Deciphering the natural history of SCA7 in children.

BACKGROUND AND PURPOSE: Childhood-onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. METHODS: We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion > 100 CAG. RESULTS: We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. CONCLUSION: SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

Simplified gyral pattern in severe developmental microcephalies? New insights from allometric modeling for spatial and spectral analysis of gyrification.

The strong positive-allometric relationship between brain size, cortical extension and gyrification complexity, recently highlighted in the general population, could be modified by brain developmental disorders. Indeed, in case of brain growth insufficiency, the pathophysiological relevance of the "simplified gyral pattern" phenotype is strongly disputed since almost no genotype-phenotype correlations have been found in primary microcephalies. Using surface scaling analysis and newly-developed spectral analysis of gyrification (Spangy), we tested whether the gyral simplification in groups of severe microcephalies related to ASPM, PQBP1 or fetal-alcohol-syndrome could be fully explained by brain size reduction according to the allometric scaling law established in typically-developing control groups, or whether an additional disease effect was to be suspected. We found the surface area reductions to be fully explained by scaling effect, leading to predictable folding intensities measured by gyrification indices. As for folding pattern assessed by spectral analysis, scaling effect also accounted for the majority of the variations, but an additional negative or positive disease effect was found in the case of ASPM and PQBP1-linked microcephalies, respectively. Our results point out the necessity of taking allometric scaling into account when studying the gyrification variability in pathological conditions. They also show that the quantitative analysis of gyrification complexity through spectral analysis can enable distinguishing between even (predictable, non-specific) and uneven (unpredictable, maybe disease-specific) gyral simplifications.

Central nervous system vasculitis in VEXAS syndrome: A rare involvemen.

INTRODUCTION: VEXAS (Vacuoles, E1 Enzyme, X-linked, autoinflammatory, Somatic) syndrome is a recently described severe adult-onset autoinflammatory disorder mediated by X-linked gene UBA1 somatic mutations, responsible of recurrent fever, skin involvement, chondritis, macrocytic anemia and inflammatory syndrome. Neurological manifestations are rarely described, and predominantly involve peripheral nervous system (PNS) impairment. RESULTS: We report the first central nervous system (CNS) vasculitis in VEXAS syndrome, characterized by headache, cognitive dysfunction and focal signs (cerebellar ataxia). Magnetic resonance imaging (MRI) revealed multifocal white-matter lesions corresponding to recent ischemic strokes, combined with cortical hemorrhagic lesions and gadolinium enhancement of the distal wall vessels. Treatment with methylprednisone, ruxolitinib and tocilizumab led to clinical improvement and a decrease of the inflammatory syndrome. The patient died few months after due to infectious complications. CONCLUSION: CNS vasculitis, occurring as a manifestation of the systemic auto-inflammatory state of VEXAS syndrome, might be a rare but severe complication. We suggest that it be added to the list of inflammatory vasculopathies. More prospective studies are needed to optimize the treatment.

The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males.

Since the first reports of polyglutamine-binding protein 1 (PQBP1) mutations in Renpenning syndrome and related disorders, the spectrum of PQBP1-linked clinical manifestations has been outlined from rare published case reports. The phenotypic description is often obtained from medical archives, and therefore, heterogeneous. Moreover, some aspects such as brain imaging or cognitive and behavioral functioning are rarely described. In this study, 13 PQBP1-mutated French patients were subjected to a standardized clinical, cognitive and behavioral assessment. Physical measurements of their relatives were also collected. We report on a recognizable clinical and radiological phenotype. All patients presented with microcephaly, leanness and mild short stature, relative to familial measurements. Three new clinical features are described: upper back progressive muscular atrophy, metacarpophalangeal ankylosis of the thumb and velar dysfunction. The specific facial dysmorphic features included at least four of the following signs: long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears and rough slightly sparse hair. An over-aged appearance was noticed in elderly patients. Cortical gyrification was normal based on available magnetic brain imaging of six patients. PQBP1-linked microcephaly (or Renpenning syndrome) is an X-linked mental retardation syndrome, which has clinically recognizable features.

Implicit procedural learning in fragile X and Down syndrome.

BACKGROUND: Procedural learning refers to rule-based motor skill learning and storage. It involves the cerebellum, striatum and motor areas of the frontal lobe network. Fragile X syndrome, which has been linked with anatomical abnormalities within the striatum, may result in implicit procedural learning deficit. METHODS: To address this issue, a serial reaction time (RT) task including six blocks of trials was performed by 14 individuals with fragile X syndrome, 12 individuals with Down syndrome and 12 mental age-matched control subjects. The first (B1) and fifth (B5) blocks were random whereas the others (B2, B3, B4 and B6) consisted of a repeated 10-step sequence. Results were analysed by Kruskal-Wallis one-way analysis of variance and Wilcoxon signed-rank test. RESULTS: For patients with fragile X syndrome, the RT was highly suggestive of preserved implicit learning as a significant difference was observed between blocks B5 and B6 (P = 0.009). However, the difference of RT between B4 and B5 did not reach significance, possibly due to a subgroup of individuals who did not learn. In contrast, in the Down syndrome group, RT decreased significantly between B4 and B5 (W = 2; P = 0.003) but not between the last ordered block (B6) and the last random block (B5), suggesting a weakness in procedural learning which was sensitive to the interfering random block. CONCLUSION: implicit learning is variable in genetic syndromes and therefore relatively independent of general intellectual capacities. The results are discussed together with previous reports.

[ANCA vasculitis preceded by isolated joint manifestations. Report of two cases and literature review]. / Vascularites à ANCA précédées d'une atteinte articulaire isolée. À propos de deux cas et revue de la littérature.

INTRODUCTION: Joint manifestations of ANCA (antineutrophil cytoplasmic antibody) associated vasculitis (AAV) are extremely common in the progression of systemic damages. However, the joint involvement is rarely isolated. The diagnosis and the treatment are difficult in this particular situation and few data are available on the topic. CASE REPORT: We have observed two cases of joint manifestation revealing AAV we are going to describe here. The evolution toward a more severe disease raises the question of the treatment managing. The place of the ANCA research in relation to other immune tests is also discussed. CONCLUSION: Isolated joint manifestations of ANCA vasculitis are rare but can lead to a delay in diagnosis. ANCA vasculitis should be considered in seronegative symmetrical polyarthritis by looking for ANCA in a second line biological test. Methotrexate is the first treatment option to be considered. In case of insufficient response or failure, rituximab seems an interesting option in this context.

Effet indésirable rare d'un anti-IL-1RA.

INTRODUCTION: Anakinra is an anti-IL-1RA targeting IL-1ß with a central role in the occurrence of auto-inflammatory diseases. Its use is not without risk. CASE REPORT: We report a case of late onset auto-inflammatory syndrome treated with anti-IL-1RA whose progression was marked by deep isolated thrombocytopenia, rapidly regressive after discontinuation of anakinra. CONCLUSION: Immuno-allergic thrombocytopenia to anakinra is a rare, but serious adverse event.