-
Journal of Medical Case Reports Feb 2024Methylmalonic acidemia is a very rare genetic metabolic disease. Patients with isolated methylmalonic acidemia typically present with acute alterations of consciousness,...
BACKGROUND
Methylmalonic acidemia is a very rare genetic metabolic disease. Patients with isolated methylmalonic acidemia typically present with acute alterations of consciousness, failure to thrive, anorexia, vomiting, respiratory distress, and muscular hypotonia. Despite the evidence-based management, affected individuals experience significant morbidity and mortality. Hyperkalemia is one of the unusual complications of methylmalonic acidemia.
CASE PRESENTATION
In this paper, we describe a 4-year-old Persian boy with methylmalonic acidemia who developed life-threatening arrhythmia following severe hyperkalemia and metabolic acidosis. Emergent management of the condition was successfully carried out, and the rhythm changed to normal sinus rhythm by effectively reducing the serum potassium level. We discuss the possible etiology of this lethal condition and describe its management on the basis of the available evidence.
CONCLUSION
During metabolic decompensation in methylmalonic acidemia, frequent blood gas and electrolyte testing to prescribe and adjust therapy and annual echocardiogram and electrocardiogram screening are essential.
Topics: Male; Humans; Child, Preschool; Hyperkalemia; Amino Acid Metabolism, Inborn Errors; Acidosis; Arrhythmias, Cardiac
PubMed: 38395924
DOI: 10.1186/s13256-024-04406-5 -
BMC Pediatrics Feb 2024This study investigated the clinical, imaging, and electroencephalogram (EEG) characteristics of methylmalonic acidemia (MMA) with nervous system damage as the primary...
OBJECTIVE
This study investigated the clinical, imaging, and electroencephalogram (EEG) characteristics of methylmalonic acidemia (MMA) with nervous system damage as the primary manifestation.
METHODS
From January 2017 to November 2022, patients with nervous system injury as the main clinical manifestation, diagnosed with methylmalonic acidemia by metabolic and genetic testing, were enrolled and analyzed. Their clinical, imaging, and electroencephalogram data were analyzed.
RESULTS
A total of 18 patients were enrolled, including 15 males and 3 females. The clinical symptoms were convulsions, poor feeding, growth retardation, disorder of consciousness, developmental delay, hypotonia, and blood system changes. There were 6 cases (33%) of hydrocephalus, 9 (50%) of extracerebral space widened, 5 (27%) of corpus callosum thinning, 3 (17%) of ventricular dilation, 3 (17%) of abnormal signals in the brain parenchyma (frontal lobe, basal ganglia region, and brain stem), and 3 (17%) of abnormal signals in the lateral paraventricular. In addition, there were 3 cases (17%) of cerebral white matter atrophy and 1 (5%) of cytotoxic edema in the basal ganglia and cerebral peduncle. EEG data displayed 2 cases (11%) of hypsarrhythmia, 3 (17%) of voltage reduction, 12(67%) of abnormal discharge, 13 (72%) of abnormal sleep physiological waves or abnormal sleep structure, 1 (5%) of immature (delayed) EEG development, and 8 (44%) of slow background. There were 2 cases (11%) of spasms, 1 (5%) of atonic seizures, and 1 (5%) of myoclonic seizures. There were 16 patients (89%) with hyperhomocysteinemia. During follow-up, 1 patient was lost to follow-up, and 1 died. In total, 87.5% (14/16) of the children had varying developmental delays. EEG was re-examined in 11 cases, of which 8 were normal, and 3 were abnormal. Treatments included intramuscular injections of vitamin B12, L-carnitine, betaine, folic acid, and oral antiepileptic therapy. Acute treatment included anti-infective, blood transfusion, fluid replacement, and correcting acidosis. The other treatments included low-protein diets and special formula milk powder.
CONCLUSION
Methylmalonic acidemia can affect the central nervous system, leading to structural changes or abnormal signals on brain MRI. Metabolic screening and genetic testing help clarify the diagnosis. EEG can reflect changes in brain waves during the acute phase.
Topics: Child; Male; Female; Humans; Amino Acid Metabolism, Inborn Errors; Vitamin B 12; Mutation; Seizures; Electroencephalography; Methylmalonic Acid; Oxidoreductases
PubMed: 38355526
DOI: 10.1186/s12887-024-04559-8 -
Translational Gastroenterology and... 2024Liver transplantation (LT) is a therapeutic option in multiple inherited metabolic diseases (IMDs), including methylmalonic acidemia (MMA), as LT reduces the risk of...
BACKGROUND
Liver transplantation (LT) is a therapeutic option in multiple inherited metabolic diseases (IMDs), including methylmalonic acidemia (MMA), as LT reduces the risk of acute metabolic decompensations and long-term complications associated with these diseases. In certain IMDs, such as maple syrup urine disease (MSUD), domino liver transplant (DLT) is an accepted and safe method which expands the donor pool. However, only one adult case of DLT using an MMA donor liver has been reported; outcome and safety are still unknown and questioned.
CASE DESCRIPTION
In this case report, we describe our experience with DLT using MMA livers. Two adult MMA patients underwent living donor liver transplant (LDLT); their MMA livers were consecutively transplanted into two patients on the liver transplant waiting list who had limited chance of receiving a liver transplant in the short term due to their low model for end-stage liver disease (MELD) scores. No severe peri- or postoperative complications occurred, however the recipients of the MMA livers biochemically now have mild MMA.
CONCLUSIONS
DLT using MMA grafts is a feasible strategy to treat end-stage liver disease and expand the donor organ pool. However, the recipient of the MMA domino liver may develop mild MMA which could affect quality of life, and long-term safety remains unclear. Further long-term of outcomes for domino recipients of MMA livers, focusing on quality of life and any metabolic complications of transplantation are needed to better define the risks and benefits.
PubMed: 38317745
DOI: 10.21037/tgh-23-55 -
JCI Insight Feb 2024A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA)...
A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.
Topics: Animals; Humans; Mice; Amino Acid Metabolism, Inborn Errors; Fibroblast Growth Factors; Lipodystrophy; Mice, Transgenic
PubMed: 38271099
DOI: 10.1172/jci.insight.174097 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jan 2024To investigate the disease spectrum and pathogenic genes of inherited metabolic disorder (IMD) among neonates in Gansu Province of China.
OBJECTIVES
To investigate the disease spectrum and pathogenic genes of inherited metabolic disorder (IMD) among neonates in Gansu Province of China.
METHODS
A retrospective analysis was conducted on the tandem mass spectrometry data of 286 682 neonates who received IMD screening in Gansu Provincial Maternal and Child Health Hospital from January 2018 to December 2021. A genetic analysis was conducted on the neonates with positive results in tandem mass spectrometry during primary screening and reexamination.
RESULTS
A total of 23 types of IMD caused by 28 pathogenic genes were found in the 286 682 neonates, and the overall prevalence rate of IMD was 0.63 (1/1 593), among which phenylketonuria showed the highest prevalence rate of 0.32 (1/3 083), followed by methylmalonic acidemia (0.11, 1/8 959) and tetrahydrobiopterin deficiency (0.06, 1/15 927). In this study, 166 variants were identified in the 28 pathogenic genes, with 13 novel variants found in 9 genes. According to American College of Medical Genetics and Genomics guidelines, 5 novel variants were classified as pathogenic variants, 7 were classified as likely pathogenic variants, and 1 was classified as the variant of uncertain significance.
CONCLUSIONS
This study enriches the database of pathogenic gene variants for IMD and provides basic data for establishing an accurate screening and diagnosis system for IMD in this region.
Topics: Child; Infant, Newborn; Humans; Retrospective Studies; Metabolic Diseases; Amino Acid Metabolism, Inborn Errors; China; Child Health
PubMed: 38269462
DOI: 10.7499/j.issn.1008-8830.2308094 -
Orphanet Journal of Rare Diseases Jan 2024Combined methylmalonic acidemia and homocystinuria, cblC type is an inborn error of intracellular cobalamin metabolism and the most common one. The age of onset ranges... (Review)
Review
INTRODUCTION
Combined methylmalonic acidemia and homocystinuria, cblC type is an inborn error of intracellular cobalamin metabolism and the most common one. The age of onset ranges from prenatal to adult. The disease is characterised by an elevation of methylmalonic acid (MMA) and homocysteine and a decreased production of methionine. The aim is to review existing scientific literature of all late onset cblC patients in terms of clinical symptoms, diagnosis, and outcome.
METHODS
A bibliographic database search was undertaken in PubMed (MEDLINE) complemented by a reference list search. We combined search terms regarding cblC disease and late onset. Two review authors performed the study selection, data extraction and quality assessment.
RESULTS
Of the sixty-five articles included in this systematic review, we collected a total of 199 patients. The most frequent clinical symptoms were neuropathy/myelopathy, encephalopathy, psychiatric symptoms, thrombotic microangiopathy, seizures, kidney disease, mild to severe pulmonary hypertension with heart failure and thrombotic phenomena. There were different forms of supplementation used in the different studies collected and, within these studies, some patients received several treatments sequentially and/or concomitantly. The general outcome was: 64 patients recovered, 78 patients improved, 4 patients did not improve, or the disease progressed, and 12 patients died.
CONCLUSIONS
Most scientific literature regarding the late onset cblC disease comes from case reports and case series. In most cases treatment initiation led to an improvement and even recovery of some patients. The lack of complete recovery underlines the necessity for increased vigilance in unclear clinical symptoms for cblC disease.
Topics: Adult; Female; Pregnancy; Humans; Amino Acid Metabolism, Inborn Errors; Hyperhomocysteinemia; Homocystinuria; Methylmalonic Acid; Vitamin B 12
PubMed: 38245797
DOI: 10.1186/s13023-024-03021-3 -
Drugs in R&D Mar 2024Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVE
Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to secondary N-acetylglutamate deficiency. Carglumic acid, a synthetic analogue of N-acetylglutamate, decreases ammonia levels by restoring the functioning of the urea cycle. However, there are limited data available on the long-term safety and effectiveness of carglumic acid. Here, we present an interim analysis of the ongoing, long-term, prospective, observational PROTECT study (NCT04176523), which is investigating the long-term use of carglumic acid in children and adults with MMA and PA.
METHODS
Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level >159 µmol/L during a patient's first month of life or >60 µmol/L thereafter, with an increased lactate level [> 1.8 mmol/L] and/or acidosis [pH < 7.35]) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months' and 18 months' follow-up.
RESULTS
Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (n = 4) and PA (n = 6) were analysed. The patients had received carglumic acid for 14-77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97-2569) before treatment to 103 µmol/L (range 97-171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of - 41% (range - 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated.
CONCLUSIONS
In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as the duration of inpatient stay due to metabolic decompensations in a subset of patients.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT04176523. Registered 25 November, 2019, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04176523 .
Topics: Humans; Propionic Acidemia; Amino Acid Metabolism, Inborn Errors; Adult; Prospective Studies; Female; Male; Child; Child, Preschool; Adolescent; Glutamates; Infant; Hyperammonemia; Young Adult; Middle Aged; Ammonia
PubMed: 38198106
DOI: 10.1007/s40268-023-00449-z -
BMC Nephrology Jan 2024Combined methylmalonic acidemia (MMA) and hyperhomocysteinemia, cobalamin C (cblC) type, also named cblC deficiency is a rare autosomal recessive genetic metabolic...
BACKGROUND
Combined methylmalonic acidemia (MMA) and hyperhomocysteinemia, cobalamin C (cblC) type, also named cblC deficiency is a rare autosomal recessive genetic metabolic disease. It progressively causes neurological, hematologic, renal and other system dysfunction. The clinical manifestations are relatively different due to the onset time of disease.
CASE PRESENTATION
This report describes a rare case of a 26 year old man with cblC deficiency who developed life-threatening aortic dissection and acute kidney injury (AKI) and showed neuropsychiatric symptoms with elevated serum homocysteine and methylmalonic aciduria. After emergent operation and intramuscular cobalamin supplementation therapy, the male recovered from aortic dissection, neurological disorder and AKI. Finally, two previously published compound heterozygous variants, c.482G > A (p.R161Q) and c.658_660del (p.K220del) in the MMACHC gene were detected in this patient and he was confirmed to have cblC deficiency.
CONCLUSIONS
Poor cognizance of presenting symptoms and biochemical features of adult onset cblC disease may cause delayed diagnosis and management. This case is the first to depict a case of adult-onset cblC deficiency with aortic dissection. This clinical finding may contribute to the diagnosis of cblC deficiency.
Topics: Adult; Male; Humans; Hyperhomocysteinemia; Vitamin B 12; Amino Acid Metabolism, Inborn Errors; Acute Kidney Injury; Oxidoreductases
PubMed: 38178022
DOI: 10.1186/s12882-023-03414-9 -
Iranian Biomedical Journal Feb 2023Methylmalonic aciduria is a rare inherited metabolic disorder with autosomal recessive inheritance pattern. There are still MMA patients without known mutations in the...
BACKGROUND
Methylmalonic aciduria is a rare inherited metabolic disorder with autosomal recessive inheritance pattern. There are still MMA patients without known mutations in the responsible genes. This study aimed to identify mutations in Iranian MMA families using autozygosity mapping and NGS.
METHODS
Multiplex PCR was performed on DNAs isolated from 12 unrelated MMA patients and their family members using 19 STR markers flanking MUT, MMAA, and MMAB genes, followed by Sanger sequencing. WES was carried out in the patients with no mutation.
RESULTS
Haplotype analysis and Sanger sequencing revealed two novel, mutations, A252Vf*5 and G87R, within the MMAA and MUT genes, respectively. Three patients showed no mutations in either autozygosity mapping or NGS analysis.
CONCLUSION
High-frequency mutations within exons 2 and 3 of MUT gene and exon 7 of MMAB gene are consistent with the global expected frequency of genetic variations among MMA patients.
PubMed: 38158783
DOI: 10.61186/ibj.3782 -
Frontiers in Neurology 2023Late-onset cobalamin C (cblC) deficiency is associated with a wide range of neurological and psychiatric symptoms, hematological manifestations, anorexia, renal failure,...
Late-onset cobalamin C deficiency type in adult with cognitive and behavioral disturbances and significant cortical atrophy and cerebellar damage in the MRI: a case report.
BACKGROUND
Late-onset cobalamin C (cblC) deficiency is associated with a wide range of neurological and psychiatric symptoms, hematological manifestations, anorexia, renal failure, ocular abnormalities, dermatitis, and pancreatitis. However, the neuroimaging characteristics of late-onset cblC deficiency remain insufficiently documented. Common findings include diffuse white matter swelling, varying degrees of severe leukoaraiosis, hydrocephalus, corpus callosum atrophy, and symmetric bilateral basal ganglia lesions. In this report, we present a case of late-onset cblC deficiency in adults presenting with cerebellar ataxia as the primary symptom. The MRI findings revealed bilateral lateral cerebellar hemispheres exhibiting symmetric hyperintensity, primarily observed in diffusion-weighted imaging (DWI), which is a rarely reported imaging change in this context.
CASE PRESENTATION
Our patient was a male who experienced symptoms starting at the age of 30 years, including unsteady walking, apparent cerebellar ataxia, and cognitive impairment upon nervous system examination. Brain magnetic resonance imaging (MRI) exhibited symmetric hyperintensity in the bilateral lateral cerebellar hemispheres, predominantly manifested in DWI, without any enhancement. Subsequently, significantly elevated blood total homocysteine and urinary methylmalonic acid levels were observed. Genetic analysis confirmed the presence of MMACHC compound heterozygous mutants c.482G > A and c.609G > A, thus confirming the diagnosis of cblC deficiency. These variants were classified as likely pathogenic following the guidelines of the American College of Medical Genetics and Genomics (ACMG) and were verified using Sanger sequencing. Following treatment, the patient experienced improvements in walking ability and cognition, a significant decrease in blood total homocysteine levels, and reversal of the imaging lesions.
IN CONCLUSION
Late-onset cblC deficiency presents with diverse clinical and imaging manifestations. Early diagnosis and treatment are crucial in achieving a favorable prognosis. This case serves as a reminder to clinicians not to overlook genetic metabolic disorders, particularly those causing multisite damage, in adult patients with undiagnosed neurological disorders, especially those affecting the cerebellum. Notably, methylmalonic acidemia should be considered within the spectrum of bilateral cerebellar lesions.
PubMed: 38148982
DOI: 10.3389/fneur.2023.1308289