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Movement disorders in valine métabolism diseases caused by HIBCH and ECHS1 deficiencies
Marie-Céline François-Heude1, Elise Lebigot2, Emmanuel Roze3
1CHU Montpellier, Département de Neuropédiatrie, Univ Montpellier, Montpellier, France.
Insights
3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1) deficiencies cause rare metabolic disorders with neurological symptoms. This study details the movement disorder spectrum in affected patients, finding dystonia to be the most common manifestation.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1) enzymes are crucial for valine catabolism.
- Deficiencies in HIBCH (HIBCHD) and ECHS1 (ECHS1D) lead to rare metabolic disorders often presenting with neurological symptoms.
Purpose of the Study:
- To characterize the spectrum of movement disorders (MDs) in patients with pathogenic variants in the ECHS1 and HIBCH genes.
- To analyze the clinical phenotypes of HIBCHD and ECHS1D, focusing on movement disorder manifestations.
Main Methods:
- Retrospective review of 18 patients (5 HIBCHD, 13 ECHS1D) with detailed phenotype analysis.
- Inclusion of 105 additional patients from existing literature for a comprehensive analysis (38 HIBCHD, 85 ECHS1D).
Main Results:
- Both HIBCHD and ECHS1D exhibit similar neurological phenotypes with early onset (before 10 years) and varied presentations like neonatal onset, Leigh-like syndrome, and paroxysmal dyskinesia.
- Movement disorders were prevalent, affecting 61% of HIBCHD and 72% of ECHS1D patients, with dystonia being the most frequent type.
- Paroxysmal dyskinesia cases often presented with pure dystonia and normal development; no genotype-phenotype correlation was identified for MDs.
Conclusions:
- Movement disorders, including abnormal eye movements, are a key feature of HIBCHD and ECHS1D.
- The spectrum of MDs is diverse, frequently involves dystonia, and can present as a combination of different movement disorder types in a single patient.
Background And Purpose:
HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC.
Methods:
We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs.
Results:
The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh-like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants.
Conclusions:
Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient.
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