[Show abstract][Hide abstract] ABSTRACT: Assessment of the upper limb strength in non-ambulant neuromuscular patients remains challenging. Although potential outcome measures have been reported, longitudinal data demonstrating sensitivity to clinical evolution in spinal muscular atrophy patients are critically lacking. Our study recruited 23 non-ambulant patients, 16 patients (males/females = 6/10; median age 15.4 years with a range from 10.7 to 31.1 years) with spinal muscular atrophy type II and 7 patients (males/females = 2/5; median age 19.9 years with a range from 8.3 to 29.9 years) with type III. The Brooke functional score was on median 3 with a range from 2 to 6. The average total vital capacity was 46%, and seven patients required non-invasive ventilation at night. Patients were assessed at baseline, 6 months, and 1 year using the Motor Function Measure and innovative devices MyoGrip, MyoPinch, and MoviPlate, which assess handgrip strength, key pinch strength, and hand/finger extension-flexion function, respectively. The study demonstrated the feasibility and reliability of these measures for all patients, and sensitivity to negative changes after the age of 14 years. The younger patients showed an increase of the distal force in the follow-up period. The distal force measurements and function were correlated to different functional scales. These data represent an important step in the process of validating these devices as potential outcome measures for future clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluations of efficacy of new treatments in non-ambulant patients. In patients who have lost ambulation, there are few validated and informative outcome measures. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures over short-term periods are lacking.
We report here the results of a one-year multicenter study using specifically designed tools to assess grip, pinch strength, and hand function in wheelchair-bound patients. Our study assessed 53 non-ambulant patients with Duchenne muscular dystrophy aged 17.1 ± 4.8 years (range: 9 - 28.1 years). The average Brooke functional score of these patients was 4.6 ± 1.1. The average forced vital capacity was 44.5% predicted and 19 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 preliminary data previously reported regarding feasibility of use and of reliability of the MyoSet and the correlation at baseline between distal strength and clinical outcomes such as FVC, Brooke score, age, and duration since loss of ambulation. A significant correlation was observed between the distal upper limb strength and clinical variables. The sensitive dynamometers (MyoGrip and MyoPinch) and MoviPlate captured a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages.
ClinicalTrials.gov NCT00993161 NCT00993161.
[Show abstract][Hide abstract] ABSTRACT: The mechanisms underlying cell response to mechanical forces are critical for muscle development and functionality. We aim to determine whether mutations of the LMNA gene causing congenital muscular dystrophy impair the ability of muscle precursors to sense tissue stiffness and to respond to mechanical challenge. We found that LMNA-mutated myoblasts (LMNA) embedded in soft matrix did not align along the gel axis whereas control myoblasts did. LMNA myoblasts were unable to tune their cytoskeletal tension to the tissue stiffness as attested by inappropriate cell-matrix adhesion sites and cytoskeletal tension in soft versus rigid substrates or after mechanical challenge. Importantly, in soft 2D and/or static 3D conditions, LMNA myoblasts demonstrated enhanced activation of Yes-Associated Protein (YAP) signaling pathway that was paradoxically reduced after cyclic stretch. SiRNA-mediated downregulation of YAP reduced adhesion and actin stress fibers in LMNA myoblasts. This is the first demonstration that human myoblasts with LMNA mutations have mechanosensing defects through a YAP-dependent pathway. In addition, our data emphasize the crucial role of biophysical attributes of cellular microenvironment to the response of mechanosensing pathways in lamin A/C mutated myoblasts.
Full-text · Article · May 2014 · Journal of Cell Science
[Show abstract][Hide abstract] ABSTRACT: Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy (NM), cap myopathy, core-rod myopathy, congenital fibre-type disproportion, distal arthrogryposes and Escobar syndrome. We correlate the clinical picture of these diseases with novel (16) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Twenty-seven distinct pathogenic variants of TPM2, and 20 of TPM3, have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca(2+) sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with non-hypercontractile ones (2/22 and 1/22), while patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to identify daytime predictors of nocturnal gas exchange anomalies in children with neuromuscular disease (NMD) and normal daytime gas exchange. Lung function tests, respiratory muscle evaluation and nocturnal gas exchange were obtained as part of routine evaluation. We included 52 consecutive children with Duchenne muscular dystrophy (n = 20), spinal muscular atrophy (n = 10) and other NMD (n = 22). 20 patients had nocturnal hypoxaemia, defined as minimal arterial oxygen saturation measured by pulse oximetry (S(p,O(2))) <90% for ≥ 2% of night time, and 22 had nocturnal hypercapnia, defined as maximal transcutaneous carbon dioxide tension (P(tc,CO(2))) >50 mmHg for ≥ 2% of night time. Forced vital capacity and helium functional residual capacity correlated with minimal nocturnal S(p,O(2)) (p = 0.009 and p = 0.01, respectively). Daytime pH correlated negatively with maximal nocturnal P(tc,CO(2)) (p=0.005) and daytime arterial carbon dioxide tension (P(a,CO(2))) correlated with the percentage of time with a P(tc,CO(2)) >50 mmHg (p = 0.02). Sniff nasal inspiratory pressure correlated with minimal nocturnal S(p,O(2)) (p = 0.02). Daytime P(a,CO(2)) was a weak predictor of nocturnal hypercapnia (sensitivity 80%; specificity 57%). Daytime lung function and respiratory muscle parameters correlate poorly with nocturnal hypoxaemia and hypercapnia in children with NMD and normal daytime gas exchange, which necessitates more systematic sleep studies in these children.
Preview · Article · Dec 2011 · European Respiratory Journal
[Show abstract][Hide abstract] ABSTRACT: The life expectancy of patients with Duchenne muscular dystrophy (DMD) has increased. A cross-sectional study of DMD patients showed that 54 % of 13-year-old patients are obese and that 54 % of 18-year-old patients are underweight. We aimed to describe the natural evolution of weight status in DMD. This retrospective multi-centre audit collected body-weight measurements for seventy DMD patients born before 1992. The body-weight:age ratio (W:A) was used to evaluate weight status in reference to the Griffiths and Edwards chart. At the age of 13 years, 73 % were obese and 4 % were underweight. At maximal follow-up (age 15-26 years, mean 18·3 (sd 2·3) years), 47 % were obese and 34 % were underweight. Obesity at the age of 13 years was associated with later obesity, whereas normal weight status and underweight in 13-year-old patients predicted later underweight. A W:A ≥ 151 % in 13-year-old patients predicted later obesity, and a W:A ≤ 126·5 % predicted later underweight. Our audit provides the first longitudinal information about the spontaneous outcome of weight status in DMD. Patients (13 years old) with a W:A ≥ 151 % were more likely to become obese in late adolescence, but obesity prevented later underweight. These data suggest that mild obesity in 13-year-old DMD patients (W:A between 120 and 150 %) should not be discouraged because it prevents later underweight.
Full-text · Article · May 2011 · The British journal of nutrition
[Show abstract][Hide abstract] ABSTRACT: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations.
Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA.
ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation).
This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials.
Full-text · Article · Oct 2010 · Annals of Neurology
[Show abstract][Hide abstract] ABSTRACT: Mutations in dynamin-2 (DNM2) cause autosomal dominant centronuclear myopathy (CNM). We report a series of 12 patients from eight families with CNM in whom we have identified a number of novel features that expand the reported clinicopathological phenotype. We identified two novel and five recurrent missense mutations in DNM2. Early clues to the diagnosis include relative weakness of neck flexors, external ophthalmoplegia and ptosis, although these are not present in all patients. Pes cavus was present in two patients, and in another two members of one family there was mild slowing of nerve conduction velocities. Whole-body MRI examination in two children and one adult revealed a similar pattern of involvement of selective muscles in head (lateral pterygoids), neck (extensors), trunk (paraspinal) and upper limbs (deep muscles of forearm). Findings in lower limbs and pelvic region were similar to that previously reported in adults with DNM2 mutations. Two patients presented with dystrophic changes as the predominant pathological feature on muscle biopsies; one of whom had a moderately raised creatine kinase, and both patients were initially diagnosed as congenital muscular dystrophy. DNM2 mutation analysis should be considered in patients with a suggestive clinical phenotype despite atypical histopathology, and MRI findings can be used to guide genetic testing. Subtle neuropathic features in some patients suggest an overlap with the DNM2 neuropathy phenotype. Missense mutations in the C-terminal region of the PH domain appear to be associated with a more severe clinical phenotype evident from infancy.
Full-text · Article · Mar 2010 · Neuromuscular Disorders
[Show abstract][Hide abstract] ABSTRACT: The presence of variable degrees of cognitive impairment, extending from severe mental retardation to specific deficits, in patients with dystrophinopathies is a well-recognized problem. However, molecular basis underlying mental retardation and its severity remain poorly understood and still a matter of debate. Here, we report one of the largest study based on the comparison of clinical, cognitive, molecular and expression data in a large cohort of 81 patients affected with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) bearing mutations predicted to affect either all dystrophin products, including Dp71 or all dystrophin products, except Dp71. In addition to the consistent data defining molecular basis underlying mental retardation in DMD, we show that BMD patients with MR have mutations that significantly affect Dp71 expression or with mutations located in exons 75 and 76. We also show that mutations upstream to exon 62, with DMD phenotype, predicted to lead to a loss-of-function of all dystrophin products, except Dp71 isoform, are associated, predominantly, with normal or borderline cognitive performances. Altogether, these reliable phenotype-genotype correlations in combination with Dp71 mRNA and protein expression studies, strongly indicate that loss-of-function of all dystrophin products is systematically associated with severe form of MR, and Dp71 deficit is a factor that contributes in the severity of MR and may account for a shift of 2 SD downward of the intelligence quotient.
Full-text · Article · Aug 2009 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: To explore clinical heterogeneity of Duchenne muscular dystrophy (DMD), viewed as a major obstacle to the interpretation of therapeutic trials
A retrospective single institution long-term follow-up study was carried out in DMD patients with both complete lack of muscle dystrophin and genotyping. An exploratory series (series 1) was used to assess phenotypic heterogeneity and to identify early criteria predicting future outcome; it included 75 consecutive steroid-free patients, longitudinally evaluated for motor, respiratory, cardiac and cognitive functions (median follow-up: 10.5 yrs). A validation series (series 2) was used to test robustness of the selected predictive criteria; it included 34 more routinely evaluated patients (age>12 yrs). Multivariate analysis of series 1 classified 70/75 patients into 4 clusters with distinctive intellectual and motor outcomes: A (early infantile DMD, 20%): severe intellectual and motor outcomes; B (classical DMD, 28%): intermediate intellectual and poor motor outcome; C (moderate pure motor DMD, 22%): normal intelligence and delayed motor impairment; and D (severe pure motor DMD, 30%): normal intelligence and poor motor outcome. Group A patients had the most severe respiratory and cardiac involvement. Frequency of mutations upstream to exon 30 increased from group A to D, but genotype/phenotype correlations were restricted to cognition (IQ>71: OR 7.7, 95%CI 1.6-20.4, p<0.003). Diagnostic accuracy tests showed that combination of "clinical onset <2 yrs" with "mental retardation" reliably assigned patients to group A (sensitivity 0.93, specificity 0.98). Combination of "lower limb MMT score>6 at 8 yrs" with "normal or borderline mental status" reliably assigned patients to group C (sensitivity: 1, specificity: 0.94). These criteria were also predictive of "early infantile DMD" and "moderate pure motor DMD" in series 2.
DMD can be divided into 4 sub-phenotypes differing by severity of muscle and brain dysfunction. Simple early criteria can be used to include patients with similar outcomes in future therapeutic trials.
[Show abstract][Hide abstract] ABSTRACT: We report four heterozygous dynamin 2 (DNM2) mutations in five centronuclear myopathy patients aged 1 to 15 years. They all presented with neonatal hypotonia with weak suckling. Thereafter, their phenotype progressively improved. All patients demonstrated muscle weakness prominent in the lower limbs, and most of them also presented with facial weakness, open mouth, arched palate, ptosis, and ophthalmoparesis. Electrophysiology showed only myopathic changes, and muscle biopsies showed central nuclei and type 1 fiber hypotrophy and predominance. Our results expand the phenotypic spectrum of dynamin 2-related centronuclear myopathy from the classic mild form to the more severe neonatal phenotype.
Full-text · Article · Dec 2007 · Annals of Neurology
[Show abstract][Hide abstract] ABSTRACT: FKRP mutations cause a muscular dystrophy which may present in the neonatal period (MDC1C) or later in life (LGMD2I). Intelligence and brain imaging have been previously reported as being normal in FKRP-associated muscular dystrophy, except in rare cases presenting with mental retardation associated with structural brain abnormalities.
We studied cerebral MRIs in twelve patients with FKRP-associated muscular dystrophy presenting in infancy or early childhood, at ages between 14 months and 43 years. Two patients had severe cognitive deficits, four had mild-moderate mental retardation and the rest were considered to have normal intelligence. All, but one were wheelchair-bound and 7 were mechanically ventilated.
Brain MRI was abnormal in 9 of 12 patients. Brain atrophy was seen in 8 patients. One child had isolated ventricular enlargement at 4 years. Cortical atrophy involved predominantly temporal and frontal lobes and was most important at later ages. In two cases with serial images this atrophy seemed progressive. Three patients, two with severe and one with moderate mental retardation, showed structural abnormalities of the posterior fossa with hypoplasia of the vermis and pons, and cerebellar hemispheric cysts. These abnormalities were stable with time. Two of these three patients also showed diffuse white matter abnormalities in early childhood, which regressed with time.
MRI abnormalities are common in patients with FKRP-associated muscular dystrophy presenting at birth or in early childhood. Progressive brain atrophy is the most frequent finding. Posterior fossa malformations and transient white matter changes may be seen in patients with associated mental retardation.
Full-text · Article · Jun 2006 · Brain and Development
[Show abstract][Hide abstract] ABSTRACT: Epilepsy is one of the main features of Menkes disease (MD), although it is not described in depth. To determine the spectrum of epilepsy, we studied its main characteristics.
Based on clinical charts, we retrospectively analyzed the evolution of electroclinical features of 12 patients with confirmed MD.
Epilepsy could be divided into three periods: (a) an early stage (median age, 3 months), characterized by focal clonic status epilepticus, usually triggered by fever (10 patients). Ictal EEG showed runs of slow spike-waves and slow waves in the posterior regions, and interictal EEG multifocal and polymorphic slow waves (three cases), or mixed slow spike-waves and slow waves (seven cases). Partial seizure control was obtained in nine patients during 5.9 months; (b) an intermediate stage (median age, 10 months) with intractable infantile spasms (11 patients) in which interictal EEG demonstrated modified hypsarrhythmia (seven cases), diffuse irregular slow waves and spike-waves (four cases). Six patients died at the median age of 15 months; and (c) a late stage in the six remaining patients (median age, 25 months), with multifocal seizures, tonic spasms, and myoclonus in four patients, whereas two patients became seizure free. Interictal EEG showed multifocal high-amplitude activity, mixed with irregular slow waves in all six cases. These patients died at the median age of 3.6 years.
Based on a relatively large series of MD patients with a quite prolonged survival, we individualized three successive periods in the course of epilepsy: early focal status, then infantile spasms, and then myoclonic and multifocal epilepsy after age 2 years.
[Show abstract][Hide abstract] ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by motoneuron degeneration in the anterior horn of the spinal cord and in the bulbar nuclei. The various types of SMA are linked to the 5q13 locus in 95 % of cases. In the absence of an effective specific treatment, orthopaedic and respiratory management can significantly improve the prognosis. To study the contemporary natural history of SMA and to identify clinical and non invasive prognostic criteria, 168 patients with SMA were recruited in 6 hospital units (Lille, Lyon, Marseille, Paris) during a 4-year prospective multicenter follow-up study (1998-2002). Follow-up has now lasted at least 4 years in 151 cases (90%), and 24 of these patients have died Disease outcome was appraised by using three criteria: muscle strength, the sum of the motor function and examination index (IFM), the respiratory muscle paralysis index (IMR), and the dorsal decubitus forced vital capacity/theoretical index (ICV/CT). Statistical analysis showed a significant worsening (about 20%) of the three criteria during follow-up. The motor function and examination index (IFM) is particularly interesting: the difference between initial and final status was significant in all age groups and in all three types of the disease. The IFM may thus be useful as the main outcome measure during therapeutic trials.
No preview · Article · Jul 2005 · Bulletin de l'Académie nationale de médecine
[Show abstract][Hide abstract] ABSTRACT: Chronic distal spinal muscular atrophy (Chronic DSMA, MIM (*)607088) is a rare autosomal recessive disorder characterized by a progressive motor weakness and muscular atrophy, predominating in the distal parts of the limbs. A form of Chronic DSMA gene has been previously mapped to chromosome 11q13 in the 10.3 cM interval defined by loci D11S1889 and D11S1321. By linkage analysis in 12 European Chronic DSMA families, we showed that a disease gene maps to chromosome 11q13.3 (Z(max)=6.66 at theta=0.00 at the DSM4 locus) and suggested that this condition is genetically homogeneous. Recombination events allowed us to reduce the genetic interval to a 2.6 cM region, telomeric to the IGHMBP2 gene, excluding this gene as the disease causing gene in Chronic DSMA. Moreover, partial linkage disequilibrium was found between three rare alleles at loci D11S1369, DSM4 and D11S4184 and the mutant chromosome in European patients. Analysis of the markers at these loci strongly suggests that most Chronic DSMA chromosomes are derived from a single ancestor. Refinement of the Chronic DSMA locus will hopefully allow to test candidate genes and lead to identification of the disease-causing mutations.
Full-text · Article · Jul 2004 · European Journal of HumanGenetics
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Feb 2004 · Neuromuscular Disorders
[Show abstract][Hide abstract] ABSTRACT: Classical congenital muscular dystrophies (CMDs) are autosomal recessive neuromuscular disorders characterized by early onset of hypotonia and weakness, atrophy of limbs and trunk muscles, contractures, and dystrophic changes in the muscle biopsy. So far, only one gene, LAMA2 (6q2), which encodes the laminin alpha2 chain (or merosin), has been identified in these disorders. Mutations in LAMA2 cause CMD with complete or partial merosin deficiency, detectable by immunocytochemistry on muscle biopsies, and account for approximately 50% of CMD cases. In a large consanguineous family (11 siblings) comprising three children affected by CMD without merosin deficiency, we undertook a genomewide search by homozygosity mapping and analyzed 380 microsatellite markers. The affected children were homozygous for several markers on chromosome 1p35-36. We identified two additional consanguineous families with affected children who also showed linkage to this locus. A maximum cumulative LOD score of 4.48, at a recombination fraction of .00, was obtained with D1S2885. A consistent feature in these three families was the presence of early rigidity of the spine, scoliosis, and reduced vital capacity, as found in rigid-spine syndrome (RSS). This study is the first description of a locus for a merosin-positive CMD and will help to better define the nosology of RSS.
Full-text · Article · Jul 1998 · The American Journal of Human Genetics