Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Methylmalonic Acidemia with Novel MUT Gene Mutations.

ABSTRACT: A 5-year-old boy presented with recurrent episodes of fever, feeding problems, lethargy, from the age of 11 months, and poor weight gain. He was admitted and evaluated for metabolic causes and diagnosed as having methylmalonic acidemia (MMA). He was treated with vit B12 and carnitine supplements and has been on follow-up for the last 3 years. Mutation analysis by next generation sequencing (NGS), supplemented with Sanger sequencing, revealed two novel variants in the MUT gene responsible for MMA in exon 5 and exon 3, respectively. Recently he developed dystonic movements including orofacial dyskinesia. With advent of NGS, judicious use of NGS with Sanger sequencing can help identify causative possibly pathogenic mutations.

SUBMITTER: Panigrahi I

PROVIDER: S-EPMC5660767 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Methylmalonic Acidemia with Novel <i>MUT</i> Gene Mutations.

Panigrahi Inusha I Bhunwal Savita S Varma Harish H Singh Simranjeet S

Case reports in genetics 20171012

A 5-year-old boy presented with recurrent episodes of fever, feeding problems, lethargy, from the age of 11 months, and poor weight gain. He was admitted and evaluated for metabolic causes and diagnosed as having methylmalonic acidemia (MMA). He was treated with vit B12 and carnitine supplements and has been on follow-up for the last 3 years. Mutation analysis by next generation sequencing (NGS), supplemented with Sanger sequencing, revealed two novel variants in the <i>MUT</i> gene responsible ...[more]

PMID: 29158924

Similar Datasets

Mitochondrial dysfunction in mut methylmalonic acidemia.

Project description:Methylmalonic acidemia is an autosomal recessive inborn error of metabolism caused by defective activity of methylmalonyl-CoA mutase (MUT) that exhibits multiorgan system pathology. To examine whether mitochondrial dysfunction is a feature of this organic acidemia, a background-modified Mut-knockout mouse model was constructed and used to examine mitochondrial ultrastructure and respiratory chain function in the tissues that manifest pathology in humans. In parallel, the liver from a patient with mut methylmalonic acidemia was studied in a similar fashion. Megamitochondria formed early in life in the hepatocytes of the Mut(-/-) animals and progressively enlarged. Liver extracts prepared from the mutants at multiple time points displayed respiratory chain dysfunction, with diminished cytochrome c oxidase activity and reduced intracellular glutathione compared to control littermates. Over time, the exocrine pancreas and proximal tubules of the kidney also exhibited megamitochondria, and older mutant mice eventually developed tubulointerstitial renal disease. The patient liver displayed similar morphological and enzymatic findings as observed in the murine tissues. These murine and human studies establish that megamitochondria formation with respiratory chain dysfunction occur in a tissue-specific fashion in methylmalonic acidemia and suggest treatment approaches based on improving mitochondrial function and ameliorating the effects of oxidative stress.

| S-EPMC2660647 | biostudies-literature

Spectrum of Mutations in 60 Saudi Patients with Mut Methylmalonic Acidemia.

Project description:Defects in the human gene encoding methylmalonyl-CoA mutase enzyme (MCM) give rise to a rare autosomal recessive inherited disorder of propionate metabolism termed mut methylmalonic acidemia (MMA). Patients with mut MMA have been divided into two subgroups: mut0 with complete loss of MCM activity and mut- with residual activity in the presence of adenosylcobalamin (AdoCbl). The disease typically presents in the first weeks or months of life and is clinically characterized by recurrent vomiting, metabolic acidosis, hyperammonemia, lethargy, poor feeding, failure to thrive and neurological deficit. To better elucidate the spectrum of mutations causing mut MMA in Saudi patients, we screened a cohort of 60 Saudi patients affected by either forms of the disease for mutations in the MUT gene. A total of 13 different mutations, including seven previously reported missense changes and six novel mutations, were detected in a homozygous state except for two compound heterozygous cases. The six novel mutations identified herein consist of three nonsense, two missense and one frameshift, distributed throughout the whole protein. This study describes for the first time the clinical and mutational spectrum of mut MMA in Saudi Arabian patients.

| S-EPMC5059185 | biostudies-literature

Mutation Analyses in Selected Exons of the MUT Gene in Indian Patients with Methylmalonic Acidemia.

Project description:Deficiency or diminished activity of a cobalamin dependent enzyme methylmalonyl-CoA mutase causes inborn error of metabolism called methylmalonic acidemia (MMA). In this study we elucidated the spectrum of mutations in 21 Indian mut MMA patients by direct sequencing. Sequence analysis identified a total of 70 mutations in exon 2, 9, 11 and 12 of MUT gene. Out of which 26 mutations were predicted to be deleterious and rest were benign. The 23 novel mutations consist of four nonsense mutations (p.N6*, p.G539*, p.E609* and p.I671*), twelve missense mutations (p.K128I, p.N547T, p.D554Y, p.A558T, p.R559P, p.A631T, p.I647T, p.E656D, p.V657E, p.Q660H, p.K679N, and p.G696Y) and seven frame shift mutations (c.375_376insA, c.1642delA, c.1655delC, c.1825_1826insT, c.1957delGA, c.2014delA and c.2062_2063insGA). All of them are point mutations or micro rearrangements. Three of these mutations (p.K621N, p.G648D, p.G630E) have been previously reported; all of them are missense mutations. The mutations are distributed throughout the exon 2, 9, 11 and 12, 38.4 % mutation are located in exon 12.

| S-EPMC5538998 | biostudies-literature

Neutralizing Antibodies Against Adeno-Associated Viral Capsids in Patients with mut Methylmalonic Acidemia.

Project description:Isolated methylmalonic acidemia (MMA), a group of autosomal recessive inborn errors of metabolism, is most commonly caused by complete (mut(0)) or partial (mut(-)) deficiency of the enzyme methylmalonyl-CoA mutase (MUT). The severe metabolic instability and increased mortality experienced by many affected individuals, especially those with mut(0) MMA, has led centers to use elective liver transplantation as a treatment for these patients. We have previously demonstrated the efficacy of systemic adeno-associated viral (AAV) gene delivery as a treatment for MMA in a murine model and therefore sought to survey AAV antibody titers against serotypes 2, 8, and 9 in a group of well-characterized MMA patients, accrued via a dedicated natural history study ( clinicaltrials.gov ID: NCT00078078). Plasma samples provided by 42 patients (8 mut(-) and 34 mut(0); 10 had received organ transplantation), who ranged in age between 2 and 31 years, were analyzed to examine AAV2 (n = 35), AAV8 (n = 41), and AAV9 (n = 42) antibody titers. In total, the seroprevalence of antibodies against AAV2, AAV8, or AAV9 was 20%, 22%, and 24%, respectively. We observed a lower-than-expected seropositivity rate (titers ≥1:20) in the pediatric MMA patients (2-18 years) for both AAV2 (p < 0.05) and AAV8 (p < 0.01) neutralizing antibodies (NAbs) compared with historical controls. Those with positive NAb titers were typically older than 18 years (p < 0.05 all serotypes) or had received solid organ transplantation (p < 0.01 AAV8, AAV9). The mut(0) patients who had not been transplanted (n = 24)-that is, the subset with the greatest need for improved treatments-represented the seronegative majority, with 21 out of 24 patients lacking Abs against all AAV capsids tested. The unexpected lack of NAbs against AAV in this patient population has encouraging implications for systemic gene delivery as a treatment for mut MMA.

| S-EPMC4841085 | biostudies-literature

A detailed analysis of methylmalonic acid kinetics during hemodialysis and after combined liver/kidney transplantation in a patient with mut (0) methylmalonic acidemia.

Project description:End stage kidney disease is a well-known complication of methylmalonic acidemia (MMA), and can be treated by dialysis, kidney transplant, or combined kidney-liver transplant. While liver and/or kidney transplantation in MMA may reduce the risk of metabolic crisis and end-organ disease, it does not fully prevent disease-related complications. We performed detailed metabolite and kinetic analyses in a 28-year-old patient with mut (0) MMA who underwent hemodialysis for 6 months prior to receiving a combined liver/kidney transplant. A single hemodialysis session led to a 54 % reduction in plasma methylmalonic acid and yielded a plasma clearance of 103 ml/min and VD0.48 L/kg, which approximates the total body free water space. This was followed by rapid reaccumulation of methylmalonic acid over 24 h to the predialysis concentration in the plasma. Following combined liver/kidney transplantation, the plasma methylmalonic acid was reduced to 3 % of pre-dialysis levels (6,965?±?1,638 (SD) ?mol/L and 234?±?100 (SD) ?mol/L) but remained >850× higher than the upper limit of normal (0.27?±?0.08 (SD) ?mol/L). Despite substantial post-operative metabolic improvement, the patient developed significant neurologic complications including acute worsening of vision in the setting of pre-existing bilateral optic neuropathy, generalized seizures, and a transient, focal leukoencephalopathy. Plasma methylmalonic acid was stable throughout the post-operative course. The biochemical parameters exhibited by this patient further define the whole body metabolism of methylmalonic acid in the setting of dialysis and subsequent combined liver/kidney transplant.

| S-EPMC4373418 | biostudies-literature

Novel c.2216T > C (p.I739T) mutation in exon 13 and c.1481T > A (p.L494X) mutation in exon 8 of MUT gene in a female with methylmalonic acidemia.

Project description:We report herein a 1.5-year-old girl with methylmalonic acidemia (MMA) in whom two missense mutations were found: a novel I739T mutation located in exon 13 and the L494X mutation in exon 8. The results of organic acid test showed a pronounced increase in methylmalonate excretion with increased methylcitrate and 3-OH-propionate excretion, leading to a diagnosis of MMA, and Vitamin B12 administration was started. Analysis of the mut gene confirmed a T-to-A substitution at nucleotide position 1481 in exon 8 and a T-to-C substitution at nucleotide position 2216 in exon 13, leading to the amino acid isoleucine at position 739 being changed to threonine, resulting in c.2216T > C (p.I739T). The patient has now been on high-dose oral administration of Vitamin B12 and carnitine therapy (900 mg of levocarnitine chloride) for 5 years without experiencing further attacks, and her cognitive and motor development is normal. Further tests on residual enzyme activity, as well as experience with more cases, may shed light on the relationship between gene mutations and phenotypes in MMA.

| S-EPMC3756855 | biostudies-literature

Different mutations in the MMUT gene are associated with the effect of vitamin B12 in a cohort of 266 Chinese patients with mut-type methylmalonic acidemia: A retrospective study.

Project description:BackgroundTo summarize the relationship between different MMUT gene mutations and the response to vitamin B12 in MMA.MethodsThis was a retrospective study of patients diagnosed with mut-type MMA. All patients with mut-type MMA were tested for responsiveness to vitamin B12.ResultsThere were 81, 27, and 158 patients in the completely responsive, partially responsive, and nonresponsive groups, respectively, and the proportions of symptom occurrence were 30/81 (37.0%), 21/27 (77.8%), and 131/158 (82.9%), respectively (p < .001). The median levels of posttreatment propionyl carnitine (C3), C3/acetyl carnitine (C2) ratio in the blood, and methylmalonic acid in the urine were all lower than pretreatment, and the median level of C3/C2 ratio in the completely responsive group was within the normal range. In 266 patients, 144 different mutations in the MMUT gene were identified. Patients with the mutations of c.1663G>A, c.2080C>T, c.1880A>G, c.1208G>A, etc. were completely responsive and with the mutations of c.1741C>T, c.1630_1631GG>TA, c.599T>C, etc. were partially responsive. The proportions of healthy/developmental delay outcomes in the three groups were 63.0%/23.5%, 33.3%/40.7%, and 13.3%/60.1%, respectively (p < .001).ConclusionDifferent mutations in the MMUT gene are associated with the effect of vitamin B12 treatment.

| S-EPMC8606212 | biostudies-literature

Mutation Profile of the MUT Gene in Chinese Methylmalonic Aciduria Patients.

Project description:The mut-type methylmalonic aciduria (MMA, MIM 251000) is caused by a deficiency of mitochondrial methylmalonyl-CoA mutase (MCM, E.C. 5.4.99.2) activity, which results from defects in the MUT gene. To elucidate the mutation spectrum of the MUT gene in Chinese MMA patients, 13 exons of the MUT gene, including untranslated regions, were analyzed by PCR-based sequencing for 42 unrelated Chinese MMA patients. All the 42 patients were found to have at least one MUT mutation. A total of 41 mutations were identified. Of these mutations, 20 were novel ones, including one nonsense mutation (c.103C>T), 12 missense mutations (c.316A>C, c.424A>G, c.494A>G, c.554C>T, c.599T>C, c.919T>C, c.1009T>C, c.1061C>T, c.1141G>A, c.1208G>A, c.1267G>A, and c.1295A>C), one duplication (c.755dupA), three small deletions (c.398_399delGA, c.1046_1058del, and c.1835delG), two mutations that might affect mRNA splicing (c.754-1G>A and c.1084-10A>G), and one major deletion. Among the mutations identified, the c.1280G>A (15.5%), c.729_730insTT (10.7%), c.1106G>A (4.8%), c.1630_1631GG>TA (4.8%), and c.2080C>T (4.8%) accounted for 40% of the diseased alleles. The c.1280G>A and c.729_730insTT mutations were found to be the most frequent mutations in Southern and Northern Chinese, respectively. The results of microsatellite analysis suggest that the spread of c.729_730insTT among the Northern Chinese and of c.1280G>A and c.1630_1631GG>TA among the Southern Chinese may have undergone founder effects. This mutation analysis of the gene responsible for mut-type MMA will help to provide a molecular diagnostic aid for differential diagnosis of MMA and could be applied for carrier detection and prenatal diagnosis among Chinese family at risk of mut-type MMA.

| S-EPMC3565679 | biostudies-literature

Novel mutation in an Indian patient with Methylmalonic Acidemia, cblA type.

Project description:We report on a girl with methylmalonic acidemia, cblA type with a novel homozygous mutation and describe the clinical phenotype and response to therapy.

| S-EPMC3656526 | biostudies-literature

Mitochondrial Distress in Methylmalonic Acidemia: Novel Pathogenic Insights and Therapeutic Perspectives.

Project description:Mitochondria are highly dynamic, double-membrane-enclosed organelles that sustain cellular metabolism and, hence, cellular, and organismal homeostasis. Dysregulation of the mitochondrial network might, therefore, confer a potentially devastating vulnerability to high-energy-requiring cell types, contributing to a broad variety of hereditary and acquired diseases, which include inborn errors of metabolism, cancer, neurodegeneration, and aging-associated adversities. In this Review, we highlight the biological functions of mitochondria-localized enzymes, from the perspective of understanding the pathophysiology of the inherited disorders destroying mitochondrial homeostasis and cellular metabolism. Using methylmalonic acidemia (MMA) as a paradigm of mitochondrial dysfunction, we discuss how mitochondrial-directed signaling pathways sustain the physiological homeostasis of specialized cell types and how these may be disturbed in disease conditions. This Review also provides a critical analysis of molecular underpinnings, through which defects in the autophagy-mediated quality control and surveillance systems contribute to cellular dysfunction, and indicates potential therapeutic strategies for affected tissues. These insights might, ultimately, advance the discovery and development of new therapeutics, not only for methylmalonic acidemia but also for other currently intractable mitochondrial diseases, thus transforming our ability to modulate health and homeostasis.

| S-EPMC9563610 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data