Malonyl-CoA decarboxylase deficiency is an uncommon inherited metabolic disease. The characteristic phenotype is variable, but may include developmental delay in...
Malonyl-CoA decarboxylase deficiency is an uncommon inherited metabolic disease. The characteristic phenotype is variable, but may include developmental delay in early childhood, seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, ketosis, abnormal urinary compounds, lactic acidemia, and hypertrophic cardiomyopathy (Sweetman and Williams, 2001).
▼ Clinical Features
Brown et al. (1984) described deficiency of malonyl-CoA decarboxylase in a 5-year-old boy who had been studied for short stature, abdominal pain, chronic constipation, episodic vomiting, and metabolic acidosis. Abnormal amounts of malonic, methylmalonic, and succinic acids were found in his urine. The parents were first cousins, and a sib had died at 3.5 months of age. The mitochondrial malonyl-CoA decarboxylase was very deficient and both parents had an intermediate level of activity.
Haan et al. (1986) reported a second boy with more severe malonyl-CoA decarboxylase deficiency who presented in a quite different way from the previous patient and whose urine contained, in addition to the above-mentioned organic acids, adipic, glutaric, and suberic acids. The child was mildly mentally retarded and presented with vomiting, seizures, hypoglycemia, and mild metabolic acidosis during a urinary tract infection. Mitochondrial malonyl-CoA decarboxylase activity in fibroblasts was 4% of normal; in both parents it was about half normal.
MacPhee et al. (1993) described 2 patients, a son of second-cousin Irish parents and a girl, the daughter of first-cousin Scottish parents. They were investigated during episodes of vomiting and febrile convulsions associated with concomitant developmental delay. Malonicaciduria and grossly reduced malonyl-CoA decarboxylase activity were demonstrated.
FitzPatrick et al. (1999) provided an analysis of the 7 reported cases of MCD deficiency. The condition was present in early childhood and was associated with malonicaciduria, methylmalonicaciduria, and developmental delay in all 7, seizure disorder and hypoglycemia in 4, and cardiomyopathy in 2.
De Wit et al. (2006) reported a 4.5-year-old girl, born of consanguineous Moroccan parents, with MCD deficiency. Family history revealed 2 neonatal deaths and several miscarriages. The patient had feeding problems, failure to thrive, and severe developmental delay with no language development. Diagnosis occurred at age 2 years when metabolic screening showed compensated metabolic acidosis, hyperammonemia, increased malonic acid, and other abnormalities. Skin fibroblasts showed complete MCD deficiency. Cardiac exam was normal. The patient also had a very poor appetite. Brain MRI showed generalized atrophy, major white matter loss, thickened cortex with pachygyria, and periventricular nodular heterotopia. These findings were consistent with a malformation of cortical development. A review of the literature found that some previously reported patients also had brain imaging abnormalities, such as frontotemporal atrophy and white matter changes.
Chapel-Crespo et al. (2019) reported clinical features and long-term follow-up of 9 individuals, ranging in age from 9 months to 14 years, with MCD deficiency. Of these individuals, 1 died from cardiomyopathy at 9 months of age. Three of the 9 had seizures, which resolved over time in 2 individuals. Seven of 9 had developmental delays. Six of 9 had cardiomyopathy, most of which were detected via screening echocardiogram. Of 7 individuals who had brain MRIs, 4 had T2 hyperintensities in the white matter and basal ganglia.
The cases reported by Brown et al. (1984), Haan et al. (1986), and MacPhee et al. (1993) supported autosomal recessive inheritance.
▼ Clinical Management
Haan et al. (1986) showed in one case that a high-fat, low-carbohydrate diet led to symptomatic hypoglycemia, moderate acidosis, and urinary excretion of the organic acids. They pointed to this experience as evidence that methyl-CoA decarboxylase has an important function in the mitochondrion in preventing accumulation of malonyl-CoA, which has complex metabolic effects. MacPhee et al. (1993) described 2 patients with the deficiency and agreed with Brown et al. (1984) and Haan et al. (1986) that a low-fat, high-carbohydrate diet would lead to near normalization of the urinary organic acid excretion with no further hypoglycemic episodes. Hospital admission was recommended during periods of infection as well as during febrile illness as the harmful effects of the disorder became apparent.
▼ Molecular Genetics
Gao et al. (1999) identified a 4-bp deletion at the 3-prime end of exon 2 of the MLYCD gene (606761.0003) in homozygosity in a patient with malonyl-CoA decarboxylase deficiency.
By RT-PCR analysis of fibroblast RNA from 2 consanguineous Scottish patients with MCD deficiency reported by MacPhee et al. (1993), FitzPatrick et al. (1999) identified homozygous mutations in the MCD gene (606761.0002-606761.0003).
Sacksteder et al. (1999) identified a 2-bp deletion (606761.0004) in a patient with severe malonicaciduria.
By genomic sequencing of the MLYCD gene, Wightman et al. (2003) succeeded in identifying 16 of 18 pathogenic alleles in 9 unrelated patients with malonyl-CoA decarboxylase deficiency. (see, e.g., 606761.0005-606761.0007).
In 3 Mexican individuals, including 2 sibs, with malonyl-CoA decarboxylase deficiency, Chapel-Crespo et al. (2019) identified homozygosity for deletion of exon 5 in the MLYCD gene (606761.0008). The deletion was identified via MLPA analysis.