Syndromic progressive neurodegenerative disease of infancy caused by novel variants in HIBCH: Report of two cases in Colombia

Abstract

3-Hydroxyisobutyryl-coenzyme A (CoA) hydrolase deficiency (HIBCHD; MIM: #250620) is a rare autosomal recessive inborn error of metabolism caused by a defect in the HIBCH enzyme, resulting in a deficiency of the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxy-isobutyric acid, a critical step in valine catabolism. This neurodegenerative disease of infancy is associated with hypotonia, developmental delay, cerebral atrophy and lesions in the basal ganglia on magnetic resonance imaging (MRI). In this study, we describe two unrelated patients with infantile-onset progressive neurodegenerative disease and mutations in HIBCH identified using whole exome sequencing (WES). In Case 1, WES revealed a novel homozygous variant in the HIBCH gene: c.808A>G (p.Ser270Gly). In Case 2, a novel compound heterozygous mutation in the HIBCH gene is described: c.808A>G (p.Ser270Gly) and c.173A>G (p. Asn58Ser). Parent analysis revealed that c.808A>G (p.Ser270Gly) was inherited from the father and c.173A>G (p. Asn58Ser) from the mother. These novel mutations were predicted as a disease-causing mutation. Plasma acylcarnitine analysis was normal in both patients. Physical examination showed similar features, such as axial hypotonia and spastic hypertonia in the legs. The first patient presented with difficult-to-treat seizures, while the second patient has not yet experienced documented seizures. In conclusion, our findings would widen the mutation spectrum of HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the correct diagnosis, treatment and integral management of patients with HIBCH deficiency.

Keywords: 3-hydroxyisobutyryl-CoA hydrolase deficiency; amino acid metabolism; hereditary neurodegenerative diseases; inborn errors; inborn errors of metabolisms; seizures.

Figure 1.

Case 1 phenotype. (A), Front profile at age 1 year shows short forehead, wide palpebral fissures, epicanthus fold, synophrys, nasal bone hypoplasia, low nasal bridge, bulbous nose, prominent philtrum groove, small mouth with cupid's bow, and microcephaly; (B), Spastic legs show generalised hypotonia. Permission was obtained from the patient's parents for presentation.

Figure 2.

Case one MRI Images. (A), Axial section diffusion-weighted imaging (DWI) shows hyperintensity in the basal ganglia; (B), Axial section shows apparent diffusion coefficient (ADC) basal ganglia restriction; (C,D), Spectral curve with echo time (TE) of 30 mseg localises in the left globus pallidus; , where lactate and lipids peak with high concentration of myo-inositol are observed; (E), Axial T1 Gadolinium (Gad), shows enhancement the basal ganglia (F), Axial T1 image shows hypointensity in the basal ganglia; (G), Axial T2, decline in brain volume. Gyrus, sulcus, subarachnoid space and ventricular system were prominent; (H), Sagital T1, section shows severe slimming of the corpus callosum and brain stem.

Figure 3.

Case two MRI Images. (A), DWI-weighted imaging shows hyperintensity in the right basal ganglia; (B), Axial section shows apparent diffusion coefficient (ADC) basal ganglia restriction; (C,D) Spectral curve with echo time (TE) of 30 mseg localises in the left globus pallidus; , where lactate and lipids peak with high concentration of myo-inositol are observed (E), Axial T2 image, shows hyperintensity in the basal ganglia and decline in brain volume; (F,G), Axial T1-weighted with and without contracts image shows hypointensity in the basal ganglia without enhanment ; (H), Sagittal section shows slimming of the corpus callosum and brain stem.

Figure 4.

Pedigree information of patients and Sanger sequencing electropherogram of patients and parents. (A), Homozygous missense mutation (c.808A>G, p.Ser270Gly), both parents are carriers of the same mutation; (B), Heterozygous compound mutation (c.808A>G, NM_014362.3) and (c.173A>G, p.Asn58Ser) at the cytoband 2q32.2 identified in patient. The first c.808A>G (p.Ser270Gly) was of paternal origin and c.173A>G (p.Asn58Ser) was of maternal origin. Variants were confirmed using Sanger sequencing. Both mutations are reported for the first time in this study to our knowledge; (C), Visualisation of HIBCH via Swiss-PDB Viewer (v4.1.0) software. The locations of the mutations in the protein are shown. The amino acid marked pink corresponds to mutation c.173A>G, (p.Asn58Ser) and green to mutation c.808A>G (p.Ser270Gly) described in this report. Both are located in principal chain (aminoacids 33 to 386).