Gait pattern in myotonic dystrophy (Steinert disease): a kinematic, kinetic and EMG evaluation using 3D gait analysis.

We investigated the gait pattern of 10 patients with myotonic dystrophy (Steinert disease; 4 females, 6 males; age: 41.5+7.6 years), compared to 20 healthy controls, through manual muscle test and gait analysis, in terms of kinematic, kinetic and EMG data. In most of patients (80%) distal muscle groups were weaker than proximal ones. Weakness at lower limbs was in general moderate to severe and MRC values evidenced a significant correlation between tibialis anterior and gastrocnemius medialis (R=0.91). An overall observation of gait pattern in patients when compared to controls showed that most spatio-temporal parameters (velocity, step length and cadence) were significantly different. As concerns kinematics, patients' pelvic tilt was globally in a higher position than control group, with reduced hip extension ability in stance phase and limited range of motion; 60% of the limbs revealed knee hyperextension during midstance and ankle joints showed a quite physiological position at initial contact and higher dorsiflexion during stance phase if compared to healthy individuals. Kinetic plots evidenced higher hip power during loading response and lower ankle power generation in terminal stance. The main EMG abnormalities were seen in tibialis anterior and gastrocnemius medialis muscles. In this study gait analysis gives objective and quantitative information about the gait pattern and the deviations due to the muscular situation of these patients; these results are important from a clinical point of view and suggest that rehabilitation programs for them should take these findings into account.

Mitochondrial respiratory chain dysfunction in muscle from patients with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a major cause of neurological disability and its pathogenesis remains elusive despite a multitude of studies. Although defects of the mitochondrial respiratory chain have been described in several ALS patients, their pathogenic significance is unclear. OBJECTIVE: To review systematically the muscle biopsy specimens from patients with typical sporadic ALS to search for possible mitochondrial oxidative impairment. DESIGN: Retrospective histochemical, biochemical, and molecular studies of muscle specimens. SETTING: Tertiary care university. Subjects Fifty patients with typical sporadic ALS (mean age, 55 years). Main Outcome Measure Number of patients showing a clear muscle mitochondrial dysfunction assessed through histochemical and biochemical muscle analysis. RESULTS: Histochemical data showed cytochrome c oxidase (COX)-negative fibers in 46% patients. Based on COX histochemical activity, patients fell into 4 groups: 27 had normal COX activity; and 8 had mild (2-4 COX-negative fibers of 100 fibers), 8 had moderate (5-10 COX-negative fibers of 100), and 7 had severe (>10 COX-negative fibers of 100) COX deficiency. Spectrophotometric measurement of respiratory chain activities showed that 3 patients with severe histochemical COX deficiency also showed combined enzyme defects. In 1 patient, COX deficiency worsened in a second biopsy taken 9 months after the first. Among the patients with severe COX deficiency, one had a new mutation in the SOD1 gene, another a mutation in the TARDBP gene, and a third patient with biochemically confirmed COX deficiency had multiple mitochondrial DNA deletions detectable by Southern blot analysis. CONCLUSIONS: Our data confirm that the histochemical finding of COX-negative fibers is common in skeletal muscle from patients with sporadic ALS. We did not find a correlation between severity of the oxidative defect and age of the patients or duration of the disease. However, the only patient who underwent a second muscle biopsy did show a correlation between severity of symptoms and worsening of the respiratory chain defect. In 7 patients, the oxidative defect was severe enough to support the hypothesis that mitochondrial dysfunction must play a role in the pathogenesis of the disease.

Muscular dystrophy: central nervous system alpha-dystroglycan glycosylation defects and brain malformation.

The authors describe the case of a patient affected with congenital muscular dystrophy with lack of muscle alpha-dystroglycan. Brain gross anatomy showed lissencephaly and pachygyria. Light microscopy showed heterotopias in white matter. The brain stem and cerebellum were normal. They found no expression of alpha-dystroglycan either in the frontal cortex or in the heterotopic nuclei, while a normal expression was found in the cerebellum. These results suggest that alpha-dystroglycan glycosylation defects may account for both the muscle disease and the brain supratentorial malformation in our patient. The authors did not identify any mutations in the genes most frequently related to these syndromes. Therefore, this case suggests that a new gene may be associated with congenital muscular dystrophy with alpha-dystroglycan glycosylation defects, cortical migration defects, and sparing of the cerebellum.

Amyotrophic lateral sclerosis linked to a novel SOD1 mutation with muscle mitochondrial dysfunction.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disorder. Mutations in Cu,Zn superoxide dismutase (SOD1) cause approximately 20% of familial ALS. One of the possible mechanisms whereby they induce disease is mitochondrial dysfunction in motor neurons. Here we describe a patient with ALS and muscle mitochondrial oxidative defect associated with a novel SOD1 mutation. Direct sequencing of SOD1 gene revealed a heterozygous mutation in codon 22 substituting a highly conserved amino acid, from glutamine to arginine (Q22R). Muscle biopsy showed a neurogenic pattern associated with cytochrome c oxidase (COX) deficiency in several muscle fibers. Western blot analysis demonstrated a reduction in SOD1 content in the cytoplasmic and mitochondrial fractions. These results suggest that a minute quantity of mutant SOD1 protein contributes to a mitochondrial toxicity also in muscle tissue.

Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects.

Six years before the present study we performed a retrospective study of 114 subjects presenting with asymptomatic / oligosymptomatic hyperckemia (raised creatine kinase blood levels), a diagnosis being made in 21 of them. We now present the results of a long-term follow-up in 55 of the still undiagnosed 93 individuals. Most of them have remained asymptomatic and did not develop specific neuromuscular disorders. One subject became frankly symptomatic manifesting limb-girdle weakness. A diagnosis of dystrophinopathy carrier and one of possible type I SMA carrier were indirectly made in another two subjects. Almost all subjects still have hyperckemia, though the mean creatine kinase (CK) value is lower than before. CK levels have become normal in 12 subjects. Two died of neoplasia, and six developed non-neuromuscular disorders. We noted no follow-up differences in terms of CK modifications between subjects with pathological EMG and/or muscle biopsy findings and those with normal findings at first examination.