Malonyl-CoA decarboxylase (MCD) is an enzyme that controls malonyl-CoA levels and regulates fatty acid synthesis and oxidation. Although its physiological relevance in peripheral tissues is well known, the role of MCD in the central nervous system remains poorly understood. MCD is expressed in mitochondria, cytosol, and peroxisomes and may be regulated by PPAR-α, AMPK, and SIRT4 in tissues such as muscle, liver and kidney. In the brain, MCD expression varies during development and can respond to nutritional states. Inherited MCD deficiency (malonic aciduria) leads to the toxic accumulation of malonic acid and predominantly affects the central nervous system. The underlying mechanisms leading to brain damage in MCD patients remain unclear. Conversely, pharmacological modulation of MCD activity has been studied in obesity, diabetes, and ischemic injury, highlighting its therapeutic potential. There are still major gaps regarding MCD cellular distribution, regulatory pathways, and metabolic interaction with CPT1c (carnitine palmitoyltransferase 1c) in neural metabolism. A deeper understanding of the role of MCD in brain physiology and pathology may indicate novel therapeutic strategies targeting metabolic disorders that involve altered malonyl-CoA dynamics. Here, we discuss the current knowns and unknowns regarding MCD physiology, regulation, and pathophysiology, emphasizing brain aspects.

Combined malonic and methylmalonic aciduria (CMAMMA) is an inherited metabolic disorder caused by ACSF3 variants leading to malonyl-CoA synthetase (MCS) deficiency. Despite its well-defined genetic basis, the clinical spectrum of CMAMMA remains highly variable. This study reports six patients from three unrelated families, aged 12 days to 30 years, presenting with heterogeneous clinical manifestations. Exome sequencing (ES) identified a homozygous ACSF3 variant, c.1470G>C [p.(Glu490Asp)], in five patients, and a novel variant, c.1145T>C [p.(Leu382Pro)], in one patient. Notably, in each family's index case, ES revealed additional pathogenic variants consistent with a dual molecular diagnosis: a homozygous CHRNG variant in one patient; compound heterozygous BTD variants in two siblings, confirming biotinidase deficiency; and a novel CDK10 frameshift variant, c.520_521del [p.(Lys174Glyfs*34)], in another patient. Half of the patients with CMAMMA demonstrated mild to moderate developmental delay. Notably, the sibling with both CMAMMA and biotinidase deficiency exhibited developmental delay, whereas the sibling with isolated CMAMMA had normal development. Symptomatic individuals showed clinical improvement following dietary protein restriction and carnitine supplementation. These findings highlight that CMAMMA may cause developmental delay, emphasizing the importance of early diagnosis and treatment. Furthermore, in patients with atypical features, high-throughput sequencing technologies offer a comprehensive approach to identifying additional pathogenic variants in genes beyond ACSF3.

Malonyl-CoA decarboxylase (MLYCD) deficiency, also known as malonic aciduria (MAD), is a rare autosomal recessive inherited metabolic defect. In this study, we aimed to investigate the clinical and molecular features of five patients with MAD in order to increase clinicians' awareness of the disease. Sanger sequencing was used to detect and genetically analyze the MLYCD variations in the preexisting patients and their parents. Five patients with MAD (5 months to 9.6 years old; two males and three females) rarely exhibited metabolic decompensation episodes or seizures. All patients exhibited varying degrees of developmental delay and hypotonia. Our study expands the spectrum of variants of the MLYCD gene. MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion. Additionally, there is no correlation between various genotypes and phenotypes. A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness. Newborn screening may aid in the early diagnosis, treatment, and prognosis of this rare disorder.

This study aimed to find the common inborn errors of metabolism in Iranian patients with autism spectrum disorder. In this cross-sectional multicenter study, 105 children and adolescents with autism spectrum disorder from six centers in different cities of Iran were enrolled between August, 2019 and October, 2020. Metabolic screening, including measuring plasma levels of amino acids, acylcarnitines, creatine, and guani-dinoacetate, and urinary levels of organic acids, purines, and pyrimidines was performed. Other data, including age, parental consanguinity, history of seizure, developmental mile-stones, and physical examination, were also recorded. An inborn error of metabolism was found in 13 (12.4%) patients. Five patients (4.8%) had cerebral creatine deficiency syndrome, 4 (3.8%) had arginine succinate aciduria, 2- methylbutyryl glycinuria, short-chain acyl-CoA dehydrogenase deficiency, and combined methylmalonic aciduria/malonic aciduria. There was a strong association between positive meta-bolic evaluation and parental consanguinity, history of seizures, microcephaly, and delayed development. Our results suggest that metabolic screening should be performed in the cases of autism associated with parental consanguinity, developmental delay, and a history of seizures. The assays to be considered as a screening panel include plasma or blood amino acids, acylcarnitines, creatine and guanidinoacetate, and urinary levels of organic acids.

Malonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe the clinical, biochemical, and genetic characteristics of patients with later-onset MLYCDD. Clinical and biochemical characteristics of two patients aged 48 and 29 years with a confirmed molecular diagnosis of MLYCDD were examined. A systematic review of published studies describing the characteristics of cardiovascular involvement of patients with MLYCDD was performed. Two patients diagnosed with MLYCDD during adulthood were identified. The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction. No other clinical manifestation typical of MLYCDD was observed. Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity. During follow-up, no deterioration of LV systolic function was observed. The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD (median age 6 months [IQR 1-12], 22 males [67%]). Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype. A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases. After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death). For the first time this study describes a later-onset phenotype of MLYCDD patients, characterized by single-organ involvement, mildly reduced enzyme activity, and a benign clinical course.