À propos d'une famille atypique d'adrénoleucodystrophie liée à l'X

Résumé en français : L'adrénoleucodystrophie récessive liée à l'X (X-ALD) est la maladie peroxysomale la plus commune, conséquence d'une mutation du gène ABCDI (Xq28). Elle est liée à une accumulation d'acides gras à très longue chaîne (AGTLC) due à un défaut de la bêta-oxydation des AGTLC dans les peroxysomes par carence d'une protéine transmembranaire appelée ALDP. L'incidence est de 1 pour 17 000 naissances, incluant les hémizygotes et les femmes hétérozygotes. Cette pathologie se manifeste par une démyélinisation progressive du système nerveux central plus ou moins associée à une maladie d'Addison. Cette maladie comporte une grande diversité phénotypique y compris intra-familiale associant des formes cérébrales progressives et graves de l'enfant à des formes médullaires lentement progressives de l'adulte dite adrénomyéloneuropathie (AMN). La pathogénie est complexe et la physiopathologie de l'atteinte reste méconnue. Notre propositus âgé de 38 ans présentait des troubles psychiatriques inauguraux à type d'apathie, d'euphorie, troubles de la personnalité. L'évolution était marquée par un syndrome démentiel et un état végétatif. L'examen clinique, l'analyse biochimique et moléculaire confirmèrent le diagnostic. Nous décrivons une famille d'X-ALD qui illustre la diversité phénotypique. Il n'y a pas de corrélation génotype et phénotype ce qui suggère l'intervention de facteurs environnementaux ou facteurs modificateurs de gènes. Le conseil génétique est indispensable pour identifier les femmes conductrices et les garçons encore asymptomatiques sur le plan neurologique d'autant qu'un traitement ne peut être proposé qu'au stade asymptomatique. La seule thérapie ayant démontré une efficacité certaine est la greffe allogénique de moelle osseuse.Résumé en anglais :The X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disorder caused by mutations of the ABCDl gene located at Xq28. The incidence is 1/17 000 births, including hemizygotes and heterozygotes women. This gene encodes for the adrenoleukodystrophy protein (ALDP), an adenosine triphosphate (ATP) binding cassette transporter, subfamily D, member 1 in the peroxisomal membrane. Phenotype is characterized by adrenal insufficiency and progressive demyelinisation of the central nervous system. This neurological disease ranges from the childhood cerebral ALD characterized by rapidly progressive demyelinisation that leads to vegetative stage or death within 2-5 years to the adult milder adrenomyeloneuropathy characterized by progressive paraparesis. The ALDP defects lead to accumulation of satured very-long-chain fatty acids (VLCFA) in the serum and tissues, due to reduced P-oxidation of VLCFA in peroxisomes. The exact role of ALDP in the metabolism of VLCFA is still not understood. Our propositus was 38-year-old and presented a gradual development of psychiatric symptomatology. Since one year, behavioural changes such as fluctuation of apathy, euphoria and personality disturbance progress. Evolution was marked by dementia and vegetative status. The clinical, biochemical and genetic examination confirmed the diagnosis. We described his family, which illustrated diversity of phenotype. No genotype phenotype correlation has been found, which suggests modifier genes or environmental factors. Diagnosis is very important because of genetic counseling and therapeutic can be performed: allogenic bone-barrow transplantation and the first autologous bone-marrow transplants genetically corrected ex vivo.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

[Multiple cervical arterial dissections in two brothers: fibro-muscular dysplasia or connective tissue disease?]

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A novel pathogenic variant in DYNC1H1 causes various upper and lower motor neuron anomalies

International audienceObjective: To perform genotype-phenotype, clinical and molecular analysis in a large 3-generation family with autosomal dominant congenital spinal muscular atrophy.Methods: Using a combined genetic approach including whole genome scanning, next generation sequencing-based multigene panel, whole genome sequencing, and targeted variant Sanger sequencing, we studied the proband and multiple affected individuals of this family who presented bilateral proximal lower limb muscle weakness and atrophy.Results: We identified a novel heterozygous variant, c.1826T > C; p.Ile609Thr, in the DYNC1H1 gene localized within the common haplotype in the 14q32.3 chromosomal region which cosegregated with disease in this large family. Within the family, affected individuals were found to have a wide array of clinical variability. Although some individuals presented the typical lower motor neuron phenotype with areflexia and denervation, others presented with muscle weakness and atrophy, hyperreflexia, and absence of denervation suggesting a predominant upper motor neuron disease. In addition, some affected individuals presented with an intermediate phenotype characterized by hyperreflexia and denervation, expressing a combination of lower and upper motor neuron defects.Conclusion: Our study demonstrates the wide clinical variability associated with a single disease causing variant in DYNC1H1 gene and this variant demonstrated a high penetrance within this large family

Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies

Phenotype and imaging features associated with APP duplications

Abstract Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA

Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia

On behalf of Queen Square Genomics On behalf of Genomics England Research ConsortiumInternational audiencePurpose: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants.Methods: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients.Results: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants.Conclusion: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA

Identification of three clinical neurofibromatosis 1 subtypes: Latent class analysis of a series of 1351 patients

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