A movement disorder with dystonia and ataxia caused by a mutation in the <i>HIBCH</i> gene

Schottmann, Gudrun; Sarpong, Akosua; Lorenz, Carmen; Weinhold, Natalie; Gill, Esther; Teschner, Lisa; Ferdinandusse, Sacha; Wanders, Ronald J. A.; Prigione, Alessandro; Schuelke, Markus

doi:10.1002/mds.26704

Cited by 28 publications

(44 citation statements)

References 19 publications

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“…In addition, developmental delay in motor milestones (14/16 cases) and regression triggered by catabolic stressors like febrile illnesses (12 cases) are frequently observed (Table S2). This is the earliest death reported in HIBCH deficiency, with previously reported patients living from 3 months up to at least 43 years old (Brown et al, ; Schottmann et al, ). Our patient also developed subclinical seizures prior to her death, which appears to be a relatively less common clinical feature, with seizures observed in only four other cases (Ferdinandusse et al, ; Loupatty et al, ; Reuter et al, ).…”

Section: Discussionmentioning

confidence: 77%

“…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, ]).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

D’Gama

Brucker

Tian

et al. 2020

American J of Med Genetics Pt A

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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.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

D’Gama

Brucker

Tian

et al. 2020

American J of Med Genetics Pt A

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“…Associated neurologic features include dystonia, ataxia, spasticity, epilepsy, and optic atrophy (Video S2). The clinical course is characterized by a continuous or infections triggered neurological decline, with death in early infancy or childhood in about one third of reported cases . Bilateral hyperintense lesions in the GP and a progressive dystonic disorder are quite typical (Fig.…”

Section: Treatments Following a Classic Diagnostic Work‐upmentioning

confidence: 99%

“…). Reversible dystonic gait or paroxysmal dystonia have been reported in patient with milder phenotypes …”

Section: Treatments Following a Classic Diagnostic Work‐upmentioning

confidence: 99%

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

Galosi

Nardecchia

Leuzzi

2020

Movement Disord Clin Pract

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Background About 80% of monogenic metabolic diseases causing movement disorders (MDs) emerges during the first 2 decades of life, and a number of these conditions offers the opportunity of a disease‐modifying treatment. The implementation of enlarged neonatal screening programs and the impressive rapid increase of the identification of new conditions are enhancing our potential to recognize and treat several diseases causing MDs, changing their outcome and phenotypic spectrum. Methods and Findings A literature review of monogenic disorders causing MDs amenable to treatment was conducted focusing on early clinical signs and diagnostic biomarkers. A classification in 3 broad categories based on the therapeutic approach has been proposed. Some disorders result in irreversible neurotoxic lesions that can only be prevented if treated in a presymptomatic stage, and others present with a progressive neurological impairment that a timely diagnosis and treatment may reverse or improve. Some MDs are the result of the failure of intracellular energy supply or altered glucose transport. The treatment in these conditions includes vitamins or a metabolic shift from a carbohydrate to a fatty acid catabolism, respectively. Finally, a group of highly treatable MDs are the result of defects of neurotransmitter metabolism. In these disorders, the supplementation of precursors or mimetics of neurotransmitters can deeply change the disease natural history. Conclusions To prevent serious and irreversible neurological impairment, the diagnostic work‐up of MDs in children should consider a number of clinical red flags and biomarkers denoting specifically treatable diseases.

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Dystonia‐ataxia syndrome with permanent torsional nystagmus caused by ECHS1 deficiency

Ronchi

Monfrini

Bonato

et al. 2020

Ann Clin Transl Neurol

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Biallelic mutations in ECHS1, encoding the mitochondrial enoyl-CoA hydratase, have been associated with mitochondrial encephalopathies with basal ganglia involvement. Here, we describe a novel clinical presentation consisting of dystonia-ataxia syndrome with hearing loss and a peculiar torsional nystagmus observed in two adult siblings. The presence of a 0.9-ppm peak at MR spectroscopy analysis suggested the accumulation of branched-chain amino acids. Exome sequencing in index probands identified two ECHS1 mutations, one of which was novel (p.V82L). ECHS1 protein levels and residual activities were reduced in patients' fibroblasts. This paper expands the phenotypic spectrum observed in patients with impaired valine catabolism.

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A movement disorder with dystonia and ataxia caused by a mutation in the HIBCH gene

Abstract: We report the first adult patients with HIBCH deficiency and a disease course much milder than previously reported, thereby expanding the HIBCH-associated phenotypic spectrum. © 2016 International Parkinson and Movement Disorder Society.

Cited by 28 publications

References 19 publications

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

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

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

Dystonia‐ataxia syndrome with permanent torsional nystagmus caused by ECHS1 deficiency

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