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PubMed2002

Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model.

Mutations of survival of the motor neuron gene (SMN1) are responsible for spinal muscular atrophy (SMA), a common genetic cause of death in childhood. The cellular mechanism by which mutations of SMN1 are responsible for the selective neuromuscular defect and motor neuron cell degeneration observed in SMA has not been described. We have previously generated mice carrying a homozygous deletion of Smn exon 7 directed to neurons. We report here that these mutant mice display a dramatic and progressive loss of motor axons involving both proximal and terminal regions, in agreement with the skeletal muscle denervation process and disease progression. Moreover, we found massive accumulation of neurofilaments, including phosphorylated forms, in terminal axons of the remaining neuromuscular junctions. This aberrant cytoskeletal organization of synaptic terminals was associated with reduction of branched structures of the postsynaptic apparatus and defect of axonal sprouting in mutant mice. Together, these findings may be responsible for severe motor neuron dysfunction, and suggest that loss of motor neuron cell bodies results from a 'dying-back' axonopathy in SMA. Smn mutant mice should represent a valuable model for elucidating the pathway linking Smn to cytoskeletal organization.

Animals↗
PubMed2004

Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration.

X-linked spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration. SBMA is caused by polyglutamine repeat expansions in the androgen receptor (AR). To determine the basis of AR polyglutamine neurotoxicity, we introduced human AR yeast artificial chromosomes carrying either 20 or 100 CAGs into mouse embryonic stem cells. The AR100 transgenic mice developed a late-onset, gradually progressive neuromuscular phenotype accompanied by motor neuron degeneration, indicating striking recapitulation of the human disease. We then tested the hypothesis that polyglutamine-expanded AR interferes with CREB binding protein (CBP)-mediated transcription of vascular endothelial growth factor (VEGF) and observed altered CBP-AR binding and VEGF reduction in AR100 mice. We found that mutant AR-induced death of motor neuron-like cells could be rescued by VEGF. Our results suggest that SBMA motor neuronopathy involves altered expression of VEGF, consistent with a role for VEGF as a neurotrophic/survival factor in motor neuron disease.

Animals↗
PubMed2003

Overexpressions of myoglobin and antioxidant enzymes in ragged-red fibers of skeletal muscle from patients with mitochondrial encephalomyopathy.

To determine the relationship between myoglobin (Mb) and the defense system against reactive oxygen species in various myopathies, we performed immunohistochemical analyses of Mb and various antioxidant enzymes, including manganese superoxide dismutase (Mn-SOD), copper zinc SOD (CuZn-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Biopsied muscle specimens were obtained from patients with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), Duchenne muscular dystrophy (DMD), and polymyositis (PM). In patients with CPEO/KSS, stainings of Mb, SOD, CAT, and GSH-Px in nonatrophic ragged-red fibers (RRFs) were more intense than those in non-RRFs. These pronounced stainings corresponded to ragged-red lesions. The staining intensities of these antioxidant enzymes were significantly correlated with that of Mb (P < 0.001). Atrophic RRFs in specimens from patients with CPEO/KSS showed intense stainings of these antioxidant enzymes but not intense staining of Mb. In specimens from patients with DMD/PM, the antioxidant enzymes but not Mb were overexpressed in degenerative fibers. These results suggest that oxidative stress is associated with Mb expression specifically in mitochondrial diseases. The antioxidant enzymes seem to be upregulated to protect against muscle damage in nonatrophic RRFs. However, the Mb-mediated oxidative damage may become more extensive and result in further mitochondrial dysfunction and progressive atrophy of RRF with impaired upregulation of Mb.

Adult↗
PubMed2001

Genetic and physical delineation of the region overlapping the progressive motor neuropathy (pmn) locus on mouse chromosome 13.

The mouse autosomal recessive mutation progressive motor neuropathy (pmn) results in early onset motor neuron disease with rapidly progressing hindlimb paralysis, severe muscular wasting, and death at 4--6 weeks of age. pmn is thus considered a good animal model for motor neuron diseases and the characterization of the causative gene should help in understanding the biological causes of human spinal muscular atrophies. Here we report the generation of a physical map based on a high-resolution and high-density genetic map encompassing the pmn locus on mouse chromosome 13. We have positioned the pmn locus and a cluster of markers cosegregating with it within a genetic interval of 0.30 cM, delineated by two clusters of markers. We have constructed an approximately 850-kb contig of BACs spanning the pmn critical region. This BAC contig contains the breakpoint of synteny between mouse chromosome 13 and human 1q and 7p regions and lays the foundation for identifying at the molecular level such a breakpoint region. The physical and genetic maps provided a support for the identification of five transcription units positioned in the nonrecombinant interval, and constitute invaluable tools for the identification of other candidate genes for the pmn mutation.

Alleles↗
PubMed2001

Reducing body myopathy with cytoplasmic bodies and rigid spine syndrome: a mixed congenital myopathy.

At the age of five years a male child started to develop a progressive rigid spine, torsion scoliosis, and flexion contractures of his elbows, knees, hips, and ankles owing to severe proximal and distal muscle weakness. He had three muscle biopsies from three different muscles at ages 7, 11, and 14 years, respectively. Myopathologically, these muscle tissues contained numerous inclusions which, at the ultrastructural level, turned out to be reducing bodies and cytoplasmic bodies, often in close spatial proximity. Similar histological inclusions, although not further identified by histochemistry and electron microscopy, were seen in his maternal grandmother's biopsied muscle tissue who had developed weakness of the legs and hands after the age of 50 years. The patient's parents were healthy, but the mother's quadriceps muscle showed an increased spectrum of muscle fibre diameters. Our patient, thus, had a neuromuscular disorder, perhaps familial, presenting as a mixed congenital myopathy, i.e., reducing body myopathy with cytoplasmic bodies, of which the morphological lesions could be consistently documented over several years in his different limb muscles. While other mixed congenital myopathies had shown cores and rods, both related to sarcomeres and thus possibly morphogenetically related, cytoplasmic bodies thought to be related to Z-bands and reducing bodies dissimilar to any muscle fibre constituent do not share any common denominator. Therefore, we suggest that this neuromuscular disorder may be a unique mixed congenital myopathy, either sporadic or genetic. In the latter case, the transmission pattern suggested X-linked recessive inheritance, but an autosomal-dominant transmission with variable penetrance could not be ruled out.

Adult↗
PubMed1986

Pathophysiological factors which limit the exercise capacity of the sick child.

While deficient exercise performance of sick children results from hypoactivity and detraining, it can also be caused by specific pathophysiological factors. These can affect one or more components of physical fitness. A low maximal aerobic power will result from a low maximal stroke volume, as in aortic stenosis or cardiomyopathy; a low maximal heart rate, as in congenital complete heart block or intake of beta-blockers; a low O2 content of the arterial blood, as in anemia or advanced cystic fibrosis; and a high O2 content of mixed-venous blood, as in muscle atrophy or severe malnutrition. A high O2 cost of locomotion, as in advanced obesity or cerebral palsy, will cause the patient to exert at a high percentage of his maximal aerobic power and thus fatigue easily. A subnormal muscle strength, as in progressive muscular dystrophy or juvenile rheumatoid arthritis, is sometimes the primary factor that limits the walking ability or other daily functions. Recent data suggest that local muscle endurance, as assessed by the Wingate anaerobic test, is particularly deficient in some neuromuscular diseases. Examples are muscular dystrophies and spastic cerebral palsy. The ratio of peak anaerobic power to peak aerobic power seems lower in such patients than in able-bodied controls.

Adolescent↗
PubMed1991

Electrophysiology and electrodiagnosis of the post-polio motor unit.

Post-poliomyelitis syndrome refers to new symptoms that may occur years after recovery from poliomyelitis. The most common of these symptoms are new weakness, fatigue, and pain. This article describes electrodiagnostic studies--conventional electromyography (EMG), single fiber electromyography (SFEMG), and macroelectromyography (macro-EMG)--that have provided information on the post-polio motor unit and on the possible etiology of some post-polio syndrome symptoms. Muscular fatigue, and indirectly, general fatigue, may be due to neuromuscular junction transmission defects in some post-polio individuals, as suggested by reduction of the compound motor action potentials on repetitive stimulation, and increased jitter and blocking on SFEMG. Progressive weakness and atrophy in post-polio syndrome is probably due to a distal degeneration of post-polio motor units with resultant irreversible muscle fiber denervation. Electrodiagnostic evidence of ongoing denervation includes fibrillation and fasciculation potentials on conventional EMG, increased jitter and blocking on SFEMG, and smaller macro-EMG amplitudes in newly weakened post-polio muscles. However, even though electrodiagnostic studies have provided insight into the possible causes of some post-polio syndrome symptoms, no specific electrodiagnostic test for the syndrome is currently available.

Action Potentials↗
PubMed2006

[Lower motor neuron diseases with predominantly upper limbs affection: are they independent forms or atypical variants of amyotrophic lateral sclerosis?].

We carried out an analysis of 5 sporadic cases of lower motor neuron disease with predominant affection of the proximal parts of arms in 2 patients and distal parts in 3 patients. From clinical point of view, our own observations, along with similar cases reported in the literature with predominantly affected upper limbs, different progression of the disease and denervation changes during needle EMG, can argue for clinical heterogeneity of lower motor neuron disease. There were some difficulties in establishment of a differential diagnosis between atypical variants of amyotrophic lateral sclerosis ("flail arm" syndrome) and primary muscular atrophy of adults at the early stages of the disease. We suppose that atypical variants of amyotrophic lateral sclerosis resultant from affection of lower motor neuron only ("flail arm" syndrome and distal amyotrophy), could be distinguished from amyotrophic lateral sclerosis and considered as an independent entity.

Adolescent↗
PubMed1989

[Secretion and clinical significance of atrial natriuretic peptide in patients with muscular dystrophy].

In patients with Duchenne muscular dystrophy (DMD), heart failure appears in later stage of the disease due to myocardial degeneration and respiratory insufficiency, and sometimes causes death. However, there have been no adequate parameters which can be used easily to evaluate the grade of heart failure in DMD, except cardiac enlargement and pulmonary congestion observed by chest X-ray picture. Thus, we measured the plasma concentrations of atrial natriuretic peptide (ANP) in the patients with muscular dystrophy of various types, and studied a relationship between plasma ANP concentration and heart failure, expecting that it could be an index of heart failure in DMD patients. The plasma ANP concentrations in patients with DMD were 35.5 +/- 3.3pg/ml (mean +/- SE) and higher than in normal subjects (19.3 +/- 1.0pg/ml). In the patients with limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy and neurogenic muscular atrophy, the plasma ANP concentration showed a tendency to elevate. However, no elevation of plasma ANP levels was observed in the patients with other types of muscular dystrophy. In DMD, number of the patients having a high plasma ANP concentration was increased with progress of disability grade, and decrease in serum creatine kinase activity and serum myoglobin concentration. There was a significant correlation (p less than 0.01) between plasma ANP concentration and cardiothoracic ratio or PEP/LVET, but no correlation between the concentration and respiratory failure. Immunohistochemistry of the atrial cardiac muscle of an autopsied DMD case revealed many ANP-positive atrial muscle cells, indicating the preservation of ANP-secreting function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

A family of Becker's progressive muscular dystrophy with severe cardiomyopathy.

A family of Becker's muscular dystrophy with marked cardiomyopathy was studied. The propositus, a 16-year-old boy with marked pseudohypertrophy in calves, showed electrocardiographic abnormalities resembling those in the Duchenne's type. Radionuclide study and endomyocardial biopsy revealed remarkable degeneration of myocardium. His uncle, who also had slight proximal muscular atrophy and weakness, and calves' pseudohypertrophy, died of heart failure at the age of 47, and autopsy showed dystrophic changes in skeletal muscles and extensive myocardial damage. Severe cardiac involvement can occur in Becker's muscular dystrophy which has been known to have an essentially benign clinical course, and radionuclide investigation is useful for the detection of preclinical cardiac lesions in patients with muscular dystrophy.

Adolescent↗
PubMed2004

Emery-Dreifuss muscular dystrophy.

The muscular dystrophies are a group of disorders, genetically determined, with progressive degeneration of muscle(s), without central nervous nor peripheral nerve abnormalities. The Emery-Dreifuss muscular dystrophy is one of these. We report a case with typical features.

Adult↗
PubMed1991

[Delayed manifestation of mitochondrial myopathy--complex I and IV deficiency of the mitochondrial respiratory chain with progressive paresis].

We describe a 53-year-old patient with a progressive mitochondrial myopathy of late-onset, restricted to skeletal muscle only without external ophthalmoplegia. The myopathy developed at the age of 46 years initially with exercise intolerance and subsequently progressive permanent muscle weakness. Muscle biopsy revealed severe myopathic changes, ragged red fibers, and a marked multifocal cytochrome-c-oxidase deficiency. Biochemical analysis showed a deficiency of complexes I and IV of the mitochondrial respiratory chain. Genetic analysis of mitochondrial DNA revealed no deletions. Mitochondrial myopathies restricted to skeletal muscle have to be considered in the differential diagnosis of late-onset progressive myopathies.

Biopsy↗
PubMed2004

Congenital form of spinal muscular atrophy predominantly affecting the lower limbs: a clinical and muscle MRI study.

We describe clinical and muscle magnetic resonance imaging (MRI) findings in 11 cases (three familial and eight sporadic) with the form of spinal muscular atrophy characterised by predominant involvement of the lower limbs with weakness of the proximal and distal muscles and marked atrophy of the distal leg and foot muscles. All patients presented at birth with talipes, which were in extension in seven of the 11. Arm muscle and function were preserved and lower limbs appeared to be disproportionately shorter compared to trunk and upper limbs. Functional abilities were markedly affected and only one of the 11 is able to walk independently for long distances, while six require support of crutches and two use callipers for walking. One child lost ambulation following a fall. The course of the disease is relatively stable and the progression of disability appeared to be related mostly to increased contractures rather than to loss of muscle strength. Respiratory and cardiac function were well preserved. A neurogenic disorder was suggested by electromyography and/or muscle biopsy in all patients, while motor nerve conduction was consistently normal. Muscle MRI of the thighs revealed diffuse atrophic appearance with relative hypertrophy of the adductor longus and of the semitendinosus. Genetic studies excluded the involvement of the survival motor neuron gene but none of these families was sufficiently informative to study linkage to the locus on chromosome 12q23-q24 previously found to be involved in patients with similar phenotype. In our experience this form of spinal muscular atrophy affecting predominantly the lower limbs is a relatively common form and should be considered in the differential diagnosis of infants with talipes and weakness in the lower limbs. The identical clinical and imaging features of the sporadic and familial cases suggest that these cases are likely to be affected by the same condition.

Adolescent↗
PubMed1999

[X-linked recessive bulbospinal neuronopathy--Kennedy's syndrome].

Kennedy's syndrome is an inherited disease which was probably first described 100 years ago. Although rare, a recent report suggests that the prevalence may show considerable regional differences. A review of 30 different names of the disease is given. Originally, the disorder was regarded as a spinal and bulbar muscular atrophy but it is now obvious that there is severe axonal degeneration, also of the sensory fibres with the pattern of a central-peripheral distal axonal neuropathy. This was also present in the two recognized cases presented here. The sensory symptoms develop slowly and it is suggested that a peripheral sprouting compensates for the loss not only of motor, but also sensory fibres. It is important to distinguish the disease from motor neuron diseases since the progression is slow and the expected life span is normal. The clinical presentation with facial palsy and perioral contraction-fasciculations is pathognomonic. However, demonstration of increased (CAG)n repeat size in the androgen receptor gene is diagnostic. A normal (CAG)n repeat size excludes the diagnosis, since the abnormal expansion is the only mutation associated with the disease. Other types of mutations in the androgen receptor gene lead to a different clinical presentation, testicular feminization.

Adult↗
PubMed1994

[Excitability of cervical lower motoneuron in juvenile muscular atrophy of the distal upper limb].

We investigated excitability of cervical lower motoneurons in 18 patients with juvenile muscular atrophy of the distal upper limb (Hirayama's disease), by F wave analysis and electrophysiological estimation of the number of motor units in the abductor pollicis brevis muscles of the affected side. In all the 18 patients, F wave persistencies and numbers of motor units were decreased, whereas amplitudes of single motor unit potentials were increased, compared to those of age-matched normal controls. Patients in a progressive phase showed markedly decreased F wave persistencies, overwhelming the degree of decreases in numbers of motor units. In half of them, F waves were significantly increased in number during neck flexion. On the other hand, patients treated with neck brace and patients having stabilized symptoms with longer duration showed F wave persistence reduction corresponded to the degree of the motor unit loss, and no changes in F wave persistencies in a posture of neck flexion. These results suggest that the disorder is characterized by decreased excitabilities of survived cervical anterior horn cells, as well as denervation and reinnervation, presumably resulting from local compression or circulatory failure by anterior shift of the posterior dural wall during neck flexion.

Adult↗
PubMed2001

T2 relaxometry of brain in myotonic dystrophy.

We investigated the nature and extent of brain involvement in myotonic dystrophy (DM), examining possible T2 relaxation abnormalities in the brain of 20 patients with adult-onset DM and 20 sex- and age-matched normal controls. Brain MRI was performed at 0.5 T, and T2 values were calculated from signal intensity in two echoes. Regions of interest included: frontal, parietal, temporal, occipital and callosal (rostral and splenial) normal-appearing white matter; frontal, occipital, insular and hippocampal cortex; caudate nucleus, putamen, globus pallidus and thalamus. All white-matter and occipital and right frontal cortex regions showed a significantly longer T2 in the patients. Multiple regression analysis, including grey- and white-matter T2 as dependent variables, plus age at onset and at imaging, disease duration, muscular disability, brain atrophy and CTG trinucleotide repeats as independent variables, revealed that only white-matter T2 elongation and disease duration correlated positively. White-matter involvement in DM is more extensive than previously reported by MRI and neuropathological studies and seems to be progressive in the course of disease.

Adolescent↗