Biomedical subjects

Georg F Hoffmann

Publications and source records attributed to Georg F Hoffmann.

At least 37 records · Page 2Linked to original sources

PubMed2005

Public, expert and patients' opinions on preimplantation genetic diagnosis (PGD) in Germany.

The regulation of reproductive medicine technologies differs significantly among Western industrialized countries. In Germany, preimplantation genetic diagnosis (PGD) is prohibited due to the Embryo Protection Act, which came into force in 1991. In the last 5 years, this prohibition has been vigorously debated. In the present studies, which are part of the German research programme on ethical implications of the Human Genome Project, representative surveys were undertaken to assess the attitudes on PGD in the general population (n = 1017), five relevant expert groups (n = 879), high genetic risk couples (n = 324) and couples undergoing IVF (n = 108). All groups surveyed clearly favoured allowing PGD in Germany. Compared with the results of recently conducted population surveys in the UK and the USA, where PGD is already carried out, public approval of PGD does not differ significantly. The influence of restrictive biopolitics on the apparently liberal public opinion towards new reproductive technology seems to be marginal according to the present data, which should carefully be considered in the ongoing legislation process on human reproduction.

Abortion, Induced↗

PubMed2004

Optimized spectrophotometric assay for the completely activated pyruvate dehydrogenase complex in fibroblasts.

BACKGROUND: Analysis of the pyruvate dehydrogenase complex (PDHc) activity in human skin fibroblasts is hampered by low enzyme activity in the cells. The most commonly used radiochemical method detects the formation of (14)CO(2), an endproduct of the E1 component of PDHc, from [1-(14)C]pyruvate. METHODS: We report a spectrophotometric method for the analysis of PDHc activity in fibroblasts based on detection of NADH formation via a p-iodonitrotetrazolium violet (INT)-coupled system. We investigated in detail the specific requirements of this assay, such as cofactor requirements and the effects of suggested stimulatory compounds and different cell disruption procedures. The reliability of the optimized assay was studied by investigation of patients previously diagnosed with PDHc deficiency and by comparison with results from the radiochemical method. RESULTS: Mean (SD) total PDHc activities were 136 (31) and 58 (21) mU/U of citrate synthase in fibroblast homogenates from 10 healthy volunteers and 7 PDHc-deficient patients, respectively, by the spectrophotometric assay. Similar results were obtained in a mitochondrial fraction. Dithiothreitol (DTT) increased the nonspecific inhibitor-insensitive rate with less pronounced effect on the specific rate of PDHc activity. Administration of DTT increased PDHc activity to 193 (3)% of control activity (without DTT), but decreased the inhibitor-sensitive rate from 99 (0.3)% (without DTT) to 69 (2)% (with 0.3 mmol/L DTT). CONCLUSION: The simple, optimized spectrophotometric assay for PDHc analysis allows reliable investigation of the enzyme complex in human skin fibroblasts.

Cells, Cultured↗

PubMed2004

beta-Ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities.

beta-Ureidopropionase deficiency is an inborn error of the pyrimidine degradation pathway, affecting the cleavage of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid. In this study, we report the elucidation of the genetic basis underlying a beta-ureidopropionase deficiency in four patients presenting with neurological abnormalities and strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in plasma, cerebrospinal fluid and urine. No beta-ureidopropionase activity could be detected in a liver biopsy obtained from one of the patients, which reflected the complete absence of the beta-ureidopropionase protein. Analysis of the beta-ureidopropionase gene (UPB1) of these patients revealed the presence of two splice-site mutations (IVS1-2A>G and IVS8-1G>A) and one missense mutation (A85E). Heterologous expression of the mutant enzyme in Escherichia coli showed that the A85E mutation resulted in a mutant beta-ureidopropionase enzyme without residual activity. Our results demonstrate that the N-carbamyl-beta-amino aciduria in these patients is due to a deficiency of beta-ureidopropionase, which is caused by mutations in the UPB1 gene. Furthermore, an altered homeostasis of beta-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in patients with a beta-ureidopropionase deficiency. An analysis of the presence of the two splice site mutations and the missense mutation in 95 controls identified one individual who proved to be heterozygous for the IVS8-1G>A mutation. Thus, a beta-ureidopropionase deficiency might not be as rare as is generally considered.

Amidohydrolases↗

PubMed2004

Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy.

Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCC alpha protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA-wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo.

Alleles↗

PubMed2004

Pathophysiology, diagnosis, and treatment of methylmalonic aciduria-recent advances and new challenges.

Classical methylmalonic aciduria is a relatively rare inborn error of branched-chain amino acid metabolism, occurring in 1:50,000 to 1:80,000 newborns. Three decades after its recognition, major progress has been made in survival and prevention of neurological sequelae in affected children, if the diagnosis is made early and treatment and follow-up care are meticulous. Therapy consists of a specially formulated protein diet, carnitine supplementation, and vigorous emergency treatment during intercurrent illnesses aimed at preventing the development of catabolism. Recently the clinician has been challenged by partially unexpected long-term complications. These include chronic neurological symptoms, specifically an extrapyramidal movement disorder caused by progressive destruction of the basal ganglia, which are similar to those observed in other organic acid disorders, such as propionic aciduria or glutaric aciduria type I. Unexpected and unique is the development of chronic renal failure in a major subset of patients. As the pathophysiological basis of renal failure is still obscure, no causative treatment is available and hemodialysis may become necessary. Experience with transplantation of liver, kidney, or kidney and liver is very limited and allows as yet no conclusions. Interdisciplinary research efforts in this field should reveal new pathophysiological links and hopefully provide additional therapeutic approaches.

Amino Acid Metabolism, Inborn Errors↗

PubMed2004

Frequencies of inherited organic acidurias and disorders of mitochondrial fatty acid transport and oxidation in Germany.

UNLABELLED: The lack of epidemiological data on the frequency and/or burden of organic acidurias (OA) and mitochondrial fatty acid transport and oxidation disorders (mtFATOD) is one reason for hesitation to expand newborn screening (NBS) by tandem mass spectrometry (MS-MS). From 1999 to 2000, the frequency of ten potentially treatable OA and mtFATOD was assessed by active nation-wide surveillance on cases presenting with clinical symptoms using the German Paediatric Surveillance Unit (ESPED) system. Case ascertainment was complemented by a second independent source: 3-monthly inquiries in the metabolic laboratories performing secondary selected screening for OA and mtFATOD. Frequency estimates for clinically symptomatic cases older than 7 days in a birth cohort of 844,575 conventionally screened children was compared to the frequency found in a cohort of 382,247 screened by MS-MS in Bavaria and Baden-Württemberg. The overall frequency of the ten conditions considered was 1:8,000 (95% CI 1:11,000-1:6,000) by MS-MS as compared to 1:23,000 (95% CI 1:36,000-1:17,000) in symptomatic cases presenting mainly with metabolic crisis. The contributions of medium-chain acyl-CoA dehydrogenase deficiency (MCADD), other mtFATOD and OA were 29, 4 and 13 among the 46 cases identified by MS-MS, and 19, 1 and 13 among the 33 clinically symptomatic cases, respectively. Acute metabolic crisis, with a lethal outcome in four patients, was reported for 22/33 clinically symptomatic cases. No clinically symptomatic cases were reported from cohorts with screened by MS-MS. CONCLUSION: ten potentially treatable organic acidurias and mitochondrial fatty acid transport and oxidations disorders were more common than phenylketonuria with organic acidurias accounting for 28% of the cases detected by newborn screening and 39% of the cases identified on high risk screening. These conditions were related to considerable morbidity and mortality. Considerations for their inclusion in expanded newborn screening programmes might be warranted.

Acyl-CoA Dehydrogenase↗

PubMed2004

Pathomechanisms of neurodegeneration in glutaryl-CoA dehydrogenase deficiency.

Glutaryl-CoA dehydrogenase deficiency is an inherited organic aciduria with predominantly neurological presentation. Biochemically, it is characterized by an accumulation and enhanced urinary excretion of two key organic acids, glutaric acid and 3-hydroxyglutaric acid. If untreated, acute striatal degeneration is often precipitated by febrile illnesses during a vulnerable period of brain development in infancy or early childhood, resulting in a dystonic dyskinetic movement disorder. The mechanism underlying these acute encephalopathic crises has been partially elucidated using in vitro and in vivo models. 3-Hydroxyglutaric and glutaric acids share structural similarities with the main excitatory amino acid glutamate and are considered to play an important role in the pathophysiology of this disease. 3-Hydroxyglutaric acid induces excitotoxic cell damage specifically via activation of N-methyl-D-aspartate receptors. Furthermore, glutaric and 3-hydroxyglutaric acids indirectly modulate glutamatergic and GABAergic neurotransmission, resulting in an imbalance of excitatory and inhibitory neurotransmission. It also has been suggested that secondary amplification loops potentiate the neurotoxic properties of these organic acids. Probable mechanisms for this effect include cytokine-stimulated nitric oxide production, a decrease in energy metabolism, and reduction of cellular creatine phosphate levels. Finally, maturation-dependent changes in the expression of neuronal glutamate receptors may affect the vulnerability to 3-hydroxyglutaric and glutaric acid toxicity.

Amino Acid Metabolism, Inborn Errors↗

PubMed2004

Levodopa-responsive aromatic L-amino acid decarboxylase deficiency.

We report three siblings, who were treated empirically with levodopa combined with carbidopa. There was an immediate therapeutic response. Biochemical investigation surprisingly showed the clinical phenotype to be caused by aromatic L-amino acid decarboxylase deficiency. Molecular characterization showed a homozygous point mutation (c.387 G-->A) in exon 3. Kinetic studies showed the mutation to decrease the binding affinity for the substrate. This, combined with structural modeling suggesting alteration of active site configuration, provided an explanation for the therapeutic response to levodopa.

Adolescent↗

PubMed2004

Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: a low-penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa.

OBJECTIVE: To describe biochemical findings and the spectrum of mevalonate kinase (MVK) gene mutations as well as an associated TNFRSF1A low-penetrance variant in a series of patients with clinical features of the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). METHODS: The MVK gene was sequenced in 8 children and 1 adult (including 2 siblings) fulfilling the clinical criteria for HIDS. In addition, sequencing of exons 2, 3, 4, and 6 of the TNFRSF1A gene was performed in patients with only one or no MVK mutation. Mevalonate kinase (MK) enzyme activity in leukocytes and renal excretion of mevalonic acid were also measured. RESULTS: Mutations in the coding region of the MVK gene were detected in 6 patients, and the most common mutation was V377I. Among these patients were 2 novel mutations, both of which were located in exon 6. These novel mutations resulted in the substitution of tryptophan (TGG) by a stop codon (TGA) at amino acid position 188 (W188X) and in the exchange of valine (GTG) for alanine (GCG) at amino acid position 203 (V203A). In 1 patient, a combination of one MVK (V377I) mutation and one TNFRSF1A (R92Q) mutation was present. The patient's clinical phenotype resembled a mixture of variant-type HIDS and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Her IgD values varied between normal and slightly increased, and the MK activity was in the low-normal range, while urinary mevalonate concentrations were always normal. CONCLUSION: The genotype findings indicate that a relatively small number of genes may be involved in the clinical manifestation of HIDS, with low-penetrance TNFRSF1A variants possibly influencing the HIDS phenotype or MVK mutations contributing to TRAPS.

Adolescent↗

PubMed2004

Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients.

Cerebrospinal fluid (CSF) and blood obtained from 22 untreated or scarcely treated patients with moderate to severe restless legs syndrome (RLS; mean age, 58.6 +/- 13 years) and 11 control subjects (mean age, 56.6 +/- 12.9 years) were investigated for biogenic amines between 6:00 and 8:00 PM. We did not find any significant differences in the CSF concentrations of homovanillic acid, 3-ortho- methyl-dopa, levodopa, 5-hydroxytryptophan, 5-hydroxyindoleacetic acid, tetrahydrobiopterin, dihydrobiopterin, 5-methyltetrahydrofolate, and neopterin. In addition, serotonin in whole blood and plasma activity of aromatic amino acid decarboxylase were all normal. Our results suggest that dopaminergic and serotonergic release is not substantially affected in RLS.

Adult↗

PubMed2004

Evidence that 3-hydroxyglutaric acid interacts with NMDA receptors in synaptic plasma membranes from cerebral cortex of young rats.

Neurological symptoms are common in patients with glutaric acidemia type I (GA-I). Although the pathophysiology of this disorder is not yet fully established, 3-hydroxyglutaric acid (3-HGA), which accumulates in affected patients, has recently been demonstrated to be excitotoxic to embryonic chick and neonatal rat neurons probably via NMDA glutamate receptors. In the present study, we investigated the in vitro effects of 3-HGA on the [(3)H]glutamate and [(3)H]MK-801 (dizocilpine) binding to rat synaptic plasma membranes from cerebral cortex of young rats in order to elucidate the interactions of 3-HGA with glutamate receptors and its possible contribution to the in vitro excitotoxic properties of 3-HGA. 3-HGA (10-100 microM) significantly decreased Na(+)-dependent (up to 62%) and Na(+)-independent (up to 30%) [(3)H]glutamate binding to synaptic membranes, reflecting a possible competition between glutamate and 3-HGA for the glutamate transporter and receptor sites, respectively. Since a decrease in Na(+)-independent glutamate binding might represent an interaction of 3-HGA with glutamate receptors, we next investigated whether 3-HGA interacts with NMDA receptors by adding NMDA alone or combined with 3-HGA and measuring Na(+)-independent [(3)H]glutamate binding to synaptic membranes (binding to receptors). We verified that 3-HGA and NMDA, at 10 and 100 microM concentrations, decreased glutamate binding by up to 20 and 45%, respectively, and that the simultaneous addition of both substances did not provoke an additive effect, implying that they bind to NMDA receptors at the same site. Furthermore, the binding of the NMDA-channel blocker [(3)H ]MK-801 was significantly increased (approximately 32-40%) by 10 and 100 microM 3-HGA, implying that 3-HGA was able to open the NMDA channel allowing MK-801 binding, which is a characteristic of NMDA agonists. On the other hand, glutamate had a much higher stimulatory effect on this binding (180% increase), reflecting its strong NMDA agonist property. Furthermore, the simultaneous addition of 3-HGA and glutamate provoked an additive stimulatory effect on [(3)H]MK-801 binding to the NMDA receptor. These data indicate that, relatively to glutamate, 3-HGA is a weak agonist of NMDA receptors. Finally, we demonstrated that 3-HGA provoked a significant increase of extracellular calcium uptake by cerebral cortex slices, strengthening therefore, the view that 3-HGA activates NMDA receptors. The present study therefore, demonstrates at the molecular level that 3-HGA modulates glutamatergic neurotransmission and may explain previous findings relating the neurotoxic actions of this organic acid with excitotoxicity.

Animals↗

PubMed2003

Beta-carotene cleavage products after oxidation mediated by hypochlorous acid--a model for neutrophil-derived degradation.

After beta-carotene failed in certain clinical efficacy trials, there is evidence that the carotenoid might even be harmful, especially to smokers, when given in high dosages. These negative effects might be mediated in part also by carotenoid cleavage products (CPs) having a high reactivity towards biomolecules. The authors postulate that in certain tissues oxidative, nonenzymatic cleavage of carotenoids is carried out primarily by oxidants liberated by polymorphonuclear leukocytes (PML). In this study, we show that beta-carotene is degraded by stimulated PML in vitro. This gives the pathophysiological meaning to our further experiments in which beta-carotene degradation by hypochlorous acid and consecutive CP formation were investigated. While formation of apo-carotenals under these conditions has been studied before, this was not the case for short chain products. Performing gas chromatography mass spectrometry, we were able to identify for the first time 5,6-epoxi-beta-ionone, ionene, beta-cyclocitral, beta-ionone, dihydroactinidiolide, and 4-oxo-beta-ionone as CPs formed after degradation of beta-carotene mediated by hypochlorous acid. Our findings may be of biological relevance because beta-carotene CPs are highly reactive and, therefore, potentially toxic.

Chromatography, High Pressure Liquid↗

PubMed2003

eIF2B-related disorders: antenatal onset and involvement of multiple organs.

Leukoencephalopathy with vanishing white matter, also called "childhood ataxia with central nervous system hypomyelination," is the first human disease related to mutations in any of the five genes encoding subunits of eukaryotic initiation factor eIF2B or any translation factor at all. eIF2B is essential in all cells of the body for protein synthesis and the regulation of this protein synthesis under different stress conditions. It is surprising that mutations in the eIF2B genes have been reported to lead to abnormalities of the white matter of the brain only, although it has been shown recently that ovarian failure may accompany the leukoencephalopathy. Another surprising observation is that the onset of the disease varies from early childhood to adulthood, with the exception of Cree leukoencephalopathy, a disease related to a particular mutation in one of the eIF2B genes, which invariably has its onset within the first year of life. We analyzed the eIF2B genes of nine patients with an antenatal- or early-infantile-onset encephalopathy and an early demise and found mutations in eight of the patients. In addition to signs of a serious encephalopathy, we found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Until now, no evidence had been found for a genotype-phenotype correlation, but the consistently severe phenotype in affected siblings among our patients and in Cree encephalopathy patients suggests an influence of the genotype on the phenotype.

Abnormalities, Multiple↗

PubMed2003

Methylmalonic acid, a biochemical hallmark of methylmalonic acidurias but no inhibitor of mitochondrial respiratory chain.

Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonic acid and alternative metabolites. An impairment of energy metabolism plays a key role in the pathophysiology of this disease, resulting in neurodegeneration of the basal ganglia and renal failure. It has become the subject of intense debates whether methylmalonic acid is the major toxin, inhibiting respiratory chain complex II. To elucidate whether methylmalonic acid is a respiratory chain inhibitor, we used spectrophotometric analysis of complex II activity in submitochondrial particles from bovine heart, radiometric analysis of 14C-labeled substrates (pyruvate, malate, succinate), and analysis of ATP production in muscle from mice. Methylmalonic acid revealed no direct effects on the respiratory chain function, i.e. on single electron transferring complexes I-IV, ATPase, and mitochondrial transporters. However, we identified a variety of variables that must be carefully controlled to avoid an artificial inhibition of complex II activity. In summary, the study verifies our hypothesis that methylmalonic acid is not the major toxic metabolite in methylmalonic acidurias. Inhibition of respiratory chain and tricarboxylic acid cycle is most likely induced by synergistically acting alternative metabolites, in particular 2-methylcitric acid, malonic acid, and propionyl-CoA.

Acyl Coenzyme A↗

PubMed2003

Lack of creatine in muscle and brain in an adult with GAMT deficiency.

Guanidinoacetate methyltransferase deficiency, which so far has been exclusively detected in children, was diagnosed in a 26-year-old man. The full-blown spectrum of clinical symptoms already had been present since infancy without progression of symptoms during adolescence. Cranial magnetic resonance imaging showed normal findings. Ophthalmological examination showed no retinal changes. Besides creatine deficiency in the brain, a distinct lack of phosphocreatine in skeletal muscle was proved by (31)P magnetic resonance spectroscopy. Creatine substitution combined with a guanidinoacetate-lowering diet introduced first at the age of 26 years was shown to be effective by an impressive improvement of epileptic seizures, mental capabilities, and general behavior and by normalization of the (31)P spectrum in the skeletal muscle.

Adult↗

PubMed2003

Approach to the diagnosis of neurotransmitter diseases exemplified by the differential diagnosis of childhood-onset dystonia.

We present our approach to the diagnosis of pediatric neurotransmitter diseases exemplified by the differential diagnosis of children presenting with dystonia. This approach is based upon the primary aim of early diagnosis of treatable conditions and the need for a logical series of investigations. We have tried to be comprehensive with our coverage but are aware that "new" pediatric neurotransmitter diseases continue to be delineated and that, similarly, a proportion of children presenting with dystonia remain undiagnosed. If this is the case, all of the investigations suggested here may need to be performed regardless of age and presentation. However, of more value is a careful clinical reevaluation.

Child↗

PubMed2003

Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia.

Tyrosine hydroxylase (TH) is the key enzyme in the biosynthesis of the catecholamines dopamine, epinephrine, and norepinephrine. Recessively inherited deficiency of TH was recently identified and incorporated into recent concepts of genetic dystonias as the cause of recessive Dopa-responsive dystonia or Segawa's syndrome in analogy to dominantly inherited GTP cyclohydrolase I deficiency. We report four patients with TH deficiency and two with GTP cyclohydrolase I deficiency. Patients with TH deficiency suffer from progressive infantile encephalopathy dominated by motor retardation similar to a primary neuromuscular disorder, fluctuating extrapyramidal, and ocular and vegetative symptoms. Intellectual functions are mostly compromised. Prenatally disturbed brain development and postnatal growth failure were observed. Treatment with levodopa ameliorates but usually does not normalize symptoms. Compared with patients with dominantly inherited GTP cyclohydrolase I deficiency, catecholaminergic neurotransmission is severely and constantly impaired in TH deficiency. In most patients, this results not in predominating dystonia, a largely nondegenerative condition, but in a progressive often lethal neurometabolic disorder, which can be improved but not cured by L-dopa. Investigations of neurotransmitter defects by specific cerebrospinal fluid determinations should be included in the diagnostic evaluation of children with progressive infantile encephalopathy.

Amino Acid Metabolism, Inborn Errors↗

PubMed2003

Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.

The conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA is the only step in leucine catametabolism yet to be characterized at enzyme and DNA levels. The deficiency of the putative mitochondrial enzyme 3-methylglutaconyl-CoA hydratase associates with the rare organic aciduria 3-methylglutaconic aciduria type I (MGA1), but neither the enzyme nor its gene have been described in any organism. Here we report that human 3-methylglutaconyl-CoA hydratase is identical with a previously described RNA-binding protein (designated AUH) possessing enoyl-CoA hydratase activity. Molecular analyses in five patients from four independent families revealed homozygosity or compound heterozygosity for mutations in the AUH gene; most mutations are predicted to completely abolish protein function. Mutations identified include c.80delG, R197X, IVS8-1G>A, A240V, and c.613_614insA. Clinical severity of MGA1 in published patients has been quite variable. Included in the present study is an additional patient with MGA1 who was detected by neonatal screening and has remained asymptomatic up to his present age of 2 years. The boy is homozygous for an N-terminal frameshift mutation in the AUH gene. Complete absence of 3-methylglutaconyl-CoA hydratase/AUH appears to be compatible with normal development in some cases. Further work is required to identify external or genetic factors associated with development of clinical problems in patients with MGA1.

Amino Acid Metabolism, Inborn Errors↗