Severe clinical manifestation of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency associated with two novel mutations: a case report

Abstract

Background: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) deficiency is an autosomal recessive inborn error of metabolism, which will give rise to failure of ketogenesis in liver during illness or fasting. It is a very rare disease with only a few patients reported worldwide, most of which had a good prognosis after proper therapies. Case presentation: We report a 9-month-old boy with mHS deficiency presenting with unusually severe and persistent acidosis after diarrhea and reduced oral food intake. The metabolic acidosis persisted even after supplementation with sugar and alkaline solution. Blood purification and assisted respiration alleviated symptoms, but a second onset induced by respiratory infection several days later led to multiple organ failure and death. Urine organic acid analysis during the acute episode revealed a complex pattern of ketogenic dicarboxylic and 3-hydroxydicarboxylic aciduria with prominent elevation of glutaric acid and adipic acid, which seem to be specific to mHS deficiency. Plasma acylcarnitine analysis revealed elevated 3-hydroxybutyrylcarnitine and acetylcarnitine. This is the first report of elevated 3hydroxybutyrylcarnitine in mHS deficiency. Whole exome sequencing revealed a novel compound heterozygous mutation in HMGCS2 (c.100C > T and c.1465delA). Conclusion: This severe case suggests the need for patients with mHS deficiency to avoid recurrent illness because it can induce severe metabolic crisis, possibly leading to death. Such patients may also require special treatment, such as blood purification. Urine organic acid profile during the acute episode may give a hint to the disease.

Clinical, Biochemical, Molecular, and Outcome Features of Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency in 10 Chinese Patients

“…We also detected the blood acylcarnitine profile in all individuals. As previously reported in the literature, blood acetylcarnitine (C2) can be either normal or increased during decompensation (Aledo et al, 2006;Ramos et al, 2013;Liu et al, 2019). In our study, the blood C2 level in 8 of the patients increased, while the free carnitine (C0) level in 7 of the patients decreased.…”

“…In our cohort, the recurrent variants were c.1201G > T/p.E401*, c.559+1G > T and c.220G > A/p.E74K. If combined with the 11 patients reported previously (Thompson et al, 1997;Ma and Yu, 2018;Liu et al, 2019;Wang et al, 2019;Wang et al, 2020a;Wang et al, 2020b;Yang et al, 2020), the most frequent mutation was c.1201G > T/p.E401*. This may result in a premature termination codon at amino acid residue 401 located in exon 7 of HMGCS2.…”

“…According to the literature, only one case had neurological sequelae (Conboy et al, 2018). However, there still were 6 patients who died of hypoglycemic crisis and serious metabolic acidosis during acute metabolic decompensation (Liu et al, 2019;Kilic et al, 2020;Wang et al, 2020a;Yang et al, 2020). These results suggest that HMGCS2D is a fatal, but treatable, hereditary metabolic disease.…”

Expanding the clinical spectrum of mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency with Turkish cases harboring novel HMGCS2 gene mutations and literature review

“…Prognosis is reported to be good if the patient is treated properly in time. However, neurological sequelae and death were also reported in severely affected cases (Conboy et al, 2018;Liu et al, 2019;Sass et al, 2013). We aimed to present clinical, biochemical findings, and molecular genetic data in new Turkish patients from two unrelated families with mHS deficiency and review the literature.…”

“…Its incidence was not estimated yet. To date, 36 patients from 29 families have been reported (Aledo et al, 2001; Aledo et al, 2006; Bouchard et al, 2001; Conboy et al, 2018; Lee et al, 2019; Liu et al, 2019; Ma & Yu, 2018; Morris et al, 1998; Pitt et al, 2009; Pitt et al, 2015; Puisac et al, 2018; Ramos et al, 2013; Sass, Kühlwein, Klauwer, Rohrbach, & Baumgartner, 2013; Shafqat, Turnbull, Zschocke, Oppermann, & Yue, 2010; Thompson et al, 1997; Wolf, Rahman, Clayton, & Zschocke, 2003; Zschocke et al, 2002). A diagnosis of mHS deficiency is suspected in patients whose clinical presentation suggests a fatty acid oxidation disorder (fatty liver, hypoketotic hypoglycemia, dicarboxylic aciduria but nondiagnostic pattern of plasma acylcarnitines) (Bouchard et al, 2001; Morris, 2016).…”