Murielle Dunand

Early Onset Collagen VI Myopathies: Genetic and Clinical Correlations

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.

Comparative efficacy of repetitive nerve stimulation, exercise, and cold in differentiating myotonic disorders

The decremental response of the compound muscle action potential (CMAP) to provocative tests is not characterized in genetically verified myotonic disorders. We therefore studied the relationship between decremental responses and mutation type in 10 patients with recessive myotonia congenita (rMC), two with paramyotonia congenita (PMC), nine with myotonic dystrophy type 1 (DM1), four with DM2, and 14 healthy people. CMAPs were measured at rest, just after a short exercise test (SET), and during short, 5‐ and 10‐HZ, repetitive nerve stimulation (RNS) trains at 32°C and at 20°C. The degree of decrement was not related to the severity of clinical myotonia. Controls and PMC patients had similar responses when warm, but with cooling PMC patients had a persistent decrement of CMAPs. In the rMC patients the decremental responses were related to the type of mutation of the CLCN1 gene, as a decrement was encountered in the T268M, R894X, IVS17+1 G>T, K248X, and 2149 del G, but not with the IVS1+3 A>T, F167L, or dominant A313T mutations. In DM1 patients there was no relationship between decrement and CTG repeats. The degree of partial inexcitability in myotonic muscle membrane therefore depends on the mutation type rather than degree of clinical myotonia. RNS at 10 HZ is more sensitive than SET for demonstrating abnormalities in rMC patients when warm; differences are less marked when cold, which is useful to diagnose PMC. Provocative tests are therefore useful in myotonias to demonstrate muscle inexcitability, which depends on the chloride or sodium channelopathy. Muscle Nerve, 2007

High cardiovascular morbidity and mortality in myofibrillar myopathies due to DES gene mutations: a 10-year longitudinal study

To determine incidence and type of major cardiac adverse events in patients with mutated desmin (DES) gene, we retrospectively reviewed baseline medical information, and examined the long-term outcomes of 28 DES patients (17 men, baseline mean age=37.7±14.4 years [min=9, max=71]) from 19 families. Baseline studies revealed skeletal muscle involvement in 21 patients and cardiac abnormalities in all but one patient. Over a mean follow-up of 10.4±9.4 years [min=1, max=35], cardiac death occurred in three patients, death due to cardiac comorbidities in two, one or more major cardiac adverse events in 13 patients. Among the 19 patients with mild conduction defects at baseline, eight developed high-degree conduction blocks requiring permanent pacing. Cardiac involvement was neither correlated with the type of DES mutation nor with the severity of skeletal muscle involvement. Our study underscores that in DES patients in-depth cardiac investigations are needed to prevent cardiac conduction system disease.

Phenotypic expression of a Pro 87 to Leu mutation in the connexin 32 gene in a large Swiss family with Charcot–Marie–Tooth neuropathy

BACKGROUND The clinical manifestations of CMTX have been well described but the natural history has not yet been studied in detail. We studied phenotype variability in a family with a Pro 87 to Leu mutation of the connexin 32 (Cx32) gene. METHODS A total of 32 family members, of which 19 patients were affected, underwent clinical, electrophysiological, and genetic studies. RESULTS Onset was in the second decade. Clinical features were similar in both sexes when quantitative scores were compared, but more males had a steppage gait and skeletal deformities. All adult patients had a predominant involvement of the thenar muscles. The median values of nerve conduction velocities (NCVs) were not statistically different in men and in women. The correlation coefficients were low between motor NCVs within the same extremities, indicating nonuniform slowing between nerves, the ulnar nerve being the least affected. When disability was rated, a strong correlation was seen in male patients between severity of motor axonal loss and duration of the disease. The main pathological features were axonal loss, clusters of regenerating fibers and paranodal demyelination, the hallmark of a Schwann cell pathology. CONCLUSIONS Our data support the hypothesis that clinical disability in CMTX is caused by loss of large myelinated axons in men. Furthermore, this study shows that the nerves are not uniformly affected in terms of axonal loss. Preventing axonal degeneration and promoting axonal regeneration in the most affected nerves might be the best therapeutic approaches to ameliorate disability in CMTX.

Autosomal dominant nemaline myopathy: A new phenotype unlinked to previously known genetic loci

We report a large family with a mild form of autosomal dominant nemaline myopathy and a new phenotype. Onset of symptoms was in infancy with hypotonia and motor delay. Weakness involved neck flexors, abdominal and proximal limb muscles. There was no bulbar, respiratory or foot dorsiflexion weakness and no slowness in movement. Patients had remarkably good physical endurance and no limitation in daily activities, but were slow runners since childhood. Nemaline rods were seen in less than 5% of muscle fibres. No linkage to the five known nemaline myopathy genes (alpha-tropomyosin-3, nebulin, alpha-actin, troponin T1 and beta-tropomyosin), to the ryanodine receptor gene (associated with core-rod myopathy) or to the 15q21-23 locus was found.

Eosinophilic perimyositis as the presenting feature of a monoclonal T-cell expansion

A 51‐year‐old physically active man was investigated for exertional myalgias and muscle stiffness. On examination he had mild proximal muscle weakness of the upper extremities and retraction of the digit flexors. Blood eosinophilia was present, but serum creatine kinase (CK) levels and an electromyographic study were normal. A skin–fascia–muscle biopsy of the calf revealed a macrophagic and CD4+T‐cell infiltration of the perimysium, and a T‐cell expansion was observed in blood, bone marrow, and muscle. A diagnosis of eosinophilic perimyositis was made, and prednisone and azathioprine were administrated with a good clinical response. This case highlights the differential diagnosis of blood eosinophilia with muscle disorders, and underscores that eosinophilic perimyositis may be the expression of a T‐cell monoclonal expansion. Although the pathogenesis behind the T‐cell expansion is unclear but probably inflammatory, we suggest regular follow‐up to allow early treatment of any T‐cell lymphoproliferative malignancy that may develop. Muscle Nerve, 2005

Marked Hemiatrophy in Carriers of Duchenne Muscular Dystrophy

OBJECTIVE To describe the clinical and molecular genetic findings in 2 carriers of Duchenne muscular dystrophy (DMD) who exhibited marked hemiatrophy. Duchenne muscular dystrophy is an X-linked disorder in which affected male patients harbor mutations in the dystrophin gene. Female patients with heterozygous mutations may be manifesting carriers. DESIGN Case study. SETTING Neurology clinic. PATIENTS Two manifesting carriers of DMD. INTERVENTIONS Clinical and radiologic examinations along with histologic and molecular investigations. RESULTS Both patients had marked right-sided hemiatrophy on examination with radiologic evidence of muscle atrophy and fatty replacement on the affected side. In each case, histologic analysis revealed a reduction in dystrophin staining on the right side. Genetic analysis of the dystrophin gene revealed a tandem exonic duplication in patient 1 and a multiexonic deletion in patient 2 with no further point mutations identified on the other chromosome. CONCLUSIONS Marked hemiatrophy can occur in DMD manifesting carriers. This is likely to result from a combination of skewed X-inactivation and somatic mosaicism.

Confirmation that abnormal desmin accumulation and migration are due to a desmin gene mutation in a familial cardiomyopathy and distal myopathy

Ten years ago, we reported a family where mother and daughter presented with an atrioventricular block and a slowly progressive distal muscular weakness [1]. The mother developed a severe global heart insufficiency necessitating heart transplantation at 56 years of age. Heart and skeletal muscle biopsies were characterised by myofibrillar changes and aggregates strongly expressing desmin and aB-crystallin. An immunoblot showed a normal desmin band at 53 kDa and a second band at 49 kDa, which was absent in healthy controls. Mitochondrial DNA as well as the respiratory chain enzymatic activities were normal. Genetic analysis at the gene locus of desmin (DES), located at chromosome 2, was not available at that time. These cases illustrated that in this distinct subtype of desminopathies the cardiac muscle alterations were comparable with those observed in skeletal muscle, and suggested the possibility of a primary desmin pathology. Shortly after publishing this paper, we asked a genetic laboratory to perform screening for mutations of the aB-crystallin (CRYAB) and DES genes, but no abnormalities were identified. The two patients, currently aged 69 and 42 years respectively, were followed yearly at our neuromuscular unit. A slow progression of distal myopathy was observed, however, both patients are still ambulant and have no major limitation in daily activities. Twelve years after the mother’s heart transplantation, she takes oral cyclosporine and mycophenolate mofetil without complications. Her daughter shows no progression of heart involvement and a recent echocardiographic study estimated her left ventricular function to be at 70% of the normal range. Despite evidence of potential benefit of an implantable cardioverter-defibrillator in arrhythmogenic cardiomyopathies [2], she did not agree to replace her pacemaker. Recently, she has given birth to dizygotic female twins. Pregnancy, birth and development of both children were normal. At 5 years of age, both twins had a normal neurological examination and a normal cardiac ultrasound and ECG. A repeat genetic analysis in another center of the DES gene in this family revealed a heterozygous splice site mutation (IVS2-2A > C) in the mother, daughter and her twins, which was absent in the healthy eldest boy currently aged 18 years [1]. This mutation was absent in 100 controls. Similar mutations in donor and acceptor splice sites flanking exon 3 result in an in-frame skipping of exon 3, which disrupts the heptad repeat pattern and interferes with the coiled-coil structure, and fails to form a filamentous network in SW13 (vim-) cells [3].