Hepatic Manifestations of 3-Hydroxy-3-Methylglutaryl-Coenzyme-A Lyase Deficiency in Saudi Patients: Experience of a Tertiary Care Center

Abstract

Abstract3-Hydroxy-3-methylglutaryl-coenzyme-A lyase (HMGCL) deficiency, a rare autosomal recessive disorder, is caused by a homozygous or compound heterozygous mutation in the HMGCL gene (chromosome 1p36.11). HMGCL catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Several studies have reported general hepatic findings (e.g., hepatomegaly) in patients with HMGCL deficiency, but currently, there are no available data regarding the incidence and epidemiology of liver involvement. The main objective of our study was to investigate the overall clinical manifestations, laboratory findings, genotype, and presence of hepatic involvement in Saudi patients with HMGCL deficiency. A retrospective chart review of patients with HMGCL deficiency including those with a documented hepatic manifestation was performed at the King Faisal Specialist Hospital & Research Centre in Riyadh, Saudi Arabia. We evaluated 50 cases of HMGCL deficiency. Hepatic findings were found in 17 patients at the time of diagnosis. The mean age of hepatic presentation was 135 days, and the median age was 56 days (range: 2–315 days). Hepatomegaly was found in 65%, abnormal biochemical profile in 47%, and an abnormal imaging in 53% of patients. The most frequent mutation in this cohort was the p.Arg41Gln founder mutation (59%). In comparison to data from the current literature, HMGCL deficiency can be considered as a diagnostic metabolite for hepatic manifestations and requires appropriate evaluation, including molecular genetic analysis.

Treatment of HMG-CoA Lyase Deficiency—Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases

“…Urine organic acids were indicative of HMGCL deficiency; glucose delivery was immediately doubled and 900 mg/kg/day S-DL-3OHB administered, leading to rapid resolution of clinical and biochemical findings. Whilst liver dysfunction is reported, liver failure is atypical for this disorder, and this type of presentation is more in keeping with a fatty acid oxidation disorder [ 6 , 28 ]. This case was the only one in our cohort that had quantifiable, though reduced, ketones in the urine and blood.…”

“…A recent systematic review identified 211 cases, with an overall mortality of 16% [ 5 ]. A recent report from Saudi Arabia showed that all patients in their cohort of 62 patients had neurological complications [ 6 ]. Approximately 40% of reported patients presented in the newborn period with a rapidly progressive encephalopathy [ 5 ].…”