Shahram Attarian

Effect of ascorbic acid in patients with Charcot–Marie–Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy that affects roughly one in 5000 births. No specific therapy currently exists for this degenerative disorder, which is characterised by distal progressive muscle atrophy and sensory loss, although ascorbic acid has been shown to reduce demyelination and improve muscle function in a transgenic mouse model of CMT1A. We tested the safety and efficacy of ascorbic acid in adults with CMT1A. METHODS This 12-month, randomised, double-blind, placebo-controlled study was undertaken between September, 2005, and October, 2008. Patients diagnosed with CMT1A according to clinical examination and confirmation by genotyping were randomly assigned in a 1:1:1 ratio to receive 1 g ascorbic acid per day, 3 g ascorbic acid per day, or placebo. Treatment allocation was based on a computer-generated list of random numbers in blocks of 12, with stratification according to study site and sex; all investigators and participants were unaware of treatment allocation. The primary outcome was the Charcot-Marie-Tooth disease neuropathy score (CMTNS) at 12 months. Analysis was by intention to treat. This study is registered with the Orphanet Database, number ORPHA60779. FINDINGS The median change in CMTNS from baseline to 12 months was 0.5 points (95% CI -0.3 to 1.4) for the placebo group (n=62), 0.7 points (0.0 to 1.4) for the 1 g ascorbic acid group (n=56), and -0.4 points (-1.2 to 0.4) for the 3 g ascorbic acid group (n=61). We did not find any significant difference in these changes between the groups (p=0.14). The occurrence of adverse events did not differ between the groups (p=0.74). INTERPRETATION Ascorbic acid at both doses was safe and well tolerated in adults with CMT1A over 12 months. However, there were no significant differences between the groups and the efficacy of ascorbic acid was not shown.

Multifocal motor neuropathy with and without conduction block A single entity

Objective: To assess if multifocal motor neuropathy (MMN) with and MMN without conduction block (CB) are similar or distinct diseases. Methods: The authors reviewed the clinical features and responses to IV immunoglobulin (IVIg) treatment of patients with MMN with and without CB at diagnosis, after 4 years of follow-up and at the last examination. They included all patients showing clinical features of MMN who had been followed for at least 4 years: All had asymmetric purely motor weakness with a peripheral nerve distribution, without any sensory, bulbar, or respiratory signs and without any upper motor neuron involvement. Results: Twenty patients had CB and 13 had no CB. Median follow-up time was 7 years. There were no differences between the two groups in term of age, sex, time from onset to diagnosis, anti-GM1 antibody titers, or CSF data. Nerve distribution, number of affected limb regions, predominant weakness in distal upper extremities, asymmetric weakness, cramps, fasciculations, and Medical Research Council sum-scores in upper and lower limbs were comparable at diagnosis, 4 years of follow-up, and last examination. Few significant differences were observed. Involvement of median nerve was less frequent at 4 years of follow-up (14/20 vs 4/13; p = 0.027) and at the last examination (17/20 vs 5/13; p = 0.009) in patients without CB. Proximal weakness was less frequent in patients with MMN without CB at the last examination (7/20 vs 0/13; p = 0.027). Fewer nerves were involved in patients without CB at the last examination (4.5 vs 2; p = 0.04). Efficacy of IVIg was similar in MNN patients without CB (8/13) and with CB (14/20; p > 0.05). Conclusion: After a median follow-up time of 7 years, patients with and without conduction block showed similar clinical features and a similar response to IV immunoglobulin treatment.

Constitutive Activation of the Calcium Sensor STIM1 Causes Tubular-Aggregate Myopathy

Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly progressive muscle weakness. We identified dominant STIM1 mutations as a genetic cause of tubular-aggregate myopathy (TAM). Stromal interaction molecule 1 (STIM1) is the main Ca(2+) sensor in the endoplasmic reticulum, and all mutations were found in the highly conserved intraluminal Ca(2+)-binding EF hands. Ca(2+) stores are refilled through a process called store-operated Ca(2+) entry (SOCE). Upon Ca(2+)-store depletion, wild-type STIM1 oligomerizes and thereby triggers extracellular Ca(2+) entry. In contrast, the missense mutations found in our four TAM-affected families induced constitutive STIM1 clustering, indicating that Ca(2+) sensing was impaired. By monitoring the calcium response of TAM myoblasts to SOCE, we found a significantly higher basal Ca(2+) level in TAM cells and a dysregulation of intracellular Ca(2+) homeostasis. Because recessive STIM1 loss-of-function mutations were associated with immunodeficiency, we conclude that the tissue-specific impact of STIM1 loss or constitutive activation is different and that a tight regulation of STIM1-dependent SOCE is fundamental for normal skeletal-muscle structure and function.

Lewis-Sumner syndrome and multifocal motor neuropathy.

We compared the clinical, electrophysiological, laboratory, and pathological features of 13 patients with Lewis–Sumner syndrome (LSS) with those of 20 patients with multifocal motor neuropathy (MMN). LSS and MMN patients have several common clinical features: age at onset, weakness in the distribution of individual peripheral nerves, mild wasting, cramps and fasciculations, partial areflexia, and frequent stepwise disease course. Cerebrospinal fluid protein level was normal or slightly elevated, but always less than 100 mg/dl. Conduction blocks are the electrophysiological hallmarks of these two neuropathies, and no differences in distribution and number of blocks were found. Contrary to MMN, lower‐limb involvement at onset was frequent in LSS but extension to the upper limbs was a frequent later feature of the disease. Cranial nerve involvement was noted in 4 LSS patients during relapses and absent in all MMN patients. The major distinguishing features were the clinical and electrophysiological sensory involvement in LSS, and the lack of anti‐GM1 antibodies in LSS, whereas IgM anti‐GM1 were found in 40% of MMN patients. Some LSS patients responded to steroid therapy, whereas this was ineffective in MMN. From these features, LSS can be considered an entity distinct from MMN, with its own clinical, laboratory, and electrophysiological characteristics, and as an intermediate link between chronic inflammatory demyelinating polyneuropathy and MMN. Muscle Nerve, 2005

Analysis of the DYSF mutational spectrum in a large cohort of patients

Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease‐causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series.

Terminal latency index and modified F ratio in distinction of chronic demyelinating neuropathies

OBJECTIVE To evaluate indexes calculated from standard electrophysiological data in differentiating chronic demyelinating polyneuropathy (CDP). METHODS Nerve conduction study of upper limbs was investigated in 19 chronic inflammatory demyelinating polyneuropathy (CIDP) patients, 25 anti-myelin-associated glycoprotein/sulfated glucuronyl paragloboside antibodies (MAG/SGPG) CDP patients, 13 Charcot-Marie-Tooth disease type 1A (CMT1A) patients and 22 controls. Terminal latency index (TLI) was used to compare the wrist-to-thenar muscle segment with the elbow-to-wrist conduction velocity. Modified F ratio (MFR) was used to compare the spinal cord-to-elbow segment latency with that of the wrist-to-thenar muscle segment. RESULTS Compared with controls, TLI was decreased in 21 anti-MAG/SGPG CDP patients while MFR was either decreased or was normal. In 16 CIDP patients, MFR was increased while TLI was either normal or increased. In CMT1A both TLI and MFR were in normal ranges. The sensitivity of MFR as a supportive finding in CIDP was found to be 84% and its specificity 89%. The sensitivity of TLI as a mean of diagnosis of anti-MAG/SGPG CDP was found to be 93% and its specificity 90%. CONCLUSIONS The results of TLI and MFR facilitates distinction between different types of CDP. In CIDP, MFR was significantly higher and TLI showed no change; in the anti-MAG/SGPG CDP, TLI and MFR were significantly lower; in CMT1A, TLI and MFR showed no change in comparison with the controls.

Disrupting the right prefrontal cortex alters moral judgement

Humans daily face social situations involving conflicts between competing moral decision. Despite a substantial amount of studies published over the past 10 years, the respective role of emotions and reason, their possible interaction, and their behavioural expression during moral evaluation remains an unresolved issue. A dualistic approach to moral evaluation proposes that the right dorsolateral prefrontal cortex (rDLPFc) controls emotional impulses. However, recent findings raise the possibility that the right DLPFc processes emotional information during moral decision making. We used repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt rDLPFc activity before measuring decision making in the context of moral dilemmas. Results reveal an increase of the probability of utilitarian responses during objective evaluation of moral dilemmas in the rTMS group (compared to a SHAM one). This suggests that the right DLPFc function not only participates to a rational cognitive control process, but also integrates emotions generated by contextual information appraisal, which are decisive for response selection in moral judgements.

Microinfusion of the Metabotropic Glutamate Receptor Agonist 1S, 3R–1‐Aminocyclopentane‐1, 3‐dicarboxylic Acid Into the Nucleus Accumbens Induces Dopamine‐dependent Locomotor Activation in the Rat

Although the striatum has one of the highest densities of metabotropic glutamate receptor (mGluR) binding sites in the brain, little is known about their physiological role. In this study we characterized the contribution of mGluRs located in the ventral part of the striatum (the nucleus accumbens) to the control of extrapyramidal motor function. Activation of mGluRs by local infusion of the selective agonist 1S, 3R–1‐aminocyclopentane‐1, 3‐dicarboxylic acid (1 S, 3R‐ACPD; 25, 50 and 100 nmol/0.5 μl) into the nucleus accumbens induced a dose‐dependent increase in locomotor activity in rats. Intra‐accumbens infusion of a selective antagonist of mGluRs, a‐methyl‐4‐carboxyphenylglycine (MCPG) did not modify spontaneous locomotion but decreased the locomotor response to 1S, 3R‐ACPD. This effect appeared to be mediated by dopamine, since blockade of dopamine receptors with haloperidol (0.05 and 0.1 mg/kg i.p.) dose‐dependently reduced 1 S3R‐ACPD‐induced locomotor activation. Furthermore, D‐amphetamine (0.5 mg/kg, i.p.) combined with intra‐accumbens infusion of 1S, 3R‐ACPD (100 nmol) potentiated the locomotor hyperactivity response to a higher level than that seen with a single treatment with either drug. In contrast, D‐amphetamine‐induced hypermotility was abolished by infusion of MCPG (100 nmol) into the nucleus accumbens. These results demonstrate that glutamate may control extrapyramidal motor function through metabotropic receptors. Furthermore, activation of metabotropic glutamate receptors appears to act in synergy with the dopamine system at the level of the nucleus accumbens to produce a motor stimulant response.

Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy.

Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts. Constitutive inactivation of the protocadherin gene Fat1 uncoupled individual myoblast polarity within chains, altering the shape of selective groups of muscles in the shoulder and face. These shape abnormalities were followed by early onset regionalised muscle defects in adult Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre reproduced muscle shape defects in limb but not face muscles, indicating a cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly, the topography of muscle abnormalities caused by Fat1 loss-of-function resembles that of human patients with facioscapulohumeral dystrophy (FSHD). FAT1 lies near the critical locus involved in causing FSHD, and Fat1 mutant mice also show retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal inner ear patterning, predictive of deafness, reminiscent of another burden of FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was observed in foetal FSHD1 cases. CGH array-based studies identified deletion polymorphisms within a putative regulatory enhancer of FAT1, predictive of tissue-specific depletion of FAT1 expression, which preferentially segregate with FSHD. Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with FSHD.

Magnetic stimulation using a triple-stimulation technique in patients with multifocal neuropathy without conduction block

It has been suggested previously that multifocal motor neuropathy (MMN) without conduction block (CB) or other features of demyelination is axonal in nature. Conventional transcranial magnetic stimulation (TMS) and the triple‐stimulation technique (TST) performed on 10 MMN patients without CB revealed a proximal focal CB in 4 patients. In 3 other patients, the amplitude ratio obtained in response to conventional TMS was abnormally low, but the area ratio was normal. The TST amplitude ratio and area ratio were normal in these 3 patients. This pattern suggested the occurrence of temporal dispersion without CB. The occurrence of temporal dispersion or CB was associated with a relatively satisfactory response to intravenous immunoglobulins. These findings suggest that some forms of MMN previously thought to be axonal are in fact proximal variants of MMN with CB. Muscle Nerve, 2005