Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome

Abstract

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH, NM_014362.3) gene mutation can cause HIBCH deficiency, leading to Leigh/Leigh-like disease. To date, few case series have investigated the relationship between metabolites and clinical phenotypes or the effects of treatment, although 34 patients with HIBCH mutations from 27 families have been reported. The purpose of this study was to analyze the phenotypic spectrum, follow-up results, metabolites, and genotypes of patients with HIBCH deficiency presenting with Leigh/Leigh-like syndrome and explore specific metabolites related to disease diagnosis and prognosis through retrospective and longitudinal studies. Applying next-generation sequencing, we identified eight patients with HIBCH mutations from our cohort of 181 cases of genetically diagnosed Leigh/Leigh-like syndrome. Six novel HIBCH mutations were identified: c.977T>G [p.Leu326Arg], c.1036G>T [p.Val346Phe], c.750+1G>A, c.810-2A>C, c.469C>T [p.Arg157*], and c.236delC [p.Pro79Leufs*5]. The Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) was employed to assess disease progression and clinical outcomes. The non-invasive approach of metabolite analysis showed that levels of some were associated with clinical phenotype severity. Five (5/7) patients presented with elevated C4-OH in dried blood spots, and the level was probably correlated with the NPMDS scores during the peak disease phase. 2,3-Dihydroxy-2-methylbutyrate in urine was elevated in six (6/7) patients and elevated S-(2-caboxypropyl)cysteamine in urine was found in three patients (3/3). The median age at initial presentation was 13 months (8-18 months), and the median follow-up was 2.3 years (range 1.3-7.2 years). We summarized and compared with all reported patients with HIBCH mutations. The most prominent clinical manifestations were developmental regression/delay, hypotonia, encephalopathy, and feeding difficulties. We administered drug and dietary treatment. During follow-up, five patients responded positively to treatment with a significant decrease in NPMDS scores. Our research is the largest case series of patients with HIBCH mutations.

Keywords: 2,3-dihydroxy-2-methylbutyrate (23DH2MB); C4-OH; HIBCH gene; Leigh/Leigh-like syndrome; children; mitochondrial disorders.

FIGURE 1

Schematic representation of the valine metabolic pathway involved in HIBCH (A), and mechanism of HIBCH deficiency with the resulting clinical phenotypes (B). SCPCM, S-(2-caboxypropyl)cysteamine; 23DH2MB, 2,3-dihydroxy-2-methylbutyrate.

FIGURE 2

Schematic representation the HIBCH gene structure showing disease-associated mutation locations and conservation of mutant amino acid residues with known protein domains. Notes: dashed line, mutations in our study; triangles, our novel mutations including missense, splicing, frameshift and nonsense mutations; solid line, mutations reported in the literature.

FIGURE 3

Urine organic acid profiles of seven patients in different phases; red arrows indicate abnormally high 23DH2MB peaks, and the black arrow represents a normal 23DH2MB peak. Patients 1, 2, 6, and 7 with elevated 23DH2MB levels in the peak stage. Patients 3 and 4 with elevated 23DH2MB levels in the recovery stage. Patient 8 with a normal 23DH2MB level after adopting a valine-restricted diet.

FIGURE 4

MRI manifestations of 2 patients (Patient 2, Patient 5) during disease onset. (a‐d): Patient 2 at age 10 months; hyperintensity of the globus pallidus, putamen, caudate nucleus, and cerebral peduncle on T2WI (a,b) and DWI (c,d). (e‐h): Patient 5 at age 13 months; hyperintensity on T2WI (e,f) and DWI (g,h) in the globus pallidus and cerebral peduncle.

FIGURE 5

NMPDS scores in the peak phase and last assessment. a, All the recruited patients (n = 8); b, Patients who received therapy (Patient 1,5,6,7,8; n = 5); c, Patients who gave up therapy (Patient 2,3,4; n = 3).

FIGURE 6

Patient 1: MRI performance in the peak and recovery phases. (a1,a2): Initial MRI obtained at age 2 years; hyperintensity on T2WI in the globus pallidus (a1), normal cerebral peduncle (a2). (b1,b2): MRI performed at 4 years 5 months during the acute stage; hyperintensity on T2WI in the globus pallidus with swelling on the left side (b1) and in the left cerebral peduncle (b2). (c1,c2): MRI performed at 6 years 1 month during the recovery stage; only slightly hyperintensity on T2WI in globus pallidus (c1), and Abnormal signal disappeared in the cerebral peduncle (c2).