Fabien Zagnoli

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France. This report describes the main clinical and molecular features, at the time of inclusion in the French registry, of 126 patients followed up in 21 hospital-based neuromuscular or metabolic centres. Sixty-five men and 61 women have been included in the registry. Median age at inclusion was 49 years, and the median age at onset of progressive limb weakness was 35 years. Fifty-five percent of the patients were walking without assistance, 24% were using a stick or a walking frame, and 21% were using a wheelchair. Forty-six percent of the patients needed ventilatory assistance, which was non-invasive in 35% of the cases. When performed, muscle biopsies showed specific features of Pompe disease in less than two-thirds of the cases, confirming the importance of acid alpha-glucosidase enzymatic assessment to establish the diagnosis. Molecular analysis detected the common c.-32-13T>G mutation, in at least one allele, in 90% of patients. The French Pompe registry is so far the largest country-based prospective study of patients with Pompe disease, and further analysis will be performed to study the impact of enzyme replacement therapy on the progression of the disease.

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.

Small-fibre neuropathies and skin: news and perspectives for dermatologists

Small-fibre neuropathies (SFNs) can be defined as diseases of small nerve fibres. Because their symptoms are mainly located in the skin in the initial stages, dermatologists may frequently be confronted with these diseases. Moreover, skin biopsies and the subsequent measurement of intraepidermal nerve fibre density have become a widely accepted technique to investigate the structural integrity of small nerve fibres. The pathogenesis of injury to small nerve fibres is poorly understood. It probably depends on the cause. SCN9A-gene variants have been reported. Diabetes mellitus is one of the main causes of SFNs. Some causes of SFNs are very well-known to dermatologists: Gougerot-Sjögren syndrome, lupus, sarcoidosis and Fabry disease. We also discuss erythermalgia, prurigo nodularis, nummular eczema, burning mouth syndrome and sensitive skin as SFNs.

Diagnostic Algorithm for Glycogenoses and Myoadenylate Deaminase Deficiency Based on Exercise Testing Parameters: A Prospective Study

Aim Our aim was to evaluate the accuracy of aerobic exercise testing to diagnose metabolic myopathies. Methods From December 2008 to September 2012, all the consecutive patients that underwent both metabolic exercise testing and a muscle biopsy were prospectively enrolled. Subjects performed an incremental and maximal exercise testing on a cycle ergometer. Lactate, pyruvate, and ammonia concentrations were determined from venous blood samples drawn at rest, during exercise (50% predicted maximal power, peak exercise), and recovery (2, 5, 10, and 15 min). Biopsies from vastus lateralis or deltoid muscles were analysed using standard techniques (reference test). Myoadenylate deaminase (MAD) activity was determined using p-nitro blue tetrazolium staining in muscle cryostat sections. Glycogen storage was assessed using periodic acid-Schiff staining. The diagnostic accuracy of plasma metabolite levels to identify absent and decreased MAD activity was assessed using Receiver Operating Characteristic (ROC) curve analysis. Results The study involved 51 patients. Omitting patients with glycogenoses (n = 3), MAD staining was absent in 5, decreased in 6, and normal in 37 subjects. Lactate/pyruvate at the 10th minute of recovery provided the greatest area under the ROC curves (AUC, 0.893 ± 0.067) to differentiate Abnormal from Normal MAD activity. The lactate/rest ratio at the 10th minute of recovery from exercise displayed the best AUC (1.0) for discriminating between Decreased and Absent MAD activities. The resulting decision tree achieved a diagnostic accuracy of 86.3%. Conclusion The present algorithm provides a non-invasive test to accurately predict absent and decreased MAD activity, facilitating the selection of patients for muscle biopsy and target appropriate histochemical analysis.

Immunohistochemical and virological features of HTLV-1-associated myosites: a study of 13 patients from West Indies and Africa

Immunohistochemical and virological features of HTLV-1-associated myosites: a study of 13 patients from West Indies and Africa Marion Desdouits, Olivier Cassar, Thierry Maisonobe, Alexandra Desrames, Achille Aouba, Olivier Hermine, Jacqueline Mikol, Marc Polivka, Isabelle Penisson-Besnier, Pascale Marcorelles, Fabien Zagnoli, Thomas Papo, Arnaud Lacour, Zahir Amoura, Julien Haroche, Patrick Cherin, Antonio Texeira, Anne-Sophie Morin, Franck Mortreux, Eric Wattel, Michel Huerre, Marie-Christine Cumont, Huot Khun, Sylviane Bassot, Sandra Martin-Latil, Graham Taylor, Antoine Gessain, Simona Ozden, Pierre-Emmanuel Ceccaldi

Exercise testing‐based algorithms to diagnose McArdle disease and MAD defects

As exercise intolerance and exercise‐induced myalgia are commonly encountered in metabolic myopathies, functional screening tests are commonly used during the diagnostic work‐up. Our objective was to evaluate the accuracy of isometric handgrip test (IHT) and progressive cycle ergometer test (PCET) to identify McArdle disease and myoadenylate deaminase (MAD) deficiency and to propose diagnostic algorithms using exercise‐induced lactate and ammonia variations.

Main et pathologies musculaires

Serrer la main d’un patient est essentiel en pathologie musculaire. S’attacher a regarder des details comme une eruption cutanee, la topographie d’un deficit moteur, des anomalies de relaxation musculaire et des retractions des doigts permet d’orienter le diagnostic etiologique.

The impact of enzyme replacement therapy on the progression of Pompe disease

G.P.8 An international, phase 3, switchover study of reveglucosidase alfa (BMN 701) in subjects with late-onset Pompe disease B. Schoser *, B. Byrne , F. Eyskens , T. Hiwot , D. Hughes , J. Kissel , E. Mengel , T. Mozaffar , A. Pestronk , M. Roberts , K. Sivakumar , J. Statland , P. Young , C. Heusner , W. Dummer 14 1 Ludwig Maximilians University, Munich, Germany; 2 University of Florida School of Medicine, Gainesville, FL, USA; 3 University Hospital of Antwerp, Antwerp, Belgium; 4 University Hospital Birmingham, Birmingham, UK; 5 Royal Free & University College Medical School, London, UK; 6 Ohio State University, Columbus, OH, USA; 7 Johannes Gutenberg University Mainz, Mainz, Germany; 8 University of California, Irvine, CA, USA; 9 Washington University School of Medicine, Saint Louis, MO, USA; 10 Salford Royal NHS Foundation Trust, Salford, UK; 11 Neuromuscular Research Center, Scottsdale, AZ, USA; 12 University of Kansas Medical Center, Kansas City, KS, USA; 13 University Hospital Munster, Munster, Germany; 14 BioMarin Pharmaceutical Inc., Novato, CA, USA

654 Le syndrome de Kearns-Sayre : à propos d’un cas

Introduction Le syndrome de Kearns-Sayre est une affection hereditaire rare entrant dans le cadre des myopathies mitochondriales dont l’expression clinique peut s’apparenter a un syndrome myasthenique. Objectifs et Methodes Nous rapportons le cas d’un homme de 67 ans qui presente depuis plusieurs annees un ptosis bilateral fluctuant a la fatigue, une ophtalmoparesie, des troubles de la deglutition et de la phonation, une dyspnee d’effort, une fatigabilite musculaire, une hypoacousie et une areflexie des 4 membres. L’anamnese retrouve un contexte familial de ptosis bilateral non etiquete. Un traitement par anticholinesterasique est instaure devant la forte presomption clinique de myasthenie. Quelques jours plus tard, le patient est hospitalise en urgence pour crise cholinergique grave. Le bilan de myasthenie est negatif. Discussion Le diagnostic de myasthenie est essentiellement clinique. Cependant, l’atteinte pluri-systemique, l’histoire familiale et l’aggravation progressive de la symptomatologie doivent egalement faire evoquer une cytopathie mitochondriale et realiser un bilan dans ce sens. Chez notre patient, la biopsie musculaire confirme le diagnostic de myopathie mitochondriale et l’analyse moleculaire detecte une deletion nucleotidique de l’ADN mitochondrial. Conclusion En cas de doute diagnostique, la biopsie musculaire est licite. Le traitement anticholinesterasique doit toujours etre instaure sous surveillance medicale etroite. Un traitement par coenzyme Q a pu etre propose dans les cytopathies par certaines equipes.