NOVEL SHORT-CHAIN ACYL-COA DEHYDROGENASE GENE MUTATION (319 C>T) PRESENTS WITH HYPOTONIA, DEVELOPMENTAL DELAY, MULTICORE MYOPATHY AND CLINICAL HETEROGENEITY AND IS CANDIDATE FOUNDER MUTATION IN ASHKENAZI JEWS

Objectives: To characterize the demographic, clinical and biochemical phenotypic spectrum of children with short-chain acyl-CoA dehydrogenase (SCAD) deficiency due to the 319C >T mutation.

Methods: Affected children were identified by elevated butyrylcarnitine on serum acylcarnitines (FAB-tandem MS), ethylmalonic aciduria on urine organic acids (GCMS) and/or deficient SCAD activity in cultured skin fibroblasts or biopsied muscle (ETF reduction assay). Genomic DNA was analyzed by PCR of 5'-flanking promoter-region & each of 10 SCAD gene exons in patients & in exon 3 of Ashkenazi Jewish controls.8.

Results: We report 7 children (4 male, 3 female), 3 homozygous for the 319 C>T mutation and 4 who are compound heterozygous for the 319C>T and 625G>A mutations. All 7 are of Ashkenazi Jewish origin in which group, on screening, we found a high 319 C>T heterozygote frequency of 1:15 suggesting that this may be a founder mutation with a predicted homozygous birth rate of 1:780 or due to selective advantage. The clinical phenotype is variable with onset from birth to early childhood. Common features include hypotonia (6/7), developmental delay (5/6), myopathy (4/7) characterized by multiminicore changes in two & lipid storage in one, facial weakness (3/7), lethargy (3/7) & congenital abnormalities (3/7). One female with multicore myopathy had progressive external ophthalmoplegia, ptosis and cardiomyopathy with pneumonia and respiratory failure. Two compound heterozygous brothers presented with psychosis, optic atrophy, pyramidal signs, & multifocal white matter abnormalities on MRI brain suggesting additional genetic factors; one had cerebellar ataxia. Biochemical analysis revealed ethylmalonic aciduria (6/6), methylsuccinic aciduria (3/4), elevated butyrylcarnitine (3/5), decreased butyrate oxidation in lymphoblasts (2/4) and decreased SCAD activity in fibroblasts or muscle (3/3). Expression studies of 319 C>T mutation in isolated mouse liver mitochondria confirmed this to be disease causing. 625G>A is a common variant conferring disease susceptibility.

Conclusion: We conclude that the wide clinical and biochemical phenotypic variability of this 319C>T mutation suggests that this is a complex multifactorial/polygenic condition that should be screened for in individuals with multicore myopathy, particularly among the Ashkenazi population.