16 research outputs found
Paroxysmal Dyskinesias Revealing 3-Hydroxy-Isobutyryl-CoA Hydrolase (HIBCH) Deficiency
International audienceParoxysmal dyskinesias (PD) are rare movement disorders characterized by recurrent attacks of dystonia, chorea, athetosis, or their combination, with large phenotypic and genetic heterogeneity. 3-Hydroxy-isobutyryl-CoA hydrolase (HIBCH) deficiency is a neurodegenerative disease characterized in most patients by a continuous decline in psychomotor abilities or a secondary regression triggered by febrile infections and metabolic crises.We describe two PD patients from two pedigrees, both carrying a homozygous c.913A > G, p.Thr305Ala mutation in the HIBCH gene, associated with an unusual clinical presentation. The first patient presented in the second year of life with right paroxysmal hemidystonia lasting for 30 minutes, without any loss of consciousness and without any triggering factor. The second patient has presented since the age of 3 recurrent exercise-induced PD episodes which have been described as abnormal equinovarus, contractures of the lower limbs, lasting for 1 to 4 hours, associated with choreic movements of the hands. Their neurological examination and metabolic screening were normal, while brain magnetic resonance imaging showed abnormal signal of the pallidi.We suggest that HIBCH deficiency, through the accumulation of metabolic intermediates of the valine catabolic pathway, leads to a secondary defect in respiratory chain activity and pyruvate dehydrogenase (PDH) activity and to a broad phenotypic spectrum ranging from Leigh syndrome to milder phenotypes. The two patients presented herein expand the spectrum of the disease to include unusual paroxysmal phenotypes and HIBCH deficiency should be considered in the diagnostic strategy of PD to enable adequate preventive treatment
Sebelipase alfa enzyme replacement therapy in Wolman disease: a nationwide cohort with up to ten years of follow-up.
[en] BACKGROUND: Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, presents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age. In clinical trials, enzyme replacement therapy (ERT) with sebelipase alfa led to improved survival, growth and biological parameters in WD patients followed up to 5 years. Long-term follow-up and health-related quality of life (HRQoL) evaluation are lacking.
RESULTS: We performed a nationwide, retrospective study of sebelipase alfa in WD patients. Five patients with abolished LAL activity and bi-allelic LIPA mutations were included with a median follow-up of 7 years (1-10). ERT was initiated at a median age of 1 month (0-4). Infusion tolerance was excellent on the long-term with only one patient requiring systematic pre-medication. Cholestyramine, fat-soluble vitamin supplements and a specific diet (high in medium-chain triglycerides and low in long-chain fatty acids) were prescribed. Liver function tests, plasma lipid profiles, fat-soluble vitamin levels and growth parameters improved. Three patients transiently exhibited a neuromyopathic phenotype (footdrop gait, waddling walk or muscle fatigue) but electromyography and muscle strength testing were normal. At last follow-up, all patients were alive with normal growth parameters and a satisfactory HRQoL, no patient had special education needs, and one patient required parenteral nutrition since an acute gastroenteritis.
CONCLUSIONS: Early ERT initiation allowed 100% survival with positive outcomes. Very long-term follow-up and hematopoietic stem cell transplantation while on ERT should be evaluated to strengthen the benefits of sebelipase alfa
Movement disorders in valine métabolism diseases caused by HIBCH and ECHS1 deficiencies
International audienceBackground 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
The EPIGENE network: A French initiative to harmonize and improve the nationwide diagnosis of monogenic epilepsies
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Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management
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Putative founder effect of Arg338* AP4M1 ( SPG50 ) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families
info:eu-repo/semantics/inPres
PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review
Large-scale screening of lipase acid deficiency in at risk population
International audienceBACKGROUND: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD). METHODS: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots. RESULTS: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel. CONCLUSION: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations
Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy
MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null. Metabolomics analyses demonstrated a significant concomitant accumulation of the MDH substrate, malate, and fumarate, its immediate precursor in the Krebs cycle, in affected subjects' fibroblasts. Lentiviral complementation with wild-type MDH2 cDNA restored MDH2 levels and mitochondrial MDH activity. Additionally, introduction of the three missense mutations from the affected subjects into Saccharomyces cerevisiae provided functional evidence to support their pathogenicity. Disruption of the Krebs cycle is a hallmark of cancer, and MDH2 has been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children
The different clinical facets of SYN1-related neurodevelopmental disorders
International audienceSynapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1 -related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1 . In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment