MLYCD – Malonic Aciduria

Malonic aciduria (MAD) is a rare autosomal recessive inborn error of fatty acid metabolism caused by deficiency of malonyl-CoA decarboxylase, encoded by MLYCD. Affected individuals present with developmental delay, seizures, cardiomyopathy and metabolic acidosis (PMID:20549361). To date, over 52 cases have been reported in the literature, illustrating wide phenotypic variability and variable age of onset (PMID:34884438).

Biallelic MLYCD variants underlie an autosomal recessive inheritance pattern, with at least 52 probands across more than 30 families described (PMID:34884438). Early reports identified 35 cases by 2013 (PMID:23177061) and nine additional enzyme-confirmed patients in 2007 (PMID:17186413). Segregation of pathogenic alleles in consanguineous pedigrees, including two affected cousins in a single family, further substantiates causality (PMID:34884438).

More than 34 distinct variants have been documented, encompassing missense, nonsense, frameshift, canonical splice-site changes and multi-exon deletions. Recurrent and founder LoF alleles include the start-codon mutation c.1A>T (p.Met1Leu) in a Korean patient (PMID:32602666) and the nonsense variant c.672G>A (p.Trp224Ter) in an Italian newborn (PMID:23177061). Novel compound heterozygous missense changes such as c.920T>G (p.Leu307Arg) have been described in Chinese patients with classic biochemical features (PMID:22104738).

Functional studies of patient fibroblasts reveal markedly reduced MCD enzymatic activity and protein levels, with mislocalization of N-terminal motif mutants to non-mitochondrial compartments (PMID:10417274; PMID:12955715). Further, the RP-Mdm2-p53 signaling axis mediates stress-induced upregulation of MCD, linking lipid homeostasis to nutritional status (PMID:24872453).

Clinical intervention with long-chain triglyceride restriction, medium-chain triglyceride supplementation and L-carnitine stabilizes and improves cardiac function, normalizing fractional shortening from 18% to 28% in infancy (PMID:20549361). Presymptomatic dietary therapy initiated after newborn screening yields normal neurodevelopmental and cardiac outcomes (PMID:23177061).

Collectively, the robust genetic, functional and clinical treatment data provide definitive evidence that biallelic MLYCD variants cause malonic aciduria. Although ongoing studies continue to expand the variant spectrum and long-term follow-up, current evidence supports reliable molecular diagnosis and targeted dietary management. Key Take-home: Autosomal recessive MLYCD deficiency leads to malonic aciduria, and early genetic diagnosis with tailored dietary therapy markedly improves clinical outcomes.

References

• Journal of inherited metabolic disease • 2010 • Use of a long-chain triglyceride-restricted/medium-chain triglyceride-supplemented diet in a case of malonyl-CoA decarboxylase deficiency with cardiomyopathy PMID:20549361
• International journal of molecular sciences • 2021 • Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family PMID:34884438
• Brain & development • 2013 • A new case of malonic aciduria with a presymptomatic diagnosis and an early treatment PMID:23177061
• Journal of inherited metabolic disease • 2007 • Clinical, enzymatic and molecular characterization of nine new patients with malonyl-coenzyme A decarboxylase deficiency PMID:17186413
• Human mutation • 2003 • MLYCD mutation analysis: evidence for protein mistargeting as a cause of MLYCD deficiency PMID:12955715
• American journal of human genetics • 1999 • The molecular basis of malonyl-CoA decarboxylase deficiency PMID:10417274
• Proceedings of the National Academy of Sciences of the United States of America • 2014 • Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation PMID:24872453
• Molecular genetics and metabolism • 2012 • Novel compound heterozygous mutation of MLYCD in a Chinese patient with malonic aciduria PMID:22104738
• Molecular genetics & genomic medicine • 2020 • A Korean child diagnosed with malonic aciduria harboring a novel start codon mutation following presentation with dilated cardiomyopathy PMID:32602666

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