Bernard Sablonnière

Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy.

BackgroundFatal lactic acidosis is a serious complication of therapy with nucleoside analogues. ObjectiveTo examine symptomatic hyperlactataemia in HIV-infected adults treated with antiretroviral drugs. MethodsIn this prospective study, arterial blood lactate levels were measured in patients presenting with unexplained clinical symptoms. When these levels were high, functional respiratory tests (FRT) were carried out. Liver or muscle biopsies were further proposed. Incidences were calculated by comparison with the entire cohort of patients treated in the department. ResultsFourteen HIV-infected adults treated with antiretroviral drugs were identified with symptomatic hyperlactataemia during a 2-year period follow-up study. The incidence of hyperlactataemia was 0.8% per year but reached 1.2% if only patients treated with a regimen including stavudine were considered. Clinical symptoms included abnormal fatigue, tachycardia, abdominal pain, weight loss, peripheral neuropathy, and more specifically exercise-induced dyspnoea occurring despite effective antiretroviral treatment. FRT showed a metabolic deviation towards anaerobiosis with a high lactate/pyruvate ratio. Ultrastructural mitochondrial abnormalities were seen in all four patients for whom this was examined. There was a marked decrease in complex IV activity in muscle biopsies from four of five patients, consistent with a mitochondrial dysfunction. Evolution was favourable in 13 patients, probably because of an early diagnosis. ConclusionsPotentially fatal adverse events occurring during antiretroviral treatment may be avoided by close monitoring of clinical signs and blood lactate levels. If other studies confirm that the cumulative long-term toxicity of antiretroviral drugs results from mitochondrial dysfunction, the incidence of hyperlactataemia and its clinical consequences may become more important.

Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial

BACKGROUND Despite optimum medical management, many patients with Parkinsons disease are incapacitated by gait disorders including freezing of gait. We aimed to assess whether methylphenidate--through its combined action on dopamine and noradrenaline reuptake--would improve gait disorders and freezing of gate in patients with advanced Parkinsons disease without dementia who also received subthalamic nucleus stimulation. METHODS This multicentre, parallel, double-blind, placebo-controlled, randomised trial was done in 13 movement disorders departments in France between October, 2009, and December, 2011. Eligible patients were younger than 80 years and had Parkinsons disease, severe gait disorders, and freezing of gate despite optimised treatment of motor fluctuations with dopaminergic drugs and subthalamic stimulation. We randomly assigned patients (1:1 with a computer random-number generator in blocks of four) to receive methylphenidate (1 mg/kg per day) or placebo capsules for 90 days. Patients, their carers, study staff, investigators, and data analysts were masked to treatment allocation. To control for confounding effects of levodopa we assessed patients under standardised conditions with an acute levodopa challenge. Our primary outcome was a change in the number of steps during the stand-walk-sit (SWS) test without levodopa. We compared the respective mean numbers of steps at day 90 in the methylphenidate and placebo groups in a covariance analysis and adjusted for baseline differences. This trial is registered with ClinicalTrials.gov, number NCT00914095. FINDINGS We screened 81 patients and randomly assigned 35 to receive methylphenidate and 34 to receive placebo. 33 patients in the methylphenidate group and 32 patients in the placebo group completed the study. Efficacy outcomes were assessed in the patients who completed the study. Compared with patients in the placebo group (median 33 steps [IQR 26-45]), the patients in the methylphenidate group made fewer steps at 90 days (31 [26-42], F((1, 62))=6·1, p=0·017, adjusted size effect 0·61). Adverse events were analysed in all randomly assigned patients. There were significantly more adverse events in the methylphenidate group compared with placebo. Patients on methylphenidate had a significant increase in heart rate (mean 3·6 [SD 7·2] beats per min) and decrease in weight (mean 2·2 [SD 1·8] kg) compared with the placebo group. INTERPRETATION Methylphenidate improved gait hypokinesia and freezing in patients with advanced Parkinsons disease receiving subthalamic nucleus stimulation. Methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stage of Parkinsons disease. The long term risk-benefit balance should be further studied. FUNDING French Ministry of Health and Novartis Pharma.

Mutation analysis and association studies of the ubiquitin carboxy-terminal hydrolase L1 gene in Huntington's disease

Huntingtons disease (HD) is attributed to a triplet CAG repeat mutation, and about 70% of the variance in age-at-onset can be explained by the size of the repeat expansion. Among potential candidates as modifier genes, we investigated the role of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene. We examined the association of HD with the I93M mutation and S18Y polymorphism in 138 HD patients and 136 control subjects, but we did not identify the I93M mutation. The S18Y polymorphism was present in 17% of HD patients. Of the variance in the age-at-onset that was not accounted for by the CAG repeat, 13% could be attributed to S18Y polymorphism. We sequenced the entire coding region of the UCH-L1 gene in seven HD patients with unexplained older or younger onset age. The S18Y polymorphism was found in three out of the four patients presenting with a later age-at-onset. We conclude that the UCH-L1 gene may be a genetic factor that influences the variability in age-at-onset of HD.

A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1

We investigated a French family with a new type of autosomal dominant spinocerebellar ataxia that was excluded from all previously identified genes and loci. The patients exhibited a slowly progressive gait and limb ataxia variably associated with akinesia, rigidity, tremor, and hyporeflexia. A mild cognitive impairment also was observed in some cases. We performed a genomewide search and found significant evidence for linkage to chromosome 7p21.3‐p15.1. Analysis of key recombinants and haplotype reconstruction traced this novel spinocerebellar ataxia locus to a 24cM interval flanked by D7S2464 and D7S516.

Clinical features and genetic analysis of a new form of spinocerebellar ataxia.

Background: The autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of disorders. The mutations for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and SCA-12 are identified and caused by an expansion of a CAG or a CTG repeat sequence of these genes. Six additional loci for SCA4, SCA5, SCA-10, SCA-11, SCA-13, and SCA-14 are mapped. The growing heterogeneity of the autosomal dominant forms of these diseases shows that the genetic etiologies of at least 20% of ADCA have yet to be elucidated. Methods: The authors ascertained and clinically characterized a four-generation pedigree segregating an autosomal dominant phenotype for SCA. Direct mutation analysis, repeat expansion detection analysis, and linkage analysis for all known SCA loci were performed. Results: Direct mutational analysis excluded SCA1, 2, 3, 6, 7, 8, and 12; genetic linkage analysis excluded SCA4, 5,10, 11, 13, and 14, giving significant negative lod scores. Examination of the family showed that all affected members had gait ataxia and akinesia with variable features of dysarthria, hyporeflexia, and mild intellectual impairment. Eye movements were normal. Head MRI showed atrophy of the cerebellum without involvement of the brainstem. In 10 parent–child pairs, median onset occurred 10.5 years earlier in offspring than in their parents, suggesting anticipation. Conclusion: This family is distinct from other families with SCA and is characterized by cerebellar ataxia and extrapyramidal signs.

New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes.

Benign hereditary chorea is a rare autosomal dominant disorder presenting with a childhood‐onset and slowly progressive chorea. The objective of this study was to describe the clinical and genetic features of 3 patients who developed childhood‐onset chorea. Three affected patients from three generations of a family with benign hereditary chorea associated with a multisystemic disorder of the basal ganglia, thyroid, lungs, salivary glands, bowels, and teeth. The TITF‐1 gene was screened by microsatellite analysis, gene sequencing, and fluorescence in situ hybridization. Genetic analysis revealed a novel 0.9‐Mb deletion on chromosome 14, which includes the TITF‐1 and PAX9 genes. We have identified a novel deletion responsible for a new syndrome of benign hereditary chorea, including symptoms of brain–thyroid–lung syndrome associated with bowels, salivary glands, and teeth disorders. Associated signs, sometimes of slight expression, remain of high interest for the clinical and genetic diagnosis of benign hereditary chorea.

A genetic variation in the ADORA2A gene modifies age at onset in Huntington's disease ☆

Based on the pathophysiological role of adenosine A(2A) receptors in HD, we have evaluated the association of the 1976C/T single-nucleotide polymorphism in the ADORA2A gene (rs5751876) with residual age at onset (AAO) in HD. The study population consisted of 791 unrelated patients belonging to the Huntington French Speaking Network. The variability in AAO attributable to the CAG repeats number was calculated by linear regression using the log (AAO) as the dependent variable, and the respective rs5751876 genotypes as independent variables. We show that the rs5751876 variant significantly influences the variability in AAO. The R(2) statistic rose slightly but significantly (p=0.019) when rs5751876 T/T genotype was added to the regression model. Patients harbouring T/T genotype have an earlier AAO of 3.8 years as compared to C/C genotype (p=0.02). Our data thus strengthens the pathophysiological role of A(2A) receptors in Huntingtons disease.

ETR-3 represses Tau exons 2/3 inclusion, a splicing event abnormally enhanced in myotonic dystrophy type I

Altered splicing of transcripts, including the insulin receptor (IR) and the cardiac troponin (cTNT), is a key feature of myotonic dystrophy type I (DM1). CELF and MBNL splicing factor members regulate the splicing of those transcripts. We have previously described an alteration of Tau exon 2 splicing in DM1 brain, resulting in the favored exclusion of exon 2. However, the factors required for alternative splicing of Tau exon 2 remain undetermined. Here we report a decreased expression of CELF family member and MBNL transcripts in DM1 brains as assessed by RT‐PCR. By using cellular models with a control‐ or DM1‐like splicing pattern of Tau transcripts, we demonstrate that ETR‐3 promotes selectively the exclusion of Tau exon 2. These results together with the analysis of Tau exon 6 and IR exon 11 splicing in brain, muscle, and cell models suggest that DM1 splicing alteration of several transcripts involves various factors.

Tau as a biomarker of neurodegenerative diseases

The microtubule-associated protein Tau is mainly expressed in neurons of the CNS and is crucial in axonal maintenance and axonal transport. The rationale for Tau as a biomarker of neurodegenerative diseases is that it is a major component of abnormal intraneuronal aggregates observed in numerous tauopathies, including Alzheimers disease. The molecular diversity of Tau is very useful when analyzing it in the brain or in the peripheral fluids. Immunohistochemical and biochemical characterization of Tau aggregates in the brain allows the postmortem classification and differential diagnosis of tauopathies. As peripheral biomarkers of Alzheimers disease in the cerebrospinal fluid, Tau proteins are now validated for diagnosis and predictive purposes. For the future, the detailed characterization of Tau in the brain and in peripheral fluids will lead to novel promising biomarkers for differential diagnosis of dementia and monitoring of therapeutics.

Cerebrospinal fluid amyloid-β 42/40 ratio in clinical setting of memory centers: a multicentric study

IntroductionThe cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ), tau and phosphorylated tau (p-tau181) are now used for the diagnosis of Alzheimer’s disease (AD). Aβ40 is the most abundant Aβ peptide isoform in the CSF, and the Aβ 42/40 ratio has been proposed to better reflect brain amyloid production. However, its additional value in the clinical setting remains uncertain.MethodsA total of 367 subjects with cognitive disorders who underwent a lumbar puncture were prospectively included at three French memory centers (Paris-North, Lille and Montpellier; the PLM Study). The frequency of positive, negative and indeterminate CSF profiles were assessed by various methods, and their adequacies with the diagnosis of clinicians were tested using net reclassification improvement (NRI) analyses.ResultsOn the basis of local optimum cutoffs for Aβ42 and p-tau181, 22% of the explored patients had indeterminate CSF profiles. The systematic use of Aβ 42/40 ratio instead of Aβ42 levels alone decreased the number of indeterminate profiles (17%; P = 0.03), but it failed to improve the classification of subjects (NRI = −2.1%; P = 0.64). In contrast, the use of Aβ 42/40 ratio instead of Aβ42 levels alone in patients with a discrepancy between p-tau181 and Aβ42 led to a reduction by half of the number of indeterminate profiles (10%; P < 0.001) and was further in agreement with clinician diagnosis (NRI = 10.5%; P = 0.003).ConclusionsIn patients with a discrepancy between CSF p-tau181 and CSF Aβ42, the assessment of Aβ 42/40 ratio led to a reliable biological conclusion in over 50% of cases that agreed with a clinician’s diagnosis.