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PubMed1976

Peripheral motor and sensory neuropathy of early childhood, simulating Werdnig-Hoffmann disease.

A five-year-old girl developed neurogenic muscular atrophy during infancy. On the basis of clinical findings and a muscle biopsy study a diagnosis of infantile spinal muscular atrophy, benign type II, was entertained. As the disease progressed, involvement of sensory pathways was detected by electrophysiological studies. Examination of a sural nerve specimen suggested a chronic polyneuropathy rather than spinal muscular atrophy. These findings were confirmed at autopsy by demonstrating severe loss of myelinated axons in ventral and dorsal spinal roots, peripheral nerves and dorsal columns of the spinal cord. In addition, islands of astroglial fibers were found in ventral and dorsal spinal roots, regarded as a secondary reaction to the breakdown of myelinated axons. This unusual scarring process seems to result from nerve fiber loss during the perinatal period, since radicular glial scar tissue is not known to occur in the spinal muscular atrophies of later onset. Examination of the sensory nervous system in patients with Werdnig-Hoffmann disease appears mandatory to clarify the precise disease entity leading to infantile neurogenic muscular atrophy.

Child, Preschool↗
PubMed1993

[Frequency of hereditary neurologic diseases. A clinical study].

INTRODUCTION: The nervous system is affected in 30% of hereditary monogenic disorders and as many as 500 single-gene disorders display major neurologic symptoms. We have studied the frequency of hereditary neurological diseases to assess their importance in daily hospital activity. Only single-gene hereditary diseases with central or peripheral nervous system involvement were considered; thus chromosomal diseases and diseases with multifactorial etiology were excluded. METHODS: We surveyed admission to in- and out-patient departments of Neurology, Pediatrics, and Dermatology of the Aosta Regional Hospital for the calendar years 1982-1991, collecting 229 cases, 95 women and 134 men. Out-patient departments held 126 patients, the others came from in-patient departments. Admission to the neurological in-patient department were 1.8% of total neurological admissions in the same period. Each diagnosis was assigned to the code number of the International Classification of Diseases (ICD-IX Revision, 1975). RESULTS: We found 33 different phenotypes. Most frequent diagnoses were: essential tremor (89 patients), hereditary sensory-motor neuropathy (HSMN) type I (28), Huntington's chorea (13), progressive muscular dystrophy limb-girdle type (8), neurofibromatosis type I (9), HSMN type II (9), spinocerebellar ataxia (9), hereditary spastic paraplegia (7), spinal muscular atrophy type IV (5), myotonic dystrophy (5), cerebellar ataxia (4), HSMN type III (4), spinal muscular atrophy type II and III (3), tuberous sclerosis (3). Essential tremor mostly affected persons in the over-50 age groups. On the contrary, the other neurologic monogenic diseases were diagnosed in all ages with the following age-group breakdown: 0-9, 11%; 10-19, 16%; 20-29, 15%; 30-39, 8%; 40-49, 11%; 50-59, 19%; 60-69, 14%, 70+, 7%. Consistently with the general rule, autosomic recessive diseases have the earliest onset and autosomic dominant ones the latest; HSMN, spinal muscular atrophy and Huntington's chorea were the disorders diagnosed in older age group. DISCUSSION: Although the frequency of the single neurologic monogenic disease is low (with the exception of essential tremor), their overall prevalence is higher than the prevalence of multiple sclerosis or the peripheral neuropathies. All age-groups are involved. We separated three groups of diseases: 1) two relatively benign diseases, essential tremor and the HSMN, affecting half of our patients; 2) five severe and more common diseases (Huntington's chorea, progressive muscular dystrophy limb-girdle type, neurofibromatosis type I, spinocerebellar ataxia, hereditary spastic paraplegia), affecting 1/4 of patients; and 3) a group of rare, mostly severe diseases, affecting the remaining 1/4 of patients.

Adolescent↗
PubMed1986

Muscle diseases in Singapore.

This study aims to establish the pattern of muscle diseases in Singapore. Two hundred consecutive muscle biopsies collected prospectively over a period of 7 yr (1978-1984) were studied using light microscopy, histochemistry and electron microscopy. Muscle diseases were not uncommon. There was no racial predilection. The common muscle diseases were polymyositis, spinal muscular atrophies and muscular dystrophies. Less common ones included congenital myopathies and storage diseases due to disorders of glycogen and lipid metabolism. Other muscle diseases were uncommon. Polymyositis was the commonest muscular disorder in adults and spinal muscular atrophy in childhood. This finding is encouraging as polymyositis is a treatable condition. The common occurrence of spinal muscular atrophies in this country was not fully appreciated. They were often misdiagnosed clinically as muscular dystrophies. It is hoped that this finding will result in greater awareness of this condition which is necessary for proper genetic counselling and management.

Age Factors↗
PubMed1973

Oculopharyngeal involvement in familial neurogenic muscular atrophy.

A Japanese family with progressive spinal muscular atrophy is presented. Seven members in two generations were affected and the mode of inheritance was probably an autosomal recessive trait. A characteristic feature of this family was the presence of oculopharyngeal involvement in some of the affected members, in addition to the variable distribution of muscular atrophy among each of the affected members, such as mainly proximal or distal atrophies in the limbs. In one case the oculopharyngeal weakness appeared without limb involvement. The changes in the extremities were thought to be of neurogenic origin, and so was the progressive external ophthalmoplegia seen characteristically in these cases, although the latter was similar to ocular myopathy.

Action Potentials↗
PubMedDate not supplied

Scapuloperoneal muscular atrophy: Davidenkow's syndrome. Family report.

The nosology of scapuloperoneal syndrome remains controversial. Is it a variant of Charcot-Marie-Tooth's disease, a form of myopathy, or of spinal muscular atrophy is still unknown. A family with a scapuloperoneal syndrome caused by anterior horn cell involvement is described. Data for sensory involvement were also found. In addition one member of the family had motor nerves and corticospinal tract involvement. The distribution of weakness and muscle wasting was unusual--only lower limbs were involved. However, electromyographic data for both upper and lower limbs involvement were evident. The combination of scapuloperoneal syndrome with sensory loss has been described by Davidenkow, but was not proved by neurographic investigation. Later only one case with proved sensory disturbances was reported. Patients with motor nerves involvement in addition were reported, but not received satisfactory explanation. Probably in some patients the disease could be manifested only with anterior horn cell involvement, while in other both motor and sensory nerves could be involved. In conclusion we suppose that the scapuloperoneal muscular atrophy is a form of spinal muscular atrophy which could be manifested by different symptoms.

Adolescent↗
PubMed1998

Muscle could be the therapeutic target in SMA treatment.

A nerve-muscle coculture model (human muscle cells innervated by embryonic rat spinal cord) was used to explore the pathogenesis of spinal muscular atrophy (SMA). Previous studies showed that myofibers from donors with SMA type I or SMA type II (but not SMA type III) undergo a characteristic degeneration 1-3 weeks after innervation (Braun et al. [1995] Lancet 345:694-695). To determine which cells are involved in degeneration, we cloned satellite cells and fibroblasts derived from muscle biopsies of normal (healthy) donors and donors with SMA. We show that fibroblasts are required for successful innervation, that fibroblasts from normal and SMA donors contribute equally well to the establishment of cocultures, and that only SMA satellite cells are responsible for the degeneration of innervated cocultures. We succeeded in preventing the degeneration of cloned satellite cells from SMA donors by adding 50% cloned satellite cells from normal donors to the culture to make heteromyotubes. In mixed cocultures, after innervation, we did not observe degeneration. This result suggests that survival of the cocultures depends on a message derived from the muscle cells. Consequently, we propose that therapeutic approaches for SMA that could repair (or compensate for) the genetic defect in muscle cells (which are otherwise much more accessible for gene therapy than neurons) might prevent motoneuron degeneration. The role of muscle cells in the establishment and the degeneration of neuromuscular junctions deserves further attention and investigation.

Animals↗
PubMed1999

Complex repetitive discharges: cause or effect of neurogenic muscle hypertrophy?

We report a patient with adult-onset spinal muscular atrophy (SMA) of the scapulohumeral type with neurogenic muscle hypertrophy (NMH) in markedly weakened biceps muscles in association with continuous complex repetitive discharges (CRDs). This is an apparently unique case due to the bilaterality of the NMH associated with CRDs as well as the well-circumscribed symmetric upper extremity distribution of the hypertrophy. The possible mechanisms of NMH in association with spontaneous motor activity are discussed.

Adult↗
PubMed1998

Deletion analysis of Bulgarian SMA families.

All three types of autosomal recessive spinal muscular atrophy map to chromosome region 5q13. Recent reports suggest that they are associated with deletions of two adjacent genes: SMN and NAIP. Here we report the first deletion analysis of Bulgarian SMA families. Homozygous deletion of exons 7 and 8 of the SMN gene were found in 85% of our patients, but the NAIP gene (exons 5 and 6) was deleted in only 26% of patients. To our knowledge, these frequencies are some of the lowest reported so far. The NAIP gene was deleted predominantly in severely affected patients (type I), while in the group with milder types SMA only deletions of the SMN gene were detected. Our phenotype-genotype correlation study confirmed that larger deletions are associated with more severe clinical course. The Bulgarian data support the thesis that the telomeric SMN gene could play a major role in determining SMA, while the NAIP or the centromeric SMN copy have a modifying effect on the phenotype.

Bulgaria↗
PubMed1993

Presymptomatic diagnosis of SMA III by genotype analysis.

Linkage analysis and prenatal prediction in families segregating autosomal recessive spinal muscular atrophy (SMA) has become feasible since the assignment of the locus responsible for type I-III SMA to region 5q12-q13.3. We have performed a segregation study of SMA in Italian families using molecular probes and highly informative PCR-based polymorphic markers. In one family, a 7-year-old boy affected with type III SMA and an 8-year-old apparently healthy brother had identical haplotypes. These findings prompted us to reexamine the apparently unaffected child. His neurological exam was normal. However, the electromyography (EMG) showed a pattern consistent with chronic SMA. To our knowledge this is the first example of presymptomatic diagnosis of SMA based on genotype analysis.

Base Sequence↗
PubMed2005

Natural history of denervation in SMA: relation to age, SMN2 copy number, and function.

Denervation was assessed in 89 spinal muscular atrophy (SMA) 1, 2, and 3 subjects via motor unit number estimation (MUNE) and maximum compound motor action potential amplitude (CMAP) studies, and results correlated with SMN2 copy, age, and function. MUNE and maximum CMAP values were distinct among SMA subtypes (p < 0.05). Changes in MUNE and maximum CMAP values over time were dependent on age, SMA type, and SMN2 copy number. SMN2 copy number less than 3 correlated with lower MUNE and maximum CMAP values (p < 0.0001) and worse functional outcomes. As SMN2 copy number increases, so does functional status (p < 0.0001). Change in MUNE longitudinally over the time intervals examined in this study was not statistically significant for any SMA cohort. However, a decline in maximum CMAP over time was apparent in SMA2 subjects (p = 0.049). Age-dependent decline in MUNE and maximum CMAP was apparent in both SMA 1 (p < 0.0001) and SMA 2 (p < 0.0001) subjects, with age as an independent factor regardless of type. Maximum CMAP at the time of the initial assessment was most predictive of functional outcome (p < 0.0001). Prospective longitudinal studies in four prenatally diagnosed infants demonstrated significant progressive denervation in association with symptomatic onset or functional decline. These data highlight the potential value of such measures in increasing our understanding of pathophysiological factors involved in denervation in SMA.

Activities of Daily Living↗
PubMed2002

Implementation of SMA carrier testing in genetic laboratories: comparison of two methods for quantifying the SMN1 gene.

The degeneration and loss of motor neurons of the anterior horn characterize children affected with spinal muscular atrophy (SMA). Mutations in the survival motor neuron gene (SMN1) are determinant for the development of the disease whereas the number of copies of SMN2, the highly homologous copy of SMN1, plays a role as a phenotypic modifier factor. The detection of SMN1 homozygous deletions is the typical test for SMA diagnosis. Owing to the limitation of this test for carrier and heterozygous deletion analysis, the demand of SMN1 quantitative tests is permanently growing. The high incidence of SMA, the notable carrier frequency, the severity of the disease, and the lack of effective treatment may justify the implementation of such an analysis in DNA diagnostic labs. The advantages and disadvantages of two reliable quantitative methods were evaluated. One of these is a competitive PCR protocol using internal standards and a genomic sequence as a reference. The other method is a real-time PCR employing an external standard as a reference. Both methods present sufficient advantages for incorporation into molecular genetic diagnostic labs. The possibility of studying samples from different labs, the versatility and reproducibility of the analysis, and cost-benefit calculations must be considered in the final choice.

Cyclic AMP Response Element-Binding Protein↗
PubMed2004

Molecular analysis of SMA patients without homozygous SMN1 deletions using a new strategy for identification of SMN1 subtle mutations.

Spinal muscular atrophy (SMA) is a common autosomal recessive disease. SMA is linked to the 5q13 locus in 95% of patients, and in at least 98% of them, the SMN1 homozygous deletion is found. Compound heterozygous patients, who have an SMN1 deletion associated with a subtle mutation, appear undeleted with the common molecular diagnostic test that detects only the homozygous absence of SMN1. In these patients, mutation screening in SMN1 is hampered by the presence of several copies of the highly homologous SMN2 gene. Here, we present a rapid and reliable strategy for detecting SMN mutations using long-range PCR, which avoids cloning and cDNA analysis. Using this method, we found 10 mutations, including five mutations never reported previously and five recurrent mutations; some of them are probably population-specific. Marker analysis of the 5q13 locus in these mutations showed common haplotypes, supporting the hypothesis of a common ancestor rather than a hot spot sequence. We also evaluate the suitability of automated SSCA and DHPLC for mutation scanning.

Automation↗
PubMed2006

Gene-based treatment of motor neuron diseases.

Motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are progressive neurodegenerative diseases that share the common characteristic of upper and/or lower motor neuron degeneration. Therapeutic strategies for MND are designed to confer neuroprotection, using trophic factors, anti-apoptotic proteins, as well as antioxidants and anti-excitotoxicity agents. Although a large number of therapeutic clinical trials have been attempted, none has been shown satisfactory for MND at this time. A variety of strategies have emerged for motor neuron gene transfer. Application of these approaches has yielded therapeutic results in cell culture and animal models, including the SOD1 models of ALS. In this study we describe the gene-based treatment of MND in general, examining the potential viral vector candidates, gene delivery strategies, and main therapeutic approaches currently attempted. Finally, we discuss future directions and potential strategies for more effective motor neuron gene delivery and clinical translation.

Amyotrophic Lateral Sclerosis↗
PubMed1991

Maximal and minimal motor nerve conduction velocities in patients with motor neuron diseases: correlation with age of onset and duration of illness.

We measured the maximal and minimal motor nerve conduction velocities of the ulnar nerve in 17 patients with spinal muscular atrophy (SMA), 27 patients with amyotrophic lateral sclerosis (ALS), and 40 age-matched control subjects. Crude values of the maximal and minimal motor nerve conduction velocities were reduced in both patient groups, but their difference in each patient was not statistically different from that of a control subject. The conduction velocities adjusted according to each patient's age were faster in SMA patients than in ALS patients. Among patients with either ALS or SMA, the age-adjusted conduction velocities were larger in those who had developed the disease at younger ages and suffered from it for shorter periods of time. These findings suggest that the motor nerve fibers regenerate more in younger patients in the early stages of the disease, particularly in SMA.

Action Potentials↗