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PubMed2006

In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate.

OBJECTIVE: Spinal muscular atrophy results from loss of the survival motor neuron 1 (SMN1) gene and malfunction of the remaining SMN2. We investigated whether valproic acid can elevate human SMN expression in vivo. METHODS: Blood was collected from 10 spinal muscular atrophy carriers and 20 spinal muscular atrophy patients treated with valproic acid. RESULTS: Seven of 10 carriers demonstrated increased SMN messenger RNA and protein levels. SMN2 messenger RNA levels were elevated in 7 patients and unchanged or decreased in 13 patients. INTERPRETATION: We provide first proof of the in vivo activation of a causative gene by valproic acid in an inherited disease and discuss strategies of monitoring drug response in patients.

Cyclic AMP Response Element-Binding Protein↗
PubMed2026

Multi-Omics Landscape of Paraspinal Muscles in Spinal Muscular Atrophy With Scoliosis.

Most spinal muscular atrophy (SMA) patients develop severe scoliosis by late adolescence. Given that the paraspinal muscles-particularly the multifidus-are indispensable for maintaining spinal stability, their site-specific multi-omics characteristics in SMA remain insufficiently defined. Herein, integrated multi-omics sequencing was performed on bilateral multifidus samples from SMA patients and surgical controls. We identified 5219 differentially expressed genes, 1063 differentially expressed proteins and 370 differential metabolites between the control and SMA, showing significant enrichment in glucose and amino acid metabolism pathways, specifically key steps of glycolysis/gluconeogenesis. Key enzymes in the glycolytic process such as PFKM, ENO3 and PKM1 were markedly downregulated. Notably, a comparative analysis of the bilateral paraspinal muscles in SMA revealed asymmetrical metabolic signatures in carbohydrate and amino acid processing between the concave and convex sides. Key regulatory enzymes exhibited significant differential expression: PYGL, a central driver of starch and sucrose metabolism; creatine kinase, involved in arginine and proline metabolism; and PGAM2, a key mediator of glycine, serine, and threonine metabolism. These metabolic signatures indicate a complex metabolic reprogramming in the multifidus, where asymmetric disparities point to the influence of mechanical loading, while systemic dysregulation aligns with the effects of SMN depletion.

Humans↗
PubMed1989

[Muscle fiber type abnormalities in bulbospinal muscular atrophy. Comparison with amyotrophic lateral sclerosis].

Bulbospinal muscular atrophy (BSA) is a distinct clinical type of chronic spinal muscular atrophy of adult onset, which was first reported by Kennedy et al. Histochemical findings of involved muscles are poorly described. In the present study, the muscle fiber type was studied on biopsied specimens by the histochemical method. The results were compared with those of amyotrophic lateral sclerosis (ALS). Muscle specimens were obtained mainly from biceps brachii muscles of 7 cases of BSA and 10 cases of ALS. Both group of patients were matched in respect to age, sex and stage of muscle weakness. The following results were obtained. Histopathological findings of BSA are classed as stage 4 abnormalities of Jennekins. Both fiber type grouping and type 2B deficiency are more frequent in BSA than in ALS. Type 2C fiber seems to be more in ALS than in BSA. Atrophy factor of Dubowitz is the same in BSA and in ALS. Hypertrophy factor is more prominent in BSA than in ALS. Significant correlation between fiber type grouping and type 2B deficiency was confirmed in muscles from other neurogenic atrophy. Since there is a significant association of the type 2B deficiency with fiber type grouping, type 2B fiber might be transformed to type 2A during the reinnervation process. The adaptation to the increased activities of the survived muscles and motoneurons might be contributory to the transformation, which is already known to occur in normal subjects during the endurance training.

Adult↗
PubMed1989

Electrocardiographic abnormalities in childhood spinal muscular atrophy.

Tremors of the isoelectric line in routine electrocardiograms have been described in patients with spinal muscular atrophy and have been interpreted as fasciculations of denervated muscles. In order to evaluate this phenomenon, 13 patients with spinal muscular atrophy have been studied (average age: 37.3 months). A first electrocardiogram was recorded routinely; a second tracing was then recorded with double sensitivity and double speed. In addition, all patients were evaluated clinically and had M-mode and cross-sectional echocardiography. Regular and constant spikes on the isoelectric electrocardiographic line were recorded in 12 patients (93.4%); their frequency ranged from 39 to 48 cycles/sec (average: 42.08 +/- 2.64). Contrary to previous reports, we found an "abnormal" electrocardiogram in all our patients with severe spinal muscular atrophy. The only patient with a normal electrocardiogram had a mild and clinically stable form of spinal muscular atrophy. We did not find any significant structural cardiac abnormality by clinical and echocardiographic evaluation. We conclude that continuous tremor on the isoelectric line of electrocardiogram represents a characteristic of spinal muscular atrophy in these patients. It is a result of muscle fasciculations and does not imply any abnormality of the heart.

Adolescent↗
PubMed1989

Downward shift in IQ in persons with Duchenne muscular dystrophy compared to those with spinal muscular atrophy.

Patients with Duchenne progressive muscular dystrophy (DMD) and those with spinal progressive muscular atrophy (SPMA) were compared on the basis of memory and IQ. The DMD group was inferior to the SPMA group in memory tests and Full Scale IQ. The DMD group showed poorer scores, despite the fact that functional disabilities and social environments were similar for the two groups. Results thus support the current view that lower IQ is one of the primary manifestations of DMD.

Adolescent↗
PubMed2005

[A clinical, neurophysiological and molecular study of 12 patients from 4 families with spinal and bulbar muscular atrophy].

INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is an X-linked, late-onset neuro-endocrine disorder resulting from an expansion of a CAG repeat in the androgen receptor gene. Material and method. We report the detailed phenotypic study in a series of 12 SBMA patients evaluated in four kindreds. RESULTS: Clinical phenotypic spectrum varied considerably, ranging from childhood-onset weakness and atrophy mimicking limb-girdle myopathy in patients with 53 CAG repeats to isolated hyperCKemia in an adult with 42 CAG repeats. All male patients had gynecomastia. Two female carriers presented with paresthesias and hand action tremor. Homozygous deletions of SMN1 and SMN2 genes were not found in any patients. CONCLUSION: This report demonstrates that SBMA may present with a wider clinical spectrum than previously described and suggests that clinical phenotype severity in SBMA is partially linked to the number of CAG repeats. It also suggests that SMN1 and SMN2 genes do not act as modifying genes in SBMA.

Adolescent↗
PubMed1976

Isoelectric focusing and electrophoresis of cerebrospinal fluid proteins in muscular dystrophies and spinal muscular atrophies.

In the very few previous investigations of the CSF-proteins in muscular dystrophies the results have generally been reported as normal. In spinal muscular atrophies a barrier-damage pattern of CSF-proteins has been found in amyotrophic lateral sclerosis (ALS). In the present investigation the CSF-proteins were examined by isoelectric focusing and quantitative paper electrophoresis in 13 patients with muscular dystrophies and in 11 patients with spinal muscular atrophies. On isoelectric focusing, CSF-protein abnormalities were found in 85% of the cases with muscular dystrophies and in all patients with spinal muscular atrophies. Differences in the CSF-protein patterns were observed within the group of muscular dystrophies and between these and the cases of spinal muscular atrophies. In ALS and in myotonic dystrophy, abnormal CSF-protein fractions occurred mainly in the alkaline pH-range, while in limb-girdle dystrophy and the patient with facioscapulohumeral dystrophy, aberrant fractions appeared mainly in the acidic region. CSF-protein abnormalities were found in both the alkaline fractions (HAFs) with pI 9.2-9.6 and a fraction with PI 7.1 were found in half of the patients with myotonic dystrophy. The CSF electrophoresis in myotonic dystrophy showed increased levels of beta1-globulin in all cases examined. Signs of barrier-damage were commonly encountered in ALS in contrast to the muscular dystrophies, except for myotonic dystrophy. The results are discussed in terms of possible diagnostic value and with regard to pathogenetic significance, particularly in relation to the current hypothesis of a neural involvement in muscular disorders.

Adult↗
PubMed2005

The ultrastructure of peripheral nerve, motor end-plate and skeletal muscle in patients suffering from spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is genetically and clinically distinct from classic spinal muscular atrophy (SMA1). It results from mutations in the gene encoding immunoglobulin mu-binding protein 2 (IGHMBP2) on chromosome 11q13. Patients develop distally pronounced muscular weakness and early involvement of the diaphragm, resulting in respiratory failure. Sensory and autonomic nerves are also affected at later stages of the disease. We investigated peripheral nerves, skeletal muscles and neuromuscular junctions (NMJ) ultrastructurally in five unrelated patients and three siblings with genetically confirmed SMARD1. In mixed motor and sensory nerves we detected Wallerian degeneration and axonal atrophy similar to the ultrastructural findings described in SMA1. Isolated axonal atrophy was evident in purely sensory nerves. All investigated NMJ of patients with SMARD1 were dysmorphic and lacked a terminal axon. Moreover, we also observed characteristics of neuropathies, such as abnormalities in myelination, that have not been described in spinal muscular atrophies so far. Based on these findings we conclude that impairment of IGHMBP2 function leads to axonal degeneration, abnormal myelin formation, and motor end-plate degeneration.

Axons↗
PubMed1999

Availability of omental flap on prevention against muscular atrophy of a latissimus dorsi cardiomyoplasty.

Dynamic cardiomyoplasty (DCMP) has been performed in more than seven hundreds cases world wide. However, despite symptomatic improvement in the majority of patients surviving the procedure, objective hemodynamic effects have not been consistently demonstrated. Previous studies reported that left ventricular function deteriorated and returned to preoperative level in the chronic phase. We previously reported that atrophy of the latissimus dorsi muscular flap (LDMF) was responsible for the effect of DCMP on improvement of cardiac function in the chronic phase. Ischemia of the muscle flap was proved to induce peripheral muscular atrophy of the flap, and thus preservation of the blood flow is important in preventing muscular atrophy. In the present study, we applied omental flap to LDMF, and postulated that the omentum would improve vascularity and perfusion of latissimus dorsi and prevent peripheral muscle atrophy. In dogs, the right and left latissimus dorsi muscles were dissected free from all attachment except for its thoracodorsal pedicles, and omental flap was wrapped around peripheral part of the left LDMF. Tissue blood flow, maximal muscle isotonic strength, morphologic features, and tissue vascular endothelial growth factor (VEGF) were examined in left LDMF with omental flap (OM group) and in the right LDMF served as the control (Control group). In the distal part of the LDMF, tissue blood flow of OM was significantly preserved than Control (86.4 +/- 6.5% in OM and 33.6 +/- 3.4% in Control, p < 0.05). Maximal isotonic tension was significantly higher in OM as compared to Control. Microscopic findings of H and E stained specimen from distal part of LDMF showed that muscle fibers were preserved in OM. And in the distal part, VEGF expression of OM was 49.6 +/- 7.9 pg/100 micrograms protein and significantly higher than that of Control. Our results indicated that induced endogenous VEGF expression in the LDMF by the omental flap preserved blood perfusion and muscular strength of the LDMF, and suggested that dynamic cardiomyoplasty might not lose its long-term direct cardiac assistance when an omental flap applied for the latissimus dorsi muscle flap.

Animals↗
PubMedDate not supplied

Spinal muscular atrophy in the neonate.

Spinal muscular atrophy (SMA) type I is an autosomal recessive disorder characterized by loss of lower motor neurons in the spinal cord. This severe hereditary neurodegenerative disorder is an important cause of morbidity in the neonate and the leading hereditary cause of infant mortality. The characteristic degeneration of anterior horn cells in the spinal cord leads to progressive muscular weakness and atrophy of the skeletal muscles. In SMA type I, the most severe form of SMA, death usually ensues by 2 years of age from respiratory failure or infection. Accurate diagnosis is now available through genetic testing, and progress is being made toward the development of therapy based on understanding of the disease mechanism. The neonatal nurse plays a pivotal role in identifying and caring for these medically fragile infants and in providing support and education for parents and families.

Chromosome Deletion↗
PubMed2003

Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease that affects males. It is caused by the expansion of a polyglutamine (polyQ) tract in androgen receptors. Female carriers are usually asymptomatic. No specific treatment has been established. Our transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear translocation of mutant androgen receptors. We examined the effect of androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing hormone-releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, leuprorelin treatment reversed the behavioral and histopathological phenotypes that were once caused by transient increases in serum testosterone. Flutamide, an androgen antagonist promoting nuclear translocation of androgen receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a promising candidate for the treatment of SBMA.

Androgen Antagonists↗
PubMed2004

Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor. Unifying mechanisms have been implicated in the pathogenesis of polyQ-dependent neurodegenerative diseases including SBMA, Huntington disease and spinocerebellar ataxias. It has been suggested that mutant protein containing polyQ inhibits histone acetyltransferase activity, resulting in transcriptional dysfunction and subsequent neuronal dysfunction. Histone deacetylase (HDAC) inhibitors alleviate neurological phenotypes in fly and mouse models of polyQ disease, although the therapeutic effect is limited by the toxicity of these compounds. We studied the therapeutic effects of sodium butyrate (SB), an HDAC inhibitor, in a transgenic mouse model of SBMA. Oral administration of SB ameliorated neurological phenotypes as well as increased acetylation of nuclear histone in neural tissues. These therapeutic effects, however, were seen only within a narrow range of SB dosage. Our results indicate that SB is a possible therapeutic agent for SBMA and other polyQ diseases, although an appropriate dose should be determined for clinical application.

Acetylation↗
PubMed1982

Gastrointestinal radiologic manifestations of proximal spinal muscular atrophy (Kugelberg-Welander syndrome).

Proximal spinal muscular atrophy (Kugelberg-Welander syndrome) is a degenerating disease of the anterior horn cells of the spinal cord with atrophy of the proximal muscles resembling muscular dystrophy. The patient in this report exhibits radiographic features in the gastrointestinal tract similar to those seen in the muscular dystrophies, including myotonic dystrophy.

Diagnosis, Differential↗
PubMed1989

Non familial juvenile distal spinal muscular atrophy of upper extremity.

An uncommon variety of non familial, juvenile onset, spinal muscular atrophy with asymmetric distal upper extremity affection is described. One hundred and two patients with a one to 14 year follow up are analysed. Spinal muscular atrophies with a distal distribution are rare. However, in the past three decades, previously unrecognised varieties of neurogenic muscular atrophy have been described in Asia (Japan, India, Sri Lanka and Singapore) under a variety of names. These provide interesting data for discussion of Asian neurogenic muscular atrophies with distal affection, in the context of diseases of the motor neuron.

Adolescent↗
PubMed2002

Stable motor and lung function throughout pregnancy in a patient with infantile spinal muscular atrophy type II.

Patients with infantile spinal muscular atrophy rarely decide to have their own children especially if there is major respiratory impairment. We studied prospectively the pregnancy course and outcome of a 34-year-old woman with spinal muscular atrophy type II who delivered a healthy boy. Pregnancy was entirely uneventful, except that for 1-2 weeks after the caesarean section, the patient was extremely weak with dyspnoea and bulbar involvement. Several weeks after delivery her motor function had returned to pre-pregnancy levels. Pulmonary function remained stable throughout pregnancy, and thereafter, at approximately 70% predicted levels for forced vital capacity and for forced expiratory volume in 1 s. Blood gases after midgestation revealed low normal PaO(2) values around 85 mmHg and concomitant hyperventilation resulting in PaCO(2) levels below 30 mmHg.

Adult↗
PubMed1991

Selective type II muscle fiber hypertrophy in severe infantile spinal muscular atrophy.

The diagnostic muscle biopsy finding in severe infantile spinal muscular atrophy (Werdnig-Hoffmann disease, SMA type 1) is considered to be large-group atrophy with isolated clusters of hypertrophic type I myofibers. We present a unique case of severe infantile spinal muscular atrophy with selective hypertrophy of type II myofibers. A male infant presented at age 2 months with breathing difficulties and by age 4 months was hypotonic and weak. Electromyography revealed denervation in all extremity muscles, and nerve conduction velocities were normal but with small compound muscle action potentials. Quadriceps muscle biopsy revealed many hypertrophied type II myofibers (myofibers with a mean least diameter of 25.4 microns). In contrast, the largest type I myofibers were 20 microns in least diameter (mean diameter, 14.9 microns), and there was a normal-size population of type II fibers (mean diameter, 15.7 microns). In addition, sheets of atrophic type I and type II fibers averaged 2.0 microns in least diameter. Sural nerve biopsy was normal. Breathing difficulties progressed, with death ensuing at age 5 1/2 months. Autopsy revealed atrophy of ventral spinal roots with normal dorsal roots. There was loss of anterior horn cells, while remnant neurons were reduced in size. No other pathologic changes were identified. This case indicates that in severe infantile spinal muscular atrophy, relative sparing of the motor units with type II myofibers may occur.

Biopsy↗
PubMed2006

Nationwide survey of juvenile muscular atrophy of distal upper extremity (Hirayama disease) in Japan.

Juvenile muscular atrophy of the distal upper extremity (JMADUE, Hirayama disease) was first reported in 1959 as 'juvenile muscular atrophy of unilateral upper extremity'. Since then, similar patients in their teens or 20s have been described, under a variety of names, not only in Japan, but also in other Asian countries, as well as Europe and North America. Biomechanical abnormalities associated with JMADUE have recently been reported through various imaging examinations, proposing its disease mechanism. Since JMADUE differs from motor neuron disease, or spinal muscular atrophy, this disease entity should be more widely recognized, and early detection and effective treatments should be considered. We report an epidemiological study in Japan. Two nationwide questionnaire-based surveys, conducted in Japan from 1996 to 1998, identified 333 cases. The numbers of patients per year, distribution of ages at onset, mode of onset, time lapse between onset and quiescence, neurological signs and symptoms, imaging findings, and the effects of conservative treatments were analyzed. The peak age was 15 to 17 years, with a marked male preponderance, usually a slow onset and progression, and quiescence six or fewer years after onset. There was a predominantly unilateral hand and forearm involvement with 'cold paresis'. The imaging findings are described.

Adolescent↗