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Biomedicines Dec 2023Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is required by the body to metabolize cobalamin (Cbl). Due to its complex structure and cofactor forms,...
Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is required by the body to metabolize cobalamin (Cbl). Due to its complex structure and cofactor forms, Cbl passes through an extensive series of absorptive and processing steps before being delivered to mitochondrial methyl malonyl-CoA mutase and cytosolic methionine synthase. Depending on the cofactor attached, MMACHC performs either flavin-dependent reductive decyanation or glutathione (GSH)-dependent dealkylation. The alkyl groups of Cbl have to be removed in the presence of GSH to produce intermediates that can later be converted into active cofactor forms. Pathogenic mutations in the GSH binding site, such as R161Q, R161G, R206P, R206W, and R206Q, have been reported to cause Cbl diseases. The impact of these variations on MMACHC's structure and how it affects GSH and Cbl binding at the molecular level is poorly understood. To better understand the molecular basis of this interaction, mutant structures involving the MMACHC-MeCbl-GSH complex were generated using in silico site-directed point mutations and explored using molecular dynamics (MD) simulations. The results revealed that mutations in the key arginine residues disrupt GSH binding by breaking the interactions and reducing the free energy of binding of GSH. Specifically, variations at position 206 appeared to produce weaker GSH binding. The lowered binding affinity for GSH in the variant structures could impact metabolic pathways involving Cbl and its trafficking.
PubMed: 38137438
DOI: 10.3390/biomedicines11123217 -
World Journal of Clinical Cases Dec 2023Methylmalonic acidemia (MMA) is characterized by non-specific symptoms such as vomiting, and feeding difficulties, along with delayed mental and physical development....
BACKGROUND
Methylmalonic acidemia (MMA) is characterized by non-specific symptoms such as vomiting, and feeding difficulties, along with delayed mental and physical development. However, no case of MMA combined with pulmonary fungal infection has been reported yet.
CASE SUMMARY
We report the case of a neonate who presented pulmonary fungal infection along with the non-specific features of MMA. Exome sequencing revealed a c.331C>T variant in exon 3 of from the father, and a c.658-c.660delAAG variant in exon 4 from the mother, which confirmed the diagnosis of cblC type MMA combined with hyperhomocysteinemia.
CONCLUSION
Invasive fungal infection might occur in some infants with MMA. Therefore, early diagnosis is recommended for unexplained pulmonary infection.
PubMed: 38130779
DOI: 10.12998/wjcc.v11.i34.8158 -
Frontiers in Neurology 2023Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from a reduction in mtDNA content in the cells, tissues,...
BACKGROUND
Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from a reduction in mtDNA content in the cells, tissues, and organ systems, leading to symptoms related to energy deficits. Deficiency of the mitochondrial succinyl-CoA ligase/synthetase enzyme secondary to pathogenic variations in the and genes is a subtype of MDDS that presents with neurological manifestations and a specific biochemical profile.
METHODS
This cross-sectional series describes five patients with MDDS secondary to pathogenic variations in the and genes from two tertiary care centers in Canada and India. Clinical data concerning the course, investigations, and outcome were gathered through chart reviews.
RESULTS
All subjects presented in early infancy with neurological manifestations, including movement disorder, psychomotor regression, developmental delay, hearing loss, behavioral issues, or a combination thereof. Elevated methylmalonic acid metabolites, an abnormal acylcarnitine profile, and lactic acidemia were noted in the biochemical profile of each patient ( = 5/5, 100%). Molecular genetic testing disclosed the presence of pathogenic homozygous mutations in four subjects and compound heterozygosity in one subject.
CONCLUSION
MDDS associated with and genes can be detected biochemically by the presence of methylmalonic aciduria besides the elevation of lactate, C3, C4DC, and C5-OH acylcarnitine. Conducting metabolic workups including MMA and acylcarnitine profiles in patients with heterogeneity of clinical symptoms associated with the presence of this biochemical marker may potentially reduce the time to diagnosis and management.
PubMed: 38073635
DOI: 10.3389/fneur.2023.1265115 -
Cureus Oct 2023Methylmalonyl coenzyme A (CoA) epimerase (MCE) converts D-methylmalonyl-CoA into L-methylmalonyl CoA in the final common degradation pathway of valine, isoleucine,...
Methylmalonyl coenzyme A (CoA) epimerase (MCE) converts D-methylmalonyl-CoA into L-methylmalonyl CoA in the final common degradation pathway of valine, isoleucine, methionine, threonine, odd-chain fatty acids, and cholesterol side chains. Methylmalonyl-CoA epimerase deficiency is an ultra-rare autosomal recessive disorder where methylmalonic acid, methylcitrate, 3-hydroxypropionate, and propionylcarnitine are accumulated. We describe two novel pediatric patients and review the previously reported cases of MCE deficiency. Including our two novel patients, at least 24 cases of MCE deficiency have been described, with a broad clinical spectrum ranging from asymptomatic to severely neurologically impaired patients. Our patients are siblings of Arabic origin who presented with metabolic decompensation with coma and epilepsy during infancy. Methylmalonic aciduria was disclosed, L-methylmalonyl-CoA mutase deficiency was assumed, and they were treated accordingly. When first seen in our country, aged 10 and four years, respectively, both presented severe intellectual disability and spasticity. The younger had an ataxic gait, and the older was wheelchair-ridden. The study of the , , , and genes was normal. Subsequently, the pathogenic variant c.139C>T (p.Arg47*) in the gene was identified in homozygosity in both patients, leading to the diagnosis of MCE deficiency (Online Mendelian Inheritance in Man (OMIM) 251120, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, MD, USA). Most patients were homozygous for that variant (83% of the alleles). Correct diagnosis allowed treatment adequacy and genetic counseling. Methylmalonyl-CoA epimerase deficiency shares a similar biochemical profile with other rare genetic disorders. Patients present with overlapping clinical features with predominant neurological manifestations; genetic testing is indispensable for diagnosis. We found no association between genotype and biochemical and clinical phenotypes.
PubMed: 38034150
DOI: 10.7759/cureus.48017 -
Cureus Oct 2023Methylmalonic acidemia (MMA) is a genetic condition affecting cobalamin metabolism causing elevated serum and urine methylmalonic acid without B12 deficiency. MMA...
Methylmalonic acidemia (MMA) is a genetic condition affecting cobalamin metabolism causing elevated serum and urine methylmalonic acid without B12 deficiency. MMA presents with ketoacidotic hyperammonemic coma in newborns and can result in neonatal death or severe neurological disability. Rarely, this diagnosis is missed, or patients do not present until later in life. Presentation of this life-threatening condition is variable in adults. Improvement is rapid with IV cobalamin and a specialized diet. This case is intended to increase clinician's awareness of the late presentation of this disease and the importance of high clinical suspicion and prompt diagnosis. We present a case of a 32-year-old man with seizures, polyneuropathy, ataxia, and memory loss which were unexplained until diagnosis with MMA. We aim to help clinicians understand the variable presentation and diagnostic work-up of MMA to prevent catastrophic missed diagnoses. After an extensive work-up, the patient was found to have methylmalonic acidemia and was promptly treated with high dose vitamin B12 and a specialized diet with low protein including restricted isoleucine, threonine, methionine, and valines as well as a high caloric content. The patient showed significant clinical improvement with this treatment. To our knowledge, this is the first case of MMA presenting with these symptoms in a medically stable adult. The patient was adopted from abroad and therefore, lacked access to normal newborn screenings, further complicating diagnosis. We aim to demonstrate to clinicians the importance of considering this diagnosis in patients in whom symptoms may be suggestive, particularly if they lack access to genetic or metabolic screening.
PubMed: 38022369
DOI: 10.7759/cureus.47577 -
Journal of Korean Medical Science Nov 2023Combined malonic and methylmalonic aciduria is a rare genetic disorder caused by biallelic variants that results in impaired protein and fat metabolism and the...
Combined malonic and methylmalonic aciduria is a rare genetic disorder caused by biallelic variants that results in impaired protein and fat metabolism and the accumulation of malonic and methylmalonic acids. A 52-day-old infant with a fever and a history of possible meningitis during the neonatal period was hospitalized. Multiple lesions of necrotizing lymphadenitis with abscesses in the left inguinal area were treated by incision and drainage along with appropriate antibiotic therapy, which revealed a methicillin-resistant infection. At 6 months of age, the patient was admitted with anal abscesses. Due to the increased suspicion of primary immunodeficiency disease, genetic testing was conducted, which revealed biallelic variants inherited from both parents. Urine organic acid analysis revealed elevated levels of malonic and methylmalonic acids. At 29 months, the patient showed normal growth and development without any dietary modifications. He had occasional colds, but severe bacterial infections were absent. The prognosis suggests a benign disease course. Here, we present the first reported case of compound heterozygote variants in Korea.
Topics: Infant; Infant, Newborn; Male; Humans; Abscess; Methicillin-Resistant Staphylococcus aureus; Methylmalonic Acid; Primary Immunodeficiency Diseases
PubMed: 37987109
DOI: 10.3346/jkms.2023.38.e387 -
Clinical Kidney Journal Nov 2023
PubMed: 37915912
DOI: 10.1093/ckj/sfad094 -
Frontiers in Neurology 2023Cobalamin C (cblC) deficiency is a rare hereditary disorder affecting intracellular cobalamin metabolism, primarily caused by mutations in . This condition is...
INTRODUCTION
Cobalamin C (cblC) deficiency is a rare hereditary disorder affecting intracellular cobalamin metabolism, primarily caused by mutations in . This condition is characterized by combined methylmalonic acidemia and hyperhomocysteinemia, displaying a wide range of clinical manifestations involving multiple organs. Owing to its uncommon occurrence and diverse clinical phenotypes, diagnosing cblC deficiency is challenging and often leads to delayed or missed diagnoses.
CASE DESCRIPTION
In this report, we present a case of late-onset cblC deficiency with brown desquamating dermatitis on the buttocks. Magnetic resonance imaging (MRI) of the brain revealed bilateral cerebellar abnormalities. The suspicion of an inherited metabolic disorder was raised by abnormal serum amino acid and acylcarnitine levels, along with increased urine methylmalonic acid and serum homocysteine levels. Whole-exome sequencing helped identify a homozygous variant (c.482G>A) in , confirming the diagnosis of cblC deficiency. However, despite receiving treatment with hydroxocobalamin and betaine, the patient did not experience clinical improvement, which may be attributed to the delayed diagnosis as indicated by the declining homocysteine and methylmalonic acid levels.
CONCLUSION
Collectively, we emphasize the significance of recognizing the skin lesions and observing serial MRI changes in patients with cblC deficiency. Our case underscores the importance of early diagnosis and timely therapeutic intervention for this severe yet frequently manageable condition.
PubMed: 37808496
DOI: 10.3389/fneur.2023.1255128 -
Orphanet Journal of Rare Diseases Sep 2023cblC defect is the most common type of methylmalonic acidemia in China. Patients with late-onset form (>1 year) are often misdiagnosed due to heterogeneous symptoms....
BACKGROUND
cblC defect is the most common type of methylmalonic acidemia in China. Patients with late-onset form (>1 year) are often misdiagnosed due to heterogeneous symptoms. This study aimed to describe clinical characteristics and evaluate long-term outcomes of Chinese patients with late-onset cblC defect.
METHODS
A total of 85 patients with late-onset cblC defect were enrolled. Clinical data, including manifestations, metabolites, molecular diagnosis, treatment and outcome, were summarized and analyzed.
RESULTS
The age of onset ranged from 2 to 32.8 years old (median age 8.6 years, mean age 9.4 years). The time between first symptoms and diagnosis ranged from a few days to 20 years (median time 2 months, mean time 20.7 months). Neuropsychiatric symptoms were presented as first symptoms in 68.2% of cases, which were observed frequently in schoolchildren or adolescents. Renal involvement and cardiovascular disease were observed in 20% and 8.2% of cases, respectively, which occurred with the highest prevalence in preschool children. Besides the initial symptoms, the disease progressed in most patients and cognitive decline became the most frequent symptom overall. The levels of propionylcarnitine, propionylcarnitine / acetylcarnitine ratio, methylmalonic acid, methylcitric acid and homocysteine, were decreased remarkably after treatment (P<0.001). Twenty-four different mutations of MMACHC were identified in 78 patients, two of which were novel. The c.482G>A variant was the most frequent mutated allele in this cohort (25%). Except for 16 patients who recovered completely, the remaining patients were still left with varying degrees of sequelae in a long-term follow-up. The available data from 76 cases were analyzed by univariate analysis and multivariate logistic regression analysis, and the results showed that the time from onset to diagnosis (OR = 1.025, P = 0. 024) was independent risk factors for poor outcomes.
CONCLUSIONS
The diagnosis of late-onset cblC defect is often delayed due to poor awareness of its various and nonspecific symptoms, thus having an adverse effect on the prognosis. It should be considered in patients with unexplained neuropsychiatric and other conditions such as renal involvement, cardiovascular diseases or even multiple organ damage. The c.482G>A variant shows the highest frequency in these patients. Prompt treatment appears to be beneficial.
Topics: Adolescent; Child, Preschool; Humans; Child; Young Adult; Adult; Homocystinuria; Oxidoreductases; Amino Acid Metabolism, Inborn Errors; Carnitine; Mutation; Methylmalonic Acid; Vitamin B 12
PubMed: 37770946
DOI: 10.1186/s13023-023-02890-4