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PubMed1998

The role of the SMN gene in proximal spinal muscular atrophy.

Childhood spinal muscular atrophy (SMA) is a common recessive autosomal disorder that results in degeneration of lower motor neurons. The identification of the disease gene, Survival of Motor Neuron (SMN), was a major advance in understanding the molecular basis underlying this devastating neuromuscular disease. This finding has greatly improved the genetic counselling of SMA families. Recently, biochemical studies demonstrated its involvement in the biogenesis of spliceosomal snRNPs, suggesting a critical role of SMN in RNA processing. Surprisingly, other studies showed a putative role of SMN in an anti-apoptotic pathway involving Bcl-2. The function of SMN protein is not fully understood. These observations emphasized the difficulty in elucidating the function of any novel protein. Therefore, multidisciplinary approaches are required to understand the pathogenesis of SMA.

Animals↗

PubMed2003

Difficult airway in a child with spinal muscular atrophy type I.

Spinal muscular atrophy (SMA) type I is a relatively common inherited neuromuscular disease of hypotonic newborns, but is not associated with craniofacial abnormalities. There is nothing in the literature about difficult intubation in patients affected by this disease. We report a case of 34-month-old girl with SMA type I who was scheduled for emergency endoscopic laser treatment of tracheal stenosis caused by granulations. Tracheostomy was performed at 17 months of age and before this, the orotracheal tube was changed periodically without difficulty. For this laser treatment, orotracheal intubation was required. Preoperative physical examination revealed micrognathia and class II malocclusion. Opening her mouth was not difficult. Although difficult orotracheal intubation was predictable, we attempted to intubate her trachea as usual, but could not visualize the epiglottis. We decided to proceed with retrograde intubation, one of the standard techniques employed in a child with a difficult airway, via the tracheostome. A feeding nasogastric catheter was used as a guide catheter, and our strategy was successful. In this study we report a case of difficult airway in a child with SMA type I. The relationship between SMA type I with a tracheostome and difficult airway are discussed.

Airway Obstruction↗

PubMed1979

Blood selenium in chronic spinal muscular atrophy.

The spinal muscular atrophies (SMA) of childhood comprise the second most common fatal recessive disease after cystic fibrosis, yet the nature of the biochemical defect causing the anterior horn cell degeneration is totally unknown. Recent reports of a cluster of adult motor neurone disease cases from a high seleniferous area in South Dakota have prompted the study of blood selenium in children with SMA in Australia. Eight children with chronic SMA were tested, in addition to 9 obligate heterozygote carriers of the gene. Blood selenium levels of patients and carriers did not differ significantly from that observed in controls. The mammalian effects of selenium toxicity are discussed.

Adolescent↗

PubMed2005

Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients.

Spinal muscular atrophy (SMA) is caused by insufficient levels of survival motor neuron (SMN) protein. Recently, we found that sodium 4-phenylbutyrate (PB), a well-tolerated FDA approved drug, enhances SMN gene expression in vitro. We provide here the first evidence that oral administration of PB (triButyrate significantly increases SMN expression in leukocytes of SMA patients. This finding provides a strong rationale to further investigate the effects of PB as also supported by preliminary clinical data.

Administration, Oral↗

PubMed1989

Functional activities in spinal muscular atrophy patients after spinal fusion.

Spinal muscular atrophy patients present with weakness, greater in the proximal muscles, leading to scoliosis and limited upper extremity function. The purpose of this study is to identify unique aspects of these patients and to understand how spinal fusion affects their function. Forty patients underwent Harrington or Luque rod instrumentation with functional evaluations preoperatively and 2 and 5 years postoperatively. Biomechanical assessment of function is important. Flexibility of the spine is functionally advantageous because distal strength is used to align weaker proximal segments. Postoperatively, lack of spinal flexibility resulted in a decline in gross motor function and increased use of UE aids due to a change in the trunk position in the weaker patients. The stronger patients' activities were maintained. Earlier mobilization in patients with Luque procedures did not improve postoperative function.

Activities of Daily Living↗

PubMed1996

[Molecular genetic diagnosis and deletion analysis in Type I-III spinal muscular atrophy].

Autosomal recessive spinal muscular atrophy (SMA) is, after cystic fibrosis, the second most common fatal monogenic disorder. The disease is characterized by degeneration of anterior horn cells leading to progressive paralysis with muscular atrophy. Depending on the clinical type (Werdnig-Hoffmann = type I, intermediate form = type II, Kugelberg-Welander = type III), SMA causes early death or increasing disability in childhood. The SMA-critical region on the long arm of chromosome 5q13.1 contains many duplicated genes and polymorphisms. Recently, two presumptive SMA genes (survival motoneuron gene = SMN, and neuronal apoptosis inhibitory protein = NAIP) have been identified. Deletions involving critical regions of these genes are very often associated with SMA, and the extent of the deletions seems to correlate in part with disease severity. We have evaluated the diagnostic and prognostic value of molecular analysis in a large number of SMA patients. 57 patients and 78 healthy relatives were molecularly screened for deletions in the SMA critical region. We demonstrated homozygous deletions removing the SMN genes in over 90% of patients, whereas nearly 45% of patients exhibited NAIP gene deletions. Large deletions involving both genes on each chromosome are generally found in patients with severe SMA (Werdnig-Hoffman cases), while mildly affected Kugelberg-Welander cases frequently show only deleted SMN genes. Molecular classification based on combined deletion sizes, however, seems not to be exact, especially for the group with chronic SMA (type II and III). Direct DNA testing of patients in whom SMA is suspected is a highly reliable, fast, and noninvasive method. The ability to detect homozygous gene deletions in a high percentage of typical SMA patients will much improve genetic counselling and prenatal diagnosis in affected families.

Adult↗

PubMed1990

Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14. The French Spinal Muscular Atrophy Investigators.

Linkage analysis in twenty-five families with acute (type I) spinal muscular atrophy (SMA) showed that the mutant gene responsible for the disorder is tightly linked to the D5S39 locus. The mutation(s) causing the intermediate (type II) and juvenile chronic (type III) forms of SMA were also mapped to DNA marker D5S39 on chromosome 5 (5q12-q14). Thus, the three forms, which have been differentiated clinically on the basis of age of onset and clinical course, are most probably due to different mutations at a single locus on chromosome 5. Prenatal diagnosis of SMA type I will now be possible.

Acute Disease↗

PubMed2003

Molecular analysis of the spinal muscular atrophy and neuronal apoptosis inhibitory protein genes in Saudi patients with spinal muscular atrophy.

OBJECTIVE: Spinal muscular atrophy (SMA) is a common, often fatal, autosomal recessive disease leading to progressive muscle wasting and paralysis as a result of degeneration of anterior horn cells of the spinal cord. The prevalence of SMA cases in the Kingdom of Saudi Arabia (KSA) is much higher than the European and North American population. Deletions or mutations in 2 genes, telomeric form of the survival motor neuron (SMN1) and the neuronal apoptosis inhibitory protein (NAIP), are known to be associated with SMA. The aim of this study is to examine the deletions or interruptions of the SMN1 and NAIP genes in Saudi patients. METHODS: The study included 121 Saudi SMA patients [type I (60 patients); type II (26 patients); and type III (35 patients)]. The deletions or interruptions of the SMN1 and NAIP genes were detected by using polymerase chain reaction. The study was carried out at the King Fahad National Guard Hospital, Riyadh, KSA between 2000 and 2002. RESULTS: The homozygous deletions of exons 7 and 8 of the SMN1 gene were found in 94% and 87% of the patients. Exon 5 of the NAIP gene was deleted in 70%, but its deletion was more frequent in SMA type I (93%) as compared to type II (54%) and type III (43%). Seven patients with SMA diagnosis did not show any of the above homozygous deletions. All 230 control subjects had at least one copy of both SMN1 and NAIP genes, as expected. CONCLUSION: Our results demonstrate that the deletion rate (94%) of the SMN1 gene in Saudi SMA patients is similar, irrespective of types, compared with patients of other ethnic groups. We also show that the incidence of NAIP deletion is higher in the more severe SMA cases and the dual deletion of the SMN1 and NAIP genes are more common in Saudi SMA type I patients compared with patients of other ethnic groups.

Cyclic AMP Response Element-Binding Protein↗

PubMedDate not supplied

Hereditary canine spinal muscular atrophy is phenotypically similar but molecularly distinct from human spinal muscular atrophy.

Hereditary canine spinal muscular atrophy (HCSMA) is an autosomal dominant motor neuron disease that is similar in pathology and clinical presentation to various forms of human motor neuron disease. We have tested the hypothesis that the canine survival motor neuron (SMN) gene is responsible for HCSMA by genetic and molecular analysis of a colony of mixed breed dogs, all descended from a single affected individual. We cloned the canine SMN gene and determined the DNA sequence in an affected and an unaffected dog. We found no germline mutations in the SMN gene of the affected individual. Using conventional linkage analysis with canine-specific microsatellite repeat markers we screened the canine genome and identified a single linkage group likely to contain the HCSMA gene. Analysis with a panel of canine/rodent hybrid cell lines revealed that the SMN gene did not map to the same chromosome as the HCSMA linkage group. Collectively these results suggest that the molecular basis for HCSMA is distinct from that of phenotypically similar human disorders caused by inherited mutations in the SMN gene. This further suggests that additional studies on the molecular nature of HCSMA may reveal an unknown element of the molecular pathway leading to motor neuron disease.

Amino Acid Sequence↗

PubMed1999

Spinal muscular atrophy: molecular pathophysiology.

Spinal muscular atrophy is an autosomal recessive disease characterized by motor neurone loss, muscle atrophy and weakness. Deletion or mutation of the SMN1 gene reduces intracellular survival motor neurone protein levels causes spinal muscular atrophy, most likely by interfering with spliceosome assembly. A range of clinical severity and corresponding survival motor neurone levels is seen because of the presence of copies of the transcriptionally inefficient SMN2 gene and possibly other modifying genes. The delineation of SMN1 as the gene that causes spinal muscular atrophy and the identification of genes that modify spinal muscular atrophy raise the prospect of gene therapy or in-vivo gene activation treatment for this frequently fatal disorder.

Autoantigens↗

PubMed1994

[Incidence of spinal muscular atrophy and Duchenne's muscular dystrophy in the juvenile population of central Slovakia].

Spinal muscular atrophy, type I-III and Duchenne muscular dystrophy belong to the most frequent neuromuscular diseases in children. The purpose of this work was to determine the incidence of these two diseases in liveborn children in the years 1975 to 1989 in the south part of middle Slovakia. The common incidence of all three types of spinal muscular atrophy was 1 in 5631 liveborn children (most frequent was the Werdnig-Hoffmann disease, type I--1 in 12,286). This fact confirms, that this disease belongs to the most frequent autosomal recessive diseases in children of our region too. The incidence of Duchenne muscular dystrophy was 1 in 4827 liveborn boys. The figure is in the range of the published data of the incidence of this disease. The deletion in the dystrofin gene was proved in 70% of affected boys. (Tab. 3, Fig. 1, Ref. 24).

Child↗

PubMed1997

Muscle fatigue in spinal muscular atrophy.

We previously reported that patients with spinal muscular atrophy do not lose muscle strength over time as measured quantitatively. However, we noted that many patients with spinal muscular atrophy suffer from what they call fatigue. We wondered if we could measure fatigue during a single maximal voluntary contraction, whether fatigue might increase with time, independent of muscle strength, and whether increasing fatigue might correlate with loss of function in some patients. We measured fatigue during a single maximal voluntary contraction in a cohort of patients having spinal muscular atrophy using quantitative strength testing. We included only patients with spinal muscular atrophy aged 5 years or older, so they could follow instructions regarding muscle contraction, and who were followed for at least 2 years. Seventy-six children with spinal muscular atrophy and 24 untrained individuals, aged 5 to 57 years (mean, 16.8 years), were studied. There was no discernible abnormal fatigue in patients with spinal muscular atrophy compared to untrained controls using our methodology. Thus, spinal muscular atrophy may not be associated with fatiguability. Moreover, spinal muscular atrophy does not appear to cause progressive muscle fatigue with age or loss of function. It is possible that fatigue was undetectable by our methods. An alternative explanation is that what patients describe as fatigue may be caused by factors outside the neuromuscular system. Such factors may include chronic respiratory insufficiency with hypoventilation and carbon dioxide retention as well as chronic malnutrition and negative nitrogen balance.

Adolescent↗

PubMed1994

Efficacy of thyrotropin-releasing hormone in the treatment of spinal muscular atrophy.

Children with spinal muscular atrophy were treated by the administration of thyrotropin-releasing hormone. In three infants with spinal muscular atrophy type I, thyrotropin-releasing hormone showed little efficacy, but in children with types II and III, there was improvement in motor function and electromyographic findings after the thyrotropin-releasing hormone therapy. Thyrotropin-releasing hormone has a neurotrophic effect on the spinal anterior motor neurons of spinal muscular atrophy patients and thus may be warranted for the management of spinal muscular atrophy.

Age of Onset↗

PubMed1999

The role of palliative care in advanced muscular dystrophy and spinal muscular atrophy.

OBJECTIVE: This study examines the potential role for palliative care services in the care of individuals with muscular dystrophy and spinal muscular atrophy, and the support of their families. METHODOLOGY: Semistructured interviews were conducted in South Australia with nine bereaved and four current family members of individuals with muscular dystrophy or spinal muscular atrophy. Issues explored during interview included: (i) the family perceptions of the difficulties in caring; (ii) the psychological and physical resources which were available to assist them; and (iii) family recall of the management of the terminal phase of the illness. RESULTS: Significant issues identified included: (i) a lack of coordination of care and access to skilled, competent carers; (ii) a lack of support for siblings; (iii) inadequate bereavement care; and (iv) limited discussion of options of ventilatory support and advance directives. CONCLUSIONS: The terminal care for individuals with muscular dystrophy and spinal muscular atrophy and their families requires improvement. Although many individuals with these conditions will die following an acute event, palliative care services may be appropriate for those who require a period of terminal care at home.

Adolescent↗

PubMedDate not supplied

Progressive juvenile segmental spinal muscular atrophy.

Juvenile segmental spinal muscular atrophy (JSSMA) typically involves the distal upper extremities and follows a benign course over 2-4 years then stabilizes. We report 2 males who presented in their teens with insidious distal upper extremity atrophy and weakness as in typical JSSMA but who then progressed to involvement of the lower extremities and hyperreflexia. There was no sensory loss. Electromyography and muscle biopsy demonstrated features consistent with localized anterior horn cell dysfunction. These patients are noteworthy because they demonstrate that some patients with JSSMA also may have involvement of the lower limbs several years after initial presentation. Progressive JSSMA may be categorized in the clinical spectrum between the spinal muscular atrophies and amyotrophic lateral sclerosis.

Adolescent↗

PubMedDate not supplied

[Neonatal muscular spinal atrophy: a case report].

Spinal Muscular Atrophy (SMA) is an autosomal recessive disease characterized by diffuse proximal and distal weakness due to deletions of the survival motor neuron (SMN) gene localised on chromosome 5q13. Pathological studies show decreased numbers of motorneurons in spinal cord. SMA was initially sub-classified clinically into three types base on age at onset and clinical course. SMA type 1, Werdnig-Hoffmann disease, has an onset within the first 6 months and death within the first two years. In contrast, SMA type II has an onset after six months of life and the children achieve the ability to sit unaided. Children with SMA type III (Kugelberg-Welander) usually have normal milestones in the first year and achieve the ability to walk but then show evidence of mild weakness. The prognosis is good and the clinical course is not (or very slowly) progressive. Recently, Dubowitz described a new form of SMA called type 0 with a neonatal onset, facial weakness, progressive and fatal clinical course. These infants show generalised hypotonia, the lower limbs are more affected than the upper with marked weakness of all axial muscles. We report a case of SMA, uncommon for the early onset and the respiratory difficulties. The diagnosis has been done by genetic analyses showing a SMN mutation.

Age Factors↗

PubMed2003

Molecular and cellular basis of spinal muscular atrophy.

Autosomal recessive spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy combined with motor neuron degeneration. SMA is caused by homozygous mutation or loss of the telomeric copy of the survival of motor neuron gene (SMN). The SMN gene is localized as an inverted repeat on chromosome 5q13. Both gene copies (SMN1 and SMN2) are expressed, but they differ in the expression of full-length protein. SMN2 gene preferentially gives rise to a truncated and less stable version of the SMN protein and thus can not compensate for SMN1 loss or mutations unless it is not present in multiple copies. The SMN protein is part of multiprotein complexes in the cytoplasm and the nucleus of all cell types. These complexes are involved in assembly of spliceosomal snRNPs. SMN interacts with RNA polymerase II and other binding proteins, indicating that the SMN protein is involved in messenger and ribosomal RNA transcription and processing. The analysis of animal models for SMA could help to identify the pathophysiological changes that are responsible for spinal muscular atrophy.

Animals↗

PubMed1995

Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy.

Molecular diagnosis of childhood proximal spinal muscular atrophy has been enhanced by the discovery of the survival motor neuron (SMN) gene, which is absent or truncated in 98.6% of patients. To determine whether deletion analysis of the SMN gene may also be diagnostic for adult-onset disease, we studied six patients and found deletions in all. This finding will facilitate the diagnosis of adult-onset spinal muscular atrophy, and provides evidence for genetic homogeneity between the clinically diverse adult and childhood forms of the disease.

Adult↗