Abstract:

Objective To analyze the clinical characteristics and gene variation for children with 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency (HMGCLD). Methods The clinical data and genetic sequencing results of children with HMGCLD were analyzed. Results There were 6 patients (3 boys and 3 girls). One patient had a positive family history. Neonatal screening in the local hospital indicated HMGCLD in 3 patients, 2 patients were clinically diagnosed after the onset of the disease, and 1 patient remained disease-free. The onset age of 5 patients ranged from 10 days to 5 years and the age of first diagnosis ranged from 1 month to 7 years. There were metabolic crisis, hypoglycemia and hyperlactatemia in different degrees at the onset of the disease. Two patients died. Blood tandem mass spectrometry showed an increase in 3-hydroxyisovaleryl carnitine (C5-OH), and some of the children were accompanied by an increase in hexanedioyl carnitine (C6DC). Urine organic acid analysis showed that 3-hydroxy-3-methylglutaric acid increased significantly, along with 3-methylpentene acid and 3-hydroxyisovaleric acid. The HMGCL gene variation was found in 4 patients. Two patients had a homozygous variation of c.122G>A (p.R41Q), 1 patient had a homozygous variation of c.697C>T (p.H233Y) and 1 patient had a complex heterozygous variation of c.145-2A>G and c.590G>A (p.C197Y). Among them, c.697C>T (p.H233Y), c.145-2A>G, and c.590G>A (p.C197Y) were all reported for the first time. Protein structure was predicted to be potentially harmful, and the grade of ACMG was likely pathogenic. The other two children did not undergo genetic testing. Conclusions The clinical phenotype of HMGCLD is diverse, which can be confirmed by combining blood tandem mass spectrometry, urine organic acid analysis and gene diagnosis. Screening of HMGCLD is helpful for early diagnosis and reasonable treatment.

Key words: 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency, HMGCL gene, 3-hydroxyisovaleryl carnitine, 3-hydroxy-3-methylglutaric