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PubMed2002

Respiratory support in spinal muscular atrophy type I: a survey of physician practices and attitudes.

OBJECTIVE: To determine whether there is variability in the attitudes and practices of physicians regarding treatment of respiratory failure in children with spinal muscular atrophy type I (SMA type I) and, if so, whether this variation is associated with professional training. METHODS: This was a descriptive, cross-sectional survey mailed to a randomly selected subset of the Child Neurology Society, pediatric members of the Society of Critical Care Medicine and to the membership of the Pediatric Interest Section of the American Academy of Physical Medicine and Rehabilitation. A scenario of a child with SMA type I in respiratory distress was followed by questions that explored practices and attitudes regarding mechanical ventilation. RESULTS: Fifty-seven percent of intensivists (75 of 132), 39% physiatrists (61 of 155), and 34% of neurologists (61 of 155) responded. Specialists differed as to whether they offered and/or recommended respiratory support to patients with SMA type I. Intensivists were less likely to offer and recommend tracheostomy than physiatrists. Intensivists were also significantly less likely than physiatrists to agree with statements supporting the ethical necessity of noninvasive mechanical ventilation (NIMV) and intubation in the setting of an acute respiratory illness, and NIMV and tracheostomy in the setting of chronic respiratory failure. Although parallel differences were found between physiatrists and neurologists regarding their attitudes toward mechanical ventilation, no significant differences were detected between intensivists and neurologists. Finally, physicians who reported that a high percentage of their patients with SMA type I received "comfort care only" also tended to view mechanical ventilation, ie, use of NIMV for chronic respiratory failure, use of intubation for an acute respiratory infection, and use of tracheostomy for chronic respiratory failure as an unreasonable intervention in most circumstances. CONCLUSIONS: We found a wide variation in physician practice regarding the mechanical ventilation of patients with SMA type I. This study suggests a wide variation not only in what is recommended but also in what is actually offered to families of these children. Furthermore, the study suggests that physician training and attitudes affect recommendations regarding mechanical ventilation and ultimately family decision making.

Attitude of Health Personnel↗
PubMed2006

Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia.

The authors report four adult-onset ataxia telangiectasia (AT) patients belonging to two families lacking pronounced cerebellar ataxia but displaying distal spinal muscular atrophy. AT was proven by genetic studies showing ATM mutations and a reduced level of ATM. ATM activity, as measured by phosphorylation of p53, was close to normal, indicating that the p53 response is not the only factor in preventing neural damage in anterior horn cells in AT.

Adult↗
PubMed1977

The peroneal muscular atrophy syndrome. Clinical genetic, electrophysiological and nerve biopsy studies. Part 3. Clinical, electrophysiological and pathological correlations.

This report analyses correlations between clinical, electrophysiological and pathological data derived from a series of families with peroneal muscular atrophy. It was found that the observed differences between families in median nerve forearm motor conduction velocity were unlikely to be due to differences in the age or severity of the cases. Similarly it it was unlikely that the pathological differences between cases were due to age or severity of the case. The conduction velocity in the Hypertrophic Neuropathy Group tended to increase slightly with age, while that in other cases tended to fall slightly. The conduction velocity and total myelinated fibre counts were inversely related to the degree of segmental demyelination. The Hypertrophic Neuropathy Group and the Intermediate Group of cases were found to behave differently in a number of correlative analyses, thus supporting the suggestion that they represent different disease entities.

Adolescent↗
PubMed1987

Nemaline bodies in spinal progressive muscular atrophy. An autopsy case.

Numerous nemaline bodies were demonstrated in the pectoralis major muscle of an autopsy case of a 52-year-old woman, who died of respiratory failure after having suffered from spinal progressive muscular atrophy for 1 year. Rod-like structures ultrastructurally indistinguishable from classical nemaline bodies were abundant in both normal-appearing and atrophic myofibers of the pectoralis major muscle but not in the appendicular skeletal muscles. Morphometric analysis of spinal anterior horn cells clearly showed severe depopulation of somatic motor neurons in the lower cervical cord segments. The present case may provide further support for the neurogenic nature of nemaline body formation.

Female↗
PubMed1996

Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy.

Previous reports have established that the telomeric copy of the survival motor neuron (SMNT) gene and the intact copy of the neuronal apoptosis inhibitory protein (NAIP) gene are preferentially deleted in patients with spinal muscular atrophy (SMA). Although deletions or mutations in the SMNT gene are most highly correlated with SMA, it is not clear to what extent NAIP or other genes influence the SMA phenotype, or whether a small fraction of SMA patients actually have functional copies of both SMNT and NAIP. To evaluate further the part of SMNT in the development of SMA, we analyzed 280 asymptomatic SMA family members for the presence or absence of SMNT exons 7 and 8. We report the following observations: (i) 4% of the sample harbored a polymorphic variant of SMNT exon 7 that looks like a homozygous deletion; (ii) approximately 1% of the parents are homozygously deleted for both exons 7 and 8; (iii) one asymptomatic parent lacking both copies of SMNT exons 7 and 8 displays a 'subclinical phenotype' characterized by mild neurogenic pathology; (iv) another asymptomatic parent lacking both SMNT exons showed no signs of motor neuron disorder by clinical and neurodiagnostic analyses. The demonstration of polymorphic variants of exon 7 that masquerade as homozygous nulls, and the identification of SMA parents who harbor two disease alleles, serve as a caution to those conducting prenatal tests with these markers.

Adolescent↗
PubMed2005

Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy.

We have exploited the existence of a second copy of the human SMN gene (SMN2) to develop a high-throughput screening strategy to identify potential small molecule therapeutics for the genetic disease spinal muscular atrophy (SMA), which is caused by the loss of the SMN1 gene. Our screening process was designed to identify synthetic compounds that increase the total amount of full-length SMN messenger RNA and protein arising from the SMN2 gene, thereby suppressing the deleterious effects of losing SMN1. A cell-based bioassay was generated that detects SMN2 promoter activity, on which greater than 550,000 compounds was tested. This resulted in the identification of 17 distinct compounds with confirmed biological activity on the cellular primary assay, belonging to nine different structural families. Six of the nine scaffolds were chosen on the basis of their drug-like features to be tested for their ability to modulate SMN gene expression in SMA patient-derived fibroblasts. Five of the six compound classes altered SMN mRNA levels or mRNA splicing patterns in SMA patient-derived fibroblasts. Two of the compound classes, a quinazoline compound series and an indole compound, also increased SMN protein levels and nuclear gem/Cajal body numbers in patient-derived cells. In addition, these two distinct scaffolds showed additive effects when used in combination, suggesting that they may act on different molecular targets. The work described here has provided the foundation for a successful medicinal chemistry effort to further advance these compounds as potential small molecule therapeutics for SMA.

Base Sequence↗
PubMed1999

No evidence of association between apolipoprotein E genotype and phenotypic severity in childhood onset proximal spinal muscular atrophy.

The survival motor neuron (SMN) gene is present in two copies on chromosome 5q13 and the evidence is now compelling that mutations in the telomeric copy (SMNt) of the gene underlie childhood onset proximal spinal muscular atrophy (SMA). There is a correlation between the number of centromeric SMN gene copies (SMNc) and the clinical severity of the disease but this relationship is not absolute. Allelic variants of the apolipoprotein E (APOE) gene encoded on chromosome 19q are known to influence the prognosis and risk in a number of neurological disorders. We have therefore genotyped 166 unrelated cases of SMA to determine whether the presence of specific APOE genotypes correlates with severity of disease. The study failed to show the influence of any particular APOE genotype on disease severity, with specifically APOE epsilon4 being no more common in the milder SMA forms and APOE epsilon2 not over represented in type I SMA. A limited study of 23 SMA families also failed to show any influence of APOE genotype on SMA disease severity. Factors other than APOE genotype must therefore be responsible for determining SMA disease severity.

Apolipoprotein E2↗
PubMed1996

X-linked bulbar and spinal muscular atrophy, or Kennedy disease: clinical, neurophysiological, neuropathological, neuropsychological and molecular study of a large family.

We report the clinical, neurophysiological, neuropsychological, neuropathological and molecular findings in a large family with X-linked bulbar and spinal muscular atrophy (X-BSMA). Molecular study, performed in 28 family members, showed an increase in the number of CAG repeats in 6 affected males (including 2 presymptomatic patients), and in 10 females, of whom 5 were obligate carriers. All symptomatic patients showed, besides the typical manifestation of X-BSMA, neurophysiological signs of sensory nerve involvement, and abnormal findings in neuropsychological tests. Sural nerve biopsy, performed in two patients, was consistent with axonal atrophy and slow-rate degeneration, with secondary demyelination. Neurophysiological alterations were also present in 6 out of 8 carriers, consisting of neurogenic EMG changes in 3 cases and abnormal sensory action potentials (SAP) and reduced conduction velocity of the sural nerve in 3 cases. Abnormalities of at last two neuropsychological tests were found in 6 out of 8 carriers. Alterations of the sensory nerves in X-BSMA patients have been previously reported in some cases; however, we demonstrate for the first time sensory nerve involvement also in carriers. Evidence of central nervous system involvement, with neuropsychological impairment in all symptomatic patients and in some carriers, is another feature of this family, not previously reported in X-BSMA. In spite of the variable phenotypic features, the number of CAG repeats ranged from 40 to 44 in the affected patients, indicating that phenotypic expression was not related to the size of the mutation, but was probably age-related.

Adolescent↗
PubMed2005

Progress in Spinobulbar muscular atrophy research: insights into neuronal dysfunction caused by the polyglutamine-expanded androgen receptor.

Spinobulbar muscular atrophy (SBMA, Kennedy's disease) results from the dysfunction and degeneration of specific motor and sensory neurons. The underlying cause of this ligand-dependent neurodegenerative disease is expansion of the CAG trinucleotide repeat in the androgen receptor (AR) gene which leads to lengthening of the polyglutamine tract in the AR protein. Recently, the effects of the polyglutamine-expanded AR have been explored in a number of cellular and animal models. Common themes include research on polyglutamine-containing nuclear inclusions and the effect of molecular chaperone overexpression on their formation. In addition, investigations have highlighted the role that abnormal transcriptional regulation, proteasome dysfunction and altered axonal transport may play in disease pathogenesis. These studies suggest a number of potential treatments for restoring neuronal function. One of the most interesting advances in SBMA research has been the creation of mouse models that recapitulate the key features of SBMA progression in men. Lowering testosterone levels in affected transgenic male mice rescued, and even reversed the polyglutamine-induced neuromuscular phenotype, indicating that manipulating androgen levels in men could be of therapeutic benefit. Although the question of why only a distinct subset of neurons is affected by polyglutamine expansion of the AR remains unsolved, future research will provide further insights into the mechanisms contributing to disease progression in SBMA.

Animals↗
PubMed1989

[Loss of spinal anterior horn cells in X-linked recessive bulbospinal muscular atrophy--a morphometric study of lower motoneuron loss].

A morphometric analysis was performed to study three-dimensional distribution of the anterior horn cells in the L1 segmens from four cases of X-linked bulbospinal muscular atrophy (X-BSMA) and three age-matched controls. At autopsy, the L4 spinal segment was removed and fixed in 4% paraformaldehyde in PBS at pH 7.4, then embedded in paraffin. Serial sections of 10 microns in thickness from the rostral end of L4 segment were obtained. Every tenth section was stained with Klüver-Barrera method. The anterior spinal horn in this study was designated as the gray matter anterior to the line from the central spinal canal perpendicular to the ventral spinal fissure. The diameter of the remaining neurons with obvious nucleolus in the anterior horn was measured with TGZ-3 particle size analyzer (Zeiss) on the 205 time-magnified picture, and their location was schematically plotted on a montage of the ventral horn. Neuronal loss was more marked in X-BSMA than in amyotrophic lateral sclerosis (ALS) and Shy-Drager syndrome (SDS). In X-BSMA, the loss was most prominent in cells with large-size, and in those located in the lateral and medial vental nuclei (lamina IX after Rexed's classification). Small or intermediate cells located in the area of inner-medial portion of the ventral horn (lamina VII & VIII after Rexed's classification) were also significantly depleted. In some cases, the loss of small neuron was more marked than SDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1978

Infantile spinal muscular atrophy. Unusual fiber typing and distribution in a muscle biopsy.

A right gastrocnemius muscle biopsy of a 13-month-old floppy male infant, which appeared at a more advanced age to suffer from an infantile spinal muscular atrophy, showed unusual histochemical changes: the chequer-board distribution was replaced by three groups of muscle fibers with a same mean narrow diameter of 12.5 micrometer. The smallest groups could easily be recognized as type I and type IIB fibers, while the largest group, involving more than 75% of the whole biopsy, revealed an intermediate hybrid fiber population, which would be classified as type I, if based on their phosphorylase and myofibrillar ATPase activities alone. The pathogenesis of this unusual finding is discussed.

Histocytochemistry↗
PubMed1997

The survival motor neuron protein in spinal muscular atrophy.

The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non-SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.

Animals↗
PubMed1991

Hereditary canine spinal muscular atrophy: an animal model of motor neuron disease.

Motor neuron diseases selectively produce degeneration and death of motor neurons; the pathogenesis of these disorders and the specificity for this population of neurons are unknown. Hereditary Canine Spinal Muscular Atrophy produces a lower motor neuron disease which is clinically and pathologically similar to human motor neuron disease: motor neurons dysfunction and degenerate. The canine model provides an opportunity to investigate early stages of disease when there are viable motor neurons still present and might be responsive to a variety of therapeutic interventions. The canine disease, like the human disease, is inherited as an autosomal dominant. The extensive canine pedigree of more than 200 characterized individuals permits genetic analysis using syntenic linkage techniques which may identify a marker for the canine trait and provide insights into homologous regions for study in human kindreds.

Animals↗
PubMed1981

Progressive peroneal muscular atrophy (Charcot-Marie-Tooth disease) associated with beta-thalassemia trait and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. A clinical and nerve biopsy case.

The case of a 22 year old woman presenting progressive peroneal muscular atrophy (PMA) is described. Electrophysiological and pathological studies demonstrated features of hereditary motor and sensory neuropathy -HMSN- type I. Laboratory findings showed two erythrocytic defects: beta-thalassemia trait and a glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Unlike the past, these inherited disorders are associated with PMA.

Adult↗
PubMed1995

Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene.

Low-copy repeats have been associated with genomic rearrangements and have been implicated in the generation of mutations in several diseases. Here we characterize a subset of low-copy repeats in the spinal muscular atrophy (SMA) region in human chromosome 5q13. We show that this repeated sequence, named c41-cad, is a highly expressed pseudogene derived from an intact neuronal cadherin gene, Br-cadherin, situated on 5p13-14. Br-cadherin is expressed specifically in the brain, whereas the c41-cad transcripts are 10-15 times more abundant and are present in all tissues examined. We speculate that the c41-cad repeats, separately or in concert with other repeats in the SMA region, are involved in the pathogenesis of SMA by promoting rearrangements and deletions.

Amino Acid Sequence↗
PubMed1997

Spinobulbar muscular atrophy can mimic ALS: the importance of genetic testing in male patients with atypical ALS.

The clinical presentation of amyotrophic lateral sclerosis (ALS) is variable and overlaps with that of other motor neuron diseases such as spinobulbar muscular atrophy (SBMA; Kennedy disease). With the identification of disease-specific mutations such as the CAG repeat expansion in the androgen receptor in SBMA, an accurate molecular diagnosis can be made in some patients with motor neuron disease. To determine the extent of misdiagnosis of ALS we screened 147 male ALS patients and 100 unrelated male patients from 100 familial ALS (FALS) kindreds for the presence of the SBMA mutation using polymerase chain reaction methods. We show that ALS was clinically misdiagnosed in 2% of sporadic cases and in two of the 100 FALS kindreds. This study underscores the difficulty in distinguishing SBMA from ALS clinically, particularly in patients who lack the classic signs of each disease.

Amyotrophic Lateral Sclerosis↗
PubMed2006

An infant with hypoplastic left heart syndrome and spinal muscular atrophy.

We report an infant with hypoplastic left heart syndrome consisting of mitral valvar atresia, aortic valvar atresia, hypoplasia of the aortic arch and coarctation of the aorta, who demonstrated respiratory failure and global hypotonia, and who was eventually diagnosed with spinal muscular atrophy.

Angiography↗