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PubMed1997

Regeneration-blocked mdx muscle: in vivo model for testing treatments.

We have refined the mdx mouse as a clinical model for Duchenne dystrophy. Our power estimates, primary measures, regular sacrifice intervals, and quality checks constitute a high-speed, low-cost system for preclinically testing therapies designed to slow muscle destruction in Duchenne dystrophy. Irradiated (18 Gy) and contralateral shielded anterior tibial muscles were studied in 21-day-old mdx and normal mice at the time of irradiation and 4, 8, 12, 16, and 20 weeks thereafter. Regeneration-blocked mdx (irradiated) muscle expressed muscular dystrophy as progressive wasting after a brief (4 week) period of growth. Regeneration-blocked normal muscle showed stunted growth but neither progressive wasting nor microscopic pathological changes.

Animals↗
PubMed1980

Muscular changes in Engelmann's disease.

In a case of Engelmann's disease in an 11-year-old Japanese boy the muscular changes were studied in detail. Muscle weakness was maximal about the pelvic girdle. Muscle biopsy showed the selective atrophy of type II fibres, and no degenerative change could be seen histologically, histochemically, or electron-microscopically. Although the distribution of muscular weakness in Engelmann's disease is similar to that of a progressive muscular dystrophy, the disease does not seem to be a myopathy.

Bone Diseases, Developmental↗
PubMed1988

[Isaacs syndrome: report of a case].

The authors report a case of Isaacs syndrome observed in a 40 years old woman. The clinical picture included progressive muscular weakness, dysphagia, dysphonia, dyspnea and increased perspiration. Fasciculations, facial myokymia and pseudomyotonia were observed on physical examination. Electromyographic study at rest revealed continuous electrical muscle activity. Muscle histochemistry showed type II fibers atrophy and an ultrastructural study of the gastrocnemius muscle disclosed marked cysternal dilatation of the sarcoplasmatic reticulum. An excellent clinical response was observed with the use of carbamazepine. Some recent aspects of this rare syndrome are reviewed and discussed.

Adult↗
PubMed2026

Advances in the Application of Adenine Base Editor (ABE) in Biology and Medicine: Prospects and Challenges.

Adenine base editors (ABEs), which achieve A·T to G·C conversions in the genome precisely, symbolize a groundbreaking development in genetic engineering across animal, plant, and microbial systems. This review systematically summed up the research progress and current challenges of ABE in medical and biological applications: it outlined the historical context and pivotal milestones of its technological development; it emphasized major therapeutic advances for genetic diseases including spinal muscular atrophy, mitochondrial genetic disorders, and hyperlipidemia; it provided a comprehensive overview of its prospective uses for enhancing genetic traits in agricultural crops, including grains and fruits; this review conducted a multidimensional assessment of ABE performance through systematic comparison with other base editing technologies, comprehensively evaluating both editing efficiency and inherent limitations. It specifically addresses biosecurity risks such as off-target effects and genomic instability. Finally, safety concerns were proposed as the central challenge hindering its clinical translation, although ABE holds immense promise for precision medicine and agricultural breeding. Unlike previous reviews that mainly summarized early ABE development and general applications, this review particularly emphasizes recently engineered ABE systems, translational bottlenecks, delivery strategies, comparative clinical feasibility, and unresolved biosafety challenges that currently limit broader therapeutic and agricultural applications.

Adenine base editors↗
PubMed2005

The biological function of insulin-like growth factor-I in myogenesis and its therapeutic effect on muscular dystrophy.

In progressive muscular dystrophy, such as Duchenne muscular dystrophy, muscles show the pathological changes characterized by hypertrophy at the early phase, while atrophic changes are seen with aging. As an experimental model for muscle hypertrophy and atrophy, insulin-like growth factor-1 (IGF-1) signaling via the activation of PI3K/Akt pathway has been well characterized. IGF-1 is also highlighted as a therapeutic agent as it has been shown to improve phenotype of dystrophic animals. In this review, the functions of IGF-1 on mitogenic proliferation and myogenic differentiation in vitro, muscle hypertrophy in vivo are discussed, as well as its possible utility for molecular therapy on muscular dystrophies.

Animals↗
PubMed1991

[Autosomal recessive oculopharyngeal "muscular dystrophy"--clinical features and association with reduced activity of myophosphorylase].

We reported two cases of brothers demonstrating oculopharyngeal muscular dystrophy (OPMD). The cases had consanguineous parents and five healthy siblings, which suggested the autosomal recessive inheritance. The initial symptom was slowly progressive blepharoptosis with onset in the third decade. On examination, total external ophthalmoplegia was observed in both patients. Additionally, the elder, a 57-year-old man, exhibited dysarthria, dysphagia and muscular weakness with atrophy of the face, bilateral proximal upper limbs and diffuse lower limbs. The younger brother, a 55-year-old man, displayed muscular weakness and atrophy distributed in the face and four limbs. Muscle biopsy of both cases revealed rimmed vacuoles and spheroid bodies in the atrophic and normal-sized fibers. Biochemical study of the biopsy specimens of the elder brother disclosed the myophosphorylase activity reduced to about 40% of the normal value, although in the younger brother, that activity was normal. OPMD is usually inherited in the autosomal dominant mode, and autosomal recessive OPMD is rare. The onset age of our cases was younger than that of the autosomal dominant OPMD. There were some differences in the clinical manifestation between the presented cases, which could be interpreted as phenotypic variation. The elder brother was thought to be associated with McArdle's disease.

Blepharoptosis↗
PubMed2002

A mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease, caused by the expansion of a trinucleotide repeat (TNR) in exon 1 of the androgen receptor (AR) gene. This disorder is characterized by degeneration of motor and sensory neurons, proximal muscular atrophy, and endocrine abnormalities, such as gynecomastia and reduced fertility. We describe the development of a transgenic model of SBMA expressing a full-length human AR (hAR) cDNA carrying 65 (AR(65)) or 120 CAG repeats (AR(120)), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR(120) transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR(120) mice and was associated with the loss of alpha-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, showing that in SBMA the polyglutamine repeat expansion causes a dominant gain-of-function mutation in the AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. These mice represent the first model to reproduce the key features of SBMA, making them a useful resource for characterizing disease progression, and for testing therapeutic strategies for both polyglutamine and motor neuron diseases.

Animals↗
PubMedDate not supplied

[Identification of T274I mutation in the SMN1 gene in a patient with spinal muscular atrophy].

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by degeneration of motor neurones in the spinal cord. The symptoms of the disease are determinated by mutations of SMN1 gene. About 98% of SMA patients show homozygous absence of exon 7 SMN1 gene, the rest carry small intragenic mutations. Molecular analysis of the presence of exon 7 SMN1 gene deletion is considered as the screening test for SMA. We present a case report of a 9 years old girl with progressive muscular weakness of limbs and trunk. Clinical examination followed by electromyography and muscle biopsy was interpreted as a diagnostic of SMA 3. Molecular analysis did not reveal deletion of exon 7 SMN1 gene. Extended molecular diagnostics using direct sequencing showed missence mutation T2741. Thus, the absence of homozygous deletion of exon 7 SMN1 gene does not exclude SMA diagnosis. All patients fulfilling the diagnostic criteria for SMA, as defined by the International SMA Consortium, without deletion of exon SMN1 gene, should be analysed using direct sequencing.

Biopsy↗
PubMed1984

Peroneal muscular atrophy with pyramidal features.

Twenty-five cases of peroneal muscular atrophy with pyramidal features from 15 families are described. This disorder has been referred to as hereditary motor and sensory neuropathy (HMSN) type V by Dyck. Onset was usually in the first two decades of life with difficulty in walking. The clinical syndrome superficially resembled that of HMSN types I and II with distal wasting and weakness involving the legs more than the arms. The tendon reflexes in the upper limbs and at the knee tended to be normal or increased but the ankle jerks were often absent. The plantar responses were extensor in 22 patients, absent in two and flexor in one. Increased tone and weakness in the proximal lower limb muscles were found in about 30% of cases. Mean motor nerve conduction velocity was lower than in normal controls and sensory nerve action potentials were reduced in amplitude or absent in two thirds of the patients studied. Inheritance was autosomal dominant in the majority of families. The disorder was slowly progressive but did not lead to severe disability.

Adolescent↗
PubMed2003

Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein.

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin-proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.

Animals↗
PubMed1994

Successful pregnancies in the presence of spinal muscular atrophy: two case reports.

We report two cases of successful pregnancy in women with chronic, infantile onset, or type II spinal muscular atrophy, both of whom delivered healthy, unaffected babies. The patients required concurrent management by a physiatrist, pulmonologist, and perinatologist throughout the pregnancy. Complications included recurrent urinary tract infections, dyspnea and worsening of pulmonary function, wheelchair seating and positioning problems, and musculoskeletal and low back pain. These problems resolved postpartum. One woman had vaginal delivery, the other had caesarean section, both of which were well-tolerated. Because of severe musculoskeletal deformity, pelvic assessment is necessary to determine the mode of delivery. The uterus has normal contractility and effective labor patterns can be established. Spinal/epidural anesthesia may be contraindicated because of spine deformity. The pregnancies had no deleterious effect on the progression of the disease in our patients, both of whom reported a positive experience with great personal fulfillment.

Adult↗
PubMedDate not supplied

[Electrophysiological evaluation of a case of sensory-motor multifocal acquired demyelinating neuropathy. The effects of immunoglobulin therapy].

INTRODUCTION: Sensory motor multifocal acquired demyelinating neuropathy (SMMADN) is a variant of the chronic multifocal neuropathies. Several reports have been published about the clinical and electrophysiological progression in motor multifocal neuropathy (MMN) prior to and following immunoglobulin (Ig) therapy, but we have found no reports that deal with SMMADN. AIMS: We describe a case of SMMADN in which we conducted a clinical and electrophysiological evaluation before and after therapy with Ig UNC Hemoderivados. CASE REPORT: Female, 40 years of age, who presented asymmetrical weakness in all four limbs which she had been suffering for 12 years. We observed distal muscular atrophies, notable weakness and paresthesias in the four limbs. Electrophysiological studies revealed demyelinating neuropathy with secondary axonal involvement. Intravenous Ig was indicated. We observed a clear improvement in muscular strength, and changes in motor and sensory conduction speeds, but not in the amplitudes of the respective potentials. CONCLUSION: SMMADN is a chronic sensory motor multiple mononeuropathy that begins in the upper limbs and progresses asymmetrically down towards the lower members. The most usual sensory disorders are distal paresthesias. Electrophysiology presents conduction blockages, temporal dispersion, prolongation of the distal latencies, diminished conduction speeds, absence or prolongation of the F wave in one or more motor nerves, and abnormal sensory conduction speed. Accepted treatment is with Ig and, in some cases, with corticoids. In our case, the variations that were obtained could be explained by myelin reconstitution following the immunomodulatory effect of Ig and the axonal involvement that existed due to the secondary sequelae of the inflammatory process.

Adult↗
PubMed1988

The effect of peripheral nerve injury on immature motor and sensory neurons and on muscle fibres. Possible relation to the histogenesis of Werdnig-Hoffmann disease.

Sciatic nerve section in newborn rats causes loss of almost all motoneurons and of two thirds of the sensory neurons. Single motor axons may regenerate but they innervate only few muscle fibres. The nonreinnervated fibres vanish and are replaced by fat cells. The reinnervated muscle fibres are overloaded, hypertrophy, and eventually necrotize. Their satellite cells regenerate new fibres; most of them develop aneurally and then disappear. The muscles, if reinnervated at all, after 1 year consist of a mixture of hypertrophic fibres, non-innervated regenerates, and fat cells, and resemble muscle from patients with infantile spinal muscular atrophy Werdnig-Hoffmann. In immature rat muscles, restricted reinnervation and functional overload of the few innervated fibres maintain a self-enhancing process which eventually leads to the replacement of the entire muscle by fat tissue. It is suggested that Werdnig-Hoffmann disease starts during fetal life and that similar mechanisms are operative. The clinical progression would then depend on the extent of degeneration due to overload and on regeneration and reinnervation in the muscles rather than on the rate of continuous loss of anterior horn cells. Immature motoneurons in rat die when they loose contact with their target; one might therefore speculate that the primary lesion in Werdnig-Hoffmann disease is peripheral rather than central, and that lack of neuronotorophic influences causes the loss of anterior horn cells.

Animals↗
PubMed2006

[A case of cervical spondylotic amyotrophy resembling post-polio syndrome].

We reported a 62-year-old man with cervical spondylotic amyotrophy, in whom differentiation from post-polio syndrome was required. At the age of 3, the patient developed acute anterior poliomyelitis that caused muscular atrophy and muscle weakness in the left arm and bilateral lower limbs. At the age of 61, after approximately 58 years of symptomatic stabilization, the patient newly developed muscular atrophy and muscle weakness localized in the triceps muscle of the left arm. Since no sensory disturbance was noted, post-polio syndrome was initially suspected. However, MRI and myelo-CT demonstrated left side compression of the spinal cord at the level of the 6th cervical spine. Therefore, the patient was diagnosed as having cervical spondylotic amyotrophy, and the progression of the disease was prevented by having the patient rest. Since this patient had a history of acute anterior poliomyelitis, the number of anterior horn cells might have been decreased before he developed cervical spondylosis. Therefore, the patient might have shown clinical symptoms of cervical spondylotic amyotrophy mainly consisting of anterior horn disturbance and scarce sensory disturbance.

Cervical Vertebrae↗
PubMed2005

SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS.

BACKGROUND: ALS is believed to be multifactorial in origin with modifying genes affecting its clinical expression. Childhood-onset spinal muscular atrophy (SMA) is an autosomal recessive disorder of motor neurons, caused by mutations of the survival motor neuron (SMN) gene. The SMN gene exists in two highly homologous variants: SMN1, the causative gene responsible for the production of the majority of functional SMN protein, and SMN2, responsible for the production of less protein but sufficient for modifying the SMA phenotype. OBJECTIVE: To test whether SMN genotypes are associated with susceptibility to and severity of sporadic ALS. METHODS: We performed competitive quantitative PCR analysis for both SMN1 and SMN2 genes in 242 clinically well-defined ALS patients and 175 controls. The combined determination of SMN1 and SMN2 copies also allowed for an estimation of the level of SMN for each patient (estimated SMN protein level = SMN1 copy number + 0.20 x SMN2 copy number). RESULTS: One copy of SMN1 was associated with an increased risk of developing ALS (odds ratio = 4.1, 95% CI = 1.2 to 14.2, p = 0.02) and ALS patients carried fewer SMN2 copy numbers (p < 0.001). Sixty-one percent of patients had an estimated protein SMN level < or = 2.2 vs only 36% of controls (p = 0.0000004). Multivariate Cox regression analyses showed that lower SMN2 copy numbers and lower levels of estimated SMN protein (hazard ratio = 1.3, 95% CI = 1.1 to 1.6, p = 0.03) were associated with an increased mortality rate. CONCLUSIONS: SMN genotypes producing less SMN protein increase susceptibility to and severity of ALS.

Adult↗
PubMed2002

Muscle MRI findings of HTLV-1-associated myelopathy.

We report here the muscle MRI findings in two patients with human T-cell lymphotropic virus type I-associated myelopathy (HAM). It is known that thigh muscles are vulnerable in HAM patients, but detailed information about the affected muscles has not been available. Muscle MRI findings of these patients showed that thigh muscles, especially adductor magnus, and semimembranosus muscles were severely affected, but lower leg muscles were comparatively preserved. In these affected muscles, neurogenic changes were observed by EMG. We concluded that muscle MRI is very useful to estimate the affected muscles in HAM patients.

Aged↗
PubMed2024

Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.

Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13+/- hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13+/- transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.

Humans↗
PubMed1993

Neuromuscular diseases of childhood.

This review covers three areas. First, dramatic progress in the discovery of abnormal loci on certain chromosomes associated with several motor unit diseases eventually will obviate the need for more invasive testing. Second, new information about the natural course of spinal muscular atrophy is beginning to clarify the nature of this disease. Third, changes in the treatment of the acute and chronic polyneuropathies has shortened hospital stays.

Charcot-Marie-Tooth Disease↗