Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review

ObjectivesHolocarboxylase synthetase deficiency (HCSD) (OMIM #253270) is a rare inborn error of metabolism with an estimated annual incidence of 1 in 200,000 people. Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia. Diagnosis is made through genetic analysis.Case presentationPatient 1 was a 7-year-old girl with normal growth and development, presenting with severe hypoglycemia and metabolic acidosis. Her family reported that she was diagnosed as having ketotic hypoglycemia; she had five episodes of hypoglycemia and metabolic acidosis in past 4 years when her oral intake decreased during acute illness. Patient 2 was a 6-month-old female infant with normal growth and development, presenting with progressive generalized eczema and metabolic acidosis for the first time. We found that they both had hyperammonemia, hyperlactatemia, hyperketonemia, organic acids detected in urine and elevated C5OH acylcarnitine level by tandem mass spectrometry. HLCS gene analysis showed a homozygous pathogenic variant p.V363D in patient 1 and a pathogenic variant p.R508W compound with a novel splice site pathogenic variant c.2010-1G>A in patient 2. They have been on biotin treatment (10 mg/day for both of them) for more than 2 years and no more symptoms have occurred.ConclusionsHCSD is a rare disease, and it can be fatal if severe metabolic acidosis occurs without timely management. Once the diagnosis is made, most of the patients with HCSD have good prognosis and normal life expectancy with biotin treatment.

Clinical, biochemical and genetic analysis of a Chinese Han pedigree with holocarboxylase synthetase deficiency: a case report

Background: Holocarboxylase synthetase (HLCS) deficiency is a rare inborn disorder of biotin metabolism, which results in the defect of several biotin-dependent carboxylases and presents with metabolic ketoacidosis and skin lesions. Case presentation : In this study, we have reported a Chinese Han pedigree with HLCS deficiency diagnosed using next-generation sequencing and validated with Sanger sequencing of HLCS and BTD gene. The Chinese proband carries a common missense mutation c.1522C>T (p.Arg508Trp) in exon 9 of HLCS gene, which generates an increased K m for biotin. A novel frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15) in exon 6 of H L CS gene produces a low Vmax and is predicted to be deleterious through PROVEAN and MutationTaster. A novel heterozygous mutation c.638_642delAACAC (p.His213Profs*4) in BTD gene is also identified. Otherwise, the proband presents abnormal BAEP suggesting hearing damage in the acute episode. Conclusions: A Chinese proband carries a reported Arg508Trp variant, a novel 2-bp frameshift mutation c.1006_1007delGA (p.Glu336Thr) expanding mutational spectrum of HLCS gene, and a novel heterozygous mutation c.638_642delAACAC (p.His213Profs*4) expanding mutational spectrum of BTD gene. Furthermore, the reversible hearing damage is rarely reported in the patients with HLCS deficiency, which deserves for further discussion.