Clinical, biochemical, molecular and therapeutic characteristics of four new patients of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Abstract Thirty patients with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS) deficiency, which is a rare autosomal recessive disorder caused by HMGCS2 gene mutation are known. Here, we present four new patients with this disease. The characteristics including several metabolites of patients were recorded. Next-generation targeted sequencing and multiple sequence alignment of PCR amplified products allowed for mutational analysis of HMGCS2. Minigene assay transcript analysis confirmed pathogenicity of a splice site mutation. All cases had recurrent episodes with infections while they had no symptoms during intermissions. Patient 1, a girl, showed recurrent severe metabolic acidosis after infections from 8 months old and presented with weakness, vomiting and lethargy but had normal blood glucose. After treatment, she revived completely. Patients 2, 3 and 4 were boys who showed episodes of hypoglycemia since 8, 27 and 10 months of age, respectively. Glucose infusion reversed the symptoms. All four patients had hepatomegaly and abdominal imaging showed fatty livers. Serum free fatty acid increased. Urinary dicarboxylic acids and urinary 4-hydroxy-6-methyl-2pyrone presented. Diagnosis was confirmed by HMGCS2 gene analysis and 7 mutations (p.R188H, p.F420S, p.R206C, IVS2 + 1G > T, p.E401*, p.A450Pfs*7 and p.Q427*) of this gene were found. Here we report on the characteristics and genetics of four new patients with HMGCS deficiency. This study will enrich our knowledge of this rare autosomal recessive disorder.