Christophe Vial

Cold extends electromyography distinction between ion channel mutations causing myotonia

Myotonias are inherited disorders of the skeletal muscle excitability. Nondystrophic forms are caused by mutations in genes coding for the muscle chloride or sodium channel. Myotonia is either relieved or worsened by repeated exercise and can merge into flaccid weakness during exposure to cold, according to causal mutations. We designed an easy electromyography (EMG) protocol combining repeated short exercise and cold as provocative tests to discriminate groups of mutations.

Guillain-Barré Syndrome, Influenzalike Illnesses, and Influenza Vaccination During Seasons With and Without Circulating A/H1N1 Viruses

The role of influenzalike illnesses and influenza vaccination in the development of Guillain-Barré syndrome (GBS), particularly the role of A/H1N1 epidemics and A/H1N1 vaccination, is debated. Data on all incident GBS cases meeting the Brighton Collaboration criteria that were diagnosed at 25 neurology centers in France were prospectively collected between March 2007 and June 2010, covering 3 influenzavirus seasons, including the 2009-2010 A/H1N1 outbreak. A total of 457 general practitioners provided a registry of patients from which 1,080 controls were matched by age, gender, index date (calendar month), and region to 145 cases. Causal relations were assessed by multivariate case-control analysis with adjustment for risk factors (personal and family history of autoimmune disorders, among others), while matching on age, gender, and calendar time. Influenza (seasonal or A/H1N1) or influenzalike symptoms in the 2 months preceding the index date was associated with GBS, with a matched odds ratio of 2.3 (95% confidence interval (CI): 0.7, 8.2). The difference in the rates of GBS occurring between influenza virus circulation periods and noncirculation periods was highly statistically significant (P = 0.004). Adjusted odds ratios for GBS occurrence within 6 weeks after seasonal and A/H1N1 vaccination were 1.3 (95% CI: 0.4, 4.1) and 0.9 (95% CI: 0.1, 7.6), respectively. Study results confirm that influenza virus is a likely risk factor for GBS. Conversely, no new concerns have arisen regarding influenza vaccination.

Regional difference and similarity of familial amyloidosis with polyneuropathy in France.

Familial amyloidosis with polyneuropathy (FAP) in France have a large genetic heterogeneity with 29 transthyretin (TTR) gene mutations; Met30-TTR is the most frequent one (62%); followed by Tyr77-TTR (11.8%) and Phe77-TTR (6.2%). Analysis of 60 FAP patients diagnosed during the period 2008–2010 showed amyloid polyneuropathy was initially suspected in only 38% patients. TTR Met30 of Portuguese ancestry is different from TTR Met30 of non Portuguese ancestry and other non Met30 variants in geographical distribution and clinical presentation. There are three additional phenotypes of the neuropathy including multifocal upper limbs neuropathy, ataxic polyneuropathy and motor neuropathy. Patients with Tyr77-TTR are characterized by a late onset (>50 years), frequent ataxic phenotype; they are localized mainly in north of France. The more frequent use of the TTR genetic tests and the French network for FAP will help in the future to improve diagnosis and care.

The use of muscle strength assessed with handheld dynamometers as a non-invasive biological marker in myotonic dystrophy type 1 patients: a multicenter study

BackgroundMyotonic dystrophy type 1 (DM1) is a multisystem disorder that demonstrates variable symptoms and rates of progression. Muscle weakness is considered one of the main problems with a clinical picture that is characterized by distal weakness of the limbs progressing to proximal weakness. The main objective of this study was to characterize the maximal strength of ankle eversion and dorsiflexion in DM1 patients. Manual and handheld dynamometer (HHD) muscle testing were also compared.MethodsThe maximal strength of 22 patients from Quebec (mean age = 41,1 ± 13,8) and 24 from Lyon (mean age = 41,6 ± 10,2) were compared to 16 matched controls.ResultsWith the use of HHD, an excellent reproducibility of the torque measurements was obtained for both centers in eversion (R2 = 0,94/Quebec; 0,89/Lyon) and dorsiflexion (R2 = 0,96/Quebec; 0,90/Lyon). The differences between 3 groups of DM1 (mild, moderate, severe) and between them and controls were all statistically significant (p < 0,001). No statistical differences between sites were observed (p > 0.05). The degree of muscle strength decline in dorsiflexion (eversion) were 60% (47%), 77% (71%), and 87% (83%) for DM1 with mild, moderate, and severe impairments, respectively. The smallest mean difference between all DM1 patients taking together was 2.3 Nm, a difference about twice than the standard error of measurement. There was a strong relationship between eversion and dorsiflexion strength profiles (R2 = 0,87;Quebec/0,80;Lyon). Using a 10-point scale, manual muscle testing could not discriminate between the 3 groups of DM1 patients.ConclusionsThe HHD protocol showed discriminative properties suitable for multicentre therapeutic trial. The present results confirmed the capacity of quantitative muscle testing to discriminate between healthy and DM1 patients with different levels of impairments. This study is a preliminary step for the implementation of a valid, reliable and responsive clinical outcome for the measurement of muscle impairments with this population.

Neurological features in adult Triple-A (Allgrove) syndrome

Triple-A or Allgrove syndrome is a rare multisystem disease classically associated with esophageal achalasia, adrenal insufficiency and alacrima. Here, we describe the poorly understood neurological characteristics often associated with this condition, through the clinical and electrophysiological analysis of eight patients. All patients were genetically confirmed and had a mutation in the ALADIN gene. They all displayed a classical picture of Triple-A syndrome: all suffered from achalasia and alacrima and half of them from adrenal insufficiency. However, all harbored a neurological picture characterized by a recognizable pattern of peripheral neuropathy. Other neurological features included cognitive deficits, pyramidal syndrome, cerebellar dysfunction, dysautonomia, neuro-ophthalmological signs and bulbar and facial symptoms. This neurological picture was prominent in all patients and misled the initial diagnosis in six of them, which had a late onset. We then review the previous neurological reports of this disease, to improve the understanding of this rare condition. Diagnosis of late-onset Triple-A syndrome is difficult when the clinical picture is mainly neurological and when endocrine or gastrointestinal signs are minor. The characteristics of the peripheral neuropathy, among other neurological signs, can be of help.

Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.

Background Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity. Methods We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301). Results Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate. Conclusion Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.

MOLECULAR ANALYSIS OF THE ANDROGEN RECEPTOR GENE IN KENNEDY'S DISEASE: REPORT OF TWO FAMILIES AND REVIEW OF THE LITERATURE

We have performed a molecular analysis of the androgen receptor gene in two families with suspected Kennedys disease (spinal and bulbar muscular atrophy, SBMA) with the aim of making a firm diagnosis of the disease. The 2 patients studied were sporadic cases. Both presented clinical signs compatible with the diagnosis of SBMA: limb and facial muscular weakness of adult onset progressing toward muscular atrophy. Clinical signs of partial androgen insensitivity syndrome usually observed in SBMA were present only in patient 2. Enzymatic amplification of the CAG repeat region of exon 1 of the androgen receptor gene was performed on genomic DNA. PCR products were submitted to agarose or acrylamide electrophoresis for size evaluation. Precise determination of the CAG number was performed by direct sequencing of purified amplification products. Androgen receptor gene analysis was also performed in 2 sisters of patient 1 and in the mother, sisters and daughter of patient 2. Androgen receptor-binding activity was also determined on cultured genital skin fibroblasts of patient 1. Analysis of PCR products showed in both patients a single band that was much larger in size than the control. The expansion of the CAG repeat number was confirmed by direct sequencing: the exact number of CAG was 47 in patient 1 and 42 in patient 2 (n = 12-32). The 2 studied sisters of patient 1 did not present the abnormal fragment, demonstrating they are not carriers for the disease. Conversely, the mother, sisters and daughter of patient 2 presented both normal and mutated alleles. The migration of the labelled PCR products on a sequencing gel revealed a meiotic instability of expanded CAG repeat in family 2. Moreover, patient 1 had a decreased androgen-binding capacity on cultured genital skin fibroblasts. In both families, analysis of the androgen receptor gene permitted us to diagnose SBMA in the patients and to establish the carrier status in siblings. These results correspond to the literature data and confirm the usefulness of CAG repeat evaluation in the diagnosis of Kennedys disease. They highlight the relationship between the androgen receptor and motoneuron growth, development and regeneration.

MRI of Tibialis Anterior Skeletal Muscle in Myotonic Dystrophy Type 1

OBJECTIVEnThe aim of this study was to evaluate whether magnetic resonance imaging (MRI) can be used as a noninvasive approach to assessment of disease severity and muscle damage in Myotonic Dystrophy type 1 (DM1).nnnMETHODSnThe MRI findings in legs of 41 patients with DM1 were evaluated with respect to the tibialis anterior (TA) skeletal muscle impairment. Magnetic resonance imaging findings were compared with TA strength measurements obtained by quantitative manual testing, duration of the disease and with the length of the CTG repeats.nnnRESULTSnMuscle MRI abnormalities were observed in 80% of DM1 patients, ranging from edema-like abnormalities alone to severe atrophy/fatty replacement. Edema-like abnormalities seem to be an earlier MRI marker of the disease. Fatty infiltration/atrophy correlated with the TA muscle force (r = 0.95), the severity (P = 0.00001) of the disease but not with the duration of the disease (P = 0.3) or the length of the CTG repeats (P > 0.10), measured in peripheral leukocytes. Evaluation of other muscles of the legs revealed that the medial gastrocnemius and soleus muscles were the most frequently and severely affected muscles, while tibialis posterior muscles were relatively spared. Edema-like abnormalities are most frequently observed in the skeletal muscles of the anterior compartment.nnnCONCLUSIONnMuscle MRI is helpful to depict muscle abnormalities but does not seem to be a reliable indicator of skeletal muscle involvement in DM1 since the decrease in TAmuscle force is not correlated with MRI abnormalities in some patients.

Cerebrospinal fluid detection of enterovirus genome in ALS: A study of 242 patients and 354 controls

Abstract Detection of enterovirus (EV) in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) has been reported on post mortem central nervous system tissues. In cases of persistent infection, it is very likely that the EV genome might be detected in the cerebrospinal fluid (CSF). A study was conducted in seven French amyotrophic lateral sclerosis (ALS) centres between 1997 and 2002. A total of 242 ALS patients and 354 age- and sex-matched controls (non-ALS patients) were enrolled. A sensitive RT-PCR method was performed on the CSF to assess the presence of EV RNA; 14.5% of ALS patients were positive compared to 7.6% of controls (χ2 value, 5.31; p = 0.02). Although EV infection has a seasonal pattern, we observed no seasonality in positive detection of the EV genome among ALS patients. There was no significant relationship among ALS patients between the initial clinical form or survival and the result of the RT-PCR. These findings suggest a relationship between the presence of EV sequences in CSF and ALS. Our study is consistent with the hypothesis that persistent EV infection can be one of the multiple factors involved in the development of ALS.

Triple-A syndrome: a wide spectrum of adrenal dysfunction

OBJECTIVEnTriple-A or Allgrove syndrome is an autosomal recessive disorder due to mutations in the AAAS gene, which encodes a nucleoporin named ALADIN. It is characterized by a classical clinical triad: alacrima, achalasia and adrenal insufficiency, the canonic symptoms that are associated with progressive peripheral neuropathy. Only a few cohorts have been reported. The objective of the present study was to characterize the various spectra of adrenal function in Triple-A patients.nnnMETHODSnA retrospective clinical and biological monitoring of 14 patients (10 families) was done in a single multidisciplinary French center. All had AAAS gene sequenced and adrenal function evaluation.nnnRESULTSnNine different AAAS mutations were found, including one new mutation: c.755G>C, p.(Trp252Ser). Regarding adrenal function, defects of the zona fasciculata and reticularis were demonstrated by increased basal ACTH levels and low DHEAS levels in all cases regardless of the degree of glucocorticoid deficiency. In contrast, mineralocorticoid function was always conserved: i.e., normal plasma renin level associated with normal aldosterone level. The main prognostic feature was exacerbation of neuropathy and cognitive disorders.nnnCONCLUSIONSnThese data suggest that, in Triple-A patients, adrenal function can be deficient, insufficient or compensated. In our cohort after the first decade of life, there does not appear to be any degradation of adrenal function over time. However, patients with compensated adrenal function should be informed and educated to manage a glucocorticoid replacement therapy in case of stressful conditions, with no need for systematic long-term treatment.