Inborn Errors of Ketogenesis: Novel Variants, Clinical Presentation, and Follow-Up in a Series of Four Patients

Abstract

Inborn errors of ketogenesis are rare disorders that result in acute and fulminant decompensation during lipolytic stress, particularly in infants and children. These include mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS) deficiency and HMG-CoA lyase (HMGCL) deficiency. In this series, we describe the clinical, biochemical, and molecular profiles of four patients along with dietary interventions and their outcomes on a long-term follow-up. Two patients each of HMGCS and HMGCL deficiency were evaluated with clinical history, biochemical investigations, including tandem mass spectrometry (TMS) and urine gas chromatography-mass spectrometry (GCMS). Molecular analysis was performed by whole-exome sequencing, as well as exon array validated by long-range polymerase chain reaction. All individuals were diagnosed with acute metabolic decompensation in the early infancy period except one with HMGCL deficiency who had the first presentation at 5 years of age. Central nervous system manifestations, severe metabolic acidosis, hyperammonemia, hypoglycemia with a normal lactate, and absence of urinary ketones were observed in all the affected individuals. The disorder was life-threatening in three individuals and one succumbed to the illness. TMS was nonspecific and urine GCMS revealed dicarboxylic aciduria in HMGCS deficiency. Both the patients with HMGCL deficiency demonstrated elevated 3 hydroxyisovaleryl carnitine levels in TMS and metabolites of leucine degradation in urine GCMS. We identified five novel variants that included a large deletion involving exon 2 in HMGCL gene. There was no evidence of long-term neurological sequelae in the living individuals. Diet with moderation of fat intake was followed in two individuals with HMGCS deficiency. Low leucine and protein diet with moderation of fat intake was followed in the individual with HMGCL deficiency. All affected individuals are thriving well with no further major metabolic decompensation.

Keywords

HMG-CoA synthase - HMG-CoA lyase - ketogenesis - exon array - hypoketotic hypoglycemia - tandem mass spectrometry - gas chromatography-mass spectrometry

• References

• 1 Mitchell GA, Fukao T. Inborn errors of ketone body catabolism. In: Scriver CR, Beaudet al, Sly WS, Valle D. eds. Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York, NY: McGraw-Hill; 2001: 2327-2356
• 2 Sass JO, Fukao T, Mitchell GA. Inborn errors of ketone body metabolism and transport: an update for the clinic and for clinical laboratories. J Inborn Errors Metab Screen 2018; 6
• 3 Bouchard L, Robert MF, Vinarov D. et al. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients. Pediatr Res 2001; 49 (03) 326-331
• 4 Lin WD, Wang CH, Lai CC. et al. Molecular analysis of Taiwanese patients with 3-hydroxy-3-methylglutaryl CoA lyase deficiency. Clin Chim Acta 2009; 401 (1-2): 33-36
• 5 Zhang P, Hu X, Guo R. et al. Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency. Pediatr Investig 2019; 3 (02) 86-90
• 6 Grünert SC, Schlatter SM, Schmitt RN. et al. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: clinical presentation and outcome in a series of 37 patients. Mol Genet Metab 2017; 121 (03) 206-215
• 7 Conboy E, Vairo F, Schultz M. et al. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: unique presenting laboratory values and a review of biochemical and clinical features. JIMD Rep 2018; 40: 63-69
• 8 Gibson KM, Breuer J, Kaiser K. et al. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients. J Inherit Metab Dis 1988; 11 (01) 76-87
• 9 Mitchell GA, Gauthier N, Lesimple A, Wang SP, Mamer O, Qureshi I. Hereditary and acquired diseases of acyl-coenzyme A metabolism. Mol Genet Metab 2008; 94 (01) 4-15
• 10 Aledo R, Mir C, Dalton RN. et al. Refining the diagnosis of mitochondrial HMG-CoA synthase deficiency. J Inherit Metab Dis 2006; 29 (01) 207-211
• 11 Pitt JJ, Peters H, Boneh A. et al. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations. J Inherit Metab Dis 2015; 38 (03) 459-466
• 12 Aoyama Y, Yamamoto T, Sakaguchi N. et al. Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Int J Mol Med 2015; 35 (06) 1554-1560
• 13 Sass JO, Grünert SC. Disorders of ketone body metabolism. In: Blau N, Duran M, Gibson K, Dionisi Vici C. eds. Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Berlin, Heidelberg: Springer; 2014: 361-371