A phenotypically severe, biochemically “silent” case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing

Abstract

3‐Hydroxyisobutyryl‐CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome‐like phenotype, mitochondrial dysfunction, and increased C4‐OH. We report the most severe case to date in a full‐term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow‐up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency in a Turkish Child with a Novel HIBCH Gene Mutation and Literature Review

“…During or following acute exacerbations, symmetrical T2-weighted hyperintensities with restricted diffusion were observed in the basal ganglia, especially in the globus pallidus. With years of progression, cystic encephalomalasia, basal ganglion atrophy and necrosis may ensue [Stiles et al, 2015;D'Gama et al, 2020]. Our findings on brain MRI were similar to the literature, showing symmetrical bilateral lesions in the basal ganglia, suggestive of a progressive mitochondrial disorder, especially Leigh syndrome (OMIM 256000) or organic acidemia.…”

“…Hydroxy-C4-carnitine level was also normal in this patient. Among the reported patients with known hydroxy-C4-carnitine levels, these were found to be increased in the all of the other severely affected patients, except one [D'Gama et al, 2020]. HIBCH enzyme activities were low in the majority of the reported patients.…”

“…So far, there seem to be no race-specific mutations. In the literature, patients carrying truncating mutations tended to have more severe phenotypes compared with missense mutations [Tan et al, 2018;D'Gama et al, 2020]. Additionally, it was also discussed that missense mutations around the catalytic site of the enzyme (p.A96D, p.Y122C, p.G317E, p.G345S), the substrate-(3-hydroxyisobutyrate) binding pouch and cofactor-(pentahydroxyflavone) binding site cause a more severe phenotype than mutations in the periphery of the enzyme (p.R66W, p.A137V, p.T305A) [Schottmann et al, 2016].…”

“…Its incidence was estimated at approximately 1: 551,545 in Europeans and 1: 127,939 in South Asian individuals [Stiles et al, 2015]. To date, 25 patients from 19 families have been reported [Brown et al, 1982;Loupatty et al, 2007;Ferdinandusse et al, 2013;Yamada et al, 2014;Reuter et al, 2014Reuter et al, , 2017Peters et al, 2015;Soler-Alfanso et al, 2015;Stiles et al, 2015;Zhu et al, 2015;Charng et al, 2016;Schottmann et al, 2016;Tan et al, 2018;Yang et al, 2018;Candelo et al, 2019;Karimzadeh et al, 2019;Xu et al, 2019;D'Gama et al, 2020]. Elevated levels of hydroxy-C4-carnitine in dried blood spots or plasma and measurement of the unusual amino acids S-(2-carboxypropyl) cysteine (SCPC) and S-(2-carboxypropyl) cysteamine (SCPCM) as well as their carnitine esters in urine by tandem mass spectrometry is effective for initial screening [Peters et al, 2015].…”

“…Symmetrical involvement of the basal ganglia, especially globi pallidi and acute changes suggestive of cytotoxic edema in acute attacks can be seen on brain MRI [Stiles et al, 2015;Xu et al, 2019;D'Gama et al, 2020]. Although there is no effective treatment, low-protein (low-valine diet), highcarbohydrate diet, and L-carnitine, N-acetylcysteine, and mitochondrial cocktail treatments have been suggested [Loupatty et al, 2007;Yamada et al, 2014;Peters et al, 2015;Soler-Alfonso et al, 2015;D'Gama et al, 2020]. We aimed to present clinical and biochemical findings as well as molecular genetic data in a new case of a Turkish girl with HIBCH deficiency and to review the literature.…”