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PubMed1977

The development of the extensor digitorium brevis muscle in progressive proximal muscular antrophies.

The development of the extensor digitorium brevis (EDB) muscle was studied in 39 healthy subjects, 27 patients with progressive proximal spinal muscular atrophy, 20 patients with limb-girdle muscular dystrophy and three with facioscapulohumeral muscular dystrophy. The EDB muscle is spared and usually hypertrophic in patients with muscular dystrophy, whereas it is often atrophic and weak in patients with spinal muscular atrophy. It is proposed that the degree of development of the EDB muscle can be used as a clinical sign in the differential diagnosis of progressive muscular atrophies.

Adolescent↗

PubMed1984

[Sex-linked familial form of progressive spinal amyotrophy in adults].

An X-linked spinal muscular atrophy is reported in one family. Four of the five patients were examined. In three, electromyography, conduction nerve velocities and muscle biopsy were consistent with anterior horn cell disease. Similar families in the literature were reviewed and characteristic data were: 1) adult-onset, 2) proximal, bulbar and facial involvement, 3) prominent perioral fasciculations, 4) frequent association of cramps, tremor and sexual dysfunction (hypogonadism and gynecomastia), 5) very slow progression and favorable prognosis. These characteristics define, among the spinal muscular atrophies, a distinct entity named by several authors Kennedy's disease.

Adult↗

PubMed1996

Calf enlargement in neuromuscular diseases: a quantitative ultrasound study in 350 patients and review of the literature.

Calf hypertrophy is a typical clinical feature in neuromuscular diseases such as X-linked muscular dystrophies of Duchenne and Becker type and can be seen as an atypical feature in numerous other diseases. The diagnosis of calf hypertrophy usually is based on subjective visual assessment. The aim of this prospective study was to examine the prevalence of calf hypertrophy in a large number of patients with various neuromuscular diseases based on quantitative ultrasound measurement of calf muscle thickness. Additionally, true and pseudohypertrophy should be distinguished according to the absence or presence of abnormal muscle echointensities caused by infiltration of fat tissue. Fifty adult normal controls and 350 patients with various neuromuscular diseases were investigated. Absolute calf hypertrophy was diagnosed if the combined thickness of the gastrocnemius and soleus muscles exceeded the mean value of the control persons by at least 3.0 standard deviations (SD). Relative calf hypertrophy was diagnosed when the ratio of the combined thicknesses of the gastrocnemius and soleus muscles divided by the combined thicknesses of the rectus femoris and vastus intermedius muscles lay at least 3.0 SD below the mean value of the controls. Pseudohypertrophy was present if the echointensities of the gastrocnemius and soleus muscles reached or exceeded 3.0 SD above the mean value of the controls. An absolute hypertrophy of the calves was detected in 80 patients (= 22,9%; 64 true and 16 pseudohypertrophies), 16 patients exhibited a relative hypertrophy of the calves (= 4.6%; 12 true and 4 pseudohypertrophies). A significantly increased portion of both absolute calf hypertrophies and pseudohypertrophies as compared to the control group were found in juvenile proximal spinal muscular atrophy type 3, central core disease, centronuclear myopathy, benign X-linked muscular dystrophy of Becker type, autosomal recessive limb girdle muscular dystrophy, acid maltase deficiency, polymyositis, and granulomatous myositis. A significantly increased number of relative calf hypertrophies was present in juvenile proximal spinal muscular atrophy type 3, facioscapulohumeral muscular dystrophy, and inclusion body myositis. In the majority of the diseases included in the study, calf hypertrophy occurred in at least some patients. In conclusion, calf hypertrophy is a frequent and unspecific clinical feature in many neuromuscular diseases. Ultrasound is a convenient method for the exact definition of calf hypertrophy.

Adolescent↗

PubMed1980

Morphometric quantification of the cervical limb motor cells in various neuromuscular diseases.

The number of motor cells was significantly reduced in the C8 segment of the cervical spinal cord in all 12 cases of amyotrophic lateral sclerosis (ALS), in the C6 and/or C8 segments in 1 case of adult onset spinal muscular atrophy, 2 cases of Werdnig-Hoffmann (W-H) disease, 3 of 4 cases of chronic polyneuropathy and in 1 case of poliomyelitis and 1 of ossification of the posterior longitudinal ligament in the cervical spine (OPLL). The numbers of motor cells were normal in the C6 or C8 segment in 6 cases of muscular dystrophy, except in one case of congenital muscular dystrophy, who showed reduced numbers of the motor cells. Examination of the distribution of motor cells per 500 micrometers thickness in serial sections revealed that reduction in numbers of the motor cells was diffuse and symmetrical in half the cases of ALS and W-H disease and in the cases of chronic polyneuropathy and congenital dystrophy; diffuse but asymmetrical in the other ALS and W-H disease cases and in a case of adult spinal muscular atrophy, and localized and asymmetrical in the cases of poliomyelitis and OPLL. In muscular dystrophy the distribution of motor cells showed segmental variations similar to controls.

Adult↗

PubMed2006

Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene.

BACKGROUND: Mitochondrial DNA depletion syndrome is an autosomal recessive disorder characterized by decreased mitochondrial DNA copy numbers in affected tissues. It has been linked to 4 genes involved in deoxyribonucleotide triphosphate metabolism: thymidine kinase 2 (TK2), deoxyguanosine kinase (DGUOK), polymerase gamma (POLG), and SUCLA2, the gene encoding the beta-subunit of the adenosine diphosphate-forming succinyl coenzyme A synthetase ligase. OBJECTIVE: To highlight the variability in the clinical spectrum of TK2-related mitochondrial DNA depletion syndrome. DESIGN: Review of patients and the literature. SETTING: Tertiary care university. PATIENTS: Four patients with mitochondrial DNA depletion syndrome and mutations in the TK2 gene. MAIN OUTCOME MEASURES: Definition of clinical variability. RESULTS: Patient 1 had evidence of lower motoneuron disease and was initially diagnosed as having spinal muscular atrophy type 3. Patient 2, who is alive and ambulatory at age 9 years, presented at age 2 years with a slowly progressive mitochondrial myopathy. Patient 3 had a more severe myopathy, with onset in infancy and death at age 6 years of respiratory failure. Patient 4 had a rapidly progressive congenital myopathy with rigid spine syndrome and he died at age 19 months. CONCLUSION: The clinical spectrum of TK2 mutations is not limited to severe infantile myopathy with motor regression and early death but includes spinal muscular atrophy type 3-like presentation, rigid spine syndrome, and subacute myopathy without motor regression and with longer survival.

Adolescent↗

PubMed2004

Association of spinal and bulbar muscular atrophy with myotonic dystrophy type 1.

A man with spinal and bulbar muscular atrophy (SBMA) had a short (CTG)n expansion in the myotonic dystrophy protein kinase gene as well as (CAG)n expansion in the androgen receptor gene in leukocytes. The patient had the characteristic clinical findings of SBMA, but none of myotonic dystrophy type 1 (DM1). All of his three children (a son and two daughters) had the DM1 phenotype with long (CTG)n expansions. The daughters also had heterozygous long (CAG)n expansions. Postmortem examination of the patient revealed the characteristic pathological changes of SBMA as well as muscle degeneration compatible with DM1. Gene analysis of the organs disclosed unstable long expansions of the (CTG)n repeats, in contrast to the stable (CAG)n expansions. We have assumed that SBMA and DM1 developed independently in our patient, but cannot exclude the possibility that interactive gene effects increased somatic instability.

Adult↗

PubMed2001

Lung function measurements in young children with spinal muscle atrophy; a cross sectional survey on the effect of position and bracing.

BACKGROUND: Spinal muscular atrophy (SMA) affects respiratory muscles, which in addition to progressive scoliosis leads to respiratory impairment. Children with developing scoliosis are usually treated with spinal bracing to delay the progress. AIMS: To assess the impact of body position and application of spinal bracing on lung function during tidal breathing in children with SMA. METHODS: Lung function was determined by tidal flow volume loops and passive respiratory mechanics (single breath occlusion technique) in all eight children in southern Norway with SMA type I and II, in both the sitting and supine position. Additional measurements were performed with and without bracing in five children. Muscle strength was assessed by the Brooks scale. RESULTS: Tidal expiratory volume (V(E)) and compliance of the respiratory system (CRS) tended to be higher in the sitting compared to the supine position, but this was not statistically significant. However, applying bracing in the sitting position significantly reduced V(E). The highest values of CRS and V(E) were found in the sitting position without bracing. CONCLUSION: Impairment of tidal respiration must be considered when applying spinal bracing in very young children developing scoliosis with SMA.

Braces↗

PubMed1993

Anti-vimentin staining in muscle pathology.

The intermediate filaments of immature muscle fibres contain desmin and vimentin; vimentin is lacking in mature fibres. Regenerating fibres react with anti-vimentin antibodies and more intensely for desmin than mature fibres. The aim of the present study was to evaluate anti-vimentin staining for muscle pathology. Anti-vimentin-reactive fibres were found in 40 of 89 biopsies assessed. Fifteen patients with progressive destructive myopathy, infantile spinal muscular atrophy, clinically suspected Leigh's disease or unclassifiable congenital myopathy had between 1% and 95% vimentin-positive fibres. Less than 1% positive fibres were found in 25 patients with neuropathy with secondary myopathy or chronic myopathic conditions. Vimentin-positive fibres were lacking in 20 normal biopsies, in eight biopsies with neuropathic and in 21 biopsies with mild or non-destructive myopathic changes. We conclude that staining with anti-vimentin antibodies is a useful indicator for muscle fibre regeneration; it may help establish the diagnosis in infantile spinal muscular atrophy when the histopathology is non-characteristic. The high incidence of reactive fibres in some congenital or early-onset disorders may indicate developmental arrest.

Adolescent↗

PubMed1996

Somatic stability of the expanded CAG trinucleotide repeat in X-linked spinal and bulbar muscular atrophy.

Expansion of trinucleotide repeats has now been associated with eight inherited diseases: X-linked spinal and bulbar muscular atrophy, two fragile X syndromes, myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type I, dentatorubral pallidoluysian atrophy and Machado-Joseph disease. It has been shown that these expanded DNA repeats are unstable in number when transmitted from parents to offspring ("meiotic instability"), while somatic variation in repeat number has also been found in the fragile X syndrome and myotonic dystrophy. Moderate meiotic instability has been demonstrated in X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease). In order to determine if the expanded CAG repeat in SBMA also shows somatic instability, we compared different tissues from two patients with SBMA. We then examined the in vitro stability of the CAG repeat expansion by analyzing fibroblast cell cultures. Length comparison of expanded CAG repeats from all these materials clearly demonstrates that the CAG trinucleotide repeat in SBMA does not exhibit somatic variation.

Cells, Cultured↗

PubMed2004

A survival motor neuron:tetanus toxin fragment C fusion protein for the targeted delivery of SMN protein to neurons.

Spinal muscular atrophy (SMA) is a degenerative disorder of spinal motor neurons caused by homozygous mutations in the survival motor neuron (SMN1) gene. Because increased tissue levels of human SMN protein (hSMN) in transgenic mice reduce the motor neuron loss caused by murine SMN knockout, we engineered a recombinant SMN fusion protein to deliver exogenous hSMN to the cytosolic compartment of motor neurons. The fusion protein, SDT, is comprised of hSMN linked to the catalytic and transmembrane domains of diphtheria toxin (DTx) followed by fragment C of tetanus toxin (TTC). Following overexpression in Escherichia coli, SDT possessed a subunit molecular weight of approximately 130 kDa as revealed by both SDS-PAGE and immunoblot analyses with anti-SMN, anti-DTx, and anti-TTC antibodies. Like wild-type SMN, purified SDT showed specific binding in vitro to an RG peptide derived from Ewing's sarcoma protein. The fusion protein also bound to cultured primary neurons in amounts similar to those achieved by TTC. Unlike the case with TTC, however, immunolabeling of SDT-treated neurons with anti-TTC and anti-SMN antibodies showed staining restricted to the cell surface. Results from cytotoxicity studies in which the DTx catalytic domain of SDT was used as a reporter protein for internalization and membrane translocation activity suggest that the SMN moiety of the fusion protein is interfering with one or both of these processes. While these studies indicate that SDT may not be useful for SMA therapy, the use of the TTC:DTx fusion construct to deliver other passenger proteins to the neuronal cytosol should not be ruled out.

Animals↗

PubMed1997

X-linked spinal and bulbar muscular atrophy with myasthenic symptoms.

We describe a patient with X-linked spinal and bulbar muscular atrophy (X-SBMA) and myasthenic symptoms. The diagnosis of X-SBMA was established by demonstration of the increased number of CAG repeats in the androgen receptor gene on the X chromosome. This patient was characterized by the clinical symptoms of fatigability, decremental motor responses to repetitive nerve stimulation, and improvement of the myasthenic symptoms with oral administration of pyridostigmine. No serum antibody to acetylcholine receptor was detected. It is suggested that, in the process of chronic denervation and reinnervation of X-SBMA, reinnervated motor endplates may be associated with the defect of neuromuscular transmission.

Genetic Linkage↗

PubMed1998

Spinal and bulbar muscular atrophy (SBMA): somatic stability of an expanded CAG repeat in fetal tissues.

Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked motor neuron degenerative disease caused by an expanded trinucleotide repeat. Unlike most other trinucleotide repeat diseases, SBMA shows limited meiotic instability, and evidence thus far indicates absence of somatic instability in adults. Data regarding the presence of fetal tissue somatic mosaicism is unavailable. We present a family in which a woman whose father had SBMA requested prenatal testing. After informed consent. molecular genetic evaluation showed the male fetus to carry the SBMA repeat elongation. Testing of fetal tissues after elective pregnancy termination showed no somatic mosaicism in the CAG repeat length. This is the first report of molecular genetic analysis of multiple tissues in an affected fetus, and only the second report of prenatal diagnosis in SBMA.

Abortion, Induced↗

PubMed1997

Learning systems in biosignal analysis.

In biosignal analysis, the utility of artificial neural networks (ANN) in classifying electromyographic (EMG) data trained with the momentum back propagation algorithm has recently been demonstrated. In the current study, the self-organizing feature map algorithm, the genetics-based machine learning (GBML) paradigm, and the K-means nearest neighbour clustering algorithm are applied on the same set of data. The aim of this exercise is to show how these three paradigms can be used in practice, given that their diagnostic performance is problem- and parameter-dependent. A total of 720 macro EMG recordings were carried out from four groups, from seven normal, nine motor neuron disease, 14 Becker's muscular dystrophy, and six spinal muscular atrophy subjects, respectively. Twenty-three of the subjects were used for training and 13 for evaluating the various models. For each subject, the mean and the standard deviation of the parameters (i) amplitude, (ii) area, (iii) average power and (iv) duration were extracted. The feature vector was structured in two different ways for input to the models: an eight-input feature vector that consisted of both the mean and the standard deviation of the four parameters measured, and a four-input feature vector that included only the mean of the parameters. Also, due to the heterogenous nature of the spinal muscular atrophy group, three class models that excluded this group were investigated. In general, self-organizing feature map and GBML models resulted in comparable diagnostic performance of the order of 80-90% correct classifications (CCs) score for the evaluation set, whereas the K-means nearest neighbour algorithm models gave lower percentage CCs. Furthermore, for all three learning paradigms: better diagnostic performance was obtained for the three class models compared with the four class models; similar diagnostic performance was obtained for both the eight- and four-input feature vectors. Finally, it is claimed that the proposed methodology followed in this work can be applied for the development of diagnostic systems in the analysis of biosignals.

Algorithms↗

PubMed1996

AAEM minimonograph #46: neurogenic muscle hypertrophy.

Muscle hypertrophy occurs uncommonly in several neurogenic disorders including neuropathies, radiculopathies, spinal muscular atrophy, and post-polio syndrome. Its pathogenesis varies in different circumstances. In the presence of generalized myokymia and neuromyotonia (Isaacs' syndrome), symmetrical hypertrophy appears to be the result of continuous spontaneous electrical stimulation of myofibers and, in some cases, results in type 1 myofiber preponderance. Focal hypertrophy occurring with radiculopathies and mononeuropathies was associated with complex repetitive discharges (CRDs) in approximately half the cases. CRDs may play a role in the pathogenesis of myofiber hypertrophy by continuous myofiber stimulation, but in some cases, with and without CRDs, myofiber hypertrophy may be related to mechanical events. Muscle enlargement seen in old polio appears to involve a significant degree of pseudohypertrophy, although some myofiber hypertrophy occurs. The symmetrical occurrence of hypertrophy in genetically determined disorders, such as spinal muscular atrophy, and hereditary motor and sensory neuropathy types 1 and 2 may have both a genetic and a mechanical basis in addition to pseudohypertrophy in some cases.

Humans↗

PubMedDate not supplied

[Hereditary neuromuscular diseases in paediatrics. Our experience over the last 14 years].

INTRODUCTION: Hereditary neuromuscular diseases are disorders which can vary largely in their age of onset, symptoms and severity. Many are severe, disabling and have an important personal, familial and social impact and can restrict the prognosis for survival. The constant progress being made in diagnostics makes it necessary to continually update knowledge and information. PATIENTS AND METHODS: We carried out a review of the hereditary neuromuscular diseases contained in the Neuropaediatrics database at the Hospital Miguel Servet in Zaragoza from May 1990 to October 2004. RESULTS: Of the 7,805 patients in the database, 123 (1.5% of the total) were patients with hereditary neuromuscular diseases, of whom 71 were males and 52 females. These included: 35 sensory-motor hereditary neuropathies, 17 dystrophinopathies, 10 myotonic dystrophies, 10 spinal muscular atrophies, four merosin-deficient congenital dystrophies, four other muscular dystrophies, three mitochondrial myopathies, three myasthenias, two familial neuropathies with insensitivity to pain, two Friedreich's ataxias, one familial neuropathy with liability to pressure palsies, one case of Walker-Warburg syndrome, five polyneuropathies associated to leukodystrophy and another 25 cases that could not be classified. Genetic studies provided a diagnosis in 36 cases (29.2%): nine myotonic dystrophies, eight dystrophinopathies, eight cases of spinal muscular atrophy, four demyelinating sensory-motor hereditary neuropathies, two instances of Friedreich's ataxia, two limb-girdle muscular dystrophies, one congenital myasthenia, one McArdle's disease and one case of Kearns-Sayre syndrome. CONCLUSIONS: Genetic studies enable us to establish diagnoses that were previously limited to the realm of assumption, and allow us to avoid the need for muscle tissue biopsies, which is a welcome development, especially when dealing with children. Immunohistochemical studies need to be updated and biological samples should be systematically saved in cases where no diagnosis is reached.

Child↗

PubMed1997

The lateral corticospinal tract and spinal ventral horn in X-linked recessive spinal and bulbar muscular atrophy: a quantitative study.

A quantitative study was performed on spinal cord lesions in seven patients with X-linked recessive spinal and bulbar muscular atrophy. The myelinated fiber density of the lateral corticospinal tracts at the T7 cord level was well preserved for both large and small myelinated fibers. On the other hand, neurons in the L4 ventral horn were markedly depleted; marked loss was noted of the large alpha and medium-sized gamma motor neurons located in the lateral and medial nuclei as well as the small neurons in the intermediate zones of the ventral horn. These results suggest that myelinated fiber density and fiber-size distribution in the corticospinal tract are well preserved and that neuronal loss in the ventral horns is not restricted to alpha and gamma motoneurons but also involves small interneurons.

Aged↗

PubMed2004

Identification of a novel cyclic AMP-response element (CRE-II) and the role of CREB-1 in the cAMP-induced expression of the survival motor neuron (SMN) gene.

Spinal muscular atrophy, an autosomal recessive disorder, is caused by loss of the SMN1 (survival motor neuron) gene while retaining the SMN2 gene. SMN1 produces a majority of full-length SMN transcript, whereas SMN2 generates mostly an isoform lacking exon 7. Here, we demonstrate a novel cAMP-response element, CRE-II, in the SMN promoter that interacts with the cAMP-response element-binding (CREB) family of proteins. In vitro DNase I protection analysis and in vivo genomic footprinting of the SMN promoter using the brain and liver nuclei from SMN2 transgenic mice revealed footprinting at the CRE-II site. Site-directed mutation of the CRE-II element caused a marked reduction in the SMN promoter activity revealed by transient transfection assay. Activation of the cAMP pathway by dibutyryl cAMP (0.5 mm) alone or in combination with forskolin (20 microm) caused a 2-5-fold increase in the SMN promoter activity but had no effect on the CRE-II mutated promoter. Electrophoretic mobility shift assay and a UV-induced DNA-protein cross-linking experiment confirmed that CREB1 binds specifically to the CRE-II site. Transient overexpression of CREB1 protein resulted in a 4-fold increase of the SMN promoter activity. Intraperitoneal injection of epinephrine in mice expressing two copies of the human SMN2 gene resulted in a 2-fold increase in full-length SMN transcript in the liver. Combined treatment with dibutyryl cAMP and forskolin significantly increased the level of both the full-length and exon 7-deleted SMN (exonDelta7SMN) transcript in primary hepatocytes from mice expressing two copies of human SMN2 gene. Similar treatments of type I spinal muscular atrophy mouse and human fibroblasts as well as HeLa cells resulted in an augmented level of SMN transcript. These findings suggest that the CRE-II site in SMN promoter positively regulates the expression of the SMN gene, and treatment with cAMP-elevating agents increases expression of both the full-length and exonDelta7SMN transcript.

Animals↗

PubMedDate not supplied

[Characteristics in the treatment of scoliosis in muscular diseases].

INTRODUCTION: Patients suffering from the most frequent muscle disorders Duchenne muscular dystrophy (DMD) and spinal muscular atrophies (SMA), who ceased walking respectively are confined from the outset to the wheel-chair, are developing commonly a progressive scoliosis (collapsing spine) due to an increasing muscle weakness. Basing on the pelvic obliquity these scolioses are leading first of all to problems in sitting as well as difficulties in trunk and head control. Along with the increasing weakness of respiratory muscles these phenomena entail a restrictive respiratory insufficiency. CONSERVATIVE TREATMENT: An effective conservative treatment is not available for these scolioses. The use of a corset, however, can only be taken into consideration as a compromise, either for very young patients or those who refused an operation respectively who have reached an inoperable stage. The exclusive use of so-called "anatomic sitting supports" in the wheel-chair in order to treat or prevent a progressive scoliosis in DMD or SMA is absolutely to be rejected. They should only be applied for very young patients with SMA type II as a transitional solution until a corset or better an surgical stabilisation of the spine will be effected, or as a palliative measure in late stages. SURGICAL TREATMENT: Only the early as possible performed surgical stabilisation of the spine using adequate instrumentation (Luque, CD or modifications), enabling an early mobilization without corset or cast, is the most effective treatment of these scoliosis. Patients with DMD or SMA type III should be stabilized after loss of walking ability and definitive confinement to wheel-chair, if the curve is more than 20 degrees-30 degrees Cobb and progressive and forced vital capacity (FVC) is > 35%. The instrumentation should be applied between D3 or D4 and sacrum. The bony fusion mass should include the lumbar and lumbosacral region. The unfused instrumentation with the telescope-rod after Naumann is a good solution for patients with SMA type II and progressive curves already in the early childhood from ca. 5 years of age. First of all surgical spinal stabilisation improves the sitting comfort. Over and above this the improved cosmetic appearance should not be underestimated for the psychological condition of these patients. Additionally it is proved, that surgical stabilisation of the spine prolongs the life expectancy of patients with DMD. Furthermore stabilization of lung function can be achieved for both DMD and SMA patients in comparison to the natural history of these diseases. Altogether a decisive improvement of quality of life can be reached for all these patients.

Adolescent↗