs, and multifocal white matter abnormalities on MRI brain suggesting additional genetic factors. Two other infants also had white matter changes. Elevated butyrylcarnitine (4/8), ethylmalonic aciduria (9/9), methylsuccinic aciduria (6/7), decreased butyrate oxidation in lymphoblasts (2/4) and decreased SCAD activity in fibroblasts or muscle (3/3) were shown. Expression studies of c.319C>T in mouse liver mitochondria showed it to be inactivating. c.625G>A is a common variant in ACADS that may confer disease susceptibility. Five healthy parents were heterozygous for c.319C>T and c.625G>A, suggesting reduced penetrance or broad clinical spectrum. We conclude that the c.319C>T mutation can lead to wide clinical and biochemical phenotypic variability, suggesting a complex multifactorial/polygenic condition. This should be screened for in individuals with multicore myopathy, particularly among the Ashkenazim.

  11. Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency. (United States)

    Tricarico, Paola Maura; Piscianz, Elisa; Monasta, Lorenzo; Kleiner, Giulio; Crovella, Sergio; Marcuzzi, Annalisa


    Mevalonate kinase deficiency is a rare disease whose worst manifestation, characterised by severe neurologic impairment, is called mevalonic aciduria. The progressive neuronal loss associated to cell death can be studied in vitro with a simplified model based on a biochemical block of the mevalonate pathway and a subsequent inflammatory trigger. The aim of this study was to evaluate the effect of the mevalonate blocking on glial cells (BV-2) and the following effects on neuronal cells (SH-SY5Y) when the two populations were cultured together. To better understand the cross-talk between glial and neuronal cells, as it happens in vivo, BV-2 and SH-SY5Y were co-cultured in different experimental settings (alone, transwell, direct contact); the effect of mevalonate pathway biochemical block by Lovastatin, followed by LPS inflammatory trigger, were evaluated by analysing programmed cell death and mitochondrial membrane potential, cytokines' release and cells' morphology modifications. In this experimental condition, glial cells underwent an evident activation, confirmed by elevated pro-inflammatory cytokines release, typical of these disorders, and a modification in morphology. Moreover, the activation induced an increase in apoptosis. When glial cells were co-cultured with neurons, their activation caused an increase of programmed cell death also in neuronal cells, but only if the two populations were cultured in direct contact. Our findings, being aware of the limitations related to the cell models used, represent a preliminary step towards understanding the pathological and neuroinflammatory mechanisms occurring in mevalonate kinase diseases. Contact co-culture between neuronal and microglial cells seems to be a good model to study mevalonic aciduria in vitro, and to contribute to the identification of potential drugs able to block microglial activation for this orphan disease. In fact, in such a pathological condition, we demonstrated that microglial cells are

  12. Hyperhomocysteinemia and B-vitamin deficiencies in infants and children. (United States)

    Ueland, Per Magne; Monsen, Anne Lise Bjørke


    Measurement of total homocysteine (tHcy) in healthy and diseased children has documented the utility of this marker in pediatric research and diagnostics. This article focuses on novel data obtained in infants, children and adolescents, with emphasis on cobalamin status in infants. In children, determinants of plasma tHcy are similar to those established in adults, and include age, gender, nutrition, B-vitamin status, and some drugs interfering with B-vitamin function. In infants (age children and throughout childhood, plasma tHcy is low (about 60% of adult levels), and folate status becomes a strong tHcy determinant. As in adults, hyperhomocysteinemia in childhood is a risk factor for stroke, and folate-responsive hyperhomocysteinemia has been detected in children with renal failure. tHcy seems to be a sensitive indicator of folate deficiency in children on a poor diet, in HIV-infected children, and in children treated with anti-folate drugs. In children at increased risk of cobalamin deficiency, which includes children born to vegetarian mothers or children in developing countries on a poor diet, tHcy and methylmalonic acid are responsive indicators of a deficiency state. In newborns and infants born to mothers with an adequate nutrition, there are consistent observations of low cobalamin, elevated tHcy and methylmalonic acid, and reduction of both metabolites by cobalamin supplementation. These data have raised the question whether cobalamin deficiency may be widespread and undetected in babies born to non-vegetarian women on a Westernized diet.

  13. AB031. Spectrum of IEMs in Vietnamese patients: data from 10 years of selected screening and diagnosis (United States)

    Dung, Vu Chi; Khánh, Nguyễn Ngọc; Mai, Nguyen Chi; Hương, Bùi Thị; Thao, Bui Phuong; Ngoc, Can Thi Bich; Hoan, Nguyen Thi; Hai, Le Thanh; Dung, Khu Thi Khanh; Fukao, Toshiyuki; Yamaguchi, Seiji


    Background and objective Vietnam is the easternmost country on the Indochina Peninsula in Southeast Asia. With an estimated 90 million inhabitants as of 2013, it is the world’s 13th-most-populous country, and the eighth-most-populous Asian country. Congenital anomalies accounted about 22% of causes of deaths in children under-5 [2010]. The first service for IEMs was set up at the Northern referral center of Pediatrics-National Hospital of Pediatrics, Hanoi (NHP) in 2004 officially. The NHP in Hanoi provides services to the population of North Vietnam (~30 million people). The aim of this report is to highlight disease spectrum of tandem mass spectrometry (MS/MS) target disease in Vietnam. Methods A total of 2,405 high-risk cases with IEMs were studied at NHP during 10 years [2005-2014]. Dry blood and urine samples were analyzed using MS/MS (amino acid & acylcarnitine analysis) & GC/MS (organic acid anaysis) at Shimane University, Japan from 2005. Organic acids analysis for fresh urine samples was performed at NHP using GC/MS at NHP from 2010. Amino acid analysis for plasma samples were performed using HPLC at NHP from 2012. Results Oganic acidemia (OAs), amino acid disorders (AAs), urea cycle disorders (UCDs) and fatty acid oxidation disorders (FAOD) were identified in 235/2,405 cases (9.8%). A total of 118/235 patients (50.2%) were OAs with 12 different disorders: BKT (33 cases), PPA (21 cases), 5-oxoprolinuria (19 cases), MMA (14 cases), Glutaricaciduria type II (GA II) (11 cases), 3-methylglutaconic aciduria (4 cases), isovaleric academia (3 cases), multiple carboxylase deficiency (MCD) (2 cases), 3-methylcrotonylCoA carboxylase deficiency (2 cases). A total of 42/235 patients (17.9%) were amino acid disorders including 35 cases with MSUD, 7 cases with PKU and 1 case with tyrosinemia type 1. The 36/235 patients (15.3%) were UCDs including OTC deficiency (13 cases), citrulinemia type 1 (1 case) and argininosuccinic aciduria (1 case). 39/235 patients (16

  14. Fatal malonyl CoA decarboxylase deficiency due to maternal uniparental isodisomy of the telomeric end of chromosome 16. (United States)

    Malvagia, S; Papi, L; Morrone, A; Donati, M A; Ciani, F; Pasquini, E; la Marca, G; Scholte, H R; Genuardi, M; Zammarchi, E


    Malonic aciduria is a rare autosomal recessive disorder caused by deficiency of malonyl-CoA decarboxylase, encoded by the MLYCD gene. We report on a patient with clinical presentation in the neonatal period. Metabolic investigations led to a diagnosis of malonyl-CoA decarboxylase deficiency, confirmed by decreased activity in cultured fibroblasts. High doses of carnitine and a diet low in lipids led to a reduction in malonic acid excretion, and to an improvement in his clinical conditions, but at the age of 4 months he died suddenly and unexpectedly. No autopsy was performed. Molecular analysis of the MLYCD gene performed on the proband's RNA and genomic DNA identified a previously undescribed mutation (c.772-775delACTG) which was homozygous. This mutation was present in his mother but not in his father; paternity was confirmed by microsatellite analysis. A hypothesis of maternal uniparental disomy (UPD) was investigated using fourteen microsatellite markers on chromosome 16, and the results confirmed maternal UPD. Maternal isodisomy of the 16q24 region led to homozygosity for the MLYCD mutant allele, causing the patient's disease. These findings are relevant for genetic counselling of couples with a previously affected child, since the recurrence risk in future pregnancies is dramatically reduced by the finding of UPD. In addition, since the patient had none of the clinical manifestations previously associated with maternal UPD 16, this case provides no support for the existence of maternally imprinted genes on chromosome 16 with a major effect on phenotype.

  15. Metabolic disorders with typical alterations in MRI; Stoffwechselstoerungen mit typischen Veraenderungen im MRT

    Energy Technology Data Exchange (ETDEWEB)

    Warmuth-Metz, M. [Klinikum der Universitaet Wuerzburg, Abteilung fuer Neuroradiologie, Wuerzburg (Germany)


    The classification of metabolic disorders according to the etiology is not practical for neuroradiological purposes because the underlying defect does not uniformly transform into morphological characteristics. Therefore typical MR and clinical features of some easily identifiable metabolic disorders are presented. Canavan disease, Pelizaeus-Merzbacher disease, Alexander disease, X-chromosomal adrenoleukodystrophy and adrenomyeloneuropathy, mitochondrial disorders, such as MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and Leigh syndrome as well as L-2-hydroxyglutaric aciduria are presented. (orig.) [German] Die Einteilung von Stoffwechselstoerungen nach ihrer Aetiologie ist fuer den diagnostischen Neuroradiologen nicht sinnvoll, da sich aus der zugrunde liegenden Stoerung keine Rueckschluesse auf die zu erwartende MR-Morphologie ziehen lassen. Deshalb sollen anhand typischer bildmorphologischer Veraenderungen in Zusammenschau mit den jeweiligen klinischen Charakteristika einige leicht einzuordnende Stoffwechselstoerungen dargestellt werden. Es handelt sich um den Morbus Canavan, Morbus Pelizaeus-Merzbacher, Morbus Alexander, die X-chromosomal vererbte Adrenoleukodystrophie und Adrenomyeloneuropathie, die mitochondrialen Stoerungen MELAS (mitochondriale Enzephalomyopathie, Laktazidose und Stroke-like-Episoden) und Leigh-Syndrom sowie die L-2-Hydroxyglutarazidurie. (orig.)

  16. Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. (United States)

    Waisbren, Susan E; Gropman, Andrea L; Batshaw, Mark L


    The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of eight enzyme deficiencies/transporter defects associated with the urea cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN]). There were 678 UCD patients enrolled in 14 sites in the U.S., Canada, and Europe at the writing of this paper. This review summarizes findings of the consortium related to outcome, focusing primarily on neuroimaging findings and neurocognitive function. Neuroimaging studies in late onset OTCD offered evidence that brain injury caused by biochemical dysregulation may impact functional neuroanatomy serving working memory processes, an important component of executive function and regulation. Additionally, there were alteration in white mater microstructure and functional connectivity at rest. Intellectual deficits in OTCD and other urea cycle disorders (UCD) vary. However, when neuropsychological deficits occur, they tend to be more prominent in motor/performance areas on both intelligence tests and other measures. In some disorders, adults performed significantly less well than younger patients. Further longitudinal follow-up will reveal whether this is due to declines throughout life or to improvements in diagnostics (especially newborn screening) and treatments in the younger generation of patients.

  17. Hyper-IgD syndrome with novel mutation in a Japanese girl. (United States)

    Naruto, Takuya; Nakagishi, Yasuo; Mori, Masaaki; Miyamae, Takako; Imagawa, Tomoyuki; Yokota, Shumpei


    Hyperimmunoglobulin D and periodic fever syndrome (HIDS) is an autosomal recessive auto-inflammatory disorder characterized by recurrent febrile attacks with lymphadenopathy, abdominal distress, skin eruptions and joint involvement. We discuss the case of a 15-year-old Japanese girl who had presented with periodic fever, hepatosplenomegaly and intractable diarrhea from seven weeks of age. At first, undifferentiated autoimmune disorder was suspected, and she was treated with prednisolone and, in turn, with immunosuppressants such as cyclosporine, methotrexate, cyclophosphamide and rituximab or with plasma exchange. However, these trials failed to relieve her symptoms, and so she was transferred to our hospital when she was 15 years old. Her parents and elder brother had no history of recurrent fever, prolonged abdominal pain or diarrhea of unknown origin. The patient had extremely elevated levels of mevalonic aciduria and had homozygosity as a novel mutation in the MVK gene (G326R). Finally, HIDS was diagnosed. She was treated with simvastatin, which resulted in a moderate decrease of the urinary mevalonic acid concentration and good clinical course. This is the first case in which homozygosity for the mutation of the MVK gene has been reported in an Asian patient, and indicated a need for differentiation.

  18. Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders?

    Directory of Open Access Journals (Sweden)

    Manuel Schiff

    Full Text Available BACKGROUND: In the investigation of autism spectrum disorders (ASD, a genetic cause is found in approximately 10-20%. Among these cases, the prevalence of the rare inherited metabolic disorders (IMD is unknown and poorly evaluated. An IMD responsible for ASD is usually identified by the associated clinical phenotype such as dysmorphic features, ataxia, microcephaly, epilepsy, and severe intellectual disability (ID. In rare cases, however, ASD may be considered as nonsyndromic at the onset of a related IMD. OBJECTIVES: To evaluate the utility of routine metabolic investigations in nonsyndromic ASD. PATIENTS AND METHODS: We retrospectively analyzed the results of a metabolic workup (urinary mucopolysaccharides, urinary purines and pyrimidines, urinary creatine and guanidinoacetate, urinary organic acids, plasma and urinary amino acids routinely performed in 274 nonsyndromic ASD children. RESULTS: The metabolic parameters were in the normal range for all but 2 patients: one with unspecific creatine urinary excretion and the other with persistent 3-methylglutaconic aciduria. CONCLUSIONS: These data provide the largest ever reported cohort of ASD patients for whom a systematic metabolic workup has been performed; they suggest that such a routine metabolic screening does not contribute to the causative diagnosis of nonsyndromic ASD. They also emphasize that the prevalence of screened IMD in nonsyndromic ASD is probably not higher than in the general population (<0.5%. A careful clinical evaluation is probably more reasonable and of better medical practice than a costly systematic workup.

  19. Papillary thyroid carcinoma shows elevated levels of 2-hydroxyglutarate. (United States)

    Rakheja, Dinesh; Boriack, Richard L; Mitui, Midori; Khokhar, Shama; Holt, Shelby A; Kapur, Payal


    Elevated levels of D: -2-hydroxyglutarate (D: -2-HG) occur in gliomas and myeloid leukemias associated with mutations of IDH1 and IDH2. L: -2-Hydroxyglutaric aciduria, an inherited metabolic disorder, predisposes to brain tumors. Therefore, we asked whether sporadic cancers, without IDH1 or IDH2 hot-spot mutations, show elevated 2-hydroxyglutarate levels. We retrieved 15 pairs of frozen papillary thyroid carcinoma (PTC) and adjacent non-neoplastic thyroid, and 14 pairs of hyperplastic nodule (HN) and adjacent non-hyperplastic thyroid. In all lesions, exon 4 sequencing confirmed the absence of known mutations of IDH1 and IDH2. We measured 2-hydroxyglutarate by liquid chromatography-tandem mass spectrometry. Compared to normal thyroid, PTCs had significantly higher D: -2-HG and L: -2-hydroxyglutarate (L: -2-HG) levels, and compared to HNs, PTCs had significantly higher D: -2-HG levels. D: -2-HG/L: -2-HG levels were not significantly different between HNs and normal thyroid. Further studies should clarify if elevated 2-hydroxyglutarate in PTC may be useful as cancer biomarker and evaluate the role of 2-hydroxyglutarate in cancer biology.

  20. A novel TAZ gene mutation and mosaicism in a Polish family with Barth syndrome. (United States)

    Zapała, Barbara; Płatek, Teresa; Wybrańska, Iwona


    Barth syndrome (BTHS) is an X-linked recessive disease primarily affecting males. Clinically, the disease is characterized by hypertrophic or dilated cardiomyopathy, skeletal myopathy, chronic/cyclic neutropenia, 3-methylglutaconic aciduria, growth retardation and respiratory chain dysfunction. It is caused by mutations in the TAZ gene coding for the tafazzin protein which is responsible for cardiolipin remodeling. In this work, we present a novel pathogenic TAZ mutation c.83T>A, p.Val28Glu, found in mosaic form in almost all female members of a Polish family. Sanger sequencing of DNA from peripheral blood and from epithelial cells showed female mosaicism in three generations. This appears to be a new mechanism of inheritance and further research is required in order to understand the mechanism of this mosaicism. We conclude that BTHS genetic testing should include two or more tissues for women that appear to be noncarriers when blood DNA is initially tested. The results of our study should not only be applicable to BTHS families, but also to families with other X-linked diseases.

  1. Epilepsy due to 20q13.33 subtelomere deletion masquerading as pyridoxine-dependent epilepsy. (United States)

    Mefford, Heather C; Cook, Joseph; Gospe, Sidney M


    A cause of antiepileptic medication resistant seizures presenting in neonates and young infants is pyridoxine-dependent epilepsy (PDE), an organic aciduria, which is due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin. Since the discovery of molecular basis of this disorder, a few patients have been reported with a similar clinical phenotype but without evidence of antiqutin dysfunction. We report on a patient who had carried a clinical diagnosis of PDE for 7 years, but who was than shown to have normal ALDH7A1 sequencing and the absence of biomarkers characteristic of this familial epilepsy. Array comparative genomic hybridization (CGH) demonstrated a 1.5-Mb terminal deletion of the long arm of chromosome 20, which included deletion of the KCNQ2 and CHRNA4 genes, both of which have been associated with specific epilepsy syndromes. We suggest that this boy's neonatal epilepsy and neurodevelopmental disabilities are secondary to this deletion and that his clinical response to pyridoxine was coincidental. This patient's history emphasizes the utility of array CGH in the evaluation of children with epilepsy of unknown etiology.

  2. Late-onset form of beta-electron transfer flavoprotein deficiency

    DEFF Research Database (Denmark)

    Curcoy, A; Olsen, R K J; Ribes, A;


    Multiple acyl-CoA-dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) are a group of metabolic disorders due to deficiency of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO). We report the clinical features...... and biochemical and molecular genetic analyses of a patient with a mild late-onset form of GAII due to beta-ETF deficiency. Biochemical data showed an abnormal urine organic acid profile, low levels of free carnitine, increased levels of C(10:1n-6), and C(14:1n-9) in plasma, and decreased oxidation of [9,10-3H......]palmitate and [9,10-3H]myristate in fibroblasts, suggesting MAD deficiency. In agreement with these findings, mutational analysis of the ETF/ETFDH genes demonstrated an ETFB missense mutation 124T>C in exon 2 leading to replacement of cysteine-42 with arginine (C42R), and a 604_606AAG deletion in exon 6...

  3. A new mouse model of mild ornithine transcarbamylase deficiency (spf-j displays cerebral amino acid perturbations at baseline and upon systemic immune activation.

    Directory of Open Access Journals (Sweden)

    Tatyana N Tarasenko

    Full Text Available Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250 is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In this report, we describe a new animal model of OTCD caused by a spontaneous mutation in the mouse Otc gene (c.240T>A, p.K80N. This transversion in exon 3 of ornithine transcarbamylase leads to normal levels of mRNA with low levels of mature protein and is homologous to a mutation that has also been described in a single patient affected with late-onset OTCD. With higher residual enzyme activity, spf-J were found to have normal plasma ammonia and orotate. Baseline plasma amino acid profiles were consistent with mild OTCD: elevated glutamine, and lower citrulline and arginine. In contrast to WT, spf-J displayed baseline elevations in cerebral amino acids with depletion following immune challenge with polyinosinic:polycytidylic acid. Our results indicate that the mild spf-J mutation constitutes a new mouse model that is suitable for mechanistic studies of mild OTCD and the exploration of cerebral pathophysiology during acute decompensation that characterizes proximal urea cycle dysfunction in humans.

  4. Metabolic, endocrine, and other genetic disorders. (United States)

    Dahmoush, Hisham M; Melhem, Elias R; Vossough, Arastoo


    Metabolic, endocrine, and genetic diseases of the brain include a very large array of disorders caused by a wide range of underlying abnormalities and involving a variety of brain structures. Often these disorders manifest as recognizable, though sometimes overlapping, patterns on neuroimaging studies that may enable a diagnosis based on imaging or may alternatively provide enough clues to direct further diagnostic evaluation. The diagnostic workup can include various biochemical laboratory or genetic studies. In this chapter, after a brief review of normal white-matter development, we will describe a variety of leukodystrophies resulting from metabolic disorders involving the brain, including mitochondrial and respiratory chain diseases. We will then describe various acidurias, urea cycle disorders, disorders related to copper and iron metabolism, and disorders of ganglioside and mucopolysaccharide metabolism. Lastly, various other hypomyelinating and dysmyelinating leukodystrophies, including vanishing white-matter disease, megalencephalic leukoencephalopathy with subcortical cysts, and oculocerebrorenal syndrome will be presented. In the following section on endocrine disorders, we will examine various disorders of the hypothalamic-pituitary axis, including developmental, inflammatory, and neoplastic diseases. Neonatal hypoglycemia will also be briefly reviewed. In the final section, we will review a few of the common genetic phakomatoses. Throughout the text, both imaging and brief clinical features of the various disorders will be discussed.

  5. Diffusion-weighted MR imaging in leukodystrophies

    Energy Technology Data Exchange (ETDEWEB)

    Patay, Zoltan [King Faisal Specialist Hospital and Research Centre, Department of Radiology, Riyadh (Saudi Arabia)


    Leukodystrophies are genetically determined metabolic diseases, in which the underlying biochemical abnormality interferes with the normal build-up and/or maintenance of myelin, which leads to hypo- (or arrested) myelination, or dysmyelination with resultant demyelination. Although conventional magnetic resonance imaging has significantly contributed to recent progress in the diagnostic work-up of these diseases, diffusion-weighted imaging has the potential to further improve our understanding of underlying pathological processes and their dynamics through the assessment of normal and abnormal diffusion properties of cerebral white matter. Evaluation of conventional diffusion-weighted and ADC map images allows the detection of major diffusion abnormalities and the identification of various edema types, of which the so-called myelin edema is particularly relevant to leukodystrophies. Depending on the nature of histopathological changes, stage and progression gradient of diseases, various diffusion-weighted imaging patterns may be seen in leukodystrophies. Absent or low-grade myelin edema is found in mucopolysaccharidoses, GM gangliosidoses, Zellweger disease, adrenomyeloneuropathy, L-2-hydroxyglutaric aciduria, non-ketotic hyperglycinemia, classical phenylketonuria, Van der Knaap disease and the vanishing white matter, medium grade myelin edema in metachromatic leukodystrophy, X-linked adrenoleukodystrophy and HMG coenzyme lyase deficiency and high grade edema in Krabbe disease, Canavan disease, hyperhomocystinemias, maple syrup urine disease and leukodystrophy with brainstem and spinal cord involvement and high lactate. (orig.)

  6. The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. (United States)

    Molenaar, Remco J; Radivoyevitch, Tomas; Maciejewski, Jaroslaw P; van Noorden, Cornelis J F; Bleeker, Fonnet E


    Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key events in the development of glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (ICC), and angioimmunoblastic T-cell lymphoma. They also cause D-2-hydroxyglutaric aciduria and Ollier and Maffucci syndromes. IDH1/2 mutations are associated with prolonged survival in glioma and in ICC, but not in AML. The reason for this is unknown. In their wild-type forms, IDH1 and IDH2 convert isocitrate and NADP(+) to α-ketoglutarate (αKG) and NADPH. Missense mutations in the active sites of these enzymes induce a neo-enzymatic reaction wherein NADPH reduces αKG to D-2-hydroxyglutarate (D-2HG). The resulting D-2HG accumulation leads to hypoxia-inducible factor 1α degradation, and changes in epigenetics and extracellular matrix homeostasis. Such mutations also imply less NADPH production capacity. Each of these effects could play a role in cancer formation. Here, we provide an overview of the literature and discuss which downstream molecular effects are likely to be the drivers of the oncogenic and survival-prolonging properties of IDH1/2 mutations. We discuss interactions between mutant IDH1/2 inhibitors and conventional therapies. Understanding of the biochemical consequences of IDH1/2 mutations in oncogenesis and survival prolongation will yield valuable information for rational therapy design: it will tell us which oncogenic processes should be blocked and which "survivalogenic" effects should be retained.

  7. Metabolic encephalopathy and lipid storage myopathy associated with a presumptive mitochondrial fatty acid oxidation defect in a dog

    Directory of Open Access Journals (Sweden)

    Vanessa R Biegen


    Full Text Available A 1-year-old spayed female Shih Tzu presented for episodic abnormalities of posture and mentation. Neurologic examination was consistent with a bilaterally symmetric multifocal encephalopathy. The dog had a waxing-and-waning hyperlactemia and hypoglycemia. Magnetic resonance imaging revealed bilaterally symmetric cavitated lesions of the caudate nuclei with less severe abnormalities in the cerebellar nuclei. Empirical therapy was unsuccessful and the patient was euthanized. Post-mortem histopathology revealed bilaterally symmetric necrotic lesions of the caudate and cerebellar nuclei and multi-organ lipid accumulation, including a lipid storage myopathy. Malonic aciduria and ketonuria were found on urinary organic acid screen. Plasma acylcarnitine analysis suggested a fatty acid oxidation defect. Fatty acid oxidation disorders are inborn errors of metabolism documented in humans, but poorly described in dogs. Although neurologic signs have been described in humans with this group of diseases, descriptions of advanced imaging and histopathology are severely lacking. This report suggests that abnormalities of fatty acid metabolism may cause severe, bilateral gray matter necrosis and lipid accumulation in multiple organs including the skeletal muscles, liver, and kidneys. Veterinarians should be aware that fatty acid oxidation disorders, although potentially fatal, may be treatable. A timely definitive diagnosis is essential in guiding therapy.

  8. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. (United States)

    Moorthie, Sowmiya; Cameron, Louise; Sagoo, Gurdeep S; Bonham, Jim R; Burton, Hilary


    Many newborn screening programmes now use tandem mass spectrometry in order to screen for a variety of diseases. However, countries have embraced this technology with a differing pace of change and for different conditions. This has been facilitated by the ability of this diagnostic method to limit analysis to specific metabolites of interest, enabling targeted screening for particular conditions. MS/MS was introduced in 2009 in England to implement newborn bloodspot screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) raising the possibility of screening for other inherited metabolic disorders. Recently, a pilot screening programme was conducted in order to evaluate the health and economic consequences of screening for five additional inherited metabolic disorders in England. As part of this study we conducted a systematic review and meta-analysis to estimate the birth prevalence of these conditions: maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidaemia and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency. We identified a total of 99 studies that were able to provide information on the prevalence of one or more of the disorders. The vast majority of studies were of screening programmes with some reporting on clinically detected cases.

  9. Inhibition of creatine kinase activity from rat cerebral cortex by D-2-hydroxyglutaric acid in vitro. (United States)

    da Silva, Cleide G; Bueno, Ana Rúbia F; Schuck, Patrícia F; Leipnitz, Guilhian; Ribeiro, César A J; Rosa, Rafael B; Dutra Filho, Carlos S; Wyse, Angela T S; Wannmacher, Clóvis M D; Wajner, Moacir


    D-2-Hydroxyglutaric acid (DGA) is the biochemical hallmark of patients affected by the neurometabolic disorder known as D-2-hydroxyglutaric aciduria (DHGA). Although this disease is predominantly characterized by severe neurological findings, the underlying mechanisms of brain injury are virtually unknown. In the present study, we investigated the effect of DGA on total, cytosolic, and mitochondrial creatine kinase (CK) activities from cerebral cortex of 30-day-old Wistar rats. Total CK activity (tCK) was measured in whole cell homogenates, whereas cytosolic and mitochondrial activities were measured in the cytosolic and mitochondrial preparations from cerebral cortex. We verified that CK activities were significantly inhibited by DGA (11-34% inhibition) at concentrations as low as 0.25 mM, being the mitochondrial fraction the most affected activity. Kinetic studies revealed that the inhibitory effect of DGA was non-competitive in relation to phosphocreatine. We also observed that this inhibition was fully prevented by pre-incubation of the homogenates with reduced glutathione, suggesting that the inhibitory effect of DGA on tCK activity is possibly mediated by oxidation of essential thiol groups of the enzyme. Considering the importance of CK activity for brain metabolism homeostasis, our results suggest that inhibition of this enzyme by increased levels of DGA may be related to the neurodegeneration of patients affected by DHGA.

  10. Diagnostic value of proton MR spectroscopy and diffusion-weighted MR imaging in childhood inherited neurometabolic brain diseases and review of the literature

    Energy Technology Data Exchange (ETDEWEB)

    Cakmakci, Handan, E-mail: [Dokuz Eylul University Faculty of Medicine, Department of Radiology, Izmir (Turkey); Pekcevik, Yeliz [Dokuz Eylul University Faculty of Medicine, Department of Radiology, Izmir (Turkey); Yis, Uluc [Dokuz Eylul University Faculty of Medicine, Department of Pediatric Neurology, Izmir (Turkey); Unalp, Aycan [Behcet Uz Hospital, Department of Pediatric Neurology, Izmir (Turkey); Kurul, Semra [Dokuz Eylul University Faculty of Medicine, Department of Pediatric Neurology, Izmir (Turkey)


    The purpose of this study is to evaluate parenchymal diffusion properties and metabolite ratios in affected brain tissues of inherited neurometabolic brain diseases with an overview of the current literature about the diagnostic data of both techniques in childhood inherited metabolic brain diseases. The study group was consisting, 19 patients (15 males, 4 females; mean age, 54 months (4.5 years); age range, 1-171 months (14.25 years)) diagnosed with inherited neurometabolic brain disease. Single- and multivoxel proton MRS was carried out and NAA/Cr, Cho/Cr, mI/Cr, Glx/Cr ratios were calculated. Presence of lactate peak and abnormal different peaks were noted. ADC values were calculated from brain lesions. Results are compared with age and sex matched normal subjects. Elevated NAA/Cr ratio (Canavan disease), galactitol peak (galactosemia) at 3.7 ppm, branched chain amino acids (Maple syrup urine disease-MSUD) at 0.9 ppm were seen on different diseases. In Leigh disease and MSUD restricted diffusion was detected. Different diffusion properties were seen only in one Glutaric aciduria lesions. NAA/Cr ratios and calculated ADC values were significantly different from normal subjects (p < 0.05). DWI combined with MRS are complementary methods to routine cranial MRI for evaluating neurometabolic diseases which can give detailed information about neurochemistry of affected brain areas.

  11. 3-Methylglutaconyl-Coenzyme-A Hydratase Deficiency and the Development of Dilated Cardiomyopathy (United States)

    Spergel, Craig D.; Milko, Mariya; Edwards, Christopher; Steinhoff, Jeff P.


    A 25-year-old Canadian male with a history of 3-methylglutaconyl-coenzyme-A hydratase deficiency, also known as 3-methylglutaconic aciduria type I, a very rare inborn error of metabolism, presented with respiratory distress, nausea, vomiting and signs of multisystem organ failure due to a suspected underlying infectious process. An electrocardiogram revealed bilateral atrial enlargement and an elevated brain natriuretic peptide on the initial laboratory studies, which prompted a more thorough cardiac workup. The transthoracic echocardiogram revealed a dilated cardiomyopathy with severe systolic dysfunction. The deficient enzyme present in this patient is involved in the pathway of leucine catabolism and is particularly important in various tissues for energy production and sterol synthesis. The dilated cardiomyopathy in this patient possibly had a variety of potential mechanisms including: a mitochondrial myopathy due to the deficiency of this enzyme leading to a defect in energy production inside cardiac myocytes; or a direct toxicity from 3-methylglutaconic acid (3-MGA) and its toxic metabolites; or a cardiac dysfunction due to a variety of other potential mechanisms. In conclusion, this patient’s clinical presentation suggested that 3-methylglutaconyl-CoA hydratase deficiency could cause a severe dilated cardiomyopathy and heart failure.

  12. [Metabolic disorders in epilepsy of early childhood]. (United States)

    Holub, V; Týnová, L; Saxl, O; Podhradská, O; Mrskos, A


    Metabolic disorders are discussed which are associated with the pathophysiological mechanisms of the origin of convulsions. Homeostasis impairment, e. g. hyponatremia, hypo- and hyperkalemia, hypocalcemia is mentioned, as well as vitamin deficiencies, such as pyridoxin deficiency, and the problem of phenylketonuria is discussed in connection with aminoacid disorders. Possible connections between aminoacid disorders and BNS, occurring in 8.1% of 1,688 children treated for epilepsy at the neurological department of the Brno Faculty Children's Hospital, are further discussed. Results of screening for amino-aciduria (according to Berry's method) were negative in 3000 healthy infants, whereas careful investigation resulted in pathologic aminoaciduria in 17 out of 20 children with BNS. Also results of hormonal treatment in children with this sort of convulsions are reported. It is concluded that early therapy, even though incapable of influencing neurological abnormities, suppresses convulsions and may lead to the disappearance of hypsarythmia from the EEG curve. A benign influence upon mental development was observed in a small group of children in whom therapy had been initiated very early. It is emphasized that this, by no means indifferent, type of therapy should only be performed in a well equipped and managed pediatric department.

  13. Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients

    Directory of Open Access Journals (Sweden)

    Grünert Sarah C


    Full Text Available Abstract Background Propionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited. Study design/methods Clinical and outcome data of 55 patients with propionic acidemia from 16 European metabolic centers were evaluated retrospectively. 35 patients were diagnosed by selective metabolic screening while 20 patients were identified by newborn screening. Endocrine parameters and bone age were evaluated. In addition, IQ testing was performed and the patients’ and their families’ quality of life was assessed. Results The vast majority of patients (>85% presented with metabolic decompensation in the neonatal period. Asymptomatic individuals were the exception. About three quarters of the study population was mentally retarded, median IQ was 55. Apart from neurologic symptoms, complications comprised hematologic abnormalities, cardiac diseases, feeding problems and impaired growth. Most patients considered their quality of life high. However, according to the parents’ point of view psychic problems were four times more common in propionic acidemia patients than in healthy controls. Conclusion Our data show that the outcome of propionic acidemia is still unfavourable, in spite of improved clinical management. Many patients develop long-term complications affecting different organ systems. Impairment of neurocognitive development is of special concern. Nevertheless, self-assessment of quality of life of the patients and their parents yielded rather positive results.

  14. The role of carnitine in the perinatal period. (United States)

    Kępka, Alina; Chojnowska, Sylwia; Okungbowa, Osazee E; Zwierz, Krzysztof


    Carnitine (2-hydroxy-4-trimethylammonium butyrate, vitamin BT) is a small hydrophilic molecule derived from protein-bound lysine, not degraded in the body but excreted via urine, bile and breast milk. Carnitine stimulates the catabolism of long-chain fatty acids (FAs), by transporting them to mitochondria for oxidation, and the intracellular decomposition of branched-chain ketoacids. It also helps to excrete toxic exogenous and nontoxic endogenous organic acids via urine. It further participates in the production of pulmonary surfactant, inhibits free radicals production and demonstrates other antioxidant properties. After delivery, infants dramatically increase energy demands for movement, growth, differentiation and maintenance of the body temperature that strongly depend on FAs oxidation which is facilitated by carnitine. At early stages of life, carnitine biosynthesis is less efficient than in adults and immature infants have less carnitine tissue reserves than term infants. Carnitine supplementation is recommended in newborns with aciduria, childhood epilepsy associated with valproate-induced hepatotoxicity, in kidney-associated syndromes, and premature infants receiving total parenteral nutrition. Concentrations of carnitine and acylcarnitines in neonatal blood have been postulated a useful tool for the diagnosis of type 1 diabetes, as well as the detection and monitoring of many inherited and acquired metabolic disorders. Taking into account the complex metabolic role of cellular FAs transporters, further studies are needed on indications and contraindications for carnitine supplementation in different clinical settings during early developmental period.

  15. Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. (United States)

    Casals, Núria; Gómez-Puertas, Paulino; Pié, Juan; Mir, Cecilia; Roca, Ramón; Puisac, Beatriz; Aledo, Rosa; Clotet, Josep; Menao, Sebastián; Serra, Dolors; Asins, Guillermina; Till, Jacqueline; Elias-Jones, Alun C; Cresto, Juan C; Chamoles, Nestor A; Abdenur, Jose E; Mayatepek, Ertan; Besley, Guy; Valencia, Alfonso; Hegardt, Fausto G


    This study describes three novel homozygous missense mutations (S75R, S201Y, and D204N) in the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase gene, which caused 3-hydroxy-3-methylglutaric aciduria in patients from Germany, England, and Argentina. Expression studies in Escherichia coli show that S75R and S201Y substitutions completely abolished the HMG-CoA lyase activity, whereas D204N reduced catalytic efficiency to 6.6% of the wild type. We also propose a three-dimensional model for human HMG-CoA lyase containing a (betaalpha)8 (TIM) barrel structure. The model is supported by the similarity with analogous TIM barrel structures of functionally related proteins, by the localization of catalytic amino acids at the active site, and by the coincidence between the shape of the substrate (HMG-CoA) and the predicted inner cavity. The three novel mutations explain the lack of HMG-CoA lyase activity on the basis of the proposed structure: in S75R and S201Y because the new amino acid residues occlude the substrate cavity, and in D204N because the mutation alters the electrochemical environment of the active site. We also report the localization of all missense mutations reported to date and show that these mutations are located in the beta-sheets around the substrate cavity.

  16. Differential diagnosis of (inherited) amino acid metabolism or transport disorders. (United States)

    Blom, W; Huijmans, J G


    Disorders of amino acid metabolism or transport are most clearly expressed in urine. Nevertheless the interpretation of abnormalities in urinary amino acid excretion remains difficult. An increase or decrease of almost every amino acid in urine can be due to various etiology. To differentiate between primary and secondary aminoacido-pathies systematic laboratory investigation is necessary. Early diagnosis of disorders of amino acid metabolism or transport is very important, because most of them can be treated, leading to the prevention of (further) clinical abnormalities. In those disorders, which cannot be treated, early diagnosis in an index-patient may prevent the birth of other siblings by means of genetic counseling and prenatal diagnosis.Primary aminoacidopathies can be due to genetically determined transport disorders and enzyme deficiencies in amino acid metabolism or degradation. Secondary aminoacidopathies are the result of abnormal or deficient nutrition, intestinal dysfunction, organ pathology or other metabolic diseases like organic acidurias.A survey of amino acid metabolism and transport abnormalities will be given, illustrated with metabolic pathways and characteristic abnormal amino acid chromatograms.

  17. Lovastatin-induced apoptosis is modulated by geranylgeraniol in a neuroblastoma cell line. (United States)

    Marcuzzi, Annalisa; Zanin, Valentina; Piscianz, Elisa; Tricarico, Paola Maura; Vuch, Josef; Girardelli, Martina; Monasta, Lorenzo; Bianco, Anna Monica; Crovella, Sergio


    Mevalonic aciduria (MA), the most severe form of mevalonate kinase deficiency (MKD), is still an orphan drug disease and the pathogenetic mechanisms underlying neuronal dysfunction is still poorly understood. In our study we have investigated the apoptotic mechanism mediated by the exposure of the cultured neuroblastoma cell line, SH-SY5Y, to lovastatin in absence or in presence of the isoprenoid, geranylgeraniol, with the aim of unraveling the pathogenesis of MA. Lovastatin, blocks the mevalonate pathway inhibiting the 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR), an enzyme of the mevalonate pathway upstream the mevalonate kinase enzyme, reproducing biochemical features similar to those found in MKD. We demonstrate that apoptosis in neuronal lovastatin treated-cells is induced by the mitochondrial pathway, with caspase-9 as the initiator and caspase-3 as the effector caspase. The presence of geranylgeraniol modulates both the caspase-9 and caspase-3 activity in a dose-dependent way, confirming that this isoprenoid enters the mevalonate pathway, is metabolized and finally is able to by-pass the statin biochemical block reconstituting the mevalonate pathway. According to our findings, it should not be the time course adopted that modulates the apoptotic response but rather the isoprenoid itself. Being aware that our results have been obtained using a biochemical model of MKD, and not cells from patients with the disease, we believe our findings increase the knowledge of MA pathogenesis, and may possibly contribute to the development of novel therapeutic strategies.

  18. Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy. (United States)

    Ikon, Nikita; Ryan, Robert O


    The Barth syndrome (BTHS) is caused by an inborn error of metabolism that manifests characteristic phenotypic features including altered mitochondrial membrane phospholipids, lactic acidosis, organic acid-uria, skeletal muscle weakness and cardiomyopathy. The underlying cause of BTHS has been definitively traced to mutations in the tafazzin (TAZ) gene locus on chromosome X. TAZ encodes a phospholipid transacylase that promotes cardiolipin acyl chain remodeling. Absence of tafazzin activity results in cardiolipin molecular species heterogeneity, increased levels of monolysocardiolipin and lower cardiolipin abundance. In skeletal muscle and cardiac tissue mitochondria these alterations in cardiolipin perturb the inner membrane, compromising electron transport chain function and aerobic respiration. Decreased electron flow from fuel metabolism via NADH ubiquinone oxidoreductase activity leads to a buildup of NADH in the matrix space and product inhibition of key TCA cycle enzymes. As TCA cycle activity slows pyruvate generated by glycolysis is diverted to lactic acid. In turn, Cori cycle activity increases to supply muscle with glucose for continued ATP production. Acetyl CoA that is unable to enter the TCA cycle is diverted to organic acid waste products that are excreted in urine. Overall, reduced ATP production efficiency in BTHS is exacerbated under conditions of increased energy demand. Prolonged deficiency in ATP production capacity underlies cell and tissue pathology that ultimately is manifest as dilated cardiomyopathy.

  19. Ataxia-telangiectasia. (Clinical and immunological aspects). (United States)

    Boder, E; Sedgwick, R P


    This syndrome was defined by the authors in 1947. Earlier publications of similar disease descriptions were by Syllaba and Henner (1926), Louis-Bar (1941). The authors at present have a stock of 253 cases. The cardinal symptoms of this phakomatosis are: Cerebellar ataxia which begin in infancy and take a slowly progressive course. In the late stages free walking and standing are no longer possible. Progressive atactic speech disorders, cerebellar atrophy in the pneumoencephalogram. Slowly progressing symmetrical skin and mucosal telangiectasia in the face and especially on the conjunctivae at the age of 3 to 6 years. Relapsing sinopulmonary infections with a tendency toward the development of bronchiectases. Apraxia of eye movements. Atrophy of facial skin and premature graying of hair. Recessively hereditary disorder with a high familial manifestation. This syndrome combines the spinocerebellar degeneration, phakomatoses, and infantile dementia processes. Such other conditions as abnormity or absence of thymus, reduction in gamma globulins, amino-aciduria, autosomal-recessive inheritance suggest a genetically determined "error of metabolism".

  20. Late-onset form of beta-electron transfer flavoprotein deficiency. (United States)

    Curcoy, A; Olsen, R K J; Ribes, A; Trenchs, V; Vilaseca, M A; Campistol, J; Osorio, J H; Andresen, B S; Gregersen, N


    Multiple acyl-CoA-dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) are a group of metabolic disorders due to deficiency of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO). We report the clinical features and biochemical and molecular genetic analyses of a patient with a mild late-onset form of GAII due to beta-ETF deficiency. Biochemical data showed an abnormal urine organic acid profile, low levels of free carnitine, increased levels of C(10:1n-6), and C(14:1n-9) in plasma, and decreased oxidation of [9,10-3H]palmitate and [9,10-3H]myristate in fibroblasts, suggesting MAD deficiency. In agreement with these findings, mutational analysis of the ETF/ETFDH genes demonstrated an ETFB missense mutation 124T>C in exon 2 leading to replacement of cysteine-42 with arginine (C42R), and a 604_606AAG deletion in exon 6 in the ETFB gene resulting in the deletion of lysine-202 (K202del). The present report delineates further the phenotype of mild beta-ETF deficiency and illustrates that the differential diagnosis of GAII is readily achieved by mutational analysis.

  1. Newborn screening with tandem mass spectrometry: 12 months' experience in NSW Australia. (United States)

    Wiley, V; Carpenter, K; Wilcken, B


    Since 1998, the NSW Newborn Screening Program has used electrospray tandem mass spectrometry (MS/MS) to analyse samples from all babies born in NSW and the ACT (approximately 95000 per year) for selected amino acids and acylcarnitines. The software rules editor initially interprets all results where ratio of analyte to internal standard is modified by input from the external standard curves per analyte. The numerical results are then downloaded to the NSW Newborn Screening database, which provides automatic, analyte specific follow-up test cascade. We have analysed samples from 137 120 consecutive newborns received by the program, requested repeat samples from 122 babies, and found abnormal levels in 17 babies with phenylketonuria, 1 tetrahydrobiopterin deficiency, 3 hyperphenylalaninaemia, 1 maple syrup urine disease, 1 tyrosinaemia type II, 1 congenital lactic acidosis, 2 medium-chain acyl CoA dehydrogenase deficiency, 1 short-chain acyl CoA dehydrogenase deficiency, 1 beta-ketothiolase deficiency, 2 vitamin B12 deficient babies of vegan mothers and 1 glutaric aciduria type I. Using population data plus that obtained from retrospective samples with proven disorders we have established cut-off levels for each analyte tested. This coupled with the ability of the database to provide ratios of various analytes gives excellent screening specificity and sensitivity for the detection of at least 40 rare inborn errors of metabolism.

  2. Approach to a case of myeloneuropathy

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    Ravindra Kumar Garg


    Full Text Available Myeloneuropathy is a frequently encountered condition and often poses a diagnostic challenge. A variety of nutritional, toxic, metabolic, infective, inflammatory, and paraneoplastic disorders can present with myeloneuropathy. Deficiencies of vitamin B12, folic acid, copper, and vitamin E may lead to myeloneuropathy with a clinical picture of subacute combined degeneration of the spinal cord. Among infective causes, chikungunya virus has been shown to produce a syndrome similar to myeloneuropathy. Vacuolar myelopathy seen in human immunodeficiency virus (HIV infection is clinically very similar to subacute combined degeneration. A paraneoplastic myeloneuropathy, an immune-mediated disorder associated with an underlying malignancy, may rarely be seen with breast cancer. Tropical myeloneuropathies are classified into two overlapping clinical entities — tropical ataxic neuropathy and tropical spastic paraparesis. Tropical spastic paraparesis, a chronic noncompressive myelopathy, has frequently been reported from South India. Establishing the correct diagnosis of myeloneuropathy is important because compressive myelopathies may pose diagnostic confusion. Magnetic resonance imaging (MRI in subacute combined degeneration of the spinal cord typically reveals characteristic signal changes on T2-weighted images of the cervical spinal cord. Once the presence of myeloneuropathy is established, all these patients should be subjected to a battery of tests. Blood levels of vitamin B12, folic acid, vitamins A, D, E, and K, along with levels of iron, methylmalonic acid, homocysteine, and calcium should be assessed. The pattern of neurologic involvement and results obtained from a battery of biochemical tests often help in establishing the correct diagnosis.

  3. Deep vein thrombosis, an unreported first manifestation of polyglandular autoimmune syndrome type III

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    M Horsey


    Full Text Available A 71-year-old woman with severe right lower leg pain, edema and erythema was presented to the Emergency Department and was found to have an extensive deep vein thrombosis (DVT confirmed by ultrasound. She underwent an extensive evaluation due to her prior history of malignancy and new hypercoagulable state, but no evidence of recurrent disease was detected. Further investigation revealed pernicious anemia (PA, confirmed by the presence of a macrocytic anemia (MCV=115.8fL/red cell, Hgb=9.0g/dL, decreased serum B12 levels (56pg/mL, with resultant increased methylmalonic acid (5303nmol/L and hyperhomocysteinemia (131μmol/L, the presumed etiology of the DVT. The patient also suffered from autoimmune thyroid disease (AITD, and both antithyroglobulin and anti-intrinsic factor antibodies were detected. She responded briskly to anticoagulation with heparin and coumadin and treatment of PA with intramuscular vitamin B12 injections. Our case suggests that a DVT secondary to hyperhomocystenemia may represent the first sign of polyglandular autoimmune syndrome III-B (PAS III-B, defined as the coexistent autoimmune conditions AITD and PA. It is important to recognize this clinical entity, as patients may not only require acute treatment with vitamin B12 supplementation and prolonged anticoagulation, as in this patient, but may also harbor other autoimmune diseases.

  4. Association of Transcobalamin II (TCN2) and Transcobalamin II-Receptor (TCblR) Genetic Variations With Cobalamin Deficiency Parameters in Elderly Women. (United States)

    Kurnat-Thoma, Emma L; Pangilinan, Faith; Matteini, Amy M; Wong, Bob; Pepper, Ginette A; Stabler, Sally P; Guralnik, Jack M; Brody, Lawrence C


    Cobalamin (vitamin B12) deficiency is a subtle progressive clinical disorder, affecting nearly 1 in 5 individuals > 60 years old. This deficiency is produced by age-related decreases in nutrient absorption, medications that interfere with vitamin B12 absorption, and other comorbidities. Clinical heterogeneity confounds symptom detection for elderly adults, as deficiency sequelae range from mild fatigue and weakness to debilitating megaloblastic anemia and permanent neuropathic injury. A better understanding of genetic factors that contribute to cobalamin deficiency in the elderly would allow for targeted nursing care and preventive interventions. We tested for associations of common variants in genes involved in cobalamin transport and homeostasis with metabolic indicators of cobalamin deficiency (homocysteine and methylmalonic acid) as well as hematologic, neurologic, and functional performance features of cobalamin deficiency in 789 participants of the Women's Health and Aging Studies. Although not significant when corrected for multiple testing, eight single nucleotide polymorphisms (SNPs) in two genes, transcobalamin II (TCN2) and the transcobalamin II-receptor (TCblR), were found to influence several clinical traits of cobalamin deficiency. The three most significant findings were the identified associations involving missense coding SNPs, namely, TCblR G220R (rs2336573) with serum cobalamin, TCN2 S348F (rs9621049) with homocysteine, and TCN2 P259R (rs1801198) with red blood cell mean corpuscular volume. These SNPs may modify the phenotype in older adults who are more likely to develop symptoms of vitamin B12 malabsorption.

  5. Nutritional Intake and Status of Cobalamin and Folate among Non-Pregnant Women of Reproductive Age in Bhaktapur, Nepal

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    Ram K. Chandyo


    Full Text Available Cobalamin and folate are especially important for women of childbearing age due to their ubiquitous role in fetal growth and development. Population-based data on cobalamin and folate status are lacking from Nepal, where diets are mostly vegetarian. The objectives of the study were to investigate cobalamin and folate intake and status, and to explore associations with socio-demographics, anthropometrics, anemia, and dietary habits. Following a random selection of geographical clusters, we collected blood samples from 500 non-pregnant women and 24-h dietary recalls and food frequency questionnaires from a subsample of 379 women. Twenty percent of the women did not consume any food containing cobalamin during the days recalled, and in 72% nutritional cobalamin intake was <1 μg/day. Eighty-four percent of the women had cobalamin intake lower than the estimated average requirement (EAR (<2 μg/day. In contrast, only 12% of the women had a folate intake less than 100 μg per day, whereas 62% had intake between 100 and 320 μg. Low plasma cobalamin (<150 pmol/L was found in 42% of the women, most of whom (88% also had elevated levels of methylmalonic acid. Our results indicated a high prevalence of nutritional cobalamin deficiency, while folate deficiency was uncommon.

  6. Impact of Pre-Pregnancy BMI on B Vitamin and Inflammatory Status in Early Pregnancy: An Observational Cohort Study

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    Anne-Lise Bjørke-Monsen


    Full Text Available Maternal nutrition and inflammation have been suggested as mediators in the development of various adverse pregnancy outcomes associated with maternal obesity. We have investigated the relation between pre-pregnancy BMI, B vitamin status, and inflammatory markers in a group of healthy pregnant women. Cobalamin, folate, pyridoxal 5′-phosphate, and riboflavin; and the metabolic markers homocysteine, methylmalonic acid, and 3-hydroxykynurenine/xanthurenic acid ratio (HK/XA; and markers of cellular inflammation, neopterin and kynurenine/tryptophan ratio (KTR were determined in pregnancy week 18 and related to pre-pregnancy body mass index (BMI, in 2797 women from the Norwegian Mother and Child Cohort Study (MoBa. Pre-pregnancy BMI was inversely related to folate, cobalamin, pyridoxal 5′-phosphate (PLP, and riboflavin (p < 0.001, and associated with increased neopterin and KTR levels (p < 0.001. Inflammation seemed to be an independent predictor of low vitamin B6 status, as verified by low PLP and high HK/XA ratio. A high pre-pregnancy BMI is a risk factor for low B vitamin status and increased cellular inflammation. As an optimal micronutrient status is vital for normal fetal development, the observed lower B vitamin levels may contribute to adverse pregnancy outcomes associated with maternal obesity and B vitamin status should be assessed in women with high BMI before they get pregnant.

  7. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. (United States)

    Tuchman, Mendel; Caldovic, Ljubica; Daikhin, Yevgeny; Horyn, Oksana; Nissim, Ilana; Nissim, Itzhak; Korson, Mark; Burton, Barbara; Yudkoff, Marc


    N-acetylglutamate (NAG) is an endogenous essential cofactor for conversion of ammonia to urea in the liver. Deficiency of NAG causes hyperammonemia and occurs because of inherited deficiency of its producing enzyme, NAG synthase (NAGS), or interference with its function by short fatty acid derivatives. N-carbamylglutamate (NCG) can ameliorate hyperammonemia from NAGS deficiency and propionic and methylmalonic acidemia. We developed a stable isotope (13)C tracer method to measure ureagenesis and to evaluate the effect of NCG in humans. Seventeen healthy adults were investigated for the incorporation of (13)C label into urea. [(13)C]urea appeared in the blood within minutes, reaching maximum by 100 min, whereas breath (13)CO(2) reached a maximum by 60 min. A patient with NAGS deficiency showed very little urea labeling before treatment with NCG and normal labeling thereafter. Correspondingly, plasma levels of ammonia and glutamine decreased markedly and urea tripled after NCG treatment. Similarly, in a patient with propionic acidemia, NCG treatment resulted in a marked increase in urea labeling and decrease in glutamine, alanine, and glycine. These results provide a reliable method for measuring the effect of NCG on nitrogen metabolism and strongly suggest that NCG could be an effective treatment for inherited and secondary NAGS deficiency.

  8. Compartmentation of Metabolism of the C12-, C9-, and C5-n-dicarboxylates in Rat Liver, Investigated by Mass Isotopomer Analysis (United States)

    Jin, Zhicheng; Bian, Fang; Tomcik, Kristyen; Kelleher, Joanne K.; Zhang, Guo-Fang; Brunengraber, Henri


    We investigated the compartmentation of the catabolism of dodecanedioate (DODA), azelate, and glutarate in perfused rat livers, using a combination of metabolomics and mass isotopomer analyses. Livers were perfused with recirculating or nonrecirculating buffer containing one fully 13C-labeled dicarboxylate. Information on the peroxisomal versus mitochondrial catabolism was gathered from the labeling patterns of acetyl-CoA proxies, i.e. total acetyl-CoA, the acetyl moiety of citrate, C-1 + 2 of β-hydroxybutyrate, malonyl-CoA, and acetylcarnitine. Additional information was obtained from the labeling patterns of citric acid cycle intermediates and related compounds. The data characterize the partial oxidation of DODA and azelate in peroxisomes, with terminal oxidation in mitochondria. We did not find evidence of peroxisomal oxidation of glutarate. Unexpectedly, DODA contributes a substantial fraction to anaplerosis of the citric acid cycle. This opens the possibility to use water-soluble DODA in nutritional or pharmacological anaplerotic therapy when other anaplerotic substrates are impractical or contraindicated, e.g. in propionic acidemia and methylmalonic acidemia. PMID:26070565

  9. Compartmentation of Metabolism of the C12-, C9-, and C5-n-dicarboxylates in Rat Liver, Investigated by Mass Isotopomer Analysis: ANAPLEROSIS FROM DODECANEDIOATE. (United States)

    Jin, Zhicheng; Bian, Fang; Tomcik, Kristyen; Kelleher, Joanne K; Zhang, Guo-Fang; Brunengraber, Henri


    We investigated the compartmentation of the catabolism of dodecanedioate (DODA), azelate, and glutarate in perfused rat livers, using a combination of metabolomics and mass isotopomer analyses. Livers were perfused with recirculating or nonrecirculating buffer containing one fully (13)C-labeled dicarboxylate. Information on the peroxisomal versus mitochondrial catabolism was gathered from the labeling patterns of acetyl-CoA proxies, i.e. total acetyl-CoA, the acetyl moiety of citrate, C-1 + 2 of β-hydroxybutyrate, malonyl-CoA, and acetylcarnitine. Additional information was obtained from the labeling patterns of citric acid cycle intermediates and related compounds. The data characterize the partial oxidation of DODA and azelate in peroxisomes, with terminal oxidation in mitochondria. We did not find evidence of peroxisomal oxidation of glutarate. Unexpectedly, DODA contributes a substantial fraction to anaplerosis of the citric acid cycle. This opens the possibility to use water-soluble DODA in nutritional or pharmacological anaplerotic therapy when other anaplerotic substrates are impractical or contraindicated, e.g. in propionic acidemia and methylmalonic acidemia.

  10. Paraoxonase and arylesterase activities in adults with vitamin B12 deficiency. (United States)

    Guney, Tekin; Alisik, Murat; Alkan, Afra; Basturk, Abdulkadir; Akinci, Sema; Hacibekiroglu, Tuba; Dilek, Imdat; Erel, Ozcan


    Objective The purpose of this study was to investigate paraoxonase (PON) and arylesterase (ARES) enzyme activity in adults with vitamin B12 deficiency, and specific changes in the activities of these enzymes following vitamin B12 treatment. Methods A total of 46 patients with vitamin B12 deficiency (aged 18-82 years) and 45 healthy volunteer controls (aged 19-64 years) participated in this study. Venous blood samples were collected, and serum vitamin B12, homocysteine (HCY), methylmalonic acid, PON1, and ARES levels were measured. Results Paired comparison showed that pre- and post-treatment values for PON and ARES were similar between patients and controls (both P > 0.05). There was no statistically significant relationship between patients' pre-/post-treatment PON or HCY levels and serum vitamin B12 levels, compared with those of the control group (P > 0.05). Discussion The results of the present study do not support the hypothesis that the antioxidant enzymes PON and ARES have an underlying role in vitamin B12 deficiency and related hyperhomocysteinemia. Our findings suggest that PON and ARES do not play a role in the systemic effects of vitamin B12 deficiency.

  11. False-normal vitamin B12 results in a patient with pernicious anaemia. (United States)

    Wainwright, P; Narayanan, S; Cook, P


    Pernicious anaemia is a common autoimmune disorder with a prevalence of approximately 4% amongst Europeans. If untreated, it can result in permanent neurological disability or death. Central to the diagnosis is establishing the presence of vitamin B12 deficiency. Concern has been raised recently regarding false-normal results obtained with competitive-binding vitamin B12 assays performed on automated biochemistry platforms in patients with pernicious anaemia due to the presence of interfering anti-intrinsic factor antibodies in the patient sample. We report a case in which diagnosis of pernicious anaemia was delayed due to false-normal vitamin B12 results. Questioning the results in light of high pre-test probability, and knowledge of the role of functional markers of vitamin B12 deficiency enabled the correct diagnosis to be made so that effective treatment could be initiated. It is crucial that those who frequently request vitamin B12 are aware of the potential problems with the available assays and how these problems can be addressed. We suggest that all patients with normal vitamin B12 levels where there is a high clinical suspicion for deficiency such as a macrocytic anaemia, neurological symptoms or megaloblastic bone marrow should have a functional assay of vitamin B12 (plasma homocysteine or methylmalonic acid) checked to further investigate for vitamin B12 deficiency.

  12. Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency. (United States)

    Hannibal, Luciana; Lysne, Vegard; Bjørke-Monsen, Anne-Lise; Behringer, Sidney; Grünert, Sarah C; Spiekerkoetter, Ute; Jacobsen, Donald W; Blom, Henk J


    Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of B12 has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12. This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders.

  13. Metabolic vitamin B12 deficiency: a missed opportunity to prevent dementia and stroke. (United States)

    Spence, J David


    The purpose of this narrative review is to highlight insights into the importance and frequency of metabolic vitamin B12 (B12) deficiency, reasons why it is commonly missed, and reasons for the widespread but mistaken belief that treatment of B12 deficiency does not prevent stroke or improve cognitive function. Metabolic B12 deficiency is common, being present in 10%-40% of the population; is frequently missed; is easily treated; and contributes importantly to cognitive decline and stroke in older people. Measuring serum B12 alone is not sufficient for diagnosis; it is necessary to measure holotranscobalamin or functional markers of B12 adequacy such as methylmalonic acid or plasma total homocysteine. B-vitamin therapy with cyanocobalamin reduces the risk of stroke in patients with normal renal function but is harmful (perhaps because of thiocyanate accumulation from cyanide in cyanocobalamin) in patients with renal impairment. Methylcobalamin may be preferable in renal impairment. B12 therapy slowed gray matter atrophy and cognitive decline in the Homocysteine and B Vitamins in Cognitive Impairment Trial. Undiagnosed metabolic B12 deficiency may be an important missed opportunity for prevention of dementia and stroke; in patients with metabolic B12 deficiency, it would be prudent to offer inexpensive and nontoxic supplements of oral B12, preferably methylcobalamin or hydroxycobalamin. Future research is needed to distinguish the effects of thiocyanate from cyanocobalamin on hydrogen sulfide, and effects of treatment with methylcobalamin on cognitive function and stroke, particularly in patients with renal failure.

  14. Isolated and Combined Remethylation Disorders

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    Eva Richard PhD


    Full Text Available Genetic defects affecting the remethylation pathway cause hyperhomocysteinemia. Isolated remethylation defects are caused by mutations of the 5, 10-methylenetetrahydrofolate reductase (MTHFR, methionine synthase reductase (MTRR, methionine synthase (MTR, and MMADHC genes, and combined remethylation defects are the result of mutations in genes involved in the synthesis of either methylcobalamin or adenosylcobalamin, that is, the active cofactors of MTRR and methylmalonyl-CoA mutase. Diagnosis is based on the biochemical analysis of amino acids, homocysteine, propionylcarnitine, methylmalonic acid, S-adenosylmethionine, and 5-methylentetrahydrofolate in physiological fluids. Gene-by-gene Sanger sequencing has long been the gold standard genetic analysis for confirming the disorder and identifying the gene involved, but massive parallel sequencing is now being used to examine all those potentially involved in one go. Early treatment to rescue metabolic homeostasis is based on the following of an appropriate diet, betaine administration, and, in some cases, oral or intramuscular administration of vitamin B12 or folate. Elevated ROS levels, apoptosis, endoplasmic reticulum (ER stress, the activation of autophagy, and alterations in Ca2+ homeostasis may all contribute toward the pathogenesis of the disease. Pharmacological agents to restore the function of the ER and mitochondria and/or to reduce oxidative stress-induced apoptosis might provide novel ways of treating patients with remethylation disorders.

  15. Maternal Risk for Down Syndrome Is Modulated by Genes Involved in Folate Metabolism

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    Bruna Lancia Zampieri


    Full Text Available Studies have shown that the maternal risk for Down syndrome (DS may be modulated by alterations in folate metabolism. The aim of this study was to evaluate the influence of 12 genetic polymorphisms involved in folate metabolism on maternal risk for DS. In addition, we evaluated the impact of these polymorphisms on serum folate and plasma methylmalonic acid (MMA, an indicator of vitamin B12 status concentrations. The polymorphisms transcobalamin II (TCN2 c.776C>G, betaine-homocysteine S-methyltransferase (BHMT c.742A>G, methylenetetrahydrofolate reductase (NAD(PH (MTHFR c.677 C>T and the MTHFR 677C-1298A-1317T haplotype modulate DS risk. The polymorphisms MTHFR c.677C>T and solute carrier family 19 (folate transporter, member 1 (SLC19A1 c.80 A>G modulate folate concentrations, whereas the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR c.66A>G polymorphism affects the MMA concentration. These results are consistent with the modulation of the maternal risk for DS by these polymorphisms.

  16. Angiotensin-converting enzyme inhibition curbs tyrosine nitration of mitochondrial proteins in the renal cortex during the early stage of diabetes mellitus in rats. (United States)

    Ishii, Naohito; Carmines, Pamela K; Yokoba, Masanori; Imaizumi, Hiroyuki; Ichikawa, Tsuyoshi; Ikenagasa, Hideki; Kodera, Yoshio; Oh-Ishi, Masamichi; Aoki, Yoshikazu; Maeda, Tadakazu; Takenaka, Tsuneo; Katagiri, Masato


    Experiments were performed to evaluate the hypothesis that ACE (angiotensin-converting enzyme) inhibition (enalapril) suppresses 3-NT (3-nitrotyrosine) production in the renal cortex during the early stage of Type 1 DM (diabetes mellitus) in the rat. Enalapril was administered chronically for 2 weeks to subsets of STZ (streptozotocin)-induced DM and vehicle-treated sham rats. O(2)(-) (superoxide anion) and NO(x) (nitrate+nitrite) levels were measured in the media bathing renal cortical slices after 90 min incubation in vitro. SOD (superoxide dismutase) activity and 3-NT content were measured in the renal cortex homogenate. Renal cortical nitrated protein was identified by proteomic analysis. Renal cortical production of O(2)(-) and 3-NT was increased in DM rats; however, enalapril suppressed these changes. DM rats also exhibited elevated renal cortical NO(x) production and SOD activity, and these changes were magnified by enalapril treatment. 2-DE (two-dimensional gel electrophoresis)-based Western blotting revealed more than 20 spots with positive 3-NT immunoreactivity in the renal cortex of DM rats. Enalapril treatment blunted the DM-induced increase in tyrosine nitration of three proteins ACO2, GDH1 and MMSDH (aconitase 2, glutamate dehydrogenase 1 and methylmalonate-semialdehyde dehydrogenase), each of which resides in mitochondria. These data are consistent with enalapril preventing DM-induced tyrosine nitration of mitochondrial proteins by a mechanism involving suppression of oxidant production and enhancement of antioxidant capacity, including SOD activation.

  17. The effect of WIN 55,212-2 suggests a cannabinoid-sensitive component in the early toxicity induced by organic acids accumulating in glutaric acidemia type I and in related disorders of propionate metabolism in rat brain synaptosomes. (United States)

    Colín-González, A L; Paz-Loyola, A L; Serratos, I N; Seminotti, B; Ribeiro, C A J; Leipnitz, G; Souza, D O; Wajner, M; Santamaría, A


    Several physiological processes in the CNS are regulated by the endocannabinoid system (ECS). Cannabinoid receptors (CBr) and CBr agonists have been involved in the modulation of the N-methyl-D-aspartate receptor (NMDAr) activation. Glutaric (GA), 3-hydroxyglutaric (3-OHGA), methylmalonic (MMA) and propionic (PA) acids are endogenous metabolites produced and accumulated in the brain of children affected by severe organic acidemias (OAs) with neurodegeneration. Oxidative stress and excitotoxicity have been involved in the toxic pattern exerted by these organic acids. Studying the early pattern of toxicity exerted by these metabolites is crucial to explain the extent of damage that they can produce in the brain. Herein, we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) on early markers of GA-, 3-OHGA-, MMA- and PA-induced toxicity in brain synaptosomes from adult (90-day-old) and adolescent (30-day-old) rats. As pre-treatment, WIN exerted protective effects on the GA- and MMA-induced mitochondrial dysfunction, and prevented the reactive oxygen species (ROS) formation and lipid peroxidation induced by all metabolites. Our findings support a protective and modulatory role of cannabinoids in the early toxic events elicited by toxic metabolites involved in OAs.

  18. [Approaches to vitamin B12 deficiency]. (United States)

    Russcher, Henk; Heil, Sandra G; Slobbe, Lennert; Lindemans, Jan


    A 28-year-old female vegetarian was referred to a specialist in internal medicine with persistent iron deficiency. Laboratory analysis revealed microcytic anaemia with low ferritin levels but normal total vitamin B12 levels. The red blood cell distribution width, however, showed a very wide variation in red blood cell sizes, indicating a coexisting vitamin B12 deficiency, which was confirmed by the low concentration of active vitamin B12. Another patient, a 69-year-old woman with a history of previous gastric surgery and renal insufficiency as a complication of diabetes mellitus, was suspected to be deficient in vitamin B12, as she had low total vitamin B12 levels and an accumulation of methylmalonic acid and homocysteine in her blood. Testing the total concentration of vitamin B12 alone has insufficient diagnostic accuracy and no accepted gold standard is available for diagnosing vitamin B12 deficiency. With the development of newer tests, such as measuring holotranscobalamin II (concentration of active vitamin B12), atypical and subclinical deficiency states can be recognized. A new approach to diagnosing vitamin B12 deficiency is presented, based upon these 2 case descriptions.

  19. Hyperhomocysteinemia is associated with low plasma pyridoxine levels in children with sickle cell disease. (United States)

    Balasa, Vinod V; Kalinyak, Karen A; Bean, Judy A; Stroop, Davis; Gruppo, Ralph A


    Elevated plasma homocysteine levels have been shown to be a risk factor for endothelial cell damage and thrombosis, which are implicated in sickle cell disease (SCD)-related vaso-occlusion. The aim of this study was to determine the prevalence of hyperhomocysteinemia in SCD. Fasting and postmethionine load (PML) homocysteine, red cell folate, and the MTHFR C677T mutation were determined in 77 patients with SCD and 110 African-American controls. Plasma methylmalonic acid and pyridoxine levels were determined in 54 patients and all controls. For analysis, the subjects were divided into two age groups (2-10 years and 10.1-21 years). In both age groups, median PML homocysteine levels were significantly elevated in patients with SCD compared with controls. Fasting homocysteine levels were elevated in patients with SCD versus controls only in those older than 10 years. Hyperhomocysteinemia was noted in 38% of patients versus 7% in controls. Folate levels were higher among patients than controls and showed a significant negative correlation with PML homocysteine levels in patients with SCD. Pyridoxine levels in patients with SCD were significantly lower than in controls and showed a negative correlation with PML homocysteine levels. Among patients with SCD, pyridoxine deficiency was more common (62%) among those with hyperhomocysteinemia compared with those with normal homocysteine levels (30%). Homozygosity for the MTHFR C677T mutation was rare. These data suggest that children with SCD have significant hyperhomocysteinemia, associated with pyridoxine and relative folate deficiencies.

  20. Vitamin B12 Deficiency in Relation to Functional Disabilities

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    Heather E. Rasmussen


    Full Text Available This study was designed to assess whether symptoms, functional measures, and reported disabilities were associated with vitamin B12 (B12 deficiency when defined in three ways. Participants, aged 60 or more years of age, in 1999–2002 National Health and Nutrition Examination Surveys (NHANES were categorized in relation to three previously used definitions of B12 deficiency: (1 serum B12 20 μmol/L; and (3 serum B12 0.21 μmol/L. Functional measures of peripheral neuropathy, balance, cognitive function, gait speed, along with self-reported disability (including activities of daily living were examined with standardized instruments by trained NHANES interviewers and technicians. Individuals identified as B12 deficient by definition 2 were more likely to manifest peripheral neuropathy OR (odds (95% confidence intervals, p value: 9.70 (2.24, 42.07, 0.004 and report greater total disability, 19.61 (6.22, 61.86 0.0001 after adjustments for age, sex, race, serum creatinine, and ferritin concentrations, smoking, diabetes, and peripheral artery disease. Smaller, but significantly increased, odds of peripheral neuropathy and total disability were also observed when definition 3 was applied. Functional measures and reported disabilities were associated with B12 deficiency definitions that include B12 biomarkers (homocysteine or methylmalonic acid. Further study of these definitions is needed to alert clinicians of possible subclinical B12 deficiency because functional decline amongst older adults may be correctable if the individual is B12 replete.

  1. Neuropathy as a potential complication of levodopa use in Parkinson's disease. (United States)

    Toth, Cory; Brown, Martin Sutton; Furtado, Sarah; Suchowersky, Oksana; Zochodne, Douglas


    The presence and potential etiologies of peripheral neuropathy (PN) in patients with Parkinson's Disease (PD) is unknown. We examined for presence of PN in patients with PD. From a PD patient population of 500 patients screened for features of symptomatic PN, patients were further selected for clinical, electrophysiological, and laboratory studies related to PN. This PD patient population with idiopathic PN (PD-IPN) was compared to a group of PD patients without PN (PD-only), and a large group of patients without PD with idiopathic PN (IPN) for abnormalities in Cbl, fasting homocysteine (Hcy), and fasting methylmalonic acid (MMA) levels. PD-IPN and IPN patients identified with abnormalities in Cbl, Hcy, or MMA levels were treated with intramuscular Cbl for 1 to 2 years. Of 49 PD patients with symptomatic PN, 34 patients (69%) had PD-IPN, and 32/34 (94%) had abnormal Hcy or MMA levels as compared to 26/258 (10%) of IPN patients. Cumulative lifetime L-dopa dosage and fasting MMA levels were associated with PN severity. Cbl therapy led to improvements in Hcy and MMA levels in all groups, and PN in PD-IPN patients stabilized during therapy. PN in PD patients may be associated with iatrogenic Cbl metabolic abnormalities. Alternatively PN may be a peripheral nervous system manifestation of PD.

  2. Mass Spectrometry-Based Metabolomic and Proteomic Strategies in Organic Acidemias

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    Esther Imperlini


    Full Text Available Organic acidemias (OAs are inherited metabolic disorders caused by deficiency of enzymatic activities in the catabolism of amino acids, carbohydrates, or lipids. These disorders result in the accumulation of mono-, di-, or tricarboxylic acids, generally referred to as organic acids. The OA outcomes can involve different organs and/or systems. Some OA disorders are easily managed if promptly diagnosed and treated, whereas, in others cases, such as propionate metabolism-related OAs (propionic acidemia, PA; methylmalonic acidemia, MMA, neither diet, vitamin therapy, nor liver transplantation appears to prevent multiorgan impairment. Here, we review the recent developments in dissecting molecular bases of OAs by using integration of mass spectrometry- (MS- based metabolomic and proteomic strategies. MS-based techniques have facilitated the rapid and economical evaluation of a broad spectrum of metabolites in various body fluids, also collected in small samples, like dried blood spots. This approach has enabled the timely diagnosis of OAs, thereby facilitating early therapeutic intervention. Besides providing an overview of MS-based approaches most frequently used to study the molecular mechanisms underlying OA pathophysiology, we discuss the principal challenges of metabolomic and proteomic applications to OAs.

  3. Vision Issues and Space Flight: Evaluation of One-Carbon Metabolism Polymorphisms (United States)

    Smith, Scott M.; Gregory, Jesse F.; Zeisel, Steven; Ueland, Per; Gibson, C. R.; Mader, Thomas; Kinchen, Jason; Ploutz-Snyder, Robert; Zwart, Sara R.


    Intermediates of the one-carbon metabolic pathway are altered in astronauts who experience vision-related issues during and after space flight. Serum concentrations of homocysteine, cystathionine, 2-methylcitric acid, and methylmalonic acid were higher in astronauts with ophthalmic changes than in those without (Zwart et al., J Nutr, 2012). These differences existed before, during, and after flight. Potential confounding factors did not explain the differences. Genetic polymorphisms could contribute to these differences, and could help explain why crewmembers on the same mission do not all have ophthalmic issues, despite the same environmental factors (e.g., microgravity, exercise, diet). A follow-up study was conducted to evaluate 5 polymorphisms of enzymes in the one-carbon pathway, and to evaluate how these relate to vision and other ophthalmic changes after flight. Preliminary evaluations of the genetic data indicate that all of the crewmembers with the MTRR GG genotype had vision issues to one degree or another. However, not everyone who had vision issues had this genetic polymorphism, so the situation is more complex than the involvement of this single polymorphism. Metabolomic and further data analyses are underway to clarify these findings, but the preliminary assessments are promising.

  4. Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans (United States)

    Watson, Emma; Olin-Sandoval, Viridiana; Hoy, Michael J; Li, Chi-Hua; Louisse, Timo; Yao, Victoria; Mori, Akihiro; Holdorf, Amy D; Troyanskaya, Olga G; Ralser, Markus; Walhout, Albertha JM


    Metabolic network rewiring is the rerouting of metabolism through the use of alternate enzymes to adjust pathway flux and accomplish specific anabolic or catabolic objectives. Here, we report the first characterization of two parallel pathways for the breakdown of the short chain fatty acid propionate in Caenorhabditis elegans. Using genetic interaction mapping, gene co-expression analysis, pathway intermediate quantification and carbon tracing, we uncover a vitamin B12-independent propionate breakdown shunt that is transcriptionally activated on vitamin B12 deficient diets, or under genetic conditions mimicking the human diseases propionic- and methylmalonic acidemia, in which the canonical B12-dependent propionate breakdown pathway is blocked. Our study presents the first example of transcriptional vitamin-directed metabolic network rewiring to promote survival under vitamin deficiency. The ability to reroute propionate breakdown according to B12 availability may provide C. elegans with metabolic plasticity and thus a selective advantage on different diets in the wild. DOI: PMID:27383050

  5. From the Gla domain to a novel small-molecule detector of apoptosis

    Institute of Scientific and Technical Information of China (English)

    Avi Cohen; Anat Shirvan; Galit Levin; Hagit Grimberg; Ayelet Reshef; Ilan Ziv


    Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, target-ing of apoptotic cells may substantially advance patient care. In our quest for novel low-molecular-weight probes for apoptosis, we focused on the uncommon amino acid γ-carboxyglutamic acid (Gla), which plays a vital role in the binding of clotting factors to negatively charged phosphofipid surfaces. Based on the aikyl-malonic acid motif of Gia, we have developed and now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid, MW=206 Da), the pro-totypical member of a novel family of small-molecule detectors of apoptosis. ML-10 was found to perform selective uptake and accumulation in apoptotic cells, while being excluded from either viable or necrotic cells. ML-10 uptake correlates with the apoptotic hallmarks of caspase activation, Annexin-V binding and disruption of mitochondrial membrane potential. The malonate moiety was found to be crucial for ML-10 function in apoptosis detection. ML-10 responds to a unique complex of features of the cell in early apoptosis, comprising irreversible loss of membrane potential, permanent acidification of cell membrane and cytoplasm, and preservation of membrane integrity. ML-10 is therefore the most compact apoptosis probe known to date. Due to its fluorine atom, ML-10 is amenable to radio-labeling with the 18SF isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.

  6. Vitamin B₁₂ and vegetarian diets. (United States)

    Zeuschner, Carol L; Hokin, Bevan D; Marsh, Kate A; Saunders, Angela V; Reid, Michelle A; Ramsay, Melinda R


    Vitamin B₁₂ is found almost exclusively in animal-based foods and is therefore a nutrient of potential concern for those following a vegetarian or vegan diet. Vegans, and anyone who significantly limits intake of animal-based foods, require vitamin B₁₂-fortified foods or supplements. Vitamin B₁₂ deficiency has several stages and may be present even if a person does not have anaemia. Anyone following a vegan or vegetarian diet should have their vitamin B₁₂ status regularly assessed to identify a potential problem. A useful process for assessing vitamin B₁₂ status in clinical practice is the combination of taking a diet history, testing serum vitamin B₁₂ level and testing homocysteine, holotranscobalamin II or methylmalonic acid serum levels. Pregnant and lactating vegan or vegetarian women should ensure an adequate intake of vitamin B₁₂ to provide for their developing baby. In people who can absorb vitamin B₁₂, small amounts (in line with the recommended dietary intake) and frequent (daily) doses appear to be more effective than infrequent large doses, including intramuscular injections. Fortification of a wider range of foods products with vitamin B₁₂, particularly foods commonly consumed by vegetarians, is likely to be beneficial, and the feasibility of this should be explored by relevant food authorities.

  7. Glial metabolism of valine. (United States)

    Murín, Radovan; Mohammadi, Ghasem; Leibfritz, Dieter; Hamprecht, Bernd


    The three essential amino acids, valine, leucine and isoleucine, constitute the group of branched-chain amino acids (BCAAs). BCAAs are rapidly taken up into the brain parenchyma, where they serve several distinct functions including that as fuel material in brain energy metabolism. As one function of astrocytes is considered the production of fuel molecules that support the energy metabolism of adjacent neural cells in brain. Astroglia-rich primary cultures (APC) were shown to rapidly dispose of the BCAAs, including valine, contained in the culture medium. While the metabolisms of leucine and isoleucine by APC have already been studied in detail, some aspects of valine metabolism remained to be determined. Therefore, in the present study an NMR analysis was performed to identify the (13)C-labelled metabolites that are generated by APC during catabolism of [U-(13)C]valine and that are subsequently released into the incubation medium. The results presented show that APC (1) are potently disposing of the valine contained in the incubation medium; (2) are capable of degrading valine to the tricarboxylic acid (TCA) cycle member succinyl-CoA; and (3) release into the extracellular milieu valine catabolites and compounds generated from them such as [U-(13)C]2-oxoisovalerate, [U-(13)C]3-hydroxyisobutyrate, [U-(13)C]2-methylmalonate, [U-(13)C]isobutyrate, and [U-(13)C]propionate as well as several TCA cycle-dependent metabolites including lactate.

  8. Metformin Lowers Serum Cobalamin without Changing Other Markers of Cobalamin Status: A Study on Women with Polycystic Ovary Syndrome

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    Ebba Nexo


    Full Text Available Treatment with the anti-diabetic drug metformin is followed by a decline in plasma cobalamin, but it is unsettled whether this denotes an impaired cobalamin status. This study has explored changes in the markers of cobalamin status in women with Polycystic Ovary Syndrome treated with metformin (1.5–2.5 g per day (n = 29 or placebo (n = 23 for six months. Serum samples were collected before and after two, four, and six months of treatment. We found serum cobalamin to decline and reach significant lower levels after six months of treatment (p = 0.003. Despite the decline in serum cobalamin, we observed no reductions in the physiological active part of cobalamin bound to transcobalamin (holotranscobalamin, or increase in the metabolic marker of cobalamin status, methylmalonic acid. Instead, the non-functional part of circulating cobalamin bound to haptocorrin declined (p = 0.0009. Our results have two implications: The data questions whether metformin treatment induces an impaired cobalamin status in PCOS patients, and further suggests that serum cobalamin is a futile marker for judging cobalamin status in metformin-treated patients.

  9. Risk of Visual Impairment and Intracranial Hypertension After Space Flight: Evaluation of the Role of Polymorphism of Enzymes Involved in One-Carbon Metabolism (United States)

    Smith, S. M.; Gregory, J. F.; Zeisel, G. H.; Gibson, C. R.; Mader, T. H.; Kinchen, J.; Ueland, P.; Ploutz-Snyder, R.; Heer, M.; Zwart, S. R.


    Data from the Nutritional Status Assessment protocol provided biochemical evidence that the one-carbon metabolic pathway may be altered in individuals experiencing vision-related issues during and after space flight (1, 2). Briefly, serum concentrations of homocysteine, cystathionine, 2-methylcitric acid, and methylmalonic acid were significantly (Penzymes in the one-carbon pathway, and to evaluate how these relate to vision and other medical aspects of the eye. Specifically, we investigated 5 polymorphisms in MTRR, MTHFR, SHMT, and CBS genes and their association with ophthalmic changes after flight in 49 astronauts. The number of G alleles of MTRR 66 and C alleles of SHMT1 1420 both contributed to the odds of visual disturbances (3). Block regression showed that B-vitamin status at landing and genetics were significant predictors for many of the ophthalmic outcomes studied (3). In conclusion, we document an association between MTRR 66 and SHMT1 1420 polymorphisms and space flightinduced vision changes. These data document that individuals with an altered 1-carbon metabolic pathway may be predisposed to anatomic and/or physiologic changes that render them susceptible to ophthalmic damage during space flight.

  10. Proteomics of vitamin B12 processing. (United States)

    Hannibal, Luciana; DiBello, Patricia M; Jacobsen, Donald W


    The causes of cobalamin (B12, Cbl) deficiency are multifactorial. Whether nutritional due to poor dietary intake, or functional due to impairments in absorption or intracellular processing and trafficking events, the major symptoms of Cbl deficiency include megaloblastic anemia, neurological deterioration and in extreme cases, failure to thrive and death. The common biomarkers of Cbl deficiency (hyperhomocysteinemia and methylmalonic acidemia) are extremely valuable diagnostic indicators of the condition, but little is known about the changes that occur at the protein level. A mechanistic explanation bridging the physiological changes associated with functional B12 deficiency with its intracellular processers and carriers is lacking. In this article, we will cover the effects of B12 deficiency in a cblC-disrupted background (also referred to as MMACHC) as a model of functional Cbl deficiency. As will be shown, major protein changes involve the cytoskeleton, the neurological system as well as signaling and detoxification pathways. Supplementation of cultured MMACHC-mutant cells with hydroxocobalamin (HOCbl) failed to restore these variants to the normal phenotype, suggesting that a defective Cbl processing pathway produces irreversible changes at the protein level.

  11. Inborn Errors of Intermediary Metabolism in Critically Ill Mexican Newborns

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    Ibarra-González Isabel MSc


    Full Text Available Inborn errors of intermediary metabolism (IEiM are complex diseases with high clinical heterogeneity, and some patients who have severe enzyme deficiencies or are subjected to stress (catabolism/infections actually decompensate in the neonatal period. In this study, we performed metabolic tests on 2025 newborns in Mexico admitted to 35 neonatal intensive care units or emergency wards (NICUs/EWs over a 6-year period, in whom a metabolic disorder was clinically suspected. Of these 2025 newborns with sickness, 11 had IEiM, revealing a prevalence of 1:184. Clinical characteristics and outcomes of the newborns with confirmed IEiM are shown. Of these 11 patients, 4 had isolated methylmalonic acidemia, 3 had maple syrup urine disease, 2 had urea cycle disorders, 1 had 3-hydroxy-3-methylglutaric acidemia, and 1 had isovaleric acidemia. During the first week of life (average 3 days, all of these newborns presented with impaired alertness, hypotonia, feeding difficulties, and vomiting along with metabolic acidosis and hyperammonemia. Of the 11 newborns with IEiM, 7 died, leading to a mortality rate of 64%. In conclusion, the differential diagnosis of newborns admitted to the NICU/EW must include IEiM, requiring systematic screening of this population.

  12. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. (United States)

    Green, Courtney R; Wallace, Martina; Divakaruni, Ajit S; Phillips, Susan A; Murphy, Anne N; Ciaraldi, Theodore P; Metallo, Christian M


    Adipose tissue plays important roles in regulating carbohydrate and lipid homeostasis, but less is known about the regulation of amino acid metabolism in adipocytes. Here we applied isotope tracing to pre-adipocytes and differentiated adipocytes to quantify the contributions of different substrates to tricarboxylic acid (TCA) metabolism and lipogenesis. In contrast to proliferating cells, which use glucose and glutamine for acetyl-coenzyme A (AcCoA) generation, differentiated adipocytes showed increased branched-chain amino acid (BCAA) catabolic flux such that leucine and isoleucine from medium and/or from protein catabolism accounted for as much as 30% of lipogenic AcCoA pools. Medium cobalamin deficiency caused methylmalonic acid accumulation and odd-chain fatty acid synthesis. Vitamin B12 supplementation reduced these metabolites and altered the balance of substrates entering mitochondria. Finally, inhibition of BCAA catabolism compromised adipogenesis. These results quantitatively highlight the contribution of BCAAs to adipocyte metabolism and suggest that BCAA catabolism has a functional role in adipocyte differentiation.

  13. Cobalamin deficiency results in severe metabolic disorder of serine and threonine in rats. (United States)

    Ebara, S; Toyoshima, S; Matsumura, T; Adachi, S; Takenaka, S; Yamaji, R; Watanabe, F; Miyatake, K; Inui, H; Nakano, Y


    Dietary cobalamin (vitamin B12; Cbl) deficiency caused significant increases in plasma serine, threonine, glycine, alanine, tyrosine, lysine and histidine levels in rats. In particular, the serine and threonine levels were over five and eight times, respectively, higher in the Cbl-deficient rats than those in the sufficient controls. In addition, some amino acids, including serine and threonine, were excreted into urine at significantly higher levels in the deficient rats. When Cbl was supplemented into the deficient rats for 2 weeks, in coincidence with the disappearance of the urinary excretion of methylmalonic acid (an index of Cbl deficiency), the plasma serine and threonine levels were normalized. These results indicate that Cbl deficiency results in metabolic disorder of certain amino acids, including serine and threonine. The expression level of hepatic serine dehydratase (SDH), which catalyzes the conversion of serine and threonine to pyruvate and 2-oxobutyrate, respectively, was significantly lowered by Cbl deficiency, even though Cbl does not participate directly in the enzyme reaction. The SDH activity in the deficient rats was less than 20% of that in the sufficient controls, and was normalized 2 weeks after the Cbl supplementation. It is thus suggested that the decrease of the SDH expression relates closely with the abnormalities in the plasma and urinary levels of serine and threonine in the Cbl-deficient rats.

  14. Binary and ternary complexation of NpO{sub 2}{sup +} with carboxylate and aminocarboxylate ligands

    Energy Technology Data Exchange (ETDEWEB)

    Thakur, Punam [Florida State Univ., Tallahassee, FL (United States). Dept. of Chemistry and Biochemistry; Van Luik, Abraham E. [Department of Energy, Carlsbad Field Office, NM (United States)


    The complex formation of NpO{sub 2}{sup +} with carboxylates: oxalic acid (Ox), malonic acid (Mal) succinic acid (Suc); glutaric acid (Glu), methylmalonic acid (Memal), oxydiacetic acid (ODA), TDA (thiodiacetic acid) and citric acid (Cit) and aminocarboxylates: iminodiacetic acid (IDA), methyliminodiacetic acid (MIDA), nitrilotriacetic acid (NTA), 2-hydroxyethylethylenediamine triacetic acid (HEDTA), ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) was studied by solvent extraction in 6.60 m NaClO{sub 4} at 25 C. The formation of only the 1: 1 NpO{sub 2}{sup +} complex was observed with the ligands under investigation. The complexation of NpO{sub 2}{sup +} with Ox, IDA, ODA and TDA was also measured at variable temperatures ranging from 25-60 C in 6.60 m NaClO{sub 4}. Results show that the complexation of NpO{sub 2}{sup +} with these ligands increases with increasing temperature. The enthalpy and entropy of complexation of NpO{sub 2}{sup +} were calculated from the temperature dependence of the stability constants using the Van't Hoff equation. Additionally, the formation of an aqueous ternary complex of the form NpO{sub 2}(X)(L) (X = EDTA or HEDTA; L = Ox or ODA) was identified for NpO{sub 2}{sup +} at 25 C. Stabilities of these complexes are measured and discussed in term of their structures and basicities.

  15. Crystallization and preliminary X-ray diffraction experiments of arylmalonate decarboxylase from Alcaligenes bronchisepticus

    Energy Technology Data Exchange (ETDEWEB)

    Nakasako, Masayoshi, E-mail: [Department of Physics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Kanagawa 223-8522 (Japan); The RIKEN Harima Institute/SPring-8, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148 (Japan); Obata, Rika; Okubo, Ryosuke; Nakayama, Shyuichi [Department of Physics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Kanagawa 223-8522 (Japan); Miyamoto, Kenji; Ohta, Hiromichi [Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Kanagawa 223-8522 (Japan); Department of Physics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Kanagawa 223-8522 (Japan)


    Crystals of arylmalonate decarboxylase from A. bronchisepticus were obtained which diffracted X-rays to a resolution of at least 3.0 Å. Arylmalonate decarboxylase catalyses the enantioselective decarboxylation of α-aryl-α-methylmalonates to produce optically pure α-arylpropionates. The enzyme was crystallized with ammonium sulfate under alkaline pH conditions with the aim of understanding the mechanism of the enantioselective reaction. X-ray diffraction data collected to a resolution of 3.0 Å at cryogenic temperature showed that the crystals belonged to the orthorhombic space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 83.13, b = 99.62, c = 139.64 Å. This suggested that the asymmetric unit would contain between four and six molecules. Small-angle X-ray scattering revealed that the enzyme exists as a monomer in solution. Thus, the assembly of molecules in the asymmetric unit was likely to have been induced during the crystallization process.

  16. Vision changes after spaceflight are related to alterations in folate- and vitamin B-12-dependent one-carbon metabolism. (United States)

    Zwart, Sara R; Gibson, C Robert; Mader, Thomas H; Ericson, Karen; Ploutz-Snyder, Robert; Heer, Martina; Smith, Scott M


    Approximately 20% (7 of 38) of astronauts on International Space Station (ISS) missions have developed measurable ophthalmic changes after flight. This study was conducted to determine if the folate- and vitamin B-12-dependent 1-carbon metabolic pathway is altered in these individuals. Since 2006, we have conducted experiments on the ISS to evaluate nutritional status and related biochemical indices of astronauts before, during, and after flight. Data were modeled to evaluate differences between individuals with ophthalmic changes (n = 5) and those without them (n = 15), all of whom were on ISS missions of 48-215 d. We also determined whether mean preflight serum concentrations of the 1-carbon metabolites and changes in measured cycloplegic refraction after flight were associated. Serum homocysteine (Hcy), cystathionine, 2-methylcitric acid (2MCA), and methylmalonic acid concentrations were 25-45% higher (P refraction (P < 0.05), and preflight serum concentrations of 2MCA tended to be associated (P = 0.06) with ophthalmic changes. The biochemical differences observed in crewmembers with vision issues strongly suggest that their folate- and vitamin B-12-dependent 1-carbon transfer metabolism was affected before and during flight. The consistent differences in markers of 1-carbon metabolism between those who did and those who did not develop changes in vision suggest that polymorphisms in enzymes of this pathway may interact with microgravity to cause these pathophysiologic changes.

  17. Mammalian ACSF3 protein is a malonyl-CoA synthetase that supplies the chain extender units for mitochondrial fatty acid synthesis. (United States)

    Witkowski, Andrzej; Thweatt, Jennifer; Smith, Stuart


    The objective of this study was to identify a source of intramitochondrial malonyl-CoA that could be used for de novo fatty acid synthesis in mammalian mitochondria. Because mammalian mitochondria lack an acetyl-CoA carboxylase capable of generating malonyl-CoA inside mitochondria, the possibility that malonate could act as a precursor was investigated. Although malonyl-CoA synthetases have not been identified previously in animals, interrogation of animal protein sequence databases identified candidates that exhibited sequence similarity to known prokaryotic forms. The human candidate protein ACSF3, which has a predicted N-terminal mitochondrial targeting sequence, was cloned, expressed, and characterized as a 65-kDa acyl-CoA synthetase with extremely high specificity for malonate and methylmalonate. An arginine residue implicated in malonate binding by prokaryotic malonyl-CoA synthetases was found to be positionally conserved in animal ACSF3 enzymes and essential for activity. Subcellular fractionation experiments with HEK293T cells confirmed that human ACSF3 is located exclusively in mitochondria, and RNA interference experiments verified that this enzyme is responsible for most, if not all, of the malonyl-CoA synthetase activity in the mitochondria of these cells. In conclusion, unlike fungi, which have an intramitochondrial acetyl-CoA carboxylase, animals require an alternative source of mitochondrial malonyl-CoA; the mitochondrial ACSF3 enzyme is capable of filling this role by utilizing free malonic acid as substrate.

  18. How prevalent is vitamin B(12) deficiency among vegetarians? (United States)

    Pawlak, Roman; Parrott, Scott James; Raj, Sudha; Cullum-Dugan, Diana; Lucus, Debbie


    Vegetarians are at risk for vitamin B(12) (B12) deficiency due to suboptimal intake. The goal of the present literature review was to assess the rate of B12 depletion and deficiency among vegetarians and vegans. Using a PubMed search to identify relevant publications, 18 articles were found that reported B12 deficiency rates from studies that identified deficiency by measuring methylmalonic acid, holo-transcobalamin II, or both. The deficiency rates reported for specific populations were as follows: 62% among pregnant women, between 25% and almost 86% among children, 21-41% among adolescents, and 11-90% among the elderly. Higher rates of deficiency were reported among vegans compared with vegetarians and among individuals who had adhered to a vegetarian diet since birth compared with those who had adopted such a diet later in life. The main finding of this review is that vegetarians develop B12 depletion or deficiency regardless of demographic characteristics, place of residency, age, or type of vegetarian diet. Vegetarians should thus take preventive measures to ensure adequate intake of this vitamin, including regular consumption of supplements containing B12.

  19. 2D NMR-based metabolomics uncovers interactions between conserved biochemical pathways in the model organism Caenorhabditis elegans. (United States)

    Izrayelit, Yevgeniy; Robinette, Steven L; Bose, Neelanjan; von Reuss, Stephan H; Schroeder, Frank C


    Ascarosides are small-molecule signals that play a central role in C. elegans biology, including dauer formation, aging, and social behaviors, but many aspects of their biosynthesis remain unknown. Using automated 2D NMR-based comparative metabolomics, we identified ascaroside ethanolamides as shunt metabolites in C. elegans mutants of daf-22, a gene with homology to mammalian 3-ketoacyl-CoA thiolases predicted to function in conserved peroxisomal lipid β-oxidation. Two groups of ethanolamides feature β-keto functionalization confirming the predicted role of daf-22 in ascaroside biosynthesis, whereas α-methyl substitution points to unexpected inclusion of methylmalonate at a late stage in the biosynthesis of long-chain fatty acids in C. elegans. We show that ascaroside ethanolamide formation in response to defects in daf-22 and other peroxisomal genes is associated with severe depletion of endocannabinoid pools. These results indicate unexpected interaction between peroxisomal lipid β-oxidation and the biosynthesis of endocannabinoids, which are major regulators of lifespan in C. elegans. Our study demonstrates the utility of unbiased comparative metabolomics for investigating biochemical networks in metazoans.

  20. 81例遗传代谢病患儿神经系统损害和症状分析%Analysis of impaired nervous system and symptoms in 81 children with inherited metabolic disorders

    Institute of Scientific and Technical Information of China (English)

    何大可; 张建明; 邵新华; 宋小青; 吴静; 顾学范


    目的 探讨遗传代谢病患儿神经系统损害的临床特征.方法 回顾总结81例遗传代谢病患儿的临床表现、生化指标及影像学等辅助检查资料,结合串联质谱、气相质谱、酶学检查等特殊检查予以综合分析.结果 81例遗传代谢病患儿中,甲基丙二酸血症14例,甲基丙二酸血症伴同型半胱氨酸血症5例,丙酸血症4例,枫糖尿病3例,鸟氨酸氨甲酰转移酶缺乏症2例,戊二酸血症1例,瓜氨酸血症1例,精氨酸血症1例,苯丙酮尿症3例,生物素酶缺乏症1例,糖原累积症17例,黏多糖病1例,脑白质营养不良4例,肝豆状核变性24例.主要临床表现有惊厥、意识障碍、运动发育落后、发育倒退、智能低下、喂养困难、呕吐;头颅CT或磁共振成像显示脑发育不良、脑软化、脑白质异常信号,脑电图显示慢波或(癎)样活动.结论 遗传代谢病患儿常以惊厥、发育落后、发育倒退、意识障碍、智能低下等神经系统表现而就诊,对患儿应尽早予遗传代谢病筛查以得到早期诊断及合理治疗而改善预后.%Objective To analyse the clinical characteristics of nervous system of children with inherited metabolic disorders. Methods The clinical manifestations, biochemical parameters and imaging data of 81 children with inherited metabolic disorders were retrospectively reviewed, and were comprehensively analysed on the basis of findings of tandem mass spectrometry, gas chromatography mass spectrometry and enzymological examinations. Results Among the 81 children with inherited metabolic disorders, there were 14 cases of methylmalonic acidemia, 5 cases of methylmalonic acidemia with hotnocysteinuria, 4 cases of propionic acidemia, 3 cases of maple syrup urine disease, 2 cases of ornithine transcarbamylase deficiency, 1 case of glutaric acidemia, 1 case of citrullinemia, 1 case of argininemia, 3 cases of phenylketonuria, 1 case of biotinidase deficiency, 17 cases of glycogenosis

  1. Clinical and neurocognitive outcome in symptomatic isovaleric acidemia

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    Grünert Sarah C


    Full Text Available Abstract Background Despite its first description over 40 years ago, knowledge of the clinical course of isovaleric acidemia (IVA, a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation. Methods Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality. Results 57% of study patients (12/21 were diagnosed within the first weeks of life and 43% (9/21 in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44% of investigated study patients (7/16 showed mild motor dysfunction and only 19% (3/16 had cognitive deficits. No other organ complications were found. The patients' intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33% if associated with neonatal diagnosis, following manifestation at an average age of 7 days. Conclusions Within the group of "classical" organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening.

  2. Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH deficiency suggest a heightened excitatory state during development

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    Snead O Carter


    Full Text Available Abstract Background SSADH (aldehyde dehydrogenase 5a1 (Aldh5a1; γ-hydroxybutyric (GHB aciduria deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1-/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives succinate semialdehyde (SSA, homocarnosine (HC, 4,5-dihydroxyhexanoic acid (DHHA and guanidinobutyrate (GB] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1-/- embryo development. Methods Embryos were obtained from pregnant dams sacrificed at E (embryo day of life 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1+/+ and Aldh5a1-/- for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95th centile. Results GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5 also revealed significantly increased GABA. Conclusion Our findings indicate early GABAergic alterations in Aldh5a1-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.

  3. HIPERAMONEMIA NEONATAL CAUSADA POR DEFECTOS DEL CICLO DE LA UREA Neonatal hyperammonemia in urea cycle disorders patients

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    Yolanda Cifuentes C


    Full Text Available Los defectos del ciclo de la úrea se deben a deficiencias de diferentes enzimas; las manifestaciones clínicas son similares y están relacionadas con la hiperamonemia. Se presentan las historias clínicas de tres neonatos a término, sin evidencia de alteración al nacimiento. Se les detectó hiperamonemia y se sospechó enfermedad metabólica. La cromatografía de aminoácidos sugirió defectos del ciclo de la úrea. El manejo incluyó dieta con restricción de proteínas, administración de benzoato de sodio, exsanguinotransfusión y diálisis peritoneal pese a lo cual fallecieron. Se revisan las causas de hiperamonemia en el neonato y se propone una secuencia para su diagnósticoThe urea cycle disorders result from deficiency of activity of enzymes N-acetyl glutamate synthetase, carbamyl phosphate synthase, ornithine transcarbamylase, argininosuccinic acid synthetase, argininosuccinic acid lyase and arginase. Except for the last one, the clinical features are similar and related with the hiperammonaemia. It reports three full term, newborn cases, they had encephalopathy and needed respiratory support after be well in neonatal period. They had hyperammonemia as inborn error. The thin layer amino acids chromatography showed alanine and glutamine, in the siblings appeared citruline, suggesting urea cycle disorders. Despite protein restriction diet, sodium benzoate administration, blood exchange and peritoneal dialysis,babies died. High argininosuccinic acid levels in the first case and high citrulline levels with argininosuccinic acid absence in the third case, which was diagnosed as argininosuccinic aciduria with citrullinemia. This report provide an overview of neonatal hyperammonemia causes and propose a secuency for diagnosis

  4. The Clinical Features and Diagnosis of Canavan’s Disease: A Case Series of Iranian Patients

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    Parvaneh KARIMZADEH


    even with normal serum and urine N-acetylaspartic acid levels. ReferencesAdornato BT, O’Brien JS, Lampert PW, Roe TF, Neustein HB. Cerebral spongy degeneration of infancy. A biochemical and ultrastructural study of affected twins. Neurology 1972;22(2:202-10.Banker BQ, Robertson JT, Victor M. Spongy Degeneration of the Central Nervous System in Infancy. Neurology 1964; 14:981-1001.Chou SM, Waisman HA. Spongy Degeneration of the Central Nervous System: Case of Homocystinuria. Arch Pathol 1965; 79:357-63.Divry P, Vianey-Liaud C, Gay C, Macabeo V, Rapin F, Echenne B. N-acetylaspartic aciduria: report of three new cases in children with a neurological syndrome associating macrocephaly and leukodystrophy. J Inherit Metab Dis 1988; 11(3:307-8.Feigenbaum A, Moore R, Clarke J, Hewson S, Chitayat D, Ray PN, et al. Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay. Am J Med Genet A 2004;124a(2:142-7.Hagenfeldt L, Bollgren I, Venizelos N. N-acetylaspartic aciduria due to aspartoacylase deficiency--a new aetiology of childhood leukodystrophy. J Inherit Metab Dis 1987; 10(2:135-41.Ishiyama G, Lopez I, Baloh RW, Ishiyama A. Canavan’s leukodystrophy is associated with defects in cochlear neurodevelopment and deafness. Neurology 2003; 60(10:1702-4.Janson CG, Kolodny EH, Zeng BJ, Raghavan S, Pastores G, Torres P, et al. Mild-onset presentation of Canavan’s disease associated with novel G212A point mutation in aspartoacylase gene. Ann Neurol 2006; 59(2:428-31.Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, Michals K, et al. Canavan disease: mutations among Jewish and non-Jewish patients. Am J Hum Genet 1994; 55(1:34-41.Kaul R, Gao GP, Balamurugan K, Matalon R. Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nat Genet 1993; 5(2:118-23.Kvittingen EA, Guldal G, Borsting S, Skalpe IO, Stokke O, Jellum E. N-acetylaspartic aciduria in a child with a

  5. Alanine-glyoxylate aminotransferase 2 (AGXT2) polymorphisms have considerable impact on methylarginine and β-aminoisobutyrate metabolism in healthy volunteers. (United States)

    Kittel, Anja; Müller, Fabian; König, Jörg; Mieth, Maren; Sticht, Heinrich; Zolk, Oliver; Kralj, Ana; Heinrich, Markus R; Fromm, Martin F; Maas, Renke


    Elevated plasma concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine have repeatedly been linked to adverse clinical outcomes. Both methylarginines are substrates of alanine-glyoxylate aminotransferase 2 (AGXT2). It was the aim of the present study to simultaneously investigate the functional relevance and relative contributions of common AGXT2 single nucleotide polymorphisms (SNPs) to plasma and urinary concentrations of methylarginines as well as β-aminoisobutyrate (BAIB), a prototypic substrate of AGXT2. In a cohort of 400 healthy volunteers ADMA, SDMA and BAIB concentrations were determined in plasma and urine using HPLC-MS/MS and were related to the coding AGXT2 SNPs rs37369 (p.Val140Ile) and rs16899974 (p.Val498Leu). Volunteers heterozygous or homozygous for the AGXT2 SNP rs37369 had higher SDMA plasma concentrations by 5% and 20% (p = 0.002) as well as higher BAIB concentrations by 54% and 146%, respectively, in plasma and 237% and 1661%, respectively, in urine (both pimpact of the amino acid exchange p.Val140Ile, we established human embryonic kidney cell lines stably overexpressing wild-type or mutant (p.Val140Ile) AGXT2 protein and assessed enzyme activity using BAIB and stable-isotope labeled [²H₆]-SDMA as substrate. In vitro, the amino acid exchange of the mutant protein resulted in a significantly lower enzyme activity compared to wild-type AGXT2 (p<0.05). In silico modeling of the SNPs indicated reduced enzyme stability and substrate binding. In conclusion, SNPs of AGXT2 affect plasma as well as urinary BAIB and SDMA concentrations linking methylarginine metabolism to the common genetic trait of hyper-β-aminoisobutyric aciduria.

  6. ETHE1 mutations are specific to ethylmalonic encephalopathy. (United States)

    Tiranti, V; Briem, E; Lamantea, E; Mineri, R; Papaleo, E; De Gioia, L; Forlani, F; Rinaldo, P; Dickson, P; Abu-Libdeh, B; Cindro-Heberle, L; Owaidha, M; Jack, R M; Christensen, E; Burlina, A; Zeviani, M


    Mutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non-EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, the 625G-->A single nucleotide polymorphism in the gene encoding the short chain acyl-coenzyme A dehydrogenase (SCAD) was previously proposed as a co-factor in the aetiology of EE and other EMA syndromes. SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients.

  7. In vivo evidence that Agxt2 can regulate plasma levels of dimethylarginines in mice. (United States)

    Kittel, Anja; Maas, Renke; König, Jörg; Mieth, Maren; Weiss, Norbert; Jarzebska, Natalia; Hohenstein, Bernd; Martens-Lobenhoffer, Jens; Bode-Böger, Stefanie M; Rodionov, Roman N


    Elevated plasma concentrations of the asymmetric (ADMA) and symmetric (SDMA) dimethylarginine have repeatedly been linked to adverse cardiovascular clinical outcomes. Both dimethylarginines can be degraded by alanine-glyoxylate aminotransferase 2 (Agxt2), which is also the key enzyme responsible for the degradation of endogenously formed β-aminoisobutyrate (BAIB). In the present study we wanted to investigate the effect of BAIB on Agxt2 expression and Agxt2-mediated metabolism of dimethylarginines. We infused BAIB or saline intraperitoneally for 7days in C57/BL6 mice via minipumps. Expression of Agxt2 was determined in liver and kidney. The concentrations of BAIB, dimethylarginines and the Agxt2-specific ADMA metabolite α-keto-δ-(N(G),N(G)-dimethylguanidino)valeric acid (DMGV) was determined by LC-MS/MS in plasma and urine. As compared to controls systemic administration of BAIB increased plasma and urine BAIB levels by a factor of 26.5 (p<0.001) and 25.8 (p<0.01), respectively. BAIB infusion resulted in an increase of the plasma ADMA and SDMA concentrations of 27% and 31%, respectively, (both p<0.05) and a 24% decrease of plasma DMGV levels (p<0.05), while expression of Agxt2 was not different. Our data demonstrate that BAIB can inhibit Agxt2-mediated metabolism of dimethylarginines and show for the first time that endogenous Agxt2 is involved in the regulation of systemic ADMA, SDMA and DMGV levels. The effect of BAIB excess on endogenous dimethylarginine levels may have direct clinical implications for humans with the relatively common genetic trait of hyper-β-aminoisobutyric aciduria.

  8. Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes. (United States)

    Marziliano, Nicola; Mannarino, Savina; Nespoli, Luisa; Diegoli, Marta; Pasotti, Michele; Malattia, Clara; Grasso, Maurizia; Pilotto, Andrea; Porcu, Emanuele; Raisaro, Arturo; Raineri, Claudia; Dore, Roberto; Maggio, Pietro Paolo; Brega, Agnese; Arbustini, Eloisa


    Barth syndrome is an X-linked recessive disorder caused by the tafazzin (TAZ) gene mutations and includes dilated cardiomyopathy (DCM) with left ventricular non-compaction, neutropenia, skeletal myopathy, abnormal mitochondria and 3-methylglutaconic aciduria. Dilated cardiomyopathy with left ventricular non-compaction transmitted as an autosomal dominant condition has also been associated with LIM domain-binding 3 (LDB3) gene defects. We describe a family in which the 12-year-old proband had left ventricular non-compaction and DCM. His mother had five miscarriages, two other sons who died in infancy, and a healthy son and daughter. The proband showed left ventricular non-compaction-DCM, skeletal myopathy, recurrent oral aphthous ulcers and cyclic neutropenia. The DCM progressively improved with age; medical therapy was discontinued at 5 years of age. At present, left ventricular function is normal and arrhythmias are absent. Magnetic resonance imaging documented left ventricular non-compaction. However, oral aphthous ulcers and cyclic neutropenia have recurred. In the proband we identified two novel mutations, one of maternal origin in the TAZ gene (p.[Glu202ValfsX15]) and one of paternal origin in the LDB3 gene (p.[Thr350Ile]). The mother, brother and father are healthy; although the latter two show prominent left ventricle trabeculation without dysfunction. Expression studies of TAZ and LDB3 genes were conducted in family members and controls. In the proband, brother and father, LDB3 expression was similar to control cases. TAZ and LDB3 expression progressively declined with age in control both blood and myocardial samples. However, an endomyocardial biopsy performed in the proband at 6 months of age, showed significantly lower TAZ and LDB3 expression than in age-matched myocardial controls. We believe that the clinical, genetic and expression data support the hypothesis that tafazzins are essential during fetal and early post-natal life.

  9. Magnetic resonance imaging findings and neurodevelopmental outcomes in neonates with urea-cycle defects

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    Gunz AC


    Full Text Available Anna Catherine Gunz,1 Karen Choong,2 Murray Potter,3 Elka Miller4 1Division of Critical Care, Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; 2Department of Pediatrics, 3Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada; 4Diagnostic Imaging Department, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada Abstract: The urea-cycle functions to facilitate ammonia excretion, a disruption of which results in the accumulation of toxic metabolites. The neurological outcome of neonatal-onset urea-cycle defects (UCDs is poor, and there are no good predictors of prognosis beyond ammonia levels at presentation. The role of neuroimaging in the prognosis of neonatal-onset UCDs is unclear. We describe the magnetic resonance imaging (MRI findings of two patients with neonatal-onset UCDs (argininosuccinic aciduria and citrullinemia at presentation and at 2-year follow-up, and present a review of the literature on neuroimaging in this age-group. We observed two potentially significant distinct patterns of cerebral involvement on MRI: (1 a central and focal pattern of involvement limited to the basal ganglia, perirolandic regions, and internal capsule; and (2 diffuse involvement of the cerebral cortex, internal capsule, basal ganglia, and variably thalami and brain stem. Patients with more diffuse findings tended to have higher serum glutamine peaks and worse neurological outcomes, while those with central involvement, aggressive acute management, and early liver transplantation tended to have better outcomes. We propose that MRI imaging of the brain may have prognostic value following presentation with neonatal UCDs, particularly in identifying patients at risk for poor outcome. The role and timing of follow-up neuroimaging is currently unclear. Further collaborative studies are necessary to evaluate whether patterns of MRI findings vary with specific UCD

  10. The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites. (United States)

    Hariharan, Vivek A; Denton, Travis T; Paraszcszak, Sarah; McEvoy, Kyle; Jeitner, Thomas M; Krasnikov, Boris F; Cooper, Arthur J L


    Many enzymes make "mistakes". Consequently, repair enzymes have evolved to correct these mistakes. For example, lactate dehydrogenase (LDH) and mitochondrial malate dehydrogenase (mMDH) slowly catalyze the reduction of 2-oxoglutarate (2-OG) to the oncometabolite l-2-hydroxyglutarate (l-2-HG). l-2-HG dehydrogenase corrects this error by converting l-2-HG to 2-OG. LDH also catalyzes the reduction of the oxo group of 2-oxoglutaramate (2-OGM; transamination product of l-glutamine). We show here that human glutamine synthetase (GS) catalyzes the amidation of the terminal carboxyl of both the l- and d- isomers of 2-HG. The reaction of 2-OGM with LDH and the reaction of l-2-HG with GS generate l-2-hydroxyglutaramate (l-2-HGM). We also show that l-2-HGM is a substrate of human ω-amidase. The product (l-2-HG) can then be converted to 2-OG by l-2-HG dehydrogenase. Previous work showed that 2-oxosuccinamate (2-OSM; transamination product of l-asparagine) is an excellent substrate of LDH. Finally, we also show that human ω-amidase converts the product of this reaction (i.e., l-2-hydroxysuccinamate; l-2-HSM) to l-malate. Thus, ω-amidase may act together with hydroxyglutarate dehydrogenases to repair certain "mistakes" of GS and LDH. The present findings suggest that non-productive pathways for nitrogen metabolism occur in mammalian tissues in vivo. Perturbations of these pathways may contribute to symptoms associated with hydroxyglutaric acidurias and to tumor progression. Finally, methods for the synthesis of l-2-HGM and l-2-HSM are described that should be useful in determining the roles of ω-amidase/4- and 5-C compounds in photorespiration in plants.

  11. The origin of free brain malonate

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    Riley, K.M.; Dickson, A.C.; Koeppen, A.H. (Research Service, Veterans Administration Medical Center, Albany, NY (United States))


    Rat brain contains substantial concentrations of free malonate (192 nmol/g wet weight) but origin and biological importance of the dicarboxylic acid are poorly understood. A dietary source has been excluded. A recently described malonyl-CoA decarboxylase deficiency is associated with malonic aciduria and clinical manifestations, including mental retardation. In an effort to study the metabolic origin of free malonate, several labeled acetyl-CoA precursors were administered by intracerebral injection. (2-14C)pyruvate or (1,5-14C)citrate produced radioactive glutamate but failed to label malonate. In contrast, (1-14C)acetate, (2-14C)acetate, and (1-14C)butyrate were converted to labeled glutamate and malonate after the same route of administration. The intracerebral injection of (1-14C)-beta-alanine as a precursor of malonic semialdehyde and possibly free malonate did not give rise to radioactivity in the dicarboxylate. The labeling pattern of malonic acid is compatible with the reaction sequence: acetyl-CoA----malonyl-CoA----malonate. The final step is thought to occur by transfer of the CoA-group from malonyl-CoA to succinate and/or acetoacetate. Labeling of malonate from acetate is most effective at the age of 7 days when the net concentration of the dicarboxylic acid in rat brain is still very low. At this age, butyrate was a better precursor of malonate than acetate. It is proposed that fatty acid oxidation provides the acetyl-CoA which functions as the precursor of free brain malonate. Compartmentation of malonate biosynthesis is likely because the acetyl-CoA precursors citrate and pyruvate are ineffective.

  12. An OTC deficiency 'phenocopy' in association with Klinefelter syndrome. (United States)

    Swarts, L; Leisegang, F; Owen, E P; Henderson, H E


    Late-onset urea cycle disorder in a 20-month-old boy is unusually associated with Klinefelter syndrome with a 47XXY karyotype. We record the typical clinical and biochemical findings of ornithine transcarbamylase (OTC) deficiency in a young boy with a short history of recurrent vomiting, self mutilating behaviour, lethargy, ataxia and seizures. Laboratory studies showed hyperammonaemia and orotic aciduria, with normal citrulline and other urea cycle amino acids. Unfortunately, a liver biopsy for OTC activity measurement was refused by the parents. A rapid reversal of phenotype was seen on the introduction of a low-protein diet with accompanying benzoate and phenylbutyrate administration. Linkage studies suggested the inheritance of two X chromosomes, which was confirmed by karyotype analysis. Sequencing of all exons and immediate splice site regions revealed no sequence alterations in these sections of the OTC gene. A search for skewing of X-inactivation in the liver was not possible but we did show a random pattern of X-inactivation in leukocytes. The possibility of maternal X chromosome iso-disomy in our patient was discounted by microsatellite analysis, which revealed the inheritance of two independent X chromosomes. Mutation analysis in the OTC gene has shown that approximately 20% of patients with liver biopsy confirmed OTC deficiency do not have mutations in the coding or immediate splice-site sequences of this gene. Their classification as OTC phenocopies remains speculative, awaiting clarification of the underlying DNA alteration. We report on the novel association of OTC deficiency and Klinefelter syndrome with the additional interest of a probable unusual genetic defect underlying the OTC abnormality.

  13. Deep vein thrombosis, an unreported first manifestation of polyglandular autoimmune syndrome type III (United States)

    Hogan, P; Oliver, T


    Summary A 71-year-old woman with severe right lower leg pain, edema and erythema was presented to the Emergency Department and was found to have an extensive deep vein thrombosis (DVT) confirmed by ultrasound. She underwent an extensive evaluation due to her prior history of malignancy and new hypercoagulable state, but no evidence of recurrent disease was detected. Further investigation revealed pernicious anemia (PA), confirmed by the presence of a macrocytic anemia (MCV=115.8fL/red cell, Hgb=9.0g/dL), decreased serum B12 levels (56pg/mL), with resultant increased methylmalonic acid (5303nmol/L) and hyperhomocysteinemia (131μmol/L), the presumed etiology of the DVT. The patient also suffered from autoimmune thyroid disease (AITD), and both antithyroglobulin and anti-intrinsic factor antibodies were detected. She responded briskly to anticoagulation with heparin and coumadin and treatment of PA with intramuscular vitamin B12 injections. Our case suggests that a DVT secondary to hyperhomocystenemia may represent the first sign of polyglandular autoimmune syndrome III-B (PAS III-B), defined as the coexistent autoimmune conditions AITD and PA. It is important to recognize this clinical entity, as patients may not only require acute treatment with vitamin B12 supplementation and prolonged anticoagulation, as in this patient, but may also harbor other autoimmune diseases. Learning points A DVT can be the first physical manifestation of a polyglandular autoimmune syndrome. Hyperhomocysteinemia secondary to pernicious anemia should be considered as an etiology of an unprovoked DVT in a euthyroid patient with autoimmune thyroid disease. Patients with DVT secondary to hyperhomocysteinemia should undergo screening for the presence of co-existent autoimmune diseases in addition to treatment with B12 supplementation and anticoagulation to prevent recurrent thromboembolism. PMID:27482386

  14. The RpiR-like repressor IolR regulates inositol catabolism in Sinorhizobium meliloti. (United States)

    Kohler, Petra R A; Choong, Ee-Leng; Rossbach, Silvia


    Sinorhizobium meliloti, the nitrogen-fixing symbiont of alfalfa, has the ability to catabolize myo-, scyllo-, and D-chiro-inositol. Functional inositol catabolism (iol) genes are required for growth on these inositol isomers, and they play a role during plant-bacterium interactions. The inositol catabolism genes comprise the chromosomally encoded iolA (mmsA) and the iolY(smc01163)RCDEB genes, as well as the idhA gene located on the pSymB plasmid. Reverse transcriptase assays showed that the iolYRCDEB genes are transcribed as one operon. The iol genes were weakly expressed without induction, but their expression was strongly induced by myo-inositol. The putative transcriptional regulator of the iol genes, IolR, belongs to the RpiR-like repressor family. Electrophoretic mobility shift assays demonstrated that IolR recognized a conserved palindromic sequence (5'-GGAA-N6-TTCC-3') in the upstream regions of the idhA, iolY, iolR, and iolC genes. Complementation assays found IolR to be required for the repression of its own gene and for the downregulation of the idhA-encoded myo-inositol dehydrogenase activity in the presence and absence of inositol. Further expression studies indicated that the late pathway intermediate 2-keto-5-deoxy-D-gluconic acid 6-phosphate (KDGP) functions as the true inducer of the iol genes. The iolA (mmsA) gene encoding methylmalonate semialdehyde dehydrogenase was not regulated by IolR. The S. meliloti iolA (mmsA) gene product seems to be involved in more than only the inositol catabolic pathway, since it was also found to be essential for valine catabolism, supporting its more recent annotation as mmsA.

  15. Megaloblastic anemia in Japan

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    Full Text Available Since 1903, 744 cases of megaloblastic anemia have been reported in Japan: 490 cases of pernicious anemia; 95 cases associated with pregnancy; 66 cases after gastrectomy; 22 cases of megaloblastic anemia of infants; 21 cases of folic acid deficiency other than pregnancy and 19 cases of vitamin B12 malabsorption after ileal resection. It is generally agreed among hematologists in Japan that pernicious anemia is relatively rare, as in other Asian countries. The diagnosis of pernicious anemia in Japan is usually made by stained marrow films, radioisotopic assay of serum vitamin B12, Schilling test and good response to vitamin B12 therapy. Serum folate level, intrinsic factor or its antibody, methylmalonic acid excretion, formiminoglutamic acid excretion and deoxyuridine suppression test are performed only at a small number of laboratories. The drugs of choice are hydroxocobalamin, deoxyadenosylcobalamin and methylcobalamin. Cyanocobalamin has nearly disappeared from commercial sources in Japan. Vitamin B12 administration is common in patients with neurological disorders. Megaloblastic anemia due to folic acid deficiency is extremely rare in Japan. Low serum folate levels are frequently observed among patients receiving anticonvulsants or in pregnant women, but in such samples megaloblastic anemia is almost never detected. The folic acid content of hospital diets indicates that satisfactory amounts of folate are taken in Japan. The intake of folic acid from rice is well over the minimum daily requirement of folate. Other factors in folic acid deficiency, such as food taboos, severe alcoholism and malabsorption syndrome are not frequently found in Japanese. The inadequate intake of folate was the critical factor in most reported cases.

  16. Laboratory assessment of vitamin B12 status. (United States)

    Harrington, Dominic J


    The detection and correction of vitamin B12 (B12) deficiency prevents megaloblastic anaemia and potentially irreversible neuropathy and neuropsychiatric changes. B12 status is commonly estimated using the abundance of the vitamin in serum, with ∼148 pmol/L (200 ng/L) typically set as the threshold for diagnosing deficiency. Serum B12 assays measure the sum of haptocorrin-bound and transcobalamin-bound (known as holotranscobalamin) B12 It is only holotranscobalamin that is taken up by cells to meet metabolic demand. Although receiver operator characteristic curves show holotranscobalamin measurement to be a moderately more reliable marker of B12 status than serum B12, both assays have an indeterminate range. Biochemical evidence of metabolic abnormalities consistent with B12 insufficiency is frequently detected despite an apparently sufficient abundance of the vitamin. Laboratory B12 status markers that reflect cellular utilisation rather than abundance are available. Two forms of B12 act as coenzymes for two different reactions. Methionine synthase requires methylcobalamin for the remethylation of methionine from homocysteine. A homocysteine concentration >20 µmol/L may suggest B12 deficiency in folate-replete patients. In the second B12-dependent reaction, methylmalonyl-CoA mutase uses adenosylcobalamin to convert methylmalonyl-CoA to succinyl-CoA. In B12 deficiency excess methylmalonyl-CoA is hydrolysed to methylmalonic acid. A serum concentration >280 nmol/L may suggest suboptimal status in young patients with normal renal function. No single laboratory marker is suitable for the assessment of B12 status in all patients. Sequential assay selection algorithms or the combination of multiple markers into a single diagnostic indicator are both approaches that can be used to mitigate inherent limitations of each marker when used independently.

  17. Role of vitamin B12 on methylmalonyl-CoA mutase activity

    Institute of Scientific and Technical Information of China (English)



    Vitamin B12 is an organometallic compound with important metabolic derivatives that act as cofactors of certain enzymes,which have been grouped into three subfamilies depending on their cofactors.Among them,methylmalonyl-CoA mutase (MCM) has been extensively studied.This enzyme catalyzes the reversible isomerization of L-methylmalonyl-CoA to succinyI-CoA using adenosylcobalamin (AdoCbl) as a cofactor participating in the generation of radicals that allow isomerization of the substrate.The crystal structure of MCM determined in Propionibacterium freudenreichii var.shermanii has helped to elucidate the role of this cofactor AdoCbl in the reaction to specify the mechanism by which radicals are generated from the coenzyme and to clarify the interactions between the enzyme,coenzyme,and substrate.The existence of human methylmalonic acidemia (MMA) due to the presence of mutations in MCM shows the importance of its role in metabolism.The recent crystallization of the human MCM has shown that despite being similar to the bacterial protein,there are significant differences in the structural organization of the two proteins.Recent studies have identified the involvement of an accessory protein called MMAA,which interacts with MCM to prevent MCM's inactivation or acts as a chaperone to promote regeneration of inactivated enzyme.The interdisciplinary studies using this protein as a model in different organisms have helped to elucidate the mechanism of action of this isomerase,the impact of mutations at a functional level and their repercussion in the development and progression of MMA in humans.It is still necessary to study the mechanisms involved in more detail using new methods.

  18. Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion

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    Taraka R. Donti


    Full Text Available Mutations in subunits of succinyl-CoA synthetase/ligase (SCS, a component of the citric acid cycle, are associated with mitochondrial encephalomyopathy, elevation of methylmalonic acid (MMA, and mitochondrial DNA (mtDNA depletion. A FACS-based retroviral-mediated gene trap mutagenesis screen in mouse embryonic stem (ES cells for abnormal mitochondrial phenotypes identified a gene trap allele of Sucla2 (Sucla2SAβgeo, which was used to generate transgenic mice. Sucla2 encodes the ADP-specific β-subunit isoform of SCS. Sucla2SAβgeo homozygotes exhibited recessive lethality, with most mutants dying late in gestation (e18.5. Mutant placenta and embryonic (e17.5 brain, heart and muscle showed varying degrees of mtDNA depletion (20–60%. However, there was no mtDNA depletion in mutant liver, where the gene is not normally expressed. Elevated levels of MMA were observed in embryonic brain. SCS-deficient mouse embryonic fibroblasts (MEFs demonstrated a 50% reduction in mtDNA content compared with wild-type MEFs. The mtDNA depletion resulted in reduced steady state levels of mtDNA encoded proteins and multiple respiratory chain deficiencies. mtDNA content could be restored by reintroduction of Sucla2. This mouse model of SCS deficiency and mtDNA depletion promises to provide insights into the pathogenesis of mitochondrial diseases with mtDNA depletion and into the biology of mtDNA maintenance. In addition, this report demonstrates the power of a genetic screen that combines gene trap mutagenesis and FACS analysis in mouse ES cells to identify mitochondrial phenotypes and to develop animal models of mitochondrial dysfunction.

  19. Proteomic identification of 3-nitrotyrosine-containing rat cardiac proteins: effects of biological aging. (United States)

    Kanski, Jaroslaw; Behring, Antje; Pelling, Jill; Schöneich, Christian


    Proteomic techniques were used to identify cardiac proteins from whole heart homogenate and heart mitochondria of Fisher 344/Brown Norway F1 rats, which suffer protein nitration as a consequence of biological aging. Soluble proteins from young (5 mo old) and old (26 mo old) animals were separated by one- and two-dimensional gel electrophoresis. One- and two-dimensional Western blots with an anti-nitrotyrosine antibody show an age-related increase in the immunoresponse of a few specific proteins, which were identified by nanoelectrospray ionization-tandem mass spectrometry (NSI-MS/MS). Complementary proteins were immunoprecipitated with an immobilized anti-nitrotyrosine antibody followed by NSI-MS/MS analysis. A total of 48 proteins were putatively identified. Among the identified proteins were alpha-enolase, alpha-aldolase, desmin, aconitate hydratase, methylmalonate semialdehyde dehydrogenase, 3-ketoacyl-CoA thiolase, acetyl-CoA acetyltransferase, GAPDH, malate dehydrogenase, creatine kinase, electron-transfer flavoprotein, manganese-superoxide dismutase, F1-ATPase, and the voltage-dependent anion channel. Some contaminating blood proteins including transferrin and fibrinogen beta-chain precursor showed increased levels of nitration as well. MS/MS analysis located nitration at Y105 of the electron-transfer flavoprotein. Among the identified proteins, there are important enzymes responsible for energy production and metabolism as well as proteins involved in the structural integrity of the cells. Our results are consistent with age-dependent increased oxidative stress and with free radical-dependent damage of proteins. Possibly the oxidative modifications of the identified proteins contribute to the age-dependent degeneration and functional decline of heart proteins.

  20. The effects of folate intake on DNA and single-carbon pathway metabolism in the fruit fly Drosophila melanogaster compared to mammals. (United States)

    Blatch, Sydella A; Stabler, Sally P; Harrison, Jon F


    Mechanisms of vitamin function in non-mammals are poorly understood, despite being essential for development. Folate and cobalamin are B-vitamin cofactors with overlapping roles in transferring various single-carbon units. In mammals, one or both is needed for nucleotide synthesis, DNA methylation, amino acid conversions and other reactions. However, there has been little investigation of the response to folate or cobalamin in insects. Here, we manipulated folate intake and potentially cobalamin levels in the fruit fly Drosophila melanogaster with chemically-defined diets, an antibiotic to reduce bacterially-derived vitamins, and the folate-interfering pharmaceutical methotrexate, to see if single-carbon metabolites and DNA synthesis rates would be affected. We found that similar to mammals with low folate intake, fruit fly larvae had significantly slower growth and DNA synthesis rates. But changes to single carbon-metabolites did not mirror that of mammals with abnormal folate or given MTX. Five of the nine metabolites measured were not significantly affected (methionine, serine, glycine, methylglycine, and dimethylglycine) and three (cystathionine, methylgycine, and methylmalonic acid) were only decreased in larvae consuming methotrexate. Metabolites expected to be elevated if flies used cobalamin from microbial symbionts were not affected by dietary sulfaquinoxaline. Our data support the role of folate in nucleotide synthesis in D. melanogaster and that microbial symbionts provide functioning folates. We could not confirm how folate intake affects single carbon pathway metabolites, nor whether Drososphila use microbially-derived cobalamin. Further work should explore which cofactors are used in fruit flies in these important and potentially novel pathways.

  1. Vitamin B-12-fortified toothpaste improves vitamin status in vegans: a 12-wk randomized placebo-controlled study. (United States)

    Siebert, Anne-Kathrin; Obeid, Rima; Weder, Stine; Awwad, Hussain M; Sputtek, Andreas; Geisel, Juergen; Keller, Markus


    Background: The oral application of vitamin B-12 may prevent its deficiency if the vitamin is absorbed via the mucosal barrier.Objectives: We studied the effect of the use of a vitamin B-12-fortified toothpaste on vitamin-status markers in vegans and assessed the efficiency of markers in the identification of vitamin-augmentation status.Design: In this 12-wk, double-blinded, randomized, placebo-controlled study, 76 vegans received either a placebo (n = 34) or vitamin B-12 (n = 42) toothpaste. Sixty-six subjects (n = 30 in the placebo arm; n = 36 in the vitamin B-12 arm) completed the intervention. Serum and plasma concentrations of vitamin B-12, holotranscobalamin, total homocysteine (tHcy), and methylmalonic acid (MMA) were measured before and after the intervention.Results: Both postintervention concentrations of vitamin B-12 and holotranscobalamin and their changes over 12 wk were higher in the vitamin B-12 group (mean ± SD change: 81 ± 135 pmol/L for vitamin B-12 and 26 ± 34 pmol/L for holotranscobalamin) than in the placebo group (-27 ± 64 and -5 ± 17 pmol/L, respectively) after adjustment for baseline concentrations. Postintervention concentrations of MMA and their changes differed significantly between groups (MMA changes: -0.169 ± 0.340 compared with -0.036 ± 0.544 μmol/L in vitamin B-12 and placebo groups, respectively; P B-12 group than in the placebo group. Changes in vitamin B-12 markers were more prominent in vegans who reported that they had not taken vitamin B-12 supplements.Conclusion: Vitamin B-12 that is applied to the oral cavity via toothpaste enters the circulation and corrects the vitamin B-12 markers in the blood of vegans who are at higher risk of vitamin B-12 deficiency. This trial was registered at as NCT02679833.

  2. Folate and Vitamin B12-Related Biomarkers in Relation to Brain Volumes (United States)

    van der Zwaluw, Nikita L.; Brouwer-Brolsma, Elske M.; van de Rest, Ondine; van Wijngaarden, Janneke P.; In ’t Veld, Paulette H.; Kourie, Daniella I.; Swart, Karin M. A.; Enneman, Anke W.; van Dijk, Suzanne C.; van der Velde, Nathalie; Kessels, Roy P. C.; Smeets, Paul A. M.; Kok, Frans J.; Dhonukshe-Rutten, Rosalie A. M.; de Groot, Lisette C. P. G. M.


    Aim: We investigated cross-sectional associations between circulating homocysteine, folate, biomarkers of vitamin B12 status and brain volumes. We furthermore compared brain volumes of participants who received daily folic acid and vitamin B12 supplementation with participants who did not. Methods: Participants of the B-PROOF study (n = 2919) were assigned to 400 µg folic acid and 500 µg vitamin B12, or a placebo. After two years of intervention, T1-weighted magnetic resonance imaging (MRI) scans were made in a random subsample (n = 218) to obtain grey and white matter volume, and total brain volume (TBV). Plasma homocysteine, serum folate, vitamin B12, holotranscobalamin, and methylmalonic acid concentrations were measured. Results: Multiple linear regression analyses showed inverse associations between plasma homocysteine with TBV (β = −0.91, 95% CI −1.85–0.03; p = 0.06) and between serum folate and TBV (β = −0.20, 95% CI −0.38, −0.02; p = 0.03). No significant associations were observed for serum vitamin B12 and holotranscobalamin. Fully adjusted ANCOVA models showed that the group that received B-vitamins had a lower TBV (adjusted mean 1064, 95% CI 1058–1069 mL) than the non-supplemented group (1072, 95% CI 1067–1078 mL, p = 0.03). Conclusions: Results were contradictory, with higher Hcy levels associated with lower TBV, but also with higher folate levels associated with lower TBV. In addition, the lack of a baseline measurement withholds us from giving recommendations on whether folic acid and vitamin B12 supplementation will be beneficial above and beyond normal dietary intake for brain health. PMID:28029114

  3. High prevalence of suboptimal vitamin B12 status in young adult women of South Asian and European ethnicity. (United States)

    Quay, Teo A W; Schroder, Theresa H; Jeruszka-Bielak, Marta; Li, Wangyang; Devlin, Angela M; Barr, Susan I; Lamers, Yvonne


    Suboptimal vitamin B12 (B12) status has been associated with an increased risk of congenital anomalies, preterm birth, and childhood insulin resistance. South Asians - Canada's largest minority group - and women of reproductive age are vulnerable to B12 deficiency. This study aimed to assess the prevalence of and factors associated with B12 deficiency and suboptimal B12 status in a convenience sample of young adult women of South Asian and European descent in Metro Vancouver. We measured serum B12, holotranscobalamin, plasma methylmalonic acid, red blood cell and plasma folate, and hematologic parameters in 206 nonpregnant, healthy women aged 19-35 years. Categorization for B12 status adhered to serum B12 cutoffs for deficiency (B12 status (148-220 pmol/L). We collected demographic, lifestyle, and dietary intake data and conducted genotyping for common genetic variants linked to B-vitamin metabolism. The prevalence of deficiency and suboptimal B12 status were 14% and 20%, respectively. Serum vitamin B12 concentrations were negatively associated with oral contraceptive use and first-generation immigrant status, and positively with dietary B12 intake and B12 supplement use. The prevalence of B12 inadequacy in this sample of highly educated women is higher than in the general Canadian population. In light of maternal and fetal health risks associated with B12 inadequacy in early-pregnancy, practitioners should consider monitoring B12 status before and during early pregnancy, especially in immigrants and women with low dietary B12 intakes including non-users of vitamin supplements.

  4. Effects of intramuscular injections of vitamin B12 on lactation performance of dairy cows fed dietary supplements of folic acid and rumen-protected methionine. (United States)

    Girard, C L; Matte, J J


    The experiment was undertaken to determine the effects of i.m. injections of vitamin B(12) on lactational performance of primiparous dairy cows fed dietary supplements of folic acid and rumen-protected methionine from 4 to 18 wk of lactation. Fourteen primiparous Holstein cows were assigned to 7 blocks of 2 cows each, according to milk production during the third week of lactation. All cows were fed a basal diet supplemented daily with rumen-protected methionine (18 g of supplement, to bring the estimated supply of methionine to 2.2% of metabolizable protein) plus folic acid (4 mg per kg of BW). Within each block, the cows received a weekly i.m. injection (2 mL) of saline or 10 mg of vitamin B(12). Milk production was recorded daily. Milk and blood were sampled every 2 wk. Supplementary vitamin B(12) increased energy-corrected milk from 25.8 to 29.0 (SE 1.6) kg/d, as well as milk yields of solids [3.52 to 3.90 (SE 0.22) kg/d], fat [0.87 to 1.01 (SE 0.06) kg/d], and lactose [1.48 to 1.64 (SE 0.11) kg/d]. Supplementation also increased concentrations and amounts of vitamin B(12) secreted in milk but had no significant effect on dry matter intake and concentrations and amounts of folates in milk. Packed cell volume, blood hemoglobin, and serum vitamin B(12) were increased by supplementary vitamin B(12), whereas serum methylmalonic acid was decreased. Serum concentrations of sulfur amino acids were unchanged by treatment. These findings support the hypothesis that, in early lactation, supply of vitamin B(12) was not optimal and limited the lactation performance of the cows.

  5. Associations of Milk Consumption and Vitamin B₂ and Β12 Derived from Milk with Fitness, Anthropometric and Biochemical Indices in Children. The Healthy Growth Study. (United States)

    Moschonis, George; van den Heuvel, Ellen G H M; Mavrogianni, Christina; Singh-Povel, Cécile M; Leotsinidis, Michalis; Manios, Yannis


    The benefits of dairy consumption seem to extend beyond its significant contribution to ensuring nutrient intake adequacy as indicated by the favourable associations with several health outcomes reported by different studies. The aims of the present study were to examine the associations of milk consumption with fitness, anthropometric and biochemical indices in children and further explore whether the observed associations are attributed to vitamins B₂ and B12 derived from milk. A representative subsample of 600 children aged 9-13 years participating in the Healthy Growth Study was examined. Data were collected on children's dietary intake, using 24 h recalls, as well as on fitness, anthropometric and biochemical indices. Regression analyses were performed for investigating the research hypothesis, adjusting for potential confounders and for B-vitamin status indices (i.e., plasma riboflavin, methylmalonic acid and total homocysteine concentrations), dietary calcium intake and plasma zinc concentrations that could possibly act as effect modifiers. Milk consumption was positively associated with the number of stages performed in the endurance run test (ERT) (β = 0.10; p = 0.017) and negatively with body mass index (BMI) (β = -0.10; p = 0.014), after adjusting for several potential confounders and effect modifiers. Dietary intakes of vitamin B₂ and B12 derived from milk were also positively associated with the number of ERT stages (β = 0.10; p = 0.015 and β = 0.10; p = 0.014 respectively). In conclusion, higher intake of milk as well as vitamin B₂ and B12 derived from milk were independently associated with higher cardiorespiratory fitness in Greek preadolescents. The key roles of these B-vitamins in substrate oxidation, energy production, haemoglobin synthesis and erythropoiesis could provide a basis for interpreting these associations. However, further research is needed to confirm this potential interpretation.

  6. Effects of intramuscular injections of folic acid, vitamin B12, or both, on lactational performance and energy status of multiparous dairy cows. (United States)

    Duplessis, M; Lapierre, H; Pellerin, D; Laforest, J-P; Girard, C L


    The purpose of this experiment was to gain understanding on changes in energy partitioning when folic acid and vitamin B12 supplements, alone or combined, were given by weekly intramuscular injections from 3 wk before the expected calving date until 7 wk postpartum. Twenty-four multiparous cows were assigned to 6 blocks of 4 cows each according to previous 305-d lactation yield to either 0 or 320 mg of folic acid and 0 or 10 mg of vitamin B12 in a 2 × 2 factorial arrangement. Plasma concentration of folates was increased by folic acid supplement, and this increase was greater with the combined supplement. Vitamin B12 supplement increased plasma concentration of vitamin B12. Even though postpartum energy balance was similar among treatments, postpartum body condition score was higher for cows receiving folic acid supplement compared with cows that did not. Milk yield of cows receiving folic acid supplement reached a plateau earlier than for cows that did not. Fat and protein, as well as total solid concentrations and yields, were unaffected by treatments. Postpartum plasma concentrations of glucose and insulin were higher and postpartum plasma concentration of nonesterified fatty acids was lower for cows that received weekly folic acid supplement compared with cows that did not. Plasma concentration of methylmalonic acid was low and unaffected by treatments, suggesting that vitamin B12 supply was not limiting, even for unsupplemented cows. Postpartum plasma concentrations of Cys, His, Phe, and Tyr were increased, whereas plasma concentration of Gly was decreased, by folic acid supplement. In the present study, supplementary folic acid altered energy partitioning in early lactation as suggested by similar milk total solid yield and postpartum energy balance, lower plasma nonesterified fatty acid concentration and body condition score losses, and higher plasma glucose and insulin concentrations for cows receiving folic acid supplement compared with cows that did not.

  7. Evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). (United States)

    England, J D; Gronseth, G S; Franklin, G; Carter, G T; Kinsella, L J; Cohen, J A; Asbury, A K; Szigeti, K; Lupski, J R; Latov, N; Lewis, R A; Low, P A; Fisher, M A; Herrmann, D; Howard, J F; Lauria, G; Miller, R G; Polydefkis, M; Sumner, A J


    Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of laboratory and genetic tests for the assessment of DSP. A literature review using MEDLINE, EMBASE, Science Citation Index, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. (1) Screening laboratory tests may be considered for all patients with polyneuropathy (Level C). Those tests that provide the highest yield of abnormality are blood glucose, serum B(12) with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Level C). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (Level C). (2) Genetic testing is established as useful for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic (EDX) features and should focus on the most common abnormalities, which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening. There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (Level U).

  8. N-acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pups.

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    Fernanda S Rodrigues

    Full Text Available BACKGROUND AND AIMS: Glutaric aciduria type I (GA-I is characterized by accumulation of glutaric acid (GA and neurological symptoms, such as cognitive impairment. Although this disease is related to oxidative stress and inflammation, it is not known whether these processes facilitate the memory impairment. Our objective was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS in spatial memory test, antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. We also evaluated the effect of N-acetylcysteine (NAC on theses markers. METHODS: Rat pups were injected with GA (5 umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life, and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period. LPS (2 mg/kg; E.coli 055 B5 or vehicle (saline 0.9% was injected intraperitoneally, once per day, from 25th to 28th day of life. Oxidative stress and inflammatory biomarkers as well as hippocampal volume were assessed. RESULTS: GA caused spatial learning deficit in the Barnes maze and LPS potentiated this effect. GA and LPS increased TNF-α and IL-1β levels. The co-administration of these compounds potentiated the increase of IL-1β levels but not TNF-α levels in the hippocampus. GA and LPS increased TBARS (thiobarbituric acid-reactive substance content, reduced antioxidant defenses and inhibited Na+, K+-ATPase activity. GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. NAC protected against impairment of spatial learning and increase of cytokines levels. NAC Also protected against inhibition of Na+,K+-ATPase activity and oxidative markers. CONCLUSIONS: These results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Thus, NAC could

  9. Alanine-glyoxylate aminotransferase 2 (AGXT2 polymorphisms have considerable impact on methylarginine and β-aminoisobutyrate metabolism in healthy volunteers.

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    Anja Kittel

    -β-aminoisobutyric aciduria.


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    Gholamreza ZAMANI


    Full Text Available Organic acidemias, also known as organic acidurias, are a group of disorders characterized by increased excretion of organic acids in urine. They result primarily from deficiencies of specific enzymes in the breakdown pathways of amino acids or from enzyme deficiencies in beta oxidation of fatty acids or carbohydrate metabolism. Organic acids also are found in the urine of some patients with mitochondrial disease.Most organic acidemias become clinically apparent during the newborn period or early infancy. After an initial period of well-being, affected children develop a life-threatening episode of metabolic acidosis characterized by an increased anion gap. This presenting episode may be mistaken for sepsis, and if unrecognized, is associated with significant mortality.Children with an organic acidemia are susceptible to metabolic decompensation during episodes of increased catabolism, such as intercurrent illness, trauma, or surgery. Parents and clinicians must be well informed about the initial signs of decompensation and trained in applying an emergency regimen . Surgeons and anesthesiologists should be aware of potential complications and their prevention during anesthesia and surgery.Diagnosis has been facilitated through the use of gas chromatograph-mass spectrometry (GC-MS and tandem mass spectrometry .Prenatal diagnosis is available for most disorders by detection of diagnostic compounds in amniotic fluid; by analysis of enzyme activities in amniocytes or chorionic villi; by molecular analysis; or by a combination of the three . Diagnosis also may be made through newborn screening by tandem mass spectrometry .Laboratory findings are an essential part of the diagnostic approach to organic acidemias. In most organic acidemias, metabolism of glucose, ketone bodies, and ammonia is deranged primarily or secondarily, in addition to derangement of the acid-base balance. Hypoglycemia, lactic and/or ketoacidosis, and hyperammonemia of varying

  11. Crystal Structures of Two Bacterial 3-Hydroxy-3-methylglutaryl-CoA Lyases Suggest a Common Catalytic Mechanism among a Family of TIM Barrel Metalloenzymes Cleaving Carbon-Carbon Bonds

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    Forouhar,F.; Hussain, M.; Farid, R.; Benach, J.; Abashidze, M.; Edstrom, W.; Vorobiev, S.; Montelione, G.; Hunt, J.; et al.


    The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase catalyzes the terminal steps in ketone body generation and leucine degradation. Mutations in this enzyme cause a human autosomal recessive disorder called primary metabolic aciduria, which typically kills victims because of an inability to tolerate hypoglycemia. Here we present crystal structures of the HMG-CoA lyases from Bacillus subtilis and Brucella melitensis at 2.7 and 2.3 {angstrom} resolution, respectively. These enzymes share greater than 45% sequence identity with the human orthologue. Although the enzyme has the anticipated triose-phosphate isomerase (TIM) barrel fold, the catalytic center contains a divalent cation-binding site formed by a cluster of invariant residues that cap the core of the barrel, contrary to the predictions of homology models. Surprisingly, the residues forming this cation-binding site and most of their interaction partners are shared with three other TIM barrel enzymes that catalyze diverse carbon-carbon bond cleavage reactions believed to proceed through enolate intermediates (4-hydroxy-2-ketovalerate aldolase, 2-isopropylmalate synthase, and transcarboxylase 5S). We propose the name 'DRE-TIM metallolyases' for this newly identified enzyme family likely to employ a common catalytic reaction mechanism involving an invariant Asp-Arg-Glu (DRE) triplet. The Asp ligates the divalent cation, while the Arg probably stabilizes charge accumulation in the enolate intermediate, and the Glu maintains the precise structural alignment of the Asp and Arg. We propose a detailed model for the catalytic reaction mechanism of HMG-CoA lyase based on the examination of previously reported product complexes of other DRE-TIM metallolyases and induced fit substrate docking studies conducted using the crystal structure of human HMG-CoA lyase (reported in the accompanying paper by Fu, et al. (2006) J. Biol. Chem. 281, 7526-7532). Our model is consistent with extensive mutagenesis

  12. Two Child Patients Misdiagnosed as Cerebral Palsy%误诊为脑性瘫痪康复治疗患儿二例分析

    Institute of Scientific and Technical Information of China (English)



    Diseasescausingdevelopmentretardationandmotionabnormalitiesinchildrenaremany,suchas,besides cerebral palsy( CP),thyroid hypofunction,chromosomal abnormalities,genetic metabolic diseases,leucodystrophy,dystonia, etc. Glutaric aciduria is a branched chain amino acid metabolism disorder,presenting with development retardation and dystonia accompanied mainly by a serious injuries to nervous system such as epilepsy and with the clinical manifestations of intermittent vomiting,hypoglycemia,metabolic acidosis and so on. Dysmyotonia has a feature of mildness in the morning and severity in the evening besides the performances of development retardation and motion abnormalities. This paper reviews 2 child patients with the above-mentioned diseases misdiagnosed as CP and their rehabilitation therapies,to deepen rehabilitation doctors′awareness about CP to make correct diagnoses and treatments timely.%引起患儿发育落后、运动异常的疾病很多,除脑性瘫痪外还可见于甲状腺功能低下、染色体异常、遗传代谢性疾病、脑白质病、肌张力障碍等。戊二酸尿症属支链氨基酸代谢障碍性疾病,除表现为发育落后及肌张力异常外,主要伴随有神经系统严重损伤(如癫痫),同时多表现有间断性呕吐、低血糖、代谢性酸中毒等临床表现。肌张力障碍性疾病表现为发育落后及运动障碍,且运动障碍具有晨轻暮重的特点。本文对将以上疾病误诊为脑性瘫痪康复治疗的2例患儿进行分析,以加深康复医生对脑性瘫痪的认识,及时做出正确诊断与治疗,避免发生误诊。

  13. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. (United States)

    Stockler, Sylvia; Plecko, Barbara; Gospe, Sidney M; Coulter-Mackie, Marion; Connolly, Mary; van Karnebeek, Clara; Mercimek-Mahmutoglu, Saadet; Hartmann, Hans; Scharer, Gunter; Struijs, Eduard; Tein, Ingrid; Jakobs, Cornelis; Clayton, Peter; Van Hove, Johan L K


    Antiquitin (ATQ) deficiency is the main cause of pyridoxine dependent epilepsy characterized by early onset epileptic encephalopathy responsive to large dosages of pyridoxine. Despite seizure control most patients have intellectual disability. Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency. ATQ functions as an aldehyde dehydrogenase (ALDH7A1) in the lysine degradation pathway. Its deficiency results in accumulation of α-aminoadipic semialdehyde (AASA), piperideine-6-carboxylate (P6C) and pipecolic acid, which serve as diagnostic markers in urine, plasma, and CSF. To interrupt seizures a dose of 100 mg of pyridoxine-HCl is given intravenously, or orally/enterally with 30 mg/kg/day. First administration may result in respiratory arrest in responders, and thus treatment should be performed with support of respiratory management. To make sure that late and masked response is not missed, treatment with oral/enteral pyridoxine should be continued until ATQ deficiency is excluded by negative biochemical or genetic testing. Long-term treatment dosages vary between 15 and 30 mg/kg/day in infants or up to 200 mg/day in neonates, and 500 mg/day in adults. Oral or enteral pyridoxal phosphate (PLP), up to 30 mg/kg/day can be given alternatively. Prenatal treatment with maternal pyridoxine supplementation possibly improves outcome. PDE is an organic aciduria caused by a deficiency in the catabolic breakdown of lysine. A lysine restricted diet might address the potential toxicity of accumulating αAASA, P6C and pipecolic acid. A multicenter study on long term outcomes is needed to document potential benefits of this additional treatment. The differential diagnosis of pyridoxine or PLP responsive seizure disorders includes PLP-responsive epileptic encephalopathy due to PNPO deficiency, neonatal/infantile hypophosphatasia (TNSALP deficiency), familial hyperphosphatasia (PIGV deficiency), as well as yet unidentified conditions and nutritional

  14. Oculocerebrorenal syndrome of Lowe: magnetic resonance imaging findings in the first six years of life

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    Carvalho-Neto, Arnolfo de; Ono, Sergio Eiji; Cardoso, Georgina de Melo; Santos, Mara Lucia Schmitz Ferreira; Celidonio, Izabela [Hospital Pequeno Principe, Curitiba, PR (Brazil)], e-mail:


    The oculocerebrorenal syndrome of Lowe (OCRL), was first recognized as a distinct disease in 1952 by Drs. Lowe, Terrey and MacLachlan at Massachusetts General Hospital, in Boston, USA, describing three male children with organic aciduria, decreased renal ammonia production, hydrophtalmos and mental retardation. The X-linked recessive inheritance pattern was recognized first by LeFebvre. It is present in all races, with a predominance in those of Caucasian and Asian ancestries. Rarely females are affected. It is a very rare disease, with estimated prevalence in the general population of 1 in 500,000. In USA the Lowe Syndrome Association (LSA) documented 190 living patients in the year 2000 (0.67 x million inhabitants). It is caused by a mutation in the gene encoding oculocerebrorenal- Lowe protein (OCRL1), isolated in 1992, linked to the Xq24-q26 region of the X chromosome,4-6. Approximately 60% of OCRL patients demonstrate a loss of OCRL gene expression, and the definitive laboratory test, that can be used for prenatal diagnosis, is the biochemical assay for deficiency of phosphatidylinositol 4,5-biphosphate 5-phosphate in cultured fibroblasts. The classic triad of eye, central nervous system, and kidney involvement are required for the diagnosis of Lowe's syndrome. Cataract is present at birth in all patients and glaucoma is detected within the first year of life. Hypotonia compromises suction and causes serious respiratory problems in the first period of life. Motor development is retarded and mental retardation is moderate or severe in almost all cases. Obsessive-compulsive behavior is typical. Seizure is seen in approximately 50% of the patients over 18 years old. Renal disease is primarily characterized by renal Fanconi syndrome but many children are asymptomatic at birth. Renal involvement is initially related to bicarbonate, salt and water wasting, causing failure to thrive. Later, a significant number of patients develop chronic renal failure. The

  15. Clinical and laboratory survey of 65 Chinese patients with Leigh syndrome

    Institute of Scientific and Technical Information of China (English)

    YANG Yan-ling; QI Zhao-yue; ZHANG Yue-hua; JIANG Yu-wu; BAO Xin-hua; QIN Jiong; WU Xi-ru; SUN Fang; ZHANG Yao; QIAN Ning; YUAN Yun; WANG Zhao-xia; QI Yu; XIAO Jiang-xi; WANG Xiao-ying


    Background Leigh syndrome is an inherited neurodegenerative disease that emerges in infancy and childhood and presents with a clinically heterogeneous variety of neuromuscular and non-neuromuscular disorders. It can result from the inheritance of mutations in either nuclear or mitochondrial DNA. In the current study, we performed a retrospective study in 65 patients in order to investigate the clinical and genetic characteristics of Leigh syndrome in Chinese patients.Methods Sixty-five unrelated cases (35 men and 30 women) who were hospitalized in the past 12 years were reviewed. Diagnosis was based on both the clinical presentation and the characteristic neuropathologic findings of bilateral symmetric necrotizing lesions in the basal ganglia and brain stem as detected using cranial computed tomography (CT) scan or magnetic resonance imaging (MRI). The differential diagnosis of organic acidurias and fatty acid β-oxidation defects were performed. Specific point mutations and deletions in mitochondrial DNA (T8993G, T8993C, T9176C, A8344G, A3243G) were screened by PCR-restriction analysis and Southern blot.The SURF1 gene was sequenced. Skeletal muscle biopsies were performed in 17 (26.2%) of the patients. The diagnosis was confirmed by autopsy in 6 (9.2%) patients.Results The patients had various forms of metabolic encephalomyopathy. Fifty-nine (90.8%) of the patients had the typical neuroradiological features of Leigh syndrome, including symmetrical necrotizing lesions scattered within the basal ganglia, thalamus and brain stem. Twenty (30.8%) patients were confirmed by genetic,biochemical analysis and autopsy. Specific point mutations in mitochondrial DNA were found in 5 cases (7.7%).Of these, the A8344G mutation was detected in 2 patients. The T8993G, T8993C, and A3243G point mutations were identified in 3 other patients, respectively. SURF1 mutations associated with cytochrome c oxidase deficiency were identified in 8 (12.3%) families by DNA sequencing. A G604C

  16. Barth Syndrome:From mitochondrial dysfunctions associated with aberrant production of reactive oxygen species to pluripotent stem cell studies

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    Ana eSaric


    Full Text Available Mutations in the gene encoding the enzyme tafazzin, TAZ, cause Barth syndrome (BTHS. Individuals with this X-linked multisystem disorder present cardiomyopathy (often dilated, skeletal muscle weakness, neutropenia, growth retardation and 3-methylglutaconic aciduria. Biopsies of the heart, liver and skeletal muscle of patients have revealed mitochondrial malformations and dysfunctions. It is the purpose of this review to summarize recent results of studies on various animal or cell models of Barth syndrome, which have characterized biochemically the strong cellular defects associated with TAZ mutations. Tafazzin is a mitochondrial phospholipid-lysophospholipid transacylase that shuttles acyl groups between phospholipids and regulates the remodeling of cardiolipin (CL, a unique inner mitochondrial membrane phospholipid dimer consisting of two phosphatidyl residues linked by a glycerol bridge. After their biosynthesis, the acyl chains of CLs may be modified in remodeling processes involving up to three different enzymes. Their characteristic acyl chain composition depends on the function of tafazzin, although the enzyme itself surprisingly lacks acyl specificity. CLs are crucial for correct mitochondrial structure and function. In addition to their function in the basic mitochondrial function of ATP production, CLs play essential roles in cardiac function, apoptosis, autophagy, cell cycle regulation and Fe-S cluster biosynthesis. Recent developments in tafazzin research have provided strong insights into the link between mitochondrial dysfunction and the production of reactive oxygen species (ROS. An important tool has been the generation of BTHS-specific induced pluripotent stem cells (iPSCs from BTHS patients. In a complementary approach, disease-specific mutations have been introduced into wild-type iPSC lines enabling direct comparison with isogenic controls. iPSC-derived cardiomyocytes were then characterized using biochemical and classical


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    Seyyed Hassan TONEKABONI


    .Sometimes these episodes can lead to death or severe sequel. Seizure disorder is one of these sequels which is generalized in type with myoclonic seizure in infancy and childhood and later tonic-clonic and atypical absence seizures predominate.Also many of the survivors have acute or progressive extra pyramidal syndrome due to bilateral necrosis of basal ganglia.Chronic progressive formsNon specific Developmental delay, hypotonia, muscular weakness, microcephaly and seizures are rarely the only revealing signs in organic acidemia without any acute presentation.Seizures may become refractory to Anti Epileptic Drugs. In addition many asymptomatic or minimally symptomatic infants have been identified during tandem mass spectrometry newborn screening program. Cognitive deterioration associated with movement disorder such as dystonia or chorea may be caused by any form of organic aciduria.

  18. Oral vitamin B12 for patients suspected of subtle cobalamin deficiency: a multicentre pragmatic randomised controlled trial

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    Ali Giuseppa


    Full Text Available Abstract Background Evidence regarding the effectiveness of oral vitamin B12 in patients with serum vitamin B12 levels between 125-200 pM/l is lacking. We compared the effectiveness of one-month oral vitamin B12 supplementation in patients with a subtle vitamin B12 deficiency to that of a placebo. Methods This multicentre (13 general practices, two nursing homes, and one primary care center in western Switzerland, parallel, randomised, controlled, closed-label, observer-blind trial included 50 patients with serum vitamin B12 levels between 125-200 pM/l who were randomized to receive either oral vitamin B12 (1000 μg daily, N = 26 or placebo (N = 24 for four weeks. The institution's pharmacist used simple randomisation to generate a table and allocate treatments. The primary outcome was the change in serum methylmalonic acid (MMA levels after one month of treatment. Secondary outcomes were changes in total homocysteine and serum vitamin B12 levels. Blood samples were centralised for analysis and adherence to treatment was verified by an electronic device (MEMS; Aardex Europe, Switzerland. Trial registration: ISRCTN 22063938. Results Baseline characteristics and adherence to treatment were similar in both groups. After one month, one patient in the placebo group was lost to follow-up. Data were evaluated by intention-to-treat analysis. One month of vitamin B12 treatment (N = 26 lowered serum MMA levels by 0.13 μmol/l (95%CI 0.06-0.19 more than the change observed in the placebo group (N = 23. The number of patients needed to treat to detect a metabolic response in MMA after one month was 2.6 (95% CI 1.7-6.4. A significant change was observed for the B12 serum level, but not for the homocysteine level, hematocrit, or mean corpuscular volume. After three months without active treatment (at four months, significant differences in MMA levels were no longer detected. Conclusions Oral vitamin B12 treatment normalised the metabolic markers of vitamin B

  19. 4-ethylphenyl-cobalamin impairs tissue uptake of vitamin B12 and causes vitamin B12 deficiency in mice.

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    Elena Mutti

    Full Text Available Coβ-4-ethylphenyl-cob(III alamin (EtPhCbl is an organometallic analogue of vitamin B12 (CNCbl which binds to transcobalamin (TC, a plasma protein that facilitates the cellular uptake of cobalamin (Cbl. In vitro assays with key enzymes do not convert EtPhCbl to the active coenzyme forms of Cbl suggesting that administration of EtPhCbl may cause cellular Cbl deficiency. Here, we investigate the in vivo effect of EtPhCbl in mice and its ability, if any, to induce Cbl deficiency. We show that EtPhCbl binds to mouse TC and we examined mice that received 3.5 nmol/24h EtPhCbl (n=6, 3.5 nmol/24h CNCbl (n=7 or NaCl (control group (n=5 through osmotic mini-pumps for four weeks. We analyzed plasma, urine, liver, spleen, submaxillary glands and spinal cord for Cbl and markers of Cbl deficiency including methylmalonic acid (MMA and homocysteine (tHcy. Plasma MMA (mean±SEM was elevated in animals treated with EtPhCbl (1.01±0.12 µmol/L compared to controls (0.30±0.02 µmol/L and CNCbl (0.29±0.01 µmol/L treated animals. The same pattern was observed for tHcy. Plasma total Cbl concentration was higher in animals treated with EtPhCbl (128.82±1.87 nmol/L than in CNCbl treated animals (87.64±0.93 nmol/L. However, the organ levels of total Cbl were significantly lower in animals treated with EtPhCbl compared to CNCbl treated animals or controls, notably in the liver (157.07±8.56 pmol/g vs. 603.85±20.02 pmol/g, and 443.09±12.32 pmol/g, respectively. Differences between the three groups was analysed using one-way ANOVA and, Bonferroni post-hoc test. EtPhCbl was present in all tissues, except the spinal cord, accounting for 35-90% of total Cbl. In conclusion, treatment with EtPhCbl induces biochemical evidence of Cbl deficiency. This may in part be caused by a compromised tissue accumulation of Cbl.

  20. 4-ethylphenyl-cobalamin impairs tissue uptake of vitamin B12 and causes vitamin B12 deficiency in mice. (United States)

    Mutti, Elena; Ruetz, Markus; Birn, Henrik; Kräutler, Bernhard; Nexo, Ebba


    Coβ-4-ethylphenyl-cob(III) alamin (EtPhCbl) is an organometallic analogue of vitamin B12 (CNCbl) which binds to transcobalamin (TC), a plasma protein that facilitates the cellular uptake of cobalamin (Cbl). In vitro assays with key enzymes do not convert EtPhCbl to the active coenzyme forms of Cbl suggesting that administration of EtPhCbl may cause cellular Cbl deficiency. Here, we investigate the in vivo effect of EtPhCbl in mice and its ability, if any, to induce Cbl deficiency. We show that EtPhCbl binds to mouse TC and we examined mice that received 3.5 nmol/24h EtPhCbl (n=6), 3.5 nmol/24h CNCbl (n=7) or NaCl (control group) (n=5) through osmotic mini-pumps for four weeks. We analyzed plasma, urine, liver, spleen, submaxillary glands and spinal cord for Cbl and markers of Cbl deficiency including methylmalonic acid (MMA) and homocysteine (tHcy). Plasma MMA (mean±SEM) was elevated in animals treated with EtPhCbl (1.01±0.12 µmol/L) compared to controls (0.30±0.02 µmol/L) and CNCbl (0.29±0.01 µmol/L) treated animals. The same pattern was observed for tHcy. Plasma total Cbl concentration was higher in animals treated with EtPhCbl (128.82±1.87 nmol/L) than in CNCbl treated animals (87.64±0.93 nmol/L). However, the organ levels of total Cbl were significantly lower in animals treated with EtPhCbl compared to CNCbl treated animals or controls, notably in the liver (157.07±8.56 pmol/g vs. 603.85±20.02 pmol/g, and 443.09±12.32 pmol/g, respectively). Differences between the three groups was analysed using one-way ANOVA and, Bonferroni post-hoc test. EtPhCbl was present in all tissues, except the spinal cord, accounting for 35-90% of total Cbl. In conclusion, treatment with EtPhCbl induces biochemical evidence of Cbl deficiency. This may in part be caused by a compromised tissue accumulation of Cbl.

  1. Radioiodinated phenylalkyl malonic acid derivatives as pH-sensitive SPECT tracers.

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    Matthias Bauwens

    Full Text Available INTRODUCTION: In vivo pH imaging has been a field of interest for molecular imaging for many years. This is especially important for determining tumor acidity, an important driving force of tumor invasion and metastasis formation, but also in the process of apoptosis. METHODS: 2-(4-[(123I]iodophenethyl-2-methylmalonic acid (IPMM, 2-(4-[(123I]iodophenethyl-malonic acid (IPM, 2-(4-[(123I]iodobenzyl-malonic acid (IBMM and 4-[(123I]iodophthalic acid (IP were radiolabeled via the Cu(+ isotopic nucleophilic exchange method. All tracers were tested in vitro in buffer systems to assess pH driven cell uptake. In vivo biodistribution of [(123I]IPMM and [(123I]IPM was determined in healthy mice and the pH targeting efficacy in vivo of [(123I]IPM was evaluated in an anti-Fas monoclonal antibody (mAb apoptosis model. In addition a mouse RIF-1 tumor model was explored in which tumor pH was decreased from 7.0 to 6.5 by means of induction of hyperglycemia in combination with administration of meta-iodobenzylguanidine. RESULTS: Radiosynthesis resulted in 15-20% for iodo-bromo exchange and 50-60% yield for iodo-iodo exchange while in vitro experiments showed a pH-sensitive uptake for all tracers. Shelf-life stability and in vivo stability was excellent for all tracers. [(123I]IPMM and [(123I]IPM showed a moderately fast predominantly biliary clearance while a high retention was observed in blood. The biodistribution profile of [(123I]IPM was found to be most favorable in view of pH-specific imaging. [(123I]IPM showed a clear pH-related uptake pattern in the RIF-1 tumor model. CONCLUSION: Iodine-123 labeled malonic acid derivates such as [(123I]IPM show a clearly pH dependent uptake in tumor cells both in vitro and in vivo which allows to visualize regional acidosis. However, these compounds are not suitable for detection of apoptosis due to a poor acidosis effect.

  2. Milk metabolome relates enteric methane emission to milk synthesis and energy metabolism pathways. (United States)

    Antunes-Fernandes, E C; van Gastelen, S; Dijkstra, J; Hettinga, K A; Vervoort, J


    Methane (CH4) emission of dairy cows contributes significantly to the carbon footprint of the dairy chain; therefore, a better understanding of CH4 formation is urgently needed. The present study explored the milk metabolome by gas chromatography-mass spectrometry (milk volatile metabolites) and nuclear magnetic resonance (milk nonvolatile metabolites) to better understand the biological pathways involved in CH4 emission in dairy cattle. Data were used from a randomized block design experiment with 32 multiparous Holstein-Friesian cows and 4 diets. All diets had a roughage:concentrate ratio of 80:20 (dry matter basis) and the roughage was grass silage (GS), corn silage (CS), or a mixture of both (67% GS, 33% CS; 33% GS, 67% CS). Methane emission was measured in climate respiration chambers and expressed as CH4 yield (per unit of dry matter intake) and CH4 intensity (per unit of fat- and protein-corrected milk; FPCM). No volatile or nonvolatile metabolite was positively related to CH4 yield, and acetone (measured as a volatile and as a nonvolatile metabolite) was negatively related to CH4 yield. The volatile metabolites 1-heptanol-decanol, 3-nonanone, ethanol, and tetrahydrofuran were positively related to CH4 intensity. None of the volatile metabolites was negatively related to CH4 intensity. The nonvolatile metabolites acetoacetate, creatinine, ethanol, formate, methylmalonate, and N-acetylsugar A were positively related to CH4 intensity, and uridine diphosphate (UDP)-hexose B and citrate were negatively related to CH4 intensity. Several volatile and nonvolatile metabolites that were correlated with CH4 intensity also were correlated with FPCM and not significantly related to CH4 intensity anymore when FPCM was included as covariate. This suggests that changes in these milk metabolites may be related to changes in milk yield or metabolic processes involved in milk synthesis. The UDP-hexose B was correlated with FPCM, whereas citrate was not. Both metabolites were

  3. An Economic Evaluation of Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Thailand.

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    Kittiphong Thiboonboon

    Full Text Available Inborn errors of metabolism (IEM are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand.A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB and health outcomes in life-years (LYs and quality-adjusted life year (QALYs presented as an incremental cost-effectiveness ratio (ICER. The results were also adjusted to international dollars (I$ using purchasing power parities (PPP (1 I$ = 17.79 THB for the year 2013. The comparisons were between 1 an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU; isovaleric acidemia (IVA; methylmalonic acidemia (MMA; propionic acidemia (PA; maple syrup urine disease (MSUD; and multiple carboxylase deficiency (MCD; and 2 the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years.The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained. The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$ over 10 years.At the current ceiling threshold, neonatal screening using MS/MS in the Thai context is not cost

  4. Anchoring secreted proteins in endoplasmic reticulum by plant oleosin: the example of vitamin B12 cellular sequestration by transcobalamin.

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    Laurent Pons

    Full Text Available BACKGROUND: Oleosin is a plant protein localized to lipid droplets and endoplasmic reticulum of plant cells. Our idea was to use it to target functional secretory proteins of interest to the cytosolic side of the endoplasmic reticulum of mammalian cells, through expressing oleosin-containing chimeras. We have designed this approach to create cellular models deficient in vitamin B12 (cobalamin because of the known problematics associated to the obtainment of effective vitamin B12 deficient cell models. This was achieved by the overexpression of transcobalamin inside cells through anchoring to oleosin. METHODOLOGY: chimera gene constructs including transcobalamin-oleosin (TC-O, green fluorescent protein-transcobalamin-oleosin (GFP-TC-O and oleosin-transcobalamin (O-TC were inserted into pAcSG2 and pCDNA3 vectors for expression in sf9 insect cells, Caco2 (colon carcinoma, NIE-115 (mouse neuroblastoma, HEK (human embryonic kidney, COS-7 (Green Monkey SV40-transfected kidney fibroblasts and CHO (Chinese hamster ovary cells. The subcellular localization, the changes in vitamin B12 binding activity and the metabolic consequences were investigated in both Caco2 and NIE-115 cells. PRINCIPAL FINDINGS: vitamin B12 binding was dramatically higher in TC-O than that in O-TC and wild type (WT. The expression of GFP-TC-O was observed in all cell lines and found to be co-localized with an ER-targeted red fluorescent protein and calreticulin of the endoplasmic reticulum in Caco2 and COS-7 cells. The overexpression of TC-O led to B12 deficiency, evidenced by impaired conversion of cyano-cobalamin to ado-cobalamin and methyl-cobalamin, decreased methionine synthase activity and reduced S-adenosyl methionine to S-adenosyl homocysteine ratio, as well as increases in homocysteine and methylmalonic acid concentration. CONCLUSIONS/SIGNIFICANCE: the heterologous expression of TC-O in mammalian cells can be used as an effective strategy for investigating the cellular

  5. The usefulness of holotranscobalamin in predicting vitamin B12 status in different clinical settings. (United States)

    Herrmann, Wolfgang; Obeid, Rima; Schorr, Heike; Geisel, Jürgen


    Serum concentrations of homocysteine (Hcy) and methylmalonic acid (MMA) become increased in B12-deficient subjects and are therefore, considered specific markers of B12 deficiency. Serum level of holotranscobalamin (holoTC) becomes decreased before the development of the metabolic dysfunction. We investigated the usefulness of holoTC in diagnosing B12 deficiency in some clinical settings. We measured serum concentrations of holoTC, MMA, Hcy and total B12 in omnivores, vegetarians, elderly people and haemodialysis patients. Our results indicated that the incidence of holoTC vegans (76%). Low holoTC and elevated MMA were detected in 64% of the vegans and 43% of the lacto- and lacto-ovovegetarians. An elevated MMA and a low holoTC were found in subjects with total serum B12 as high as 300 pmol/L. The distribution of holoTC in elderly people was similar to that in younger adults (median holoTC 55 pmol/L in both groups). A low holoTC and an elevated MMA were found in 16% of the elderly group. An elevated MMA and a normal holoTC were found in 20% of the elderly group who had a relatively high median serum concentration of creatinine (106.1 micromol/L). Serum concentrations of holoTC in dialysis patients were considerably higher than all other groups (median 100 pmol/L). This was also associated with severely increased serum levels of MMA (median 987 nmol/L). From these results it can be concluded that serum concentration of holoTC is a much better predictor of B12 status than total B12. This was particularly evident in case of dietary B12 deficiency. Serum concentrations of holoTC as well as MMA can be affected by renal dysfunction. Elevated MMA and normal holoTC in patients with renal insufficiency may not exclude vitamin B12 deficiency. HoloTC seems not to be a promising marker in predicting B12 status in renal patients.

  6. 儿童难治性癫痫的遗传代谢异常筛查%Screening of inherited metabolic disorder in children with intractable epilepsy

    Institute of Scientific and Technical Information of China (English)

    马远宁; 陈国洪; 王莉; 许淑静; 索军芳


    showed 12 types of abnormalities,including double acid aciduria in 14 cases,lactic aciduria in 8 cases. Screening blood phenylalanine increased in 28 cases,phenylalanine increased in 8 cases,propionyl carnitine,acetyl carnitine,glutaryl carnitine and oc-tanoyl carnitine increased in every 4 cases. Among 56 cases of children with abnormal urine screening,28 cases showed infantile spasms,6 cases showed generalized or partial seizures,various forms of attack were showed in 4 cases. Compared with other types of abonormal urine screening,in-fantile spasms abnormalities was higher and the differences was statistically significant( P < 0. 05). Conclusion Genetic metabolic abnormalities is risk factors of intractable epilepsy. Hereditary metabolic abnormalities screening,especially urine screening for infantile spasm type,has high detection specificity,which can favor the early diagnosis and treatment of intractable epilepsy and has important clinical value.

  7. 基于目的基因捕获的高通量测序技术在遗传代谢病诊断中的应用%Application of high throughput targeted exome sequencing in the molecular diagnosis of inherited metabolic diseases

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    郝虎; 石聪聪; 吴鹰军; 王弘; 李思涛; 蔡尧; 董玛拉; 马艳梅; 肖昕


    errors of metabolism detected by tandem mass spectrometry combined with gas chromatography mass spectrometry in the testing center of the Sixth Affiliated Hospital of Sun Yat-Sen University.One hundred and fifty-three genes related to genetics metabolic disorders were analyzed to obtain the positive mutations utlizing the high throughput targeted exome sequencing technology.Then all the mutations were validated by Sanger sequencing, as well as their parents' corresponding sites.Results Eight of the 10 patients with suspected IMD were confirmed by high throughput sequencing targeted exome sequencing.Among the 8 patients, 1 patient with methylmalonic academia-mut type, 1 patient with methylmalonic academia-cblB type, 1 patient with maple syrup urine disease-I a type, 1 patient with ornithine carbamoyltransferase deficiency, 1 patient with citrin deficiency,and 3 patients with holocarboxylase synthetase deficiency.However,there were still 2 cases which could not be verified, 1 patient with the suspected isovaleric acidaemia diagnosed by gas chromatography-mass spectrome spectrometry who had a missense mutation c.158G > C(p.R53P) and a same sense mutation c.732C > T(p.D244D) ,the other one with citrin suspected deficiency had a missense mutation c.1156G > A(p.G386S) and a same sense mutation c.1194A > G(p.L398L).Moreover, the positive gene sites of the patient with ornithine carbamoyltransferase deficiency (X-linked recessive inheritance) mutated spontaneously which differed from the other 9 cases inherited from their own parents.Besides, all the data of high-throughput sequencing were confirmed by Sanger sequencing and in accordance with each other.Conclusions The use of high throughput targeted exome sequencing can make a precise diagnosis for patients with high risk of IMD.It can not only provide reliable molecular diagnosis, but also proceed accurate disease classification affording the basis for clinical and genetic conseling.

  8. Spliced leader-based analyses reveal the effects of polycyclic aromatic hydrocarbons on gene expression in the copepod Pseudodiaptomus poplesia. (United States)

    Zhuang, Yunyun; Yang, Feifei; Xu, Donghui; Chen, Hongju; Zhang, Huan; Liu, Guangxing


    Polycyclic aromatic hydrocarbons (PAHs) are a group of toxic and carcinogenic pollutants that can adversely affect the development, growth and reproduction of marine organisms including copepods. However, knowledge on the molecular mechanisms regulating the response to PAH exposure in marine planktonic copepods is limited. In this study, we investigated the survival and gene expression of the calanoid copepod Pseudodiaptomus poplesia upon exposure to two PAHs, 1, 2-dimethylnaphthalene (1, 2-NAPH) and pyrene. Acute toxicity responses resulted in 96-h LC50 of 788.98μgL(-1) and 54.68μgL(-1) for 1, 2-NAPH and pyrene, respectively. Using the recently discovered copepod spliced leader as a primer, we constructed full-length cDNA libraries from copepods exposed to sublethal concentrations and revealed 289 unique genes of diverse functions, including stress response genes and novel genes previously undocumented for this species. Eighty-three gene families were specifically expressed in PAH exposure libraries. We further analyzed the expression of seven target genes by reverse transcription-quantitative PCR in a time-course test with three sublethal concentrations. These target genes have primary roles in detoxification, oxidative defense, and signal transduction, and include different forms of glutathione S-transferase (GST), glutathione peroxidases (GPX), peroxiredoxin (PRDX), methylmalonate-semialdehyde dehydrogenase (MSDH) and ras-related C3 botulinum toxin substrate (RAC1). Expression stability of seven candidate reference genes were evaluated and the two most stable ones (RPL15 and RPS20 for 1, 2-NAPH exposure, RPL15 and EF1D for pyrene exposure) were used to normalize the expression levels of the target genes. Significant upregulation was detected in GST-T, GST-DE, GPX4, PRDX6 and RAC1 upon 1, 2-NAPH exposure, and GST-DE and MSDH upon pyrene exposure. These results indicated that the oxidative stress was induced and that signal transduction might be affected by PAH

  9. 无高危因素的精神发育迟滞患儿遗传代谢病的筛查及随访%Screening and Follow-up of Congenital Metabolic Abnormalities of Children with Mental Retardation without High Risk Factors

    Institute of Scientific and Technical Information of China (English)

    赵立明; 王福顺; 刘海燕; 刘玉洁


    Objective To investigate the rate of genetic metabolic diseases of children with mental retardation without high risk factors and to understand the follow - up of the confirmed cases. Methods 28 children with mental retardation without high risk factors admitted to our hospital from February 2009 to December 2011 were given genetic metabolic disease screening by using tandem mass spectrometry. All the patients were given corresponding treatment and were followed up by monitoring nervous system and the growth and development of the whole body. Targeted intelligence and physical training were also provided. Results Among the 28 children with mental retardation without high risk factors, 7 cases were confirmed as genetic metabolic disease ( 25.0% ), including 3 cases of methylmalonic acidemia ( 42. 8% ), one case of glutaric acidemia ( 14. 3% ), one case of phenylketonuria ( 14. 3% ), one case of mitochondrial encephalomyopathy ( 14. 3% ) and one case of carbohydrate metabolism disorder ( 14. 3% ) . Follow - up and monitoring of nervous system showed that 2 cases had recurring acidosis and needed alkali solution to alleviate the symptoms and the backward intelligence and motor development. The other 5 cases showed no clinical symptoms after treatment but had psychomotor retardation. The intellectual development and motor development of the 21 cases that were not confirmed as genetic metabolic disease were significantly improved after regular professional rehabilitation training. Conclusion Children with mental retardation without high risk factors should participate in genetic metabolic disease screening as soon as possible. The earlier the diagnosis and intervention are, the better the long - term outcomes will be.%目的 了解无高危因素精神发育迟滞患儿遗传代谢病的发生率及确诊病例的随访情况.方法 采用串联质谱法,2009年2月-2011年12月对28例无高危因素的精神发育迟滞患儿进行遗传代谢病筛查,给予相应

  10. Cobalamin deficiency, hyperhomocysteinemia, and dementia

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    Steven F Werder


    : 200 picograms per milliliter or less is low, and 201 to 350 picograms per milliliter is borderline low. Other tests may be indicated, including plasma homocysteine, serum methylmalonic acid, antiparietal cell and anti-intrinsic factor antibodies, and serum gastrin level. In B12 deficiency dementia with versus without pernicious anemia, there appear to be different manifestations, need for further workup, and responses to treatment. Dementia of the Alzheimer’s type is a compatible diagnosis when B12 deficiency is found, unless it is caused by pernicious anemia. Patients with pernicious anemia generally respond favorably to supplemental B12 treatment, especially if pernicious anemia is diagnosed early in the course of the disease. Some patients without pernicious anemia, but with B12 deficiency and either mild cognitive impairment or mild to moderate dementia, might show some degree of cognitive improvement with supplemental B12 treatment. Evidence that supplemental B12 treatment is beneficial for patients without pernicious anemia, but with B12 deficiency and moderately-severe to severe dementia is scarce. Oral cyanocobalamin is generally favored over intramuscular cyanocobalamin.Keywords: Alzheimer, dementia, cognitive impairment, cognitive dysfunction, cobalamin, cyanocobalamin, B12, homocysteine, hyperhomocysteinemia, homocystinuria

  11. Diagnosis of inborn errors of metabolism using tandem mass spectrometry and gas chromatography mass spectrometry%串联质谱联合气相色谱-质谱检测遗传性代谢病

    Institute of Scientific and Technical Information of China (English)

    韩连书; 叶军; 邱文娟; 高晓岚; 王瑜; 金晶; 顾学范


    Objective To investigate the effects of tandem mass spectrometry (MS/MS) combined with gas chromatography mass spectrometry (GC-MS) in the diagnosis of inborn errors of metabolism in children. Methods Amino acids and acylcarnitines in the dry blood filter papers were tested by MS/MS, and the organic acid profiles in urea were tested by GC-MS among 4981 children suspected to be with inborn errors of metabolism from more than 100 hospitals in China. A few pediatric patients underwent analysis of activity of enzyme and gene mutation analysis too. Results 319 of the 4981 children (6.4%) were diagnosed as with 24 kinds of diseases: 155 of the 319 cases (48.6%) with 8 kinds of amino acid diseases (97 with hyperphenylalaninemia, 14 with maple syrup urine disease 13 with ornithine transcarbamylase deficiency, 13 with citrullinemia type Ⅱ, 10 with tyrosinemia type Ⅰ , 5 with citrullinemia type Ⅰ ,2 with homocystinuria, and 1 with arginasemia) ; 150 of the 319 cases (47.0%) were diagnosed as with 10 kinds of organic acidemias (81 with methylmalonic acidemia, 17 with propionic acidemia, 17 with multiple CoA carboxylase deficiency, 11 with glutaric acidemia type Ⅱ, 8 with isovaleric acidemia, 6 with β-keto thiolase deficiency, 5 with 3-methylcrotonyl-CoA carboxylase deficiency, and 3 with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency) ; 14 cases (4.4%) were diagnosed as with 6 kinds of fatty acid disorders (5 with medium chain acyl-CoA dehydrogenase deficiency, 3 with very long chain acyl CoA dehydrogenase deficiency, 2 with short chain acyl-CoA dehydrogenase deficiency, 2 with multiple acyl-CoA dehydrogenase deficiency, 1 with carnitine palmitoyl transferase type Ⅱ , and 1 with carnitine palmitoyl transferase type Ⅰ ). Conclusion MS/MS is specific for amino acid diseases and fatty acid disorders. GC-MS is specific for detect organic acidemias. And the diagnoses of part of amino acid diseases need the combination of both methods.%目的 应用串联质谱检测

  12. The clinical features and follow-up of neonatal convulsion with unknown reasons%病因不明新生儿惊厥的临床特征及随访观察

    Institute of Scientific and Technical Information of China (English)



    ObjectiveTo evaluate the clinical manifestations and follow-up of the neonatal convulsion with unknown reasons.MethodsThe clinical manifestations and the outcome of 12 patients with the agnogenic neonatal convulsion have been summarized.ResultsAll the patients were full term infants,7 boys,5 girls;The behaviour of convulsion was subtle;The AEEG of 2 patients show interrupted low voltage,the other 10 patients' were normal;The AEEG of all 12 patients were reexamined,3 patients show spike and slow wave,the other 9 patients' were normal;The MRI of 12 patients were normal during in hospital;4 patients' MRI were reexamined,normal;3 patients were diagnosed as epilepsy,One has growth retardation,who was diagnosised methylmalon academia;6 patients had no convulsion after treatment in hospital,At present they developed normally,The convulsion of 3 patients discontinued in 10 weeks after discharge,They had a good follow-up till now.ConclusionBoth epilepsy and benign idiopathic neonatal convulsions was the potential origin of neonatal convulsion with unknown reasons. It is important to follow-up and find reason for the neonatal convulsion with unknown reasons.%目的:探讨病因不明新生儿惊厥的临床特征及转归。方法总结12例病因不明的新生儿惊厥病例的临床特征及随访结果。结果12例患儿均为足月儿,男7例,女5例;惊厥发作以微小型发作为主;2例住院期动态脑电图示间断低电压改变,10例正常;12例均复查动态脑电图,3例出现爆发棘慢波,9例正常;12例住院期颅部MRI均正常,4例复查颅部MRI未见异常;3例随访中诊断为癫痫,其中1例合并发育迟缓,遗传代谢病筛查诊断为甲基丙二酸血症;6例出院后未再抽搐,3例出院10周内未特殊治疗抽搐停止,目前均生长发育良好。结论病因不明新生儿惊厥的潜在原因可能为癫痫、某种遗传代谢病或良性特发性新生儿惊厥等,应加强随访,追

  13. Selected Abstracts of the 6th International Congress of UENPS; Valencia (Spain; November 23rd-25th 2016; Session “Neonatology and NICU clinical care and practices”

    Directory of Open Access Journals (Sweden)

    --- Various Authors



  14. Acylcarnitine profile in children of malnutrition%营养不良患儿酰基肉碱谱变化

    Institute of Scientific and Technical Information of China (English)

    王燕敏; 龚振华; 田国力; 景虹


    目的 探讨营养不良患儿血酰基肉碱谱特点及用于代谢病的鉴别.方法 收集营养不良患儿13例,同期同年龄段非代谢病患儿214例作为对照组.入院时空腹采集末梢血制成千血片,串联质谱非衍生化法检测其肉碱和多种酰基肉碱浓度.结果 脂肪酸氧化分解相关的脂酰基肉碱,营养不良组从十八碳脂酰基肉碱至乙酰基肉碱,包括酮体酰基肉碱,即丙二酰基肉碱和羟基丁酰基肉碱都有不同程度增高,以中链酰基肉碱增高明显,其中营养不良组癸酰基肉碱为(0.203 ±0.105) μmol/L,超出正常参考值范围(0~0.200 μmol/L),显著高于对照组[0.054±0.030)μmol/L,P<0.001].氨基酸分解相关的丙酰基肉碱、戊酰基肉碱、羟基戊酰基肉碱和戊二酰基肉碱等,营养不良组和对照组比较差异均无统计学意义(均P>O.05).结论 营养不良患儿血中脂肪酸代谢相关的酰基肉碱增高,以中链酰基肉碱增高明显,癸酰基肉碱略超出正常值等特点,可与中链酰基辅酶A脱氢酶缺乏症和多种酰基肉碱辅酶A脱氢酶缺乏症等疾病鉴别.%Objective To summarize the acylcarnitine profile in children with malnutrition,with an attempt to distinguish it from those of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency,multiple acylCoA dehydrogenase (MAD) deficiency,or glutaric aciduria type Ⅱ (GA Ⅱ).Methods Thirteen pediatric patients with malnutrition and 214 children of the same age but without malnutrition,which was set as the control group,were included in this study.The blood samples were collected at admission,and the concentration of carnitine and acylcarnitines were measured in bloodspots by tandem mass spectrometry using samples nnderivatized.Results The concentrations of acylcarnitines which were involved in fatty acid oxidation,including octadecanoyl (C18) to acetyl (C2) acylcarnitines and ketonic acylcarnitines,were higher in malnutrition group than in the control group

  15. 遗传代谢病类婴儿肝炎综合征的临床分析%Clinical analysis of infantile hepatitis syndrome complicated with inherited metabolic diseases

    Institute of Scientific and Technical Information of China (English)

    董红; 欧榕琼; 欧阳颖


    mass spectrometry analysis re-sults,diagnosis,treatment and clinical prognosis were recorded and analyzed.Results Physical examination revealed yellow skin and sclera in 1 0 cases.All infants presented with complications,including anemia in nine cases,cytomegalovirus (CMV)infection in four infants and epstein-barr virus (EBV)infection in two infants.Elevated levels of total bilirubin,direct bilirubin,AST,bile acid,alpha fetal protein and lactic acid were found in all 1 0 infants had.Three infants presented with hypoglycemia,six with hypoproteinemia,three with metabolic acidosis and nine with coagulation disorders.Based upon the urine GC-MS,blood MS /MS,clinical characteristics,laboratory and auxiliary examination outcomes,1 0 infants were eventually diagnosed with inher-ited metabolic diseases complicated with IHS including two cases of galactosemia,four cases of neonatal intra-hepatic cholestasis induced by Citrin deficiency,one case of acidaemia,one case of urea circulatory disorders and citrullinemia,one case of urea circulatory disorders and organic aciduria and one case of tyrosinemia.One NICCD infant had a SLC25A1 3 gene sequence of c.851 854delGTAT p.(Met285Ts).After diagnosis was confirmed,all infants received ademetionine 1 ,4-butanedisulfonate and ursodesoxycholic acid therapy.Eight infants had alleviated jaundice and were discharged,and the other two abandoned the treatment.Conclusions Infants with inherited metabolic diseases complicated with IHS had persistent and severe jaundice,and con-stantly complicated with metabolic acidosis,hypoglycemia,hyperlactatemia,hyperammonemia,high level of alpha fetal protein and hypoproteinemia,etc.Urine GC-MS and blood MS /MS were of diagnostic significance.Effective therapy should be delivered immediately after the diagnosis is confirmed.

  16. 伴代谢危象的有机酸血症患儿53例临床分析%Clinical features of infantile organic acidemia accompanied with acute metabolic crisis

    Institute of Scientific and Technical Information of China (English)

    刘兆娥; 韩波; 孙正芸; 郭雷鸣


    目的 分析伴代谢危象的有机酸血症患儿的临床及实验室特点,提高儿科医生对该病的认识,提高临床治愈率,减少后遗症的发生.方法 分析我科2006年4月至2014年10月确诊的病例资料,总结其临床表现、血和尿有机酸测定结果、血气分析、血糖、乳酸、血氨等特点,并对其诊断、治疗及转归情况进行回顾性分析.结果 53例患儿中,男37例,女16例,年龄均小于1岁;甲基丙二酸血症28例,丙酸血症11例,戊二酸血症Ⅱ型、生物素酶缺乏症各3例,异戊酸血症、戊二酸血症Ⅰ型各2例,多种辅酶A羧化酶缺乏症、甘油激酶缺乏症、3-甲基巴豆酰辅酶A羧化酶缺乏症、全羧化酶合成酶缺乏症各1例,其中25例(47.2%)起病后7d内发生危象.主要临床表现为喂养困难、频繁抽搐、呼吸困难;实验室检查以严重低血糖、顽固的代谢性酸中毒、高氨血症最为常见.12例有阳性家族史.所有患儿入院后均给予对症支持治疗,包括纠正低血糖、降低高血氨,维持水、电解质、酸碱平衡,维护重要脏器的功能;明确诊断后给予补充代谢辅助因子及特殊奶粉等保守治疗.给予相应处理后,32例(60.4%)好转出院,15例(28.3%)死亡.结论 1岁以内的有机酸血症患儿易发生代谢危象,起病急,病情进展快,救治难度大.喂养困难、频繁抽搐、呼吸困难是最常见的临床表现,早期诊断、早期治疗是改善预后的关键;对于原因不明的低血糖、难以纠正的代谢性酸中毒等患儿应及早进行筛查.%Objective To investigate the clinical and laboratory characters of infantile organic acidemia(OA) accompanied with acute metabolic crisis.Methods We analyzed retrospectively datum of infants with OA diagnosed in our unit from April 2006 to October 2014.Results Fity-three cases(37 male and 16 female,aged under 1 year old) were enrolled in this study,in which,28 cases were methylmalonic acidemia,11

  17. The determination of organic acids in urine with gas chromatography-mass spectrometry and its application in clinical diagnosis%气-质联用技术测定尿有机酸方法的建立及在遗传代谢病诊断中的应用

    Institute of Scientific and Technical Information of China (English)

    孙卫华; 杨毅; 曹迪; 王艺; 陆炜


    Objectivo To analyze urine organic acids in the urine using gas chromatography-mass spectrometry(GC/MS)for diagnosis of inherited metabolic diseases,especially for organic acids metabolic disorders.Methods 195 clinical urine samples from the patients with suspected organic acids metabolic disorders and 5 normal urine from adults were collected.After mixing some urine with intemal standards according to the concentration creatinine and adding hydroxylamine hydrochloride to mixture,the organic acids with hydroxyl group were oximated to the ketobodies.Organic acids were extracted twice with ethyl acetate and ethyl ether and derivatized with BSTFA-TMCS.An the organic acids were determined with Agilent GC/MS 6890/5973i with scan model.the mass-to-charge ratio range is 50-550 m/z,all data were nalyzed with Agilent GCMSD ChemStationG1701DA.We also investigated the linearity, accurate,precision.recovery and Carry-over by determining the internal standards in normal samples and positive organic acids in spiked control samples.Results More than one hundred kinds of organic acids in urine samples can be analyzed with this method.According to the two internal standards in normal urine samples,the minimal detection limit MMA and 2.PA was 2.5-2.8 μmol/L.Intra-and interassay coefficient of variation for MMA and 2-PA are both less than 10%.Pre-processing Interassay coefficient by sequential preparations of the same sample was 14%.The recoveries of the spiked samples were 95%-105%.Carryover analysis was less than 1%.All the parameters meet the requirement for clinical diagnosis.12 samples demonstrated positive including 6 cases of methylmalonic acidemia,1 case of propionic acidemia,3 cases of tyrosinemia Ⅰ,1 case of maple syrup urine disease and 1 cases of ketosis.Conclusions The method for the determination of organic acids in urine by GC/MS has been successfully established.It can be used for clinical screening and diagnosis for inherited genetic metabolic diseases.%目的

  18. SUCLA2相关脑肌病型线粒体DNA耗竭综合征一例并文献复习%SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome: a case report and review of literature

    Institute of Scientific and Technical Information of China (English)

    刘志梅; 方方; 丁昌红; 吴沪生; 吕俊兰; 伍妘


    丙二酸轻度升高,血C3和C4DC轻度升高.头颅MRI为基底节受累和脑萎缩样改变,以双侧尾状核、壳核对称性病变为主.25例中19例来自欧洲,其中的13例来自法罗群岛,为SUCLA2 c.534+ 1G>A纯合突变.结论 SUCLA2相关脑肌病型线粒体DNA耗竭综合征临床特征为:生后或婴儿早期出现严重肌张力低下、喂养困难、生长迟缓、发育迟滞(尤其是运动)、听力损害等;血乳酸增高,尿甲基丙二酸轻度增高,血C3和C4DC轻度升高;头颅MRI为双侧对称性尾状核、壳核受累,伴有脑萎缩样改变.发现SUCLA2致病性突变可确诊.%Objective To analyze the clinical characteristics of SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome (MDS) in one patient,and review the latest clinical research reports.Method Clinical,laboratory and genetic data of one case of SUCLA2-related encephalomyopathic MDS diagnosed by department of Neurology,Beijing Children's Hospital in November,2013 were reported,and through taking "SUCLA2" as key words to search at CNKI,Wanfang,PubMed and the Human Gene Mutation Database (HGMD) professional to date,the clinical characteristics of 24 reported cases of SUCLA2-related encephalomyopathic MDS in international literature in combination with our case were analyzed.Result (1) The patient was 5 years and 9 months old,born as a term small for gestational age infant whose birth weight was 2 400 g,and presented since birth with severe muscular hypotonia,feeding difficulties,failure to thrive,psychomotor retardation and hearing impairment.Until now,he still showed severe developmental retardation,together with muscular atrophy,thoracocyllosis and scoliosis,and facial features.The patient is the first born from consanguineous healthy parents,whose relationship is cousins.Laboratory tests showed urinary excretion of mild methylmalonic acid (MMA),elevated plasma lactate concentration,and increased C3-carnitine and C4-dicarboxylic-carnitine in plasma carnitine ester