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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 -
Clinical Laboratory Feb 2024Based on research, c.609G>A (p.W203X) is a universal mutation site for MMACHC in methylmalonic acidemia (MMA) combined with homocystinuria, cblC type (cblC disease), and...
BACKGROUND
Based on research, c.609G>A (p.W203X) is a universal mutation site for MMACHC in methylmalonic acidemia (MMA) combined with homocystinuria, cblC type (cblC disease), and c.467G>A (p.G156D) mutation in families with such disease have not yet been reported. To conduct clinical and molecular genetic analysis of a family with cblC disease.
METHODS
This work followed the Declaration of Helsinki. All testing methods were performed under the informed consent of our children patients' parents. A second-generation cblC family with 5 members, was selected as the research subject, including sick siblings and parents and an older sister with normal phenotype, given newborn screening for acylcarnitine spectrum via liquid chromatography tandem mass spectrometry (LC-MS/MS), and diagnosed through combining urine organic acid with homocysteine detection via gas chromatography-mass spectrometry (GC-MS) with second-generation gene sequencing technology. The peripheral blood of five family members was collected for genomic DNA extraction, and the changes were screened in disease-related MMACHC sequence via PCR and direct DNA sequencing.
RESULTS
The family conformed to the autosomal recessive inheritance, the proband and younger sister were cblC patients, diagnosed in February and at 22d given relevant treatment. The proband died, whereas the younger sister received follow-up treatment. Their parents and sister had normal phenotype. In 2 cases, there was compound heterozygous mutation in MMACHC called c.609G>A (p.W203X) nonsense mutation and c.467G>A (p.G156D) missense mutation in exon 4, while the father with normal phenotype had heterozygous mutation c.609G>A in exon 4 coding area. In its protein, the 203rd amino acid changed from tryptophan to a stop codon (p.W203 x). The normal mother and sister had a heterozygous mutation c.467G>A in exon 4 coding area. In its protein, the 156th amino acid changed from glycine to aspartic acid (p.G156D).
CONCLUSIONS
The cblC family results from c.609G>A (p.W203X) and c.467G>A (p.G156D) compound heterozygous mutations in MMACHC, which has a pathogenic impact.
Topics: Infant, Newborn; Child; Humans; Homocystinuria; Chromatography, Liquid; Tandem Mass Spectrometry; Amino Acid Metabolism, Inborn Errors; Mutation; Amino Acids; Molecular Biology; Vitamin B 12; Methylmalonic Acid; Oxidoreductases
PubMed: 38345966
DOI: 10.7754/Clin.Lab.2022.220126 -
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 -
Retina (Philadelphia, Pa.) Jun 2024Serine (Ser) and glycine (Gly) levels were reported to differ between patients with macular telangiectasia type 2 (MacTel) compared with healthy controls. Because they...
PURPOSE
Serine (Ser) and glycine (Gly) levels were reported to differ between patients with macular telangiectasia type 2 (MacTel) compared with healthy controls. Because they are closely related to methylation metabolism, this report investigates methylation-associated metabolite levels in patients with MacTel and retinal changes in monogenetic methylation disorders.
METHODS
Prospective, monocentric study on patients with MacTel and healthy controls underwent a standardized protocol including a blood draw. Methylation-associated metabolite levels in plasma were determined using targeted quantitative metabolomics. Furthermore, patient records of cystathionine beta-synthase, methylenetetrahydrofolate reductase, and methylmalonic aciduria and homocystinuria type C protein (MMACHC) deficiency were screened for reported retinal changes.
RESULTS
In total, 29 patients with MacTel and 27 healthy controls were included. Patients with MacTel showed lower plasma Ser ( P = 0.02 and P = 0.01) and Gly ( P = 0.11 and P = 0.11) levels than controls. Principal component analyses revealed that methylation-associated metabolite, especially homocysteine, contributed to a distinct clustering of patients with MacTel. No retinal changes were seen in cystathionine beta-synthase (n = 1) and methylenetetrahydrofolate reductase (n = 2) deficiency, while two patients with MMACHC (n = 4) deficiency displayed extensive macular dystrophy.
CONCLUSION
Patients with MacTel show distinct clustering of methylation-associated metabolite compared with controls. Of the three homocystinurias, only MMACHC resulted in macular dystrophy, possibly due to distinct compensatory pathways.
Topics: Humans; Female; Male; Prospective Studies; Retinal Telangiectasis; Middle Aged; Tomography, Optical Coherence; Adult; Aged; Methylation; Amino Acid Metabolism, Inborn Errors; Fluorescein Angiography; Glycine; Homocystinuria
PubMed: 38261977
DOI: 10.1097/IAE.0000000000004052 -
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 -
World Journal of Pediatrics : WJP Jan 2024Liver transplantation (LT) has been proposed as a viable treatment option for selected methylmalonic acidemia (MMA) patients. However, there are still controversies...
Long-term clinical outcomes and health-related quality of life in patients with isolated methylmalonic acidemia after liver transplantation: experience from the largest cohort study in China.
BACKGROUND
Liver transplantation (LT) has been proposed as a viable treatment option for selected methylmalonic acidemia (MMA) patients. However, there are still controversies regarding the therapeutic value of LT for MMA. The systematic assessment of health-related quality of life (HRQoL)-targeted MMA children before and after LT is also undetermined. This study aimed to comprehensively assess the long-term impact of LT on MMA, including multiorgan sequelae and HRQoL in children and families.
METHODS
We retrospectively evaluated 15 isolated MMA patients undergoing LT at our institution between June 2013 and March 2022. Pre- and post-transplant data were compared, including metabolic profiles, neurologic consequences, growth parameters, and HRQoL. To further assess the characteristics of the HRQoL outcomes in MMA, we compared the results with those of children with biliary atresia (BA).
RESULTS
All patients had early onset MMA, and underwent LT at a mean age of 4.3 years. During 1.3-8.2 years of follow-up, the patient and graft survival rates were 100%. Metabolic stability was achieved in all patients with liberalized dietary protein intake. There was a significant overall improvement in height Z scores (P = 0.0047), and some preexisting neurological complications remained stable or even improved after LT. On the Pediatric Quality of Life Inventory (PedsQL™) generic core scales, the mean total, physical health, and psychosocial health scores improved significantly posttransplant (P < 0.05). In the family impact module, higher mean scores were noted for all subscales post-LT, especially family function and daily activities (P < 0.01). However, the total scores on the generic core scales and transplant module were significantly lower (Cohen's d = 0.57-1.17) when compared with BA recipients. In particular, social and school functioning (Cohen's d = 0.86-1.76), treatment anxiety, and communication (Cohen's d = 0.99-1.81) were far behind, with a large effect size.
CONCLUSIONS
This large single-center study of the mainland of China showed an overall favorable impact of LT on isolated MMA in terms of long-term survival, metabolic control, and HRQoL in children and families. The potential for persistent neurocognitive impairment and inherent metabolic fragility requires long-term special care. Video Abstract (MP4 153780 KB).
PubMed: 38190010
DOI: 10.1007/s12519-023-00780-0 -
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