A recurrent homozygous LMNA missense variant p.Thr528Met causes atypical progeroid syndrome characterized by mandibuloacral dysostosis, severe muscular dystrophy, and skeletal deformities.

Atypical progeroid syndromes (APS) are premature aging syndromes caused by pathogenic LMNA missense variants, associated with unaltered expression levels of lamins A and C, without accumulation of wild-type or deleted prelamin A isoforms, as observed in Hutchinson-Gilford progeria syndrome (HGPS) or HGPS-like syndromes. A specific LMNA missense variant, (p.Thr528Met), was previously identified in a compound heterozygous state in patients affected by APS and severe familial partial lipodystrophy, whereas heterozygosity was recently identified in patients affected by Type 2 familial partial lipodystrophy. Here, we report four unrelated boys harboring homozygosity for the p.Thr528Met, variant who presented with strikingly homogeneous APS clinical features, including osteolysis of mandibles, distal clavicles and phalanges, congenital muscular dystrophy with elevated creatine kinase levels, and major skeletal deformities. Immunofluorescence analyses of patient-derived primary fibroblasts showed a high percentage of dysmorphic nuclei with nuclear blebs and typical honeycomb patterns devoid of lamin B1. Interestingly, in some protrusions emerin or LAP2α formed aberrant aggregates, suggesting pathophysiology-associated clues. These four cases further confirm that a specific LMNA variant can lead to the development of strikingly homogeneous clinical phenotypes, in these particular cases a premature aging phenotype with major musculoskeletal involvement linked to the homozygous p.Thr528Met variant.

Les troubles cognitifs dans les syndromes cliniquement isolés: Etude cas-témoins / Cognitive impairment in clinically isolated syndromes: A control-case study

ntroduction - L'atteinte cognitive est fréquente dans la Sclérose en Plaques (SEP) mais son diagnostic se fait souvent tardivement, au stade de désinsertion sociale et professionnelle. Les études portant sur les aspects cognitifs dans les formes pré-coces de la SEP tels que les syndromes cliniquement isolés (SCI) et les syndromes radiologiquement isolés (SRI) sont rares.Objectifs - Analyserles fonctions cognitives d'un premier événement démyélinisant et identifier les domainesqui seraient les plus précocement atteints.Patients et méthodes - Le profil cognitif d'une populationhomogène de 13 patients présentant unSCI a été évalué, eta été comparé à 15 témoins sains appareillés en fonction de l'âge, du sexe et du niveau d'éducation. Une batterie de tests neu-ropsychologiques(BCCogSEP, batterie courte d'évaluation cognitive de la SEP),vali-dée dans la SEP, a été utilisée. Ses composants explorent les capacités mnésiques et verbales, l'attention, la vitesse de traitement de l'information (VTI) et les fonctions exécutives.Résultats - Lesperformances cognitives globales étaient amoindries dans le groupe SCI, comparativement au groupe témoin. Sur les 13 patients atteints de SCI, cinq (38%) présentaient une altération cognitive globale qui a été objectivée par l'at-teinte d'au moins deux ou trois tests de la batterie. La PASAT (Paced Auditory Serial Addition Test)était le test le plus altéré (84,6% d'atteinte). La VTI et la mémoire de travail étaient les fonctions les plus atteintes chez les patients.Conclusion - Les dysfonctions cognitives peuvent se voir très précocement et peuvent grever lourdement le pronostic de la SEP.

Introduction - Cognitive impairment is common in multiple sclerosis (MS) but its diagnosis is often made late, at the stage of social and professional disinsertion. Studies of the cognitive aspects in early forms of MS such as clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) are rare. Objectives - To analysis the cognitive functions of a first demyelinating event and identify the areas that would be most affected early. Patients and methods - The cognitive profile of a homogeneous population of 13 patients with a CIS was evaluated, and compared with 15 healthy controls, matched according to age, sex and level of education. A battery of neuropsychological tests (BCCogSEP, Short battery for cognitive assessment of MS) validated in MS,was used. Its components explore memory and verbal skills, attention, information processing speed (IPS) and executive functions. Results - The overall cognitive performance was reduced in the CIS group,compared to control group. Five out of thirteen CIS patients (38%) had an overall cognitive impairment, demonstrated by the achievement of at least two or three battery tests. The Paced Auditory Serial Addition Test (PASAT) was the most altered test (84.6% impairment). IPS and working memory were the most affected functions in the patients. Conclusion - Cognitive dysfunctions can be seen very early and can severely affect the prognosis of MS.

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.

Importance: Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. Design, Setting, and Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016. Main Outcomes and Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001). Conclusions and Relevance: The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.

Multicenter transversal two-phase study to determine a national prevalence of epilepsy in Algeria.

BACKGROUND/AIMS: The prevalence of epilepsy in Algeria is unknown. The aims of this multicenter transversal study were to determine the national prevalence and clinical characteristics of epilepsy in the Algerian population. METHODS: This two-phase study was conducted in 5 circumscriptions and included 8,046 subjects aged over 2 months who attended the randomly selected public and private primary care clinics. In the phase 1 study, a questionnaire was submitted to the sample of patients. In the phase 2 study, all potentially epileptic people were examined by neurologists and a second questionnaire was submitted, eventually assessed by appropriate investigations. RESULTS: Sixty-seven patients were identified as having active epilepsy, giving a crude prevalence ratio of 8.32 per 1,000 (95% CI, 6.34-10.3) and an age-adjusted prevalence ratio of 8.9 per 1,000. The highest age-specific ratio was found in patients aged 10-19 years (16.92 per 1,000). Generalized seizures (68.7%) were more common than partial seizures (29.8%). Perinatal injuries were the major leading putative causes (11.9%). CONCLUSION: The prevalence of epilepsy of 8.32 determined in this study is relatively high. These results provide new epidemiological data and suggest that epilepsy remains an important public health issue to consider in Algeria.