Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.

Purpose: Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketogenesis caused by biallelic variants in HMGCS2. Only 59 patients with this disorder have been reported so far.

Patients and methods: We performed a comprehensive literature search to identify all published cases of HMGCS2D (n=59). Additionally, data of 16 yet undescribed patients with this disorder were collected. Clinical course, biochemical findings and mutation data are highlighted and discussed. An overview on all HMGCS2 variants reported in patients is provided.

Results: Sixty-eight patients (91%) presented with an acute metabolic decompensation, mostly within the first year of life, but beyond the neonatal period. Asymptomatic individuals were identified in several families. Six patients (8%) had died, mainly during the initial metabolic crisis. The neurologic long-term outcome of surviving patients was favorable with almost all patients (98%) showing normal development. Only one variant was identified to be common, (HMGCS2) NM_005518.4: c.634G>A, p.(Gly212Arg), and found in 6 families. No genotype-phenotype correlation can be established.

Discussion: This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D including a list of HMGCS2 variants identified in affected individuals.