MLYCD gene
Also known as: Malonyl-CoA decarboxylase deficiency (MLYCD)
OMIM#248360 https://omim.org/entry/248360
1. The disease
Malonic aciduria is a metabolic disorder caused by deficiency of malonyl-CoA decarboxylase (MLYCD). This disease is caused by mutations in the malonyl-CoA decarboxylase gene (MLYCD, chromosome 16q24) and is inherited as an autosomal recessive trait. The MLYCD enzyme is involved in the degradation of malonyl-CoA and it appears that inhibition of fatty acid synthesis as a result of malonyl-CoA accumulation is responsible for at least some of the clinical manifestations of the disorder.
2. The Symptoms
This condition usually presents in early childhood and the manifestations are variable. The majority of patients have developmental delay with hypotonia, seizures, hypoglycaemia, metabolic acidosis, ketosis, cardiomyopathy and diarrhea.
- Developmental delay is the most prominent feature, and cardiomyopathy is the leading cause of morbidity and mortality.
- Brain abnormalities characterized by malformation in cortical development and white matter involvement have been reported in some patients. Chapel-Crespo, 20191 described 9 patients with speech, fine motor delay and microcephaly.
- If not detected by newborn screening, most cases of MLYCDD present with metabolic decompensation characterized by severe metabolic acidosis and hypoglycemia, associated with poor prognosis. As a result of expanded newborn screening, more patients with MLYCDD have been identified prior to the onset of symptoms, allowing for early initiation of treatment and potential prevention of complications such as hypoglycemia, cognitive impairment and cardiomyopathy.
3. Actions to take in case of early diagnosis
- Babies with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the MLYCD gene) should continue breastfeeding, avoid fasting or high-protein baby formulas.
- Early treatment is essential in preventing chronic symptoms.
- Correlation with the biochemical NBS electrospray ionisation tandem mass spectrometry (ESI-MS/MS) is essential for confirming the diagnosis (increased malonylcarnitine – C3DC and C3DC/C10). Urinary organic acids analysis by gas-liquid chromatography or mass spectrometry includes increased malonic and methylmalonic acid.
- MLYCD is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from a multidisciplinary approach to care.
- Early implementation of a diet restricted in long-chain fat and high MCT in combination with cardiac medications (ACE inhibitors and beta-blockers) improve the outcome of cardiac disease, however, these interventions may not completely prevent other disease complications such as neurodevelopmental disabilities and brain MRI abnormalities.
- Carnitine supplements may also be recommended.
- Monitoring for CNS disease (neurodevelopmental testing/brain MRI) and cardiomyopathy (serial echocardiograms) should be implemented as standard of care for this disorder.
- The prognosis for patients is variable but the disease can be lethal in the neonatal period.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.
4. For more information
Biblio: Chapel-Crespo C, Gavrilov D, Sowa M, et al. Clinical, biochemical and molecular characteristics of malonyl-CoA decarboxylase deficiency and long-term follow-up of nine patients. Mol Genet Metab. 2019;128(1-2):113-121. PMID: 31395333.