TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment.

Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.

Amyotrophic lateral sclerosis associated with a pathological expansion in the ATXN7 gene.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant hereditary neurodegenerative disease caused by the expansion of a CAG-repeat in the ataxin-7 (ATXN7) gene, usually characterized by progressive cerebellar ataxia and retinal dystrophy. We report the case of a 45-year-old woman presenting with a rapid-onset amyotrophic lateral sclerosis (ALS) phenotype associated with a 39-CAG-repeat expansion in ATXN7. This patient had neither ataxia nor retinal dystrophy, but she had an oculomotor cerebellar syndrome and a family history suggestive of SCA7. In SCA7, shorter expansions may be associated with less severe and incomplete clinical phenotypes, which could explain the patient's phenotype. Unknown genetic and environmental factors may also influence the patient's phenotype. We suggest that a pathological expansion in ATXN7 should be considered in cases of ALS-like phenotype, particularly when associated with oculomotor abnormalities or a family history of ataxia or blindness.

Spinocerebellar ataxia Type 7: clinical and genetic study of a new Moroccan family (case report).

Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disease. Its clinical presentation is a progressive cerebellar ataxia associated with cone and retinal dystrophy. The CAG repeat expansion in the ataxin-7 gene (ATXN7) causes spinocerebellar ataxia type 7 - a mutation that results in the degeneration of the brain stem cells, retina and cerebellum. We report in this study the clinical and genetic features of a new Moroccan family of SCA7, from the South of Morocco. We performed the molecular genetic testing to confirm the diagnosis of SCA7. The objective of this study is to report a new Moroccan case of SCA7 and to illustrate the role of the geneticist in the diagnosis, management and development of genetic counseling of SCA7 disease.

Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy.

INTRODUCTION: Spinocerebellar ataxia types 19 and 22 (SCA19/22) are rare conditions in which relatively isolated cerebellar involvement is frequently associated with cognitive impairment. Here, we report on new clinical features and provide details of the cognitive profile in two SCA19/22 families. METHODS: Two families displaying an autosomal-dominant form of cerebellar ataxia underwent clinical examinations and genetic testing. RESULTS: In addition to the classical clinical features of SCA, a wide spectrum of cognitive disorders (including visuospatial impairments) was observed. Eight patients had mild Parkinsonism, and five had epilepsy. Genetic testing showed that the KCND3 mutation (c.679_681delTTC, p.F227del) was present in both families. CONCLUSIONS: Our findings broaden the phenotypic spectrum of SCA19/22, and suggest that KCND3 should be included in the list of candidate genes for epilepsy, Parkinsonism and cognitive impairment.

Gentle blood aspiration and tube cushioning reduce pneumatic tube system interference in lactate dehydrogenase assays.

BACKGROUND: Use of a hospital pneumatic tube system may be associated with measurement errors. METHODS: A venous blood sample was collected from 79 patients into a pair of lithium heparin tubes; one tube was sent to the laboratory by porter and the other was sent via the pneumatic tube system. Plasma lactate dehydrogenase concentrations were then assayed. RESULTS: Lactate dehydrogenase concentrations were overestimated (median bias: 18.8%) when evacuated vacuum lithium heparin tubes were sent by pneumatic tube system. This bias was reduced by bubble-wrapping the standard lithium heparin tube or using Monovette lithium heparin tubes in aspiration mode (median bias: +8.7% and -0.3%, respectively). CONCLUSIONS: Cushioning and aspiration-mode sampling may limit pneumatic tube system-associated overestimation of lactate dehydrogenase concentrations.

Targeting chelatable iron as a therapeutic modality in Parkinson's disease.

AIMS: The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments. RESULTS: For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial. INNOVATION: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. CONCLUSIONS: The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD.