Truncating mutations of HIBCH tend to cause severe phenotypes in cases with HIBCH deficiency: a case report and brief literature review

Abstract

3-hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare inborn error of valine metabolism characterized by neurodegenerative symptoms and caused by recessive mutations in the HIBCH gene. In this study, utilizing whole exome sequencing, we identified two novel splicing mutations of HIBCH (c.304+3A>G; c.1010_1011+3delTGGTA) in a Chinese patient with characterized neurodegenerative features of HIBCH deficiency and bilateral syndactyly which was not reported in previous studies. Functional tests showed that both of these two mutations destroyed the normal splicing and reduced the expression of HIBCH protein. Through a literature review, a potential phenotype-genotype correlation was found that patients carrying truncating mutations tended to have more severe phenotypes compared with those with missense mutations. Our findings would widen the mutation spectrum of HIBCH causing HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the treatment and management of patients with HIBCH deficiency.

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

“…Twenty‐one patients from 15 families have previously been reported, and here we present the 22nd and most severe case to date, significant for no characteristic biochemical findings including no elevations in either C4‐OH or urinary 2,3 dihydroxy‐2‐methyl butyric acid even in a deteriorated state. In Table S2, we summarize the clinical features and identified HIBCH mutations for our patient and 18 previously reported patients (Brown et al, ; Ferdinandusse et al, ; Karimzadeh et al, ; Loupatty et al, ; Peters et al, ; Reuter et al, ; Schottmann et al, ; Soler‐Alfonso et al, ; Stiles et al, ; Tan et al, ; Yamada et al, ; three patients did not have sufficient clinical information available [Charng et al, ; Yang et al, ; Zhu et al, ]).…”

“…In Table S2, we summarize the clinical features and identified HIBCH mutations for our patient and 18 previously reported patients (Brown et al, 1982;Ferdinandusse et al, 2013;Karimzadeh et al, 2019;Loupatty et al, 2007;Peters et al, 2015;Reuter et al, 2014;Schottmann et al, 2016;Soler-Alfonso et al, 2015;Stiles et al, 2015;Tan et al, 2018;Yamada et al, 2014; three patients did not have sufficient clinical information available [Charng et al, 2016;Yang et al, 2018;Zhu et al, 2015]).…”

“…3‐Hydroxyisobutyryl‐CoA dehydrogenase (HIBCH) deficiency (OMIM #250620) is a rare inborn error of metabolism in valine catabolism that is caused by homozygous or compound heterozygous HIBCH mutations (Brown et al, ; Loupatty et al, ). The disease was first described in 1982 (Brown et al, ), and to date, 21 patients from 15 families have been reported (Charng et al, ; Ferdinandusse et al, ; Karimzadeh, Saberi, Sheidaee, Nourbakhsh, & Keramatipour, ; Loupatty et al, ; Peters et al, ; Reuter et al, ; Schottmann et al, ; Soler‐Alfonso et al, ; Stiles et al, ; Tan et al, ; Yamada et al, ; Yang, Wu, Deng, Yin, & Yang, ; Zhu, Bao, & Zhang, ). Patients usually present in infancy with hypotonia, feeding difficulties, progressive developmental delay, and regression triggered by catabolic stressors like febrile illnesses.…”

“…Patients usually present in infancy with hypotonia, feeding difficulties, progressive developmental delay, and regression triggered by catabolic stressors like febrile illnesses. Additional clinical features reported include ataxia, dystonia, seizures, and optic nerve atrophy (Tan et al, ). Magnetic resonance imaging (MRI) demonstrates basal ganglia involvement similar to Leigh syndrome (OMIM #256000; Karimzadeh et al, ).…”

“…She #250620) is a rare inborn error of metabolism in valine catabolism that is caused by homozygous or compound heterozygous HIBCH mutations (Brown et al, 1982;Loupatty et al, 2007). The disease was first described in 1982 (Brown et al, 1982), and to date, 21 patients from 15 families have been reported (Charng et al, 2016;Ferdinandusse et al, 2013;Karimzadeh, Saberi Reuter et al, 2014;Schottmann et al, 2016;Soler-Alfonso et al, 2015;Stiles et al, 2015;Tan et al, 2018;Yamada et al, 2014;Yang, Wu, Deng, Yin, & Yang, 2018;Zhu, Bao, & Zhang, 2015).…”