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International audience; Spinal muscular atrophy type 1 (SMA-1) is a severe neurodegenerative disorder, which in the absence of curative treatment, leads to death before 1 year of age in most cases. Caring for these short-lived and severely impaired infants requires palliative management. New drugs (nusinersen) have recently been developed that may modify SMA-1 natural history and thus raise ethical concerns about the appropriate level of care for patients. The national Hospital Clinical Research Program (PHRC) called "Assessment of clinical practices of palliative care in children with Spinal Muscular Atrophy Type 1 (SMA-1)" was a multicenter prospective study conducted in France between 2012 and 2016 to report palliative practices in SMA-1 in real life through prospective caregivers' reports about their infants' management. Thirty-nine patients were included in the prospective PHRC (17 centers). We also studied retrospective data regarding management of 43 other SMA-1 patients (18 centers) over the same period, including seven treated with nusinersen, in comparison with historical data from 222 patients previously published over two periods of 10 years (1989-2009). In the latest period studied, median age at diagnosis was 3 months [0.6-10.4]. Seventy-seven patients died at a median 6 months of age[1-27]: 32% at home and 8% in an intensive care unit. Eighty-five percent of patients received enteral nutrition, some through a gastrostomy (6%). Sixteen percent had a non-invasive ventilation (NIV). Seventy-seven percent received sedative treatment at the time of death. Over time, palliative management occurred more frequently at home with increased levels of technical supportive care (enteral nutrition, oxygenotherapy, and analgesic and sedative treatments). No statistical difference was found between the prospective and retrospective patients for the last period. However, significant differences were found between patients treated with nusinersen vs. those untreated. Our data confirm that palliative care is essential in management of SMA-1 patients and that parents are extensively involved in everyday patient care. Our data suggest that nusinersen treatment was accompanied by significantly more invasive supportive care, indicating that a re-examination of standard clinical practices should explicitly consider what treatment pathways are in infants' and caregivers' best interest. This study was registered on clinicaltrials.gov under the reference NCT01862042 (https://clinicaltrials.gov/ct2/show/study/NCT01862042?cond=SMA1&rank=8).

Introduction Necrotizing autoimmune myopathies (NAMs) are acquired myopathies with myofibrillar necrosis and weak or absent inflammatory component, sometimes associated with anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. Observation The patient, a girl now aged 20 years, was first assessed at the age of 5 years for abnormal gait revealing frank pelvic deficit. Creatine kinase (CK) levels were as high as 7,500 IU/L. Subsequent muscle biopsy showed some necrosis, fiber regeneration, and fibrosis consistent with muscular dystrophy (MD). Protein immunohistochemistry was normal. The disease course was progressive until wheelchair use at the age of 9 years. At 12 years of age, a second muscle biopsy found an advanced MD with some perivascular inflammatory mononuclear cells. All molecular analyses done through 14 years of follow-up were negative till anti-HMGCR antibodies were detected at a significant amount when she was 19 years old. Discussion NAMs begin at a pediatric age and may have a chronic course mimicking MDs. Muscular biopsy can be misleading with a predominantly dystrophic pattern without inflammation. Conclusion This observation should prompt the assessment of NAMs in all MDs, even pediatric, without molecular solutions.

In 2005, the French law on patients' rights at the end of life required that decisions to withdraw or withhold life-sustaining treatments be made and carried out by the physician in charge of the patient, after obtaining advice from an independent consulting colleague and the caregiving team. The purpose of this study was to identify theoretical and practical obstacles to this collaborative deliberation and to propose practical guidelines to organize it.

Resume L’encephalite auto-immune a anticorps antirecepteurs au N-Methyl-D-Aspartate (NMDA) est une atteinte grave du systeme nerveux central, encore peu connue des cliniciens, pouvant etre a l’origine de symptomes psychiatriques frustres comportant des symptomes psychotiques ou catatoniques. Nous rapportons ici le cas d’une jeune fille de 15 ans, sans antecedent personnel notable, hospitalisee pour decompensation psychotique de debut brutal, rapidement compliquee d’une catatonie agitee puis stuporeuse, repondant insuffisamment au traitement par benzodiazepines. Le diagnostic d’encephalite a anticorps anti-RNMDA a pu etre confirme par le dosage des auto-anticorps dans le liquide cephalorachidien (LCR). L’evolution sera favorable sous corticoides et immunosuppresseurs. Nous proposons a l’issue de ce cas, une mise au point sur l’encephalite a auto-anticorps anti-RNMDA et sur l’hypothese d’un desequilibre de la balance excitation/inhibition a l’origine de la catatonie.

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Pulmonary function loss in patients with Duchenne muscular dystrophy (DMD) is progressive and leads to pulmonary insufficiency. The purpose of this study in 10-18 year old patients with DMD is the assessment of the inter-correlation between pulmonary function tests (PFTs), their reliability and the association with the general disease stage measured by the Brooke score. Dynamic PFTs (peak expiratory flow [PEF], forced vital capacity [FVC], forced expiratory volume in one second [FEV1]) and maximum static airway pressures (MIP, MEP) were prospectively collected from 64 DMD patients enrolled in the DELOS trial (ClinicalTrials.gov, number NCT01027884). Baseline PEF percent predicted (PEF%p) was

Resume Etat actuel du probleme La place des soins palliatifs dans des pathologies neurodegeneratives de l’enfant a conduit la commission neuromusculaire de la Societe francaise de neuropediatrie a realiser une enquete a propos de l’amyotrophie spinale de type 1, pathologie genetique neuromusculaire le plus souvent lethale avant l’âge de 1 an. Materiel et methode Une enquete retrospective multicentrique aupres de neuropediatres integres dans des centres de reference des maladies neuromusculaires pediatriques a ete realisee sur deux periodes de 10 ans (1989–1998 et 1999–2009). Resultats La periode (1989–1998) avait inclus 12 centres avec 106 patients, la periode (1999–2009), 13 centres avec 116 enfants. La comparaison des donnees des deux periodes a revele une histoire naturelle de la maladie comparable : âge moyen d’apparition des premiers signes cliniques de 2,1 mois [0–5,5 mois], âge median au diagnostic de 4 mois [0–9 mois] versus (vs) 3 mois, âge median de deces de 7,5 mois [0–24 mois] vs 6 mois. Les modalites de soins avaient evolue avec des soins devenus plus actifs : kinesitherapie motrice (90 %), kinesitherapie respiratoire (93 %), les installations de confort (61 % vs 26 %), nutrition enterale par sonde gastrique (54 % vs 24 %). Les aides respiratoires au domicile etaient plus utilisees dans la seconde periode : aspiration nasopharyngee dans 64 % des cas (vs 41 %), oxygene dans 8 % et ventilation non invasive dans 7 %. Le delai moyen entre le diagnostic et le deces etait reste tres court : 4 mois vs 3 mois. Le deces avait eu lieu au domicile dans 23 % vs 17 % et dans un service de pediatrie pour 62 % vs 41 %. L’usage de traitements antalgiques et sedatifs au moment du deces etait rapporte dans 60 % des cas : morphiniques 40 % (vs 18 %), benzodiazepines 48 % (vs 29 %). Au moment du deces, le support respiratoire etait variable : oxygenotherapie (55 %), ventilation non invasive (9 %), ventilation mecanique assistee (2 %). Discussion et conclusion Ces resultats confirment une evolution de nos pratiques et le developpement des soins palliatifs chez l’enfant avec des positions differentes des standards de soins nord-americains et plus proches de la reflexion des equipes anglosaxonnes. Une etude prospective dans le cadre d’un Programme hospitalier de recherche clinique (PHRC) national 2011 a debute en juin 2012 impliquant les familles dans l’evaluation de ses soins.

Background Juvenile dermatomyositis (JDM) is the main cause of chronic idiopathic inflammatory myopathy of autoimmune origin in children. The aim of this multicenter prospective study was to describe respiratory status and treatment of children followed for JDM. Methods and patients Clinical manifestations, pulmonary function tests (PFT), chest high-resolution computed tomography (HRCT) scan results, and treatments and their adverse effects were analyzed in children followed for JDM. Results Twenty-one patients (median age: 9.9 years; range: 20 months–18 years) were included. The median of disease duration at the time of the analysis was 3 years (range: 6 months–9 years 4 months). Overall 16 (76%) of 21 children presented with a respiratory involvement related to JDM including interstitial lung disease (n = 3) and/or respiratory muscle involvement (n = 7). Seven patients presented with other nonspecific manifestations. Three children had aspiration pneumonia. A chest HRCT was performed in 15 children, and abnormalities were observed in 12. PFT were performed in 20 of 21 patients. Seven showed functional abnormalities: restrictive ventilatory defect (n = 3) or obstructive ventilatory defect (n = 4). Six patients had abnormal respiratory muscle tests, including three with a restrictive ventilatory defect and one with an obstructive ventilatory defect. One other child with an acute aspiration pneumonia had a clearly muscle respiratory involvement but was too young to perform respiratory muscle tests and confirm this diagnosis. Treatment comprised systemic corticosteroid for all patients and adjuvant immunosuppressive therapy for 11. Adverse effects linked to treatment were reported in eight patients. Conclusion The frequency of lung involvement in children with JDM justifies systematic respiratory assessment with PFT including measures of respiratory muscle strength. We suggest that a chest HRCT scan is indicated in cases of respiratory symptoms and/or PFT abnormalities. Longitudinal studies are needed to assess pediatric characteristics, long-term outcomes, and responses to treatment taking into account the risk–benefit ratio. Pediatr Pulmonol. 2013; 48:1016–1025. © 2012 Wiley Periodicals, Inc.

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Aim To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1). Method Twenty-eight individuals (15 females, 13 males) with childhood DM1 (mean age 17y, SD 4.6, range 7–24y) were assessed using standardized instruments and cognitive testing of general intelligence, visual attention, and visual–spatial construction abilities. Results Nineteen patients had repeated a school grade. The mean (SD) Full-scale IQ was 73.6 (17.5) and mean Verbal IQ was significantly higher than the mean Performance IQ: 80.2 (19.22) versus 72.95 (15.58), p=0.01. Fifteen patients had one or more diagnoses on the DSM-IV axis 1, including internalizing disorders (phobia, n=7; mood disorder, n=6; other anxiety disorders, n=5) and attention-deficit–hyperactivity disorder, inattentive subtype (n=8). Twelve out of 22 patients had alexithymia (inability to express feelings with words and to recognize and share emotional states). Cognitive testing found severe impairments in visual attention and visual–spatial construction abilities in four out of 18, and 14 out of 24 patients respectively. No diagnosis was correlated with the transmitting parent’s sex or with cytosine–thymine–guanine (CTG) repeat numbers. Patients with severe visual–spatial construction disabilities had a significantly longer CTG expansion size than those with normal visual–spatial abilities (p=0.04). Interpretation Children and adolescents with childhood DM1 have frequent diagnoses on DSM-IV axis 1, with internalizing disorders being the most common type of disorder. They also have borderline low intelligence and frequent impairments in attention and visual–spatial construction abilities.

The dystrophin gene involved in Duchenne and Becker muscular dystrophy is expressed in three main tissues resulting in clinical manifestations: skeletal muscle, heart and central nervous system. The 6 different existing dystrophins in the brain may play a role in the maturation and plasticity of neuronal synapses in particular by their functions in clustering and stabilization of different receptors at the post synaptic membrane. The possibility of an intellectual deficiency in Duchenne muscular dystrophy is known from the original description by Duchenne himself. Current data are in line with a constant cognitive impairment with a Gaussian curve shifted intellectual quotient (IQ) at -1 standard deviation from the standard population with an average IQ around 80. Clinical manifestations suggestive of a central nervous system involvement can affect all dystrophinopathies, including isolated central presentations without myopathic sign. The phenotypic spectrum appears broader and more subtle than non specific intellectual deficiency. The isolated or shared involvement of specific cognitive functions is possible (memory functions, executive functions, attention) with or without intellectual deficiency. Autism spectrum disorders are also among the encountered events. In clinical practice, it seems worth to ask for a measurement of serum creatine kinase (CK) in these different situations, keeping in mind that pure forms of central dystrophinopathies with a normal CK level have been recently reported.

Gastrointestinal symptoms are very frequent in myotonic dystrophy but largely unrecognized. They can be the revealing factors of the disease. We report 2 cases of 10 and 17-year-old children with persistent encopresis starting at the age of 3 and 5 years in spite of laxative treatment. Neurological examination and anorectal manometry provided the diagnosis of myotonic dystrophy. Procainamide treatment was introduced and the digestive symptoms improved. Any child with encopresis should have complete evaluation to rule out the diagnosis of myotonic dystrophy and physicians should look for upper and/or lower gastrointestinal symptoms in every patient with myotonic dystrophy.

Chronic daily headache (CDH) affects 2-4% of adolescent females and 0.8-2% of adolescent males. Chronic daily headache is diagnosed when headaches occur more than 4h/day, 15 headache days per month or more, over a period of 3 consecutive months, without an underlying pathology. It is manifested by severe intermittent, migraine-like headaches as well as by chronic baseline headaches. Both Silberstein-Lipton criteria and the second edition of the International Classification of Headache Disorders (ICHD) can be used to classify chronic daily headache in children and adolescents. Chronic daily headache is classified into four diagnostic categories: transformed (Silberstein-Lipton criteria)/chronic (ICHD) migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Children and adolescents with chronic daily headache frequently have sleep disturbance, pain at other sites, dizziness, medication-overuse headache, and a psychiatric comorbidity (anxiety and mood disorders). Chronic daily headache frequently results in school absence. Successful approaches to treatment include reassurance, education, use of preventative medication, avoidance of analgesics, and helping the child return to a functional daily routine and a regular school schedule.

Spinal Muscular Atrophies (SMA) are a group of degenerative diseases primarily affecting the anterior horn cells of the spinal cord and resulting in muscle weakness and atrophy. Diagnostic criteria were proposed by the International SMA Consortium (ISMAC) to differentiate“classical” proximal SMA caused by homozygous deletion or conversion of the SMN1 gene (5q13) from atypical SMA unlinked to chromosome 5q (non-5q-SMA entities). The aim of our study was to emphasize the unusual clinical features encountered in infantile SMA. Patients and methods: We retrospectively analyzed 63 children with SMA hospitalized between 1985 and 2006. Results: Forty-eight children suffered from classical SMA and 15 from atypical SMA, including 4 distal SMA, 2 scapuloperoneal SMA, one pontocerebellar hypoplasia type I, 7 neurogenic arthrogryposis multiplex congenita (2 of them associated with a central nervous system (CNS) involvement) and one undetermined case. Conclusion: This study confirmed the clinical variety of proximal SMA and put in perspective some exclusion criteria (CNS involvement, phrenic or facial palsy). Some symptoms allowed us to anticipate the normality of the SMN1 gene : improvement of motor condition, distal predominance and, more relatively, assymetry of motor weakness. Diagnosis difficulties were especially encountered in case of predominant distal deficit, arthrogryposis multiplex congenita and associated clinical abnormalities. Detailed phenotypical description and syndromic regrouping of cases of atypical SMA lead to a better understanding of underlying physiopathological processes and to the identification of other genes involved in infantile SMA.

International audience

We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of 'cap myopathy'. This case report suggests that 'cap myopathy' and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as 'Z-line disorders' possibly caused by defective myofibrillogenesis.

Autism is defined by 3 main criteria: disturbance of reciprocal social interaction, disturbance of communication (including language comprehension and spoken language) and disturbance of normal variation in behaviour and imaginative activities; an onset before age 36 months is also required. The neuropediatric contribution to autism is dominated by the search for an underlying organic etiology, especially if there are arguments for an associated encephalopathy: ante- or perinatal medical history, dysmorphic signs, skin spots, neurological abnormalities, somatic abnormalities compatible with a neurometabolic disorder. The main associated conditions with autism are: chromosome anomalies, monogenic syndrome (including fragile X syndrome), neurocutaneous syndromes, epileptic encephalopathies, neurometabolic diseases, and dystrophinopathies. The identification of an associated medical condition to autism is primordial in prospect of genetic counselling, and by the change induced in familial perception of autism.

Although the majority (65%) of boys with Duchenne muscular dystrophy (DMD) carry a deletion in the dystrophin gene, finding mutations in the remaining families is vital for counselling. We have provided a comprehensive mutation service as a national referral centre for France for over 10 years and we report here our experience. Mutation screening is on mRNA from a muscle biopsy. We have detected 79 mutations in 89 samples referred with a diagnosis of DMD, which is the most comprehensive survey to date of the full range of nondeletion mutations. Although some mutations were nonsense mutations, some frameshift mutations and some splicing mutations, all of them led to the generation of premature stop codons or a shortened product which could be detected using the Protein Truncation Test. We recommend a protocol which is robust and sensitive applied to the entire coding region reverse-transcribed from dystrophin transcripts from muscle biopsy.

In the course of a mutation search performed by muscle dystrophin transcript analysis in 72 Duchenne and Becker Muscular Dystrophies (DMD/BMD) patients without gross gene defect, we encountered four unrelated cases with additional out-of-frame sequences precisely intercalated between two intact exons of the mature muscle dystrophin mRNA. An in silico search of the whole dystrophin genomic sequence revealed that these inserts correspond to cryptic exons flanked by one strong and one weak consensus splice site and located in the mid-part of large introns (introns 60, 9, 1M, and 62, respectively). In each case we identified an intronic point mutation activating the cryptic donor or acceptor splice site. The patients exhibited a BMD/intermediate phenotype consistent with the presence of reduced amounts of normally spliced transcript and normal dystrophin. The frequency of this new type of mutation is not negligible (6% of our series of 65 patients with ‘small’ mutations). It would be missed if the exploration of the DMD gene is exclusively performed on exons and flanking sequences of genomic DNA.

International audience

X-linked myotubular myopathy (XLMTM) is the most severe form of centronuclear myopathy affecting approximately 1 in 50,000 male newborns. Phenotype varies from mild to severe. Several cases of affected females are also reported.presently, there is no effective treatment for the muscle weakness in XLMTM patients. Several promising strategies, including protein replacement therapy and gene therapy, are currently in development.due to the variability of the phenotype, it is important to determine the best outcome measure to assess the efficacy of potential therapies and the prognostic factors for the disease. We present here a prospective study of the pathophysiology of XLMTM to characterize the disease course by using standardized evaluations. A total of 60 patients with XLMTM, male or symptomatic female of any age, are planned to be enrolled in North America and Europe. Visit frequency and assessments are adjusted to age, ambulatory and respiratory status. Evaluations include standard liver ultrasound, clinical exam, ophthalmoplegia assessment, pulmonary function tests, strength and motor function assessment by using upper limb-specific devices and common scales, six-minute walk test, activity monitoring using the Actimyo device and quality of life assessment. Blood samples are collected to test immunization against AAV and to quantify MTM1 protein level. Urinary creatinine excretion is assessed every 6 months. Data from the patients’ usual follow-up care are collected from their medical files including psychomotor development, respiratory, cardiac, hematology kidney and liver functions, feeding status and ophthalmologic assessment. According to the weakness of the patient, if needed, the assessments by a physiotherapist can be performed at home. The obtained data will help to characterize the course of disease and the disease spectrum of XLMTM and may help to empower future therapeutic studies as well as to eventually substitute for placebo groups.

The authors report a 5-year follow-up examination of two sisters diagnosed as having a juvenile form of type II sialidosis. Diagnosis occurred during a routine ophthalmic examination when the girls were 5 and 3 years old after bilateral macular cherry-red spots were revealed. Main clinical findings were hypotonia, hepatosplenomegaly, hearing loss, dysostosis, and respiratory distress. Ophthalmic symptoms were low visual acuity and nystagmus. Spectral-domain optical coherence tomography examination showed increased reflectivity of the retinal ganglion cells. Sialidosis may present as a mild form with slow progression. The cherry-red spots may be the first clue for proper diagnosis of storage disease. Spectral-domain optical coherence tomography examination unveiled the accumulation of sialic acid in the retinal ganglion cells and could potentially be used to monitor the progression of storage diseases. [J Pediatr Ophthalmol Strabismus 2013;50:e33–e36.]

Olesoxime (TRO19622) was identified as a potential treatment of SMA based on its beneficial effects in multiple preclinical neurodegeneration models. Olesoxime promotes neuron survival, neurite outgrowth, recovery from nerve injury and accelerates myelination or remyelination in models of demyelinating diseases. Maintaining motor neuron architecture and survival is highly relevant to SMA, a disease associated with progressive motor neuron compromise mainly affecting neuromuscular function. A clinical study has been performed to evaluate the effects of olesoxime treatment in patients with spinal muscular atrophy (SMA). 165 type 2 or non-ambulant type 3 SMA patients, aged 3–25 years old were enrolled from 22 sites in 7 European countries beginning in November 2010. Patients were randomized to olesoxime, 10 mg/kg, administered as a liquid oral formulation or matching placebo in a 2:1 ratio and treatment duration was for 104 weeks. The last patient completed the study in October 2013. The primary outcome measure was the change in motor function using the MFM scale. The secondary outcome measures included the HFMS for SMA, electromyography, pulmonary function, and patient-reported outcomes as well as safety. Patients in the placebo arm of the study experienced a loss of motor function at a similar rate to that previously reported (Vuillerot et al. 2013). This loss of function, assessed as the primary endpoint, was prevented for two years in olesoxime-treated patients, with fewer disease-related adverse events. Other secondary endpoints were consistent with these effects. Results from this pivotal double blind placebo-controlled clinical trial provide clinical proof of concept of olesoxime’s neuroprotective effect that is sustained over two years. This combined with fewer adverse events caused by the disease itself will be submitted for the registration of olesoxime as the first neuroprotection treatment for SMA.

CAP-disease is a rare congenital myopathy characterized by the presence of demarcated areas of subsarcolemmal myofibrillar disorganization that are devoid of myosin ATPase, stained with NADH-TR and strongly immunolabeled for desmin. Mutations in ACTA1, TPM2 or TPM3 have been reported so far. We report on 5 cases: 1 sporadic severe case and four patients from 2 families, respectively. In family 1 mother and daughter were affected; in family 2, two siblings manifested the disease. Mutations in the three documented genes were excluded. Age at onset ranged from birth to childhood. The main clinical phenotype consisted of clear dysmorphic features with elongated face and high-arched palate associated with axial, lower and upper limbs muscle weakness. The most severe cases presented early respiratory distress, and feeding difficulties. One patient had arthrogryposis. Muscle biopsies performed at different ages (from newborn to adult age) showed severe changes with marked variation of fiber size, increased internal nuclei, and type I fiber predominance. Several fibers contained a variable number of CAP in subsarcolemal areas. By electron microscopy, well-delineated CAP structures were constantly encountered. These showed disorganization of myofibrils, loss of thick filaments, and thickened fragments of Z bands without nemaline rod bodies. CAP contained segments of sarcomeres constituted by fragments of Z-lines from where arising thin filaments (”butterfly-like” aspect). Furthermore dense thin filamentous material was found in the subsarcolemmal region and less frequently between the myofibrils. In longitudinal sections, the Z lines appeared occasionally jagged and partially misaligned in some myofibrils. No basal membrane abnormalities were observed. To identify the causative mutation whole exome sequencing is ongoing. In conclusion, we attempt to characterize the clinical and morphological particularities of five cases presenting CAP disease, not-related to known genes.

Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluate efficacy of new treatments in non-ambulant patients. Adequate outcome measures are scarce for patients who have lost ambulation. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures on a short term period are lacking. We report here the results of a one-year multicenter study using specifically designed tools to assess grip and key pinch strength and hand function in wheelchair bound patients. Our study recruited 53 non-ambulant patients with Duchenne muscular atrophy aged 17.1 ± 4.8 years (range: 9–28.1 years). The Brooke functional score was 4.6 ± 1.1. The average forced vital capacity was 44.5 % and nineteen patients used non-invasive ventilation. Patients were assessed at baseline, 6 months and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of MyoGrip, MyoPinch and MoviPlate). Our study confirmed the preliminary data previously reported regarding feasibility, reliability of the MyoSet and correlation between the distal strength and clinical variables. We demonstrated that the use of sensitive dynamometers could capture a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages.

Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that skip exon 51, 44, 45, and 53 are currently evaluated in clinical trials. Knowing the precise phenotype of potentially eligible patients is important for designing the clinical trials. It is generally believed that there are few if any phenotypic differences between these different groups of patients or between these patients and the general DMD population. In preparation of exon 53 skipping mediated by an AAV8 construct, we recruited 24 patients aged from 6 to 20 years in an observational study of upper limb strength and function, using the Motor Function Measure (MFM), the Myogrip, the MyoPinch and the MoviPlate, three tools already validated in a large non ambulant DMD population. Data of 14 non ambulant DMD patients (13.8 ± 2.7 years) at inclusion were compared with 14 age and size-matched DMD controls (13.7 ± 2.6 years) with all types of mutation. DMD 53 patients scored significantly lower in the MFM (D3: 66 ± 17% vs. 82 ± 13% for DMD 53 vs. DMD control), had significant lower handgrip and key pinch strength on both hands. They had lost ambulation 13 months earlier (Age: 105 ± 20 vs. 118 ± 19 p = 0.04 for DMD 53 vs. DMD control). In order to rule out that this is due to a selection bias, we compared DMD 53 patients with other DMD patients carrying a deletion not involving the 45–55 region and looked at DMD patient cohort identified at the Cochin hospital’s routine diagnostic laboratory. We found that 91 DMD ex53 patients had lost ambulation at 108 ± 15 months, whilst other 400 non 45–55 DMD patients with a deletion had lost ambulation at 139 ± 54 months. Taken together, these preliminary data demonstrate that non-ambulant patients treatable by exon 53 skipping present a more severe phenotype than the general DMD population. This must be taken into account in the design of studies concerning this population.

Spinal muscular atrophy (SMA) is recessive hereditary disease of the anterior horn cells caused by deletions or mutations of the SMN1 gene. The loss of muscle strength and function in these patients is gradual. The assessment of the upper limbs in non-ambulant neuromuscular patients remains a challenge and data is even scarcer for SMA patients. Our study recruited a total of 23 non-ambulant SMA patients: 12 SMA type II (4 males/8 females) and 11 SMA type III (4 males/7 females) with an average age of 17.08 ± 6.5 (17.11 for SMA II and 17.05 for SMA III). The follow-up was at 6 months and at 1 year and consisted of strength and function evaluation. We used newly designed tools to precisely assess pinch (MyoPinch), grip (MyoGrip) and to assess the flexion/extension movements of wrist and fingers (MoviPlate). Existing measures, such as Motor Function Measure, Tapping, and the Brooke Upper Extremity Functional Rating Scale were also performed. Five patients prematurely terminated the study (one was lost to follow-up, two refused to continue and 2 for other reasons). The Brooke score of the patients was on average 3,7. The median total vital capacity was 45,5% and seven patients were non-invasively ventilated at night. Results demonstrated that assessments were feasible in nearly all upper limbs tested for MyoGrip, MyoPinch and MoviPlate. The results showed better scores of the upper limbs in function than strength. This study demonstrates the feasibility of a panel of upper limb muscle strength and function measures for Spinal Muscular atrophy which can be applied even to extremely weak patients.