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PubMed1998

Molecular basis of neuromuscular diseases.

For many neuromuscular disorders, the chromosomal location is known, the causal gene has been identified, and direct application of this knowledge may be made in a clinical setting. The benefits resulting from molecular-based methods include improved diagnostic accuracy and genetic counseling for patients and other at risk family members. This chapter discusses in detail four of the most frequently encountered neuromuscular disorders. These diseases include spinal muscular atrophy, Charcot-Marie-Tooth neuropathy, Duchenne/Becker type muscular dystrophy, and myotonic dystrophy.

Charcot-Marie-Tooth Disease↗
PubMed2000

Sensory involvement in spinal-bulbar muscular atrophy (Kennedy's disease).

Spinal-bulbar muscular atrophy (SBMA) is a rare X-linked neuronopathy associated with an abnormal representation of androgen receptors in the nervous system. Standard nerve conduction and histopathological studies have disclosed the involvement of large myelinated sensory fibers in the spinal nerves of SBMA patients. Little is known about the involvement of small sensory neurons and trigeminal nerves. Laser evoked potentials (LEPs) were studied in 6 unrelated patients with SBMA; 5 of these patients also underwent trigeminal reflex recordings, and 3 a sural nerve biopsy. LEPs were markedly abnormal, indicating a dysfunction in pain pathways. Given the sparing of small fibers in the sural nerve specimens, we hypothesize a dysfunction in spinothalamic cells, possibly due to an abnormal representation of the androgen receptors. Except for the jaw-jerk, all the trigeminal reflexes were markedly abnormal. Since the afferents for the jaw-jerk have their cell body within the central nervous system instead of the ganglion, the selective sparing of the jaw-jerk indicates a trigeminal ganglionopathy.

Aged↗
PubMed1996

Disaggregation of polyribosomes in the spinal anterior horn cells in a patient with X-linked spinal and bulbar muscular atrophy.

The spinal anterior horn cells (AHCs) in a patient with X-linked spinal and bulbar muscular atrophy (SBMA) were examined by light and electron microscopy, giving special attention to alterations in the rough endoplasmic reticulum (ER). Seven age-matched subjects were used as controls. The patient with SBMA showed a severe decrease of AHCs, but the Nissl substance in the remaining AHCs appeared well preserved on light microscopy. Electron microscopy revealed a relatively well preserved parallel lamellar pattern of ER and marked disaggregation of the polyribosomes surrounding the ER in the remaining AHCs. These findings indicate that the Nissl substance was affected in spite of its light microscopic appearance in SBMA, and that the AHCs degenerate through disaggregation of the polyribosomes of the ER.

Anterior Horn Cells↗
PubMed1988

[Chronic proximal spinal amyotrophies in Tunisia. Clinical, genetic, epidemiologic and histopathologic study].

The results of a clinical, pathological, genetic and epidemiological study of 101 cases of chronic proximal spinal muscular atrophy are reported. Ages at onset allow to distinguish clearly an infantile, a juvenile and an adult groups. The infantile and juvenile groups comprising 93 p. 100 of the patients, were characterized by onset before the age of 20 (54 p. 100 before age 5) and by a large intra- and interfamilial clinical variability. The severity of the disease was unrelated either to sex or the sporadic or familial nature of the disease. On the other hand it was closely related to age at onset and to the pathology of the muscles. There seems to be no genetic heterogeneity in this group. Inheritance is of the autosomal recessive type in the great majority of cases. Certain sporadic cases may be due to a dominant mutation or to a phenocopy, as suggested by segregation analysis. The adult group, comprising 6 patients, included 4 cases of autosomal dominant inheritance without consanguinity of the parents, and one case of dominant inheritance.

Adolescent↗
PubMed1987

Neuropsychological performance of children with Duchenne muscular dystrophy and spinal muscle atrophy.

Neuropsychological examinations were conducted on 39 boys with Duchenne muscular dystrophy (DMD) and 12 children with spinal muscular atrophy (SMA). There were no significant group differences in the pattern or level of test-score profiles, indicating that the performances of the two patient groups were very similar. However, pattern analysis indicated that while scores on verbal and non-verbal intelligence tests were within the average range for the children with DMD, there were deficits on tests of immediate memory.

Adolescent↗
PubMed2003

Sporadic lower motor neuron disease with adult onset: classification of subtypes.

The discovery of the genetic basis of hereditary lower motor neuron disease (LMND) and the recognition of multifocal motor neuropathy as a distinct clinical entity necessitate a new classification of LMND. To this end, we studied the clinical and electrophysiological features of 49 patients with sporadic adult-onset LMND in a cross-sectional study. Disease duration was more than 4 years to exclude the majority of patients with amyotrophic lateral sclerosis. Based on the pattern of weakness, we identified three groups: 13 patients with generalized weakness (group 1); eight patients with symmetrical, distal muscle weakness (group 2); and 28 patients with non-generalized asymmetrical weakness of the arms in most patients (group 3). Group 3 could be subdivided into patients with weakness in predominantly the distal (group 3a) or the proximal (group 3b) muscle groups, both with disease progression to adjacent spinal cord segments. Distinctive features of group 1 were an older age at onset, more severe weakness and muscle atrophy, lower reflexes, greater functional impairment, more widespread abnormalities on concentric needle EMG, respiratory insufficiency and serum M-protein. In groups 2 and 3, concentric needle EMG findings also suggested a more widespread disease process. Retrospectively, the prognosis of sporadic adult-onset LMND appears to be favourable, because clinical abnormalities were still confined to one limb in most patients after a median disease duration of 12 years. We propose to classify the patients in the different subgroups as slowly progressive spinal muscular atrophy (group 1), distal spinal muscular atrophy (group 2), segmental distal spinal muscular atrophy (group 3a) and segmental proximal spinal muscular atrophy (group 3b). The described clinical phenotypes may help to distinguish between different LMND forms.

Adult↗
PubMed1987

Juvenile-onset bulbospinal muscular atrophy with deafness: Vialetta-van Laere syndrome or Madras-type motor neuron disease?

A girl with rapid-onset, bulbospinal muscular atrophy and deafness is described. The patient's mother and brother showed EMG features consistent with subclinical involvement. T is bulbospinal form of spinal muscular atrophy associated with deafness described by Vialetto and van Laere closely resembles the Madras type of motor neuron disease, also associated with deafness, described by Jagganathan and colleagues.

Adolescent↗
PubMed2005

Choline acetyltransferase expression does not identify early pathogenic events in fetal SMA spinal cord.

We investigated the expression of choline acetyltransferase, a specific marker for cholinergic neurons, in control and spinal muscular atrophy fetuses and newborns. By immunoblot we observed at 12 and 15 weeks a similar pattern of choline acetyltransferase expression in spinal muscular atrophy with respect to controls, although at 22 weeks this expression was reduced, probably due to a smaller number of motor neurons in the spinal muscular atrophy spinal cord. By immunohistochemistry, the counting of positive and negative motor neurons for choline acetyltransferase immunostaining in control and spinal muscular atrophy fetuses showed a similar proportion at all stages analyzed. The choline acetyltransferase-negative motor neurons were of similar appearance in both groups. After birth, chromatolytic motor neurons were detected in spinal muscular atrophy, all of which were choline acetyltransferase-negative. Our results in spinal muscular atrophy fetuses indicate that choline acetyltransferase immunostaining does not identify early events in neuronal pathogenesis and suggest that the spinal muscular atrophy surviving motor neurons may not be dysfunctional during this period. Furthermore, spinal muscular atrophy choline acetyltransferase-negative motor neurons showed detectable pathological changes only after birth, indicating that choline acetyltransferase is a late marker for motor neuron degeneration and not a primary contributing factor in this process.

Age Factors↗
PubMed1999

Cervical cord tethering mimicking focal muscular atrophy.

Spinal cord tethering rarely occurs in the cervical region. In adults, it usually results from previous operations. However, congenital origin is always diagnosed and treated early in the infant period. We report a 12-year-old boy with cervical spinal dysraphism which was erroneously diagnosed as focal muscular atrophy, a benign form of motor neuron disease. The patient was brought to our hospital because of rapid deterioration of symptoms. Careful evaluation disclosed a hairy dimple at the nuchal area, which led to the correct diagnosis. X-ray of the cervical spine showed spina bifida from C(4) to C(6) levels and fusion of the laminae of C(4) and C(5). Spine MRI studies disclosed that the cervical cord was tethered caudally and dorsally, and the ventral nerve roots were markedly stretched, especially over the left side. Surgical intervention was undertaken and the patient's muscle power improved after untethering. The purpose of this report is to acquaint the reader with a surgically treatable condition that may appear to be benign focal amyotrophy. Skin lesion at the nuchal area should be carefully looked for.

Brachial Plexus↗
PubMed1992

[Differential diagnosis in early muscular hypotonia: spinal atrophy].

Changes in type, size and structure of muscle fibres were analyzed in 68 biopsies with clinical and morphological signs of spinal atrophy. Reliability of clinical prebioptic diagnosis was evaluated in comparison with bioptic finding and final diagnosis. Muscle biopsy is often to be performed in spite of apparently unambiguous clinical and electromyographical finding. Contribution of biopsy to the diagnosis of spinal atrophy with characteristical grouping of atrophic fibres is undisputable in most cases. However, unproper sampling in excessively atrophic areas and structural "myogenic" changes can made the bioptic diagnosis difficult or impossible. Size analysis of muscle fibres proved participation of both the basic fibre types in atrophy with increase in number of immature type 2c fibres, and prevalence of type 1 fibres in hypertrophic areas (compensatory hypertrophy or re-innervation respectively) where also hybrid fibres can often be found during transformation of their type. Angular atrophic fibres occurring in hypertrophic fibre groups gave evidence of continuous or secondary denervation in benign forms of spinal atrophy. The author found regressive structural changes in benign form and in malignant Werdnig-Hoffman atrophy either--though less extensive.

Diagnosis, Differential↗
PubMed1990

Early diaphragmatic paralysis. In infants with genetic disorders.

Three infants with recently diagnosed genetic diseases presented with respiratory failure and required assisted ventilation. One infant had spinal muscular atrophy (Werdnig-Hoffmann disease), and two had acid maltase deficiency. The cause of the respiratory failure in all was diaphragmatic paralysis, and they became ventilator dependent. Early diaphragmatic paralysis must be considered as a manifestation of genetic neuromuscular disorders.

Female↗
PubMed2000

The Schizosaccharomyces pombe protein Yab8p and a novel factor, Yip1p, share structural and functional similarity with the spinal muscular atrophy-associated proteins SMN and SIP1.

The motor neuron disease spinal muscular atrophy (SMA) is caused by reduced levels of functional survival of motor neurons (SMN) protein. Previous studies have shown that SMN binds to the SMN-interacting protein SIP1 and mediates the assembly of spliceosomal U snRNPs in the cytoplasm. In addition, a nuclear function for SMN in pre-mRNA splicing has recently been proposed. Here, we describe the analysis of the Schizo-saccharomyces pombe protein Yab8p and provide evidence that it is structurally and functionally related to SMN found in higher eukaryotes. We show that Yab8p interacts via its N-terminus with a novel protein termed Yip1p. Importantly, Yip1p exhibits homology to SIP1, and the mode of binding to Yab8p is remarkably similar to the SMN-SIP1 interaction. Hence, Yip1p is likely to be the homologue of SIP1 in S.pombe. Yab8p and Yip1p localize predominantly in the nucleus. Genetic studies demonstrate that Yab8p is essential for viability. Strikingly, suppression of YAB8 expression in a conditional knock-out strain causes nuclear accumulation of poly(A) mRNA and inhibition of splicing. These data identify Yab8p as a novel factor involved in splicing and suggest that Yab8p exerts a function similar or identical to the nuclear pool of SMN. Our studies provide a model system to study the cellular function of SMN in yeast, and should help in understanding the molecular events leading to SMA.

Amino Acid Sequence↗
PubMed2000

Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases.

There are several incurable diseases of motor neuron degeneration, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, hereditary spastic hemiplegia, spinal muscular atrophy, and bulbospinal atrophy. Advances in gene transfer techniques coupled with new insights into molecular pathology have opened promising avenues for gene therapy aimed at halting disease progression. Nonviral preparations and recombinant adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses may ultimately transduce sufficient numbers of cerebral, brainstem, and spinal cord neurons for therapeutic applications. This could be accomplished by direct injection, transduction of lower motor neurons via retrograde transport after intramuscular injection, or cell-based therapies. Studies using transgenic mice expressing mutant superoxide dismutase 1 (SOD1), a model for one form of ALS, established that several proteins were neuroprotective, including calbindin, bcl-2, and growth factors. These same molecules promoted neuronal survival in other injury models, suggesting general applicability to all forms of ALS. Potentially correctable genetic lesions have also been identified for hereditary spastic hemiplegia, bulbospinal atrophy, and spinal muscular atrophy. Finally, it may be possible to repopulate lost corticospinal and lower motor neurons by transplanting stem cells or stimulating native progenitor populations. The challenge ahead is to translate these basic science breakthroughs into workable clinical practice.

Amyotrophic Lateral Sclerosis↗