Heterogeneity of muscle fat infiltration in children with spina bifida

Children with spina bifida have well recognized functional deficits of muscle, but little is known about the associated changes in muscle anatomy and composition. This study used water-fat magnetic resonance imaging (MRI) to measure fat infiltration in the lower extremity muscles of 11 children with myelomeningocele, the most severe form of spina bifida. MRI measurements of muscle fat fraction (FF) were compared against manual muscle test (MMT) scores for muscle strength. The FF measurements were objective and reliable with mean inter-rater differences of <2% and intraclass correlation coefficients > 0.98. There was a significant inverse relationship between muscle FF and MMT scores (P ≤ 0.001). Surprisingly, however, muscles with negligible strength (MMT 0–1) exhibited a bimodal distribution of FF with one group having FF > 70% and another group having FF < 20%. The MRI also revealed striking heterogeneity amongst individual muscles in the same muscle group (e.g., 4% fat in one participant's lateral gastrocnemius vs. 88% in her medial gastrocnemius), as well as significant asymmetry in FF in one participant with asymmetric strength and sensation. These results suggest that quantitative water-fat MRI may serve as a biomarker for muscle degeneration which may reveal subclinical changes useful for predicting functional potential and prognosis.     

Power spectral analysis of surface electromyography (EMG) at matched contraction levels of the first dorsal interosseous muscle in stroke survivors

ObjectiveThe objective of this study was to help assess complex neural and muscular changes induced by stroke using power spectral analysis of surface electromyogram (EMG) signals.MethodsFourteen stroke subjects participated in the study. They were instructed to perform isometric voluntary contractions by abducting the index finger. Surface EMG signals were collected from the paretic and contralateral first dorsal interosseous (FDI) muscles with forces ranging from 30% to 70% maximum voluntary contraction (MVC) of the paretic muscle. Power spectral analysis was performed to characterize features of the surface EMG in paretic and contralateral muscles at matched forces. A Linear Mixed Model was applied to identify the spectral changes in the hemiparetic muscle and to examine the relation between spectral parameters and contraction levels. Regression analysis was performed to examine the correlations between spectral characteristics and clinical features.ResultsDifferences in power spectrum distribution patterns were observed in paretic muscles when compared with their contralateral pairs. Nine subjects showed increased mean power frequency (MPF) in the contralateral side (>15 Hz). No evident spectrum difference was observed in 3 subjects. Only 2 subjects had higher MPF in the paretic muscle than the contralateral muscle. Pooling all subjects’ data, there was a significant reduction of MPF in the paretic muscle compared with the contralateral muscle (paretic: 168.7 ± 7.6 Hz, contralateral: 186.1 ± 8.7 Hz, mean ± standard error, F = 36.56, p < 0.001). Examination of force factor on the surface EMG power spectrum did not confirm a significant correlation between the MPF and contraction force in either hand (F = 0.7, p > 0.5). There was no correlation between spectrum difference and Fugl–Meyer or Chedoke scores, or ratio of paretic and contralateral MVC (p > 0.2).ConclusionsThere appears to be complex muscular and neural processes at work post stroke that may impact the surface EMG power spectrum. The majority of the tested stroke subjects had lower MPF in the paretic muscle than in the contralateral muscle at matched isometric contraction force. The reduced MPF of paretic muscles can be attributed to different factors such as increased motor unit synchronization, impairments in motor unit control properties, loss of large motor units, and atrophy of muscle fibers.SignificanceSurface EMG power spectral analysis can serve as a useful tool to indicate complex neural and muscular changes after stroke.     

Long-term clinical and MRI follow-up in two POMT2-related limb girdle muscular dystrophy (LGMDR14) patients

IntroductionPOMT2-related limb girdle muscular dystrophy (LGMDR14) is a rare muscular dystrophy caused by mutations in the POMT2 gene. Thus far only 26 LGMDR14 subjects have been reported and no longitudinal natural history data are available.Case reportWe describe two LGMDR14 patients followed for 20 years since infancy. Both patients presented a childhood-onset, slowly progressive pelvic girdle muscular weakness leading to loss of ambulation in the second decade in one patient, and cognitive impairment without detectable brain structural abnormalities. Glutei, paraspinal, and adductor muscles were the primarily involved muscles at MRI.DiscussionThis report provides natural history data on LGMDR14 subjects, with a focus on longitudinal muscle MRI. We also reviewed the LGMDR14 literature data, providing information on the LGMDR14 disease progression. Considering the high prevalence of cognitive impairment in LGMDR14 patients, a reliable application of functional outcome measures can be challenging, therefore a muscle MRI follow-up to assess disease evolution is recommended.     

Comparing clinical data and muscle imaging of DYSF and ANO5 related muscular dystrophies

In this retrospective cross-sectional study clinical and muscle imaging data of patients with Miyoshi distal myopathy phenotype (MMD1 and MMD3) and limb girdle muscular dystrophy 2L (LGMD2L) were described. MMD1 and MMD3 are genetically heterogenous diseases based on DYSF and ANO5 gene defects. MMD3 and LGMD2L are clinically different diseases caused by an ANO5 gene defect. All groups showed predominant fatty degeneration of the gluteus minimus muscle and of the posterior segments of the thigh and calf muscles with sparing of the gracilis muscle. Muscle atrophy, hypertrophy and asymmetric muscle involvement on muscle imaging did not differ between groups. The pattern of fatty degeneration of muscles and of muscle weakness shows only minor differences between MMD1 (n = 6) and MMD3 (n = 8) patients with more frequently fatty degeneration of the rectus femoris, anterior tibial, and extensor digitorum muscles and more frequently muscle weakness in the anterior tibial, peroneal and calf muscle in MMD1. In the ANO5 related phenotypes the lateral head of the gastrocnemius muscle was less frequently involved in LGMD2L (n = 13) and no differences in the incidence of muscle weakness was found. Therefore, MMD3 and LGMD2L should be considered as part of one spectrum of ANO5 related muscle disease.     

Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations

The mitochondrial DNA (mtDNA) depletion syndrome is a genetically heterogeneous group of diseases caused by nuclear gene mutations and secondary reduction in mtDNA copy number. We describe a patient with progressive muscle weakness and increased creatine kinase and lactate levels. Muscle weakness was first noted at age 1.5 years and he died of respiratory failure and bronchopneumonia at age 3.5 years. The muscle biopsy showed dystrophic features with ragged red fibers and numerous cytochrome c oxidase (COX)-negative fibers. qPCR analysis demonstrated depletion of mtDNA and sequence analysis of the mitochondrial thymidine kinase 2 (TK2) gene revealed two novel heterozygous variants, c.332C > T, p.(T111I) and c.156 + 5G > C. Quantitative analysis of mtDNA in single muscle fibers demonstrated that COX-deficient fibers showed more pronounced depletion of mtDNA when compared with fibers with residual COX activity (P < 0.01, n = 25). There was no evidence of manifestations from other organs than skeletal muscle although there was an apparent reduction of mtDNA copy number also in liver. The patient showed a pronounced, albeit transient, improvement in muscle strength after onset of treatment with coenzyme Q10, asparaginase, and increased energy intake, suggesting that nutritional modulation may be a therapeutic option in myopathic mtDNA depletion syndrome.     

A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy

Defects in glycosylations of α-dystroglycan are associated with mutations in several genes, including the fukutin gene (FKTN). Hypoglycosylation of α-dystroglycan results in several forms of muscular dystrophy with variable phenotype. Outside Japan, the prevalence of muscular dystrophies related to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due to episodes of tachycardia caused by Wolff–Parkinson–White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal <150 IU/L). A homozygous, novel c.917A>G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations as a cause of LGMD2M without mental retardation and expands the phenotypic spectrum for LGMD2M to include cardiomyopathy and rigid spine syndrome in the mildest affected non-Japanese patient reported so far.     

A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations

Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker–Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker–Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles.     

Muscle MRI reveals distinct abnormalities in genetically proven non-dystrophic myotonias

We assessed the presence, frequency and pattern of MRI abnormalities in non-dystrophic myotonia patients. We reviewed T1-weighted and STIR (short-tau-inversion-recovery) 3T MRI sequences of lower limb muscles at thigh and calf level in 21 patients with genetically confirmed non-dystrophic myotonia: 11 with CLCN1 mutations and 10 with SCN4A mutations, and 19 healthy volunteers. The MRI examinations of all patients showed hyperintensity within muscles on either T1-weighted or STIR images. Mild extensive or marked T1-weighted changes were noted in 10/21 patients and no volunteers. Muscles in the thigh were equally likely to be affected but in the calf there was sparing of tibialis posterior. Oedema was common in calf musculature especially in the medial gastrocnemius with STIR hyperintensity observed in 18/21 patients. In 10/11 CLCN1 patients this included a previously unreported “central stripe”, also present in 3/10 SCN4A patients but no volunteers. Degree of fatty infiltration correlated with age (rho = 0.46, p < 0.05). Muscle MRI is frequently abnormal in non-dystrophic myotonia providing evidence of fatty infiltration and/or oedema. The pattern is distinct from other myotonic disorders; in particular the “central stripe” has not been reported in other conditions. Correlations with clinical parameters suggest a potential role for MRI as a biomarker.     

Anoctamin 5 muscular dystrophy associated with a silent p.Leu115Leu mutation resulting in exon skipping

We report a 45 year-old patient with an asymmetrical proximal muscle weakness affecting the quadriceps muscle of the right leg starting at the age of 32 years. CK was 25-fold increased. MRI of the legs showed signs of fatty degeneration more pronounced in the right side. Biopsy of a thigh muscle showed dystrophic pattern and amyloid deposition in blood vessel walls. The coding region and exon/intron boundaries of the ANO5 gene were amplified and sequenced. The common c.191dupA mutation and a silent novel p.Leu115Leu (c.345G>A) variant were identified. This silent variant was listed neither in the LOVD database nor in the SNP database. To evaluate the pathogenicity of the novel silent mutation in ANO5, cDNA analysis was performed that demonstrated skipping of exon 6. So far, no case with a silent mutation leading to abnormal splicing has been identified in Anoctamin 5 muscular dystrophy. Present findings emphasize that cDNA analysis should be done if a silent variant is not annotated in the databases. In Anoctamin 5 muscular dystrophy a molecular diagnosis is even more important as protein investigation through Western blotting or immunohistochemistry is not yet established.     

The ABCC2 c.-24C > T polymorphism increases the risk of resistance to antiepileptic drugs: A meta-analysis

Several studies examined a possible link between multidrug resistance-associated protein 2 (ABCC2) gene variants and the risk of resistance to antiepileptic drugs (AEDs) in epilepsy, but the results were contradictory. In this study, a meta-analysis was conducted to assess the relevance of ABCC2 common variants (c.-24C > T, c.1249G > A, c.3972C > T) with the response risk of AEDs. We searched Embase, PubMed, the Cochrane Library and CNKI databases for case-control studies published through May 2016 that evaluated the role of ABCC2 gene variants in pharmacoresistance to AEDs. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to assess the strength of associations between the ABCC2 c.-24C > T, c.1249G > A and c.3972C > T variants and the risk of resistance to AEDs using an allele frequency model, dominant model and recessive model. Subgroup analyses were performed by ethnicity and the definition of drug-resistance. A total of 13 published studies involving 4300 patients (2261 patients with drug-resistant epilepsy and 2039 controls with drug-responsive epilepsy) met the selection criteria. We observed that the variant c.-24C > T was associated with a significantly increased risk of AED resistance (TT + CT vs CC: OR = 1.24, 95%CI = 1.06–1.46, p = 0.009; TT vs CT + CC: OR = 1.90, 95%CI = 1.31–2.76, p = 0.0008; T vs C: OR = 1.27, 95%CI = 1.11–1.46, p = 0.0006). However, we identified no significant association of the ABCC2 c.1249G > A, c.3972C > T variants and haplotypes with the response to anticonvulsant drug in the overall population. In summary, these observations suggest that the ABCC2 c.-24C > T polymorphism is a likely risk factor for resistance to AEDs.     

Facilitation handlings induce increase in electromyographic activity of muscles involved in head control of Cerebral Palsy children

This study aimed to investigate the electromyographic (EMG) activation of the main cervical muscles involved in the head control during two postures widely used for the facilitation of head control in children with Cerebral Palsy (CP). A crossover trial involving 31 children with clinical diagnosis of CP and spastic quadriplegia was conducted. Electromyography was used to measure muscular activity in randomized postures. Three positions were at rest: (a) lateral decubitus, (b) ventral decubitus on the floor and (c) ventral decubitus on the wedge. Handlings for facilitating the head control were performed using the hip joint as key point of control in two postures: (a) lateral decubitus and (b) ventral decubitus on wedge. All children underwent standardized handlings, performed by the same researcher with experience in the neurodevelopmental treatment. EMG signal was recorded from muscles involved in the head control (paraspinal and sternocleidomastoid muscles) in sagittal, frontal and transverse planes, at the fourth cervical vertebra (C4), tenth thoracic vertebra (T10) and sternocleidomastoid muscle (SCM) levels. The results showed a significant increase in muscle activation when handling was performed in the lateral decubitus at C4 (P < 0.001), T10 (P < 0.001) and SCM (P = 0.02) levels. A significant higher muscle activation was observed when handling was performed in lateral decubitus when compared to ventral decubitus at C4 level (P < 0.001). Handling in ventral decubitus also induced an increase in EMG activation at T10 (P = 0.018) and SCM (P = 0.004) levels but not at C4 level (P = 0.38). In conclusion, handlings performed in both positions may induce the facilitation of head control, as evaluated by the activity of cervical and upper trunk muscles. Handling performed in lateral decubitus may induce a slightly better facilitation of head control. These findings contribute to evidence-based physiotherapy practice for the rehabilitation of severely spastic quadriplegic CP children.     

The effects of prednisone and steroid-sparing agents on decay accelerating factor (CD55) expression: Implications in myasthenia gravis

Decay accelerating factor (DAF) expression at the muscle endplate is an important defence against complement-mediated damage in myasthenia gravis. Previously we implicated the c.-198C > G DAF polymorphism with the development of treatment-resistant myasthenia-associated ophthalmoplegia by showing that the C > G DAF polymorphism prevented lipopolysaccharide-induced upregulation of lymphoblast DAF. We postulated that drugs used in myasthenia gravis may increase the susceptibility of extraocular muscles to complement-mediated damage and studied their effects on endogenous DAF using patient-derived lymphoblasts as well as mouse myotubes. We show that prednisone repressed C > G DAF expression in lymphoblasts and increased their susceptibility to cytotoxicity. Methotrexate, but not azathioprine or cyclosporine, increased DAF in C > G lymphoblasts. In mouse myotubes expressing wild-type Daf, prednisone also repressed Daf expression. Although cyclosporine, azathioprine, and methotrexate increased muscle Daf levels when used alone, upon co-treatment with prednisone only azathioprine maintained myotube Daf levels close to basal. Therefore, prednisone negatively influences DAF expression in C > G lymphoblasts and in myotubes expressing wild-type Daf. We speculate that myasthenic individuals at risk of developing the ophthalmoplegic complication, such as those with C > G DAF, may have inadequate endogenous levels of complement regulatory protein protection in their extraocular muscle in response to prednisone, increasing their susceptibility to complement-mediated damage.     

Longitudinal measurements of MRI-T2 in boys with Duchenne muscular dystrophy: Effects of age and disease progression

Duchenne muscular dystrophy (DMD) is characterized by an increased muscle damage and progressive replacement of muscle by noncontractile tissue. Both of these pathological changes can lengthen the MRI transverse proton relaxation time (T₂). The current study measured longitudinal changes in T₂ and its distribution in the lower leg of 16 boys with DMD (5–13 years, 15 ambulatory) and 15 healthy controls (5–13 years). These muscles were chosen to allow extended longitudinal monitoring, due to their slow progression compared with proximal muscles in DMD. In the soleus muscle of boys with DMD, T₂ and the percentage of pixels with an elevated T₂ (⩾2 SD above control mean T₂) increased significantly over 1 year and 2 years, while the width of the T₂ histogram increased over 2 years. Changes in soleus T₂ variables were significantly greater in 9–13 years old compared with 5–8 years old boys with DMD. Significant correlations between the change in all soleus T₂ variables over 2 years and the change in functional measures over 2 years were found. MRI measurement of muscle T₂ in boys with DMD is sensitive to disease progression and shows promise as a clinical outcome measure.     

Assessment of intramuscular lipid and metabolites of the lower leg using magnetic resonance spectroscopy in boys with Duchenne muscular dystrophy

The purpose of this study was to use proton magnetic resonance spectroscopy to assess intramuscular lipid and metabolites of lower leg muscles in boys with Duchenne muscular dystrophy (DMD) and determine its relationship with strength and functional ability. Spectroscopic measurements were obtained from four muscles of the lower leg in 25 boys with DMD (9.2 ± 3.1 years) and 10 healthy boys (10.2 ± 2.6 years). Lipid fractions and metabolite concentrations were also determined. Muscle strength, a timed functional test, and the Modified Brooke Lower Extremity Functional Scale were also determined. Lipid fractions were higher (p < 0.01) for the DMD group than healthy subjects for all muscles, and lipid fraction was found to be greater in the older DMD boys. The peroneal muscle demonstrated a significant difference in lipid fraction in all DMD age groups. Lipid fractions in all muscles correlated with functional measures (r = 0.52–0.70, p < 0.001), with smaller inverse correlations with the strength measure (r = −0.36 to −0.56, p < 0.05). These findings provide quantifiable information regarding intramuscular lipid and metabolite levels of different muscles across various age groups in boys with DMD and may be used in determining the effect of interventions in future clinical trials.     

Sporadic centronuclear myopathy with muscle pseudohypertrophy,neutropenia, and necklace fibers due to a DNM2 mutation

Dynamin 2 gene (DNM2) mutations result in an autosomal dominant centronuclear myopathy (CNM) and a Charcot-Marie-Tooth (CMT) neuropathy. DNM2-CMT but not DNM2-CNM patients were noted to have neutropenia. We here report a man with paravertebral muscles hypertrophy and mild neutropenia. His muscle biopsy was typical for CNM with additional “necklace” fibers. Sequencing of DNM2 revealed a known heterozygous c.1269C > T (p.Arg369Trp) mutation. Necklace fibers were considered as a pathological hallmark of late onset X-linked CNM due to mutations in MTM1 but have not been observed in DNM2-CNM. The findings broaden the features of DNM2-myopathy.     

Effect of repetitive afferent electrical stimulation of the lower limb on corticomotor excitability and implications for rehabilitation

Despite the extensive work published on the effects of electrical stimulation on corticomotor excitability, very few studies have focused on lower limb muscles. The aim of the present study was to determine the effect of high-frequency afferent electrical stimulation of the anterior thigh area on the corticomotor excitability of lower limb muscles. Twenty-two healthy subjects (mean age 23 ± 7 years) participated in the study. Electrical stimulation was applied for 60 minutes on the anterior thigh area (frequency 100 Hz, pulse duration 60 μs, intensity below motor threshold). Motor-evoked potentials (MEP) of the rectus femoris (RF) and biceps femoris (BF) muscles were recorded before, and after, the electrical stimulation paradigm with a Magstim 200 stimulator. Analyses revealed a significant modulation in MEP amplitude for the RF but not for the BF muscle. Specifically, there was a significant reduction in MEP amplitude for the RF muscle immediately, 15 minutes and 30 minutes after the end of electrical stimulation when compared with baseline. Our results indicate that a 60-minute high-frequency electrical stimulation protocol applied on the anterior thigh area decreases the corticomotor excitability of the RF muscle. Although the exact duration remains unknown, the pattern of modulation observed indicates that the inhibitory effect lasts for more than 30 minutes after the end of stimulation, giving enough time for clinicians to work on the desired motor task during rehabilitation.     

Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy

Congenital myopathies are difficult to classify correctly through molecular testing due to the size and heterogeneity of the genes involved. Therefore, the prevalence of the various genetic causes of congenital myopathies is largely unknown. In our cohort of 94 patients with congenital myopathy, two related female patients and two sporadic, male patients were found to carry mutations in the tropomyosin 2 (TPM2) and tropomyosin 3 (TPM3) genes, respectively. This indicates a low (4.3%) frequency of TPM2 and TPM3 mutations as a cause of congenital myopathy. Compared to previously described patients carrying the same mutations as found in our study (c.503G > A, and c.502C > T in TPM3, and c.415_417delGAG in TPM2), clinical presentation and muscle morphological findings differed in our patients. Differences included variation in distribution of muscle weakness, presence of scoliosis and ptosis, physical performance and joint contractures. The variation in clinical profiles emphasizes the phenotypic heterogeneity. However, common features were also present, such as onset of symptoms in infancy or childhood, musculoskeletal deformities and normal or low plasma levels of creatine kinase.One patient had nemaline myopathy and fiber size disproportion, while three patients had congenital fiber type disproportion (CFTD) on muscle biopsies. TPM2-related CFTD has only been described in two cases, indicating that mutations in TPM2 are rare causes of CFTD.     

Muscle ultrasound measurements and functional muscle parameters in non-dystrophic myotonias suggest structural muscle changes

Patients with non-dystrophic myotonias, including chloride (myotonia congenita) and sodium channelopathies (paramyotonia congenita/potassium aggravated myotonias), may show muscular hypertrophy in combination with some histopathological abnormalities. However, the extent of muscle changes has never been assessed objectively in a large group genetically confirmed patients. This study quantitatively determines echo intensities, thicknesses, ranges-of-motion and force of four skeletal muscles in 63 genetically confirmed patients. The main findings revealed elevated echo intensities in all muscles except the rectus femoris (+1.3–2.2 SD, p < 0.0001), and hypertrophy in the arms (+0.5–0.9 SD, p < 0.01). Muscle echo intensities were inversely correlated to the corresponding ranges-of-motion (biceps brachii: r = ?0.43; p < 0.001, forearm flexors: r = ?0.47; p < 0.001, rectus femoris: r = ?0.40; p = 0.001, and tibial anterior: r = ?0.27; p = 0.04) and correlated positively to age (r = 0.22; p = 0.05). The echo intensity of the forearm flexors was inversely correlated to their muscles’ force (r = ?0.30; p = 0.02). Together, these data suggest that non-dystrophic myotonias may lead to structural muscle changes.     

Intérêt de la biopsie musculaire chez l’enfant en 2012

Muscle biopsy is a mainstay diagnostic tool for investigating neuromuscular disorders in children. We report the yield of pediatric muscle biopsy in a population of 415 children by a retrospective study of 419 biopsies performed between 1/01/2000 and 31/12/2009 in a neuropediatric department, including mitochondrial respiratory chain analysis for 87 children. Two hundred and fifty-five biopsies were from boys (61%) 164 from girls (39%). Their mean age at biopsy was 6.5 years; 155 (37%) biopsies were obtained before the child was 5 years old. Final histopathological diagnoses were: congenital myopathy (n = 193, including 15 structural congenital myopathies); progressive muscular dystrophy (n = 75 [18%] including 57 dystrophinopathies); congenital muscular dystrophy (n = 17, including six primary merosinopathies); dermatomyositis (n = 11); spinal muscular atrophy (n = 9, including six atypical spinal muscular atrophies); metabolic myopathy (n = 32, including 19 mitochondrial myopathies); encephalomyopathy (n = 53 [13%], including 27 with a mitochondrial respiratory chain defect). Pathological diagnosis remained undetermined in 16 cases. In 184 patients (44%), the muscle biopsy revealed specific histopathological anomalies (dystrophic process; specific ultrastructural abnormalities; perifascicular atrophy; neurogenic atrophy; metabolic anomalies) enabling a precise etiological diagnosis. For 85% of progressive muscular dystrophies, the biopsy resulted in a genetic diagnosis after identification of the protein defect. In 15% of the congenital myopathies, histopathological anomalies focused attention on one or several genes. Concerning dystrophinopathies, quantification of dystrophin deficiency on the biopsy specimen contributed to the definition of the clinical phenotype: Duchenne, or Becker. In children with a myopathy, muscle biopsy is often indispensable to establish the etiological diagnosis. Based on the results from this series, muscle biopsy can provide a precise orientation in 45% of patients, leading to a genetic hypothesis.     

Somatropin treatment of spinal muscular atrophy: A placebo-controlled,double-blind crossover pilot study

In preclinical studies growth hormone and its primary mediator IGF-1 have shown potential to increase muscle mass and strength. A single patient with spinal muscular atrophy reported benefit after compassionate use of growth hormone. Therefore we evaluated the efficacy and safety of growth hormone treatment for spinal muscular atrophy in a multicenter, randomised, double-blind, placebo-controlled, crossover pilot trial. Patients (n = 19) with type II/III spinal muscular atrophy were randomised to receive either somatropin (0.03 mg/kg/day) or placebo subcutaneously for 3 months, followed by a 2-month wash-out phase before 3 months of treatment with the contrary remedy. Changes in upper limb muscle strength (megascore for elbow flexion and hand-grip in Newton) were assessed by hand-held myometry as the primary measure of outcome. Secondary outcome measures included lower limb muscle strength, motor function using the Hammersmith Functional Motor Scale and other functional tests for motor function and pulmonary function. Somatropin treatment did not significantly affect upper limb muscle strength (point estimate mean: 0.08 N, 95% confidence interval (CI:−3.79;3.95, p = 0.965), lower limb muscle strength (point estimate mean: 2.23 N, CI:−2.19;6.63, p = 0.302) or muscle and pulmonary function. Side effects occurring during somatropin treatment corresponded with well-known side effects of growth hormone substitution in patients with growth hormone deficiency. In this pilot study, growth hormone treatment did not improve muscle strength or function in patients with spinal muscular atrophy type II/III.