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PubMed2005

[Diagnostic difficulties in spinal muscular atrophy].

OBJECTIVE: To describe the clinical findings of patients with spinal muscular atrophy (SMA) with survival motor neuron (SMN) gene deletion. METHOD: Descriptive study of SMA cases confirmed with the deletion of the SMN gene. Frequency determination of positive clinical and laboratory revised diagnostic criteria. RESULTS: All of the 22 included patients had symmetrical muscle weakness, which was diffuse in those with onset of symptoms up to 6 months of age (75 %), and either proximal or predominant in lower limbs in the remaining group (67 %). Fasciculations and atrophy were both frequent findings (82 %). Laboratory tests findings were variable, with a positivity of 57 % for electrophysiology and of 58 % for muscle biopsy. CONCLUSION: The presence of a deletion in the SMN gene can help to confirm this diagnosis in unclear presentations.

Age of Onset↗
PubMedDate not supplied

Molecular diagnosis of spinal muscular atrophy in Egyptians.

This study was carried out with 33 spinal muscular atrophy (SMA) patients. DNA molecular studies of the SMA gene on the long arm of chromosome 5 (5q11.2q13.3) revealed homozygous deletion of exon 7 in 55% of cases, 36% of whom also had a homozygous delition of exon 8. The adult patients were heterozygous for an abnormal size exon 8. The remaining patients had either compound heterozygote deletion of exons 7 and 8 or were normal for both. There may therefore be 5q-unlinked SMA or SMA due to other mutations. Detection of deletions of SMA exons 7 and 8 is a powerful diagnostic test in patients with SMA, but other mutations among Egyptians must also be sought.

Adult↗
PubMed1971

The genetic heterogeneity of spinal muscular atrophy (SMA).

The clinical picture of the spinal muscular atrophy varies greatly with respect to age of onset, speed of progression, severity and distribution of muscular atrophy, weakness and contractures, yet cases occurring within a family usually show concordant clinical features. Thus, genetic heterogeneity has to be assumed. This is supported by the various genetic transmission patterns (autosomal dominant, recessive, X-linked recessive) found by accurate pedigree analysis.

Age Factors↗
PubMed1996

Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease.

Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor-neuron gene (SMN), a strong candidate for SMA, is present in two highly homologous copies (telSMN and cenSMN) within the SMA region. Only five nucleotide differences within the region between intron 6 and exon 8 distinguish these homologues. Independent of the severity of the disease, 90%-98% of all SMA patients carry homozygous deletions in telSMN, affecting either exon 7 or both exons 7 and 8. We present the molecular analysis of 42 SMA patients who carry homozygous deletions of telSMN exon 7 but not of exon 8. The question arises whether in these cases the telSMN is truncated upstream of exon 8 or whether hybrid SMN genes exist that are composed of centromeric and telomeric sequences. By a simple PCR-based assay we demonstrate that in each case the remaining telSMN exon 8 is part of a hybrid SMN gene. Sequencing of cloned hybrid SMN genes from seven patients, as well as direct sequencing and single-strand conformation analysis of all patients, revealed the same composition in all but two patients: the base-pair differences in introns 6 and 7 and exon 7 are of centromeric origin whereas exon 8 is of telomeric origin. Nonetheless, haplotype analysis with polymorphic multicopy markers, Ag1-CA and C212, localized at the 5' end of the SMN genes suggests different mechanisms of occurrence, unequal rearrangements, and gene conversion involving both copies of the SMN genes. In approximately half of all patients, we identified a consensus haplotype, suggesting a common origin. Interestingly, we identified a putative recombination hot spot represented by recombination-stimulating elements (TGGGG and TGAGGT) in exon 8 that is homologous to the human deletion-hot spot consensus sequence in the immunoglobulin switch region, the alpha-globin cluster, and the polymerase alpha arrest sites. This may explain why independent hybrid SMN genes show identical sequences.

Biomarkers↗
PubMed2002

Molecular genetics of spinal muscular atrophy: contribution of the NAIP gene to clinical severity.

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders characterized by degeneration of anterior horn cells in the spinal cord, and leads to progressive muscular weakness and atrophy. At least three SMA-related genes have been identified: SMN1, NAIP and p44t. We analyzed these genes in 32 SMA patients and found that the SMN1 gene was deleted in 30 of 32 patients (94 %), irrespective of clinical type. The NAIP gene was deleted in 6 patients and its deletion rate was higher in type I patients than that in type U or V. Further, in type I patients lacking the NAIP gene, deterioration in their respiratory function is more rapid than in those type I patients retaining the NAIP gene. Since complete p44t deletion was observed in only 3 patients, the correlation between the p44t deletion and severity of SMA remained ambiguous. We concluded that the NAIP deletion was closely related to the clinical severity of SMA and was a predictive marker of SMA prognosis, while the SMN1 deletion did not correlate with clinical severity.

Adult↗
PubMed1990

Population data on acute infantile and chronic childhood spinal muscular atrophy in Warsaw.

This study provides epidemiological data on acute infantile (ASMA) and chronic childhood spinal (CSMA) muscular atrophy in Warsaw for the period 1976-1985. All calculations are based on the assumption that ASMA and CSMA result from mutations at two different gene loci. The incidence of ASMA and CSMA was 1 in 19474 live births with a corresponding gene and carrier frequency of 714 x 10(-5) and 1 in 70, respectively. The prevalence of CSMA for the year 1985 was 1.26 x 10(-5). These figures are higher than in similar studies in other countries. This fact might be connected with the careful ascertainment in this study.

Chronic Disease↗
PubMed1993

The use of chromosome 5q markers for confirming the diagnosis of proximal spinal muscular atrophy.

1. Five Brazilian families referred to us with a probable diagnosis of chronic proximal spinal muscular atrophy (Kugelberg-Welander) were identified, and permanent (Epstein Barr virus transformed) cell lines were established from members of four of the families. 2. A genetic linkage study was carried out on 70 individuals using nine polymorphic DNA markers (eight RFLP and one microsatellite) from chromosome 5q11.2-13.3 which have been shown to flank the spinal muscular atrophy (SMA) gene. 3. The segregation of the markers in two of the five families was compatible with the disease-causing locus being located in this same region. In one family the pattern of segregation clearly excludes the causative gene from this region. In one of the remaining two families the analysis was inconclusive because the markers were not informative. In the fifth family the possibility of two concurrent neuromuscular diseases did not permit a definite conclusion. 4. These results further support the location of the major SMA gene at 5q11.2-13.3. 5. The possibility of non-allelic heterogeneity for the spinal muscular atrophy gene is discussed.

Adolescent↗
PubMed2024

Concomitant telomere attrition is associated with spinal muscular atrophy in highly inbred region of North India: unraveling the thread in Kashmir region.

Spinal muscular atrophy (SMA) is a rare genetic disorder that unequivocally results in the degeneration of motor neurons, leading to muscle weakness and atrophy. This condition is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which inevitably results in a deficiency of the SMN protein. In present study, we investigated the potential role of telomere attrition in SMA patients. Relative telomere length in peripheral blood lymphocytes was measured by Monochrome Multiplex Quantitative Polymerase Chain Reaction (MMQPCR) in 98 subjects and we conclusively found that SMA cases exhibit telomere attrition compared to healthy controls (P = 4 × 10- 2). Moreover, significant attrition was also observed in severe form of SMA, i.e. SMA type 0 (P = 0.04) as well.Although, the exact mechanism through which telomere shortening contributes to the pathogenesis of SMA is not fully understood and is yet to be delineated. However, one possibility is that telomere shortening leads to genomic instability and DNA damage, which can contribute to motor neuron degeneration. Another possibility is that telomere shortening leads to cellular senescence, which can impair the ability of motor neurons to regenerate and repair themselves. Recent studies have suggested that telomere shortening may be a potential therapeutic target in SMA. Thus, understanding the role of SMN1 gene in disease pathogenesis & its effect on telomere length will aid in estimating the risk & prognosis of SMA in genetically less explored & highly inbred region of Kashmir, Northern India.

Humans↗
PubMed1988

Clinical and morphometric analysis of biopsied biceps brachii muscles in adult-onset chronic proximal spinal muscular atrophy. With special reference to intramuscular nerves.

In a group of 16 cases with adult-onset chronic proximal spinal muscular atrophy, we performed a morphometric analysis of 88 intramuscular nerves in biopsied biceps brachii muscles and correlated this analysis with clinical and histochemical parameters. The total number of large and small myelinated fibres in all fascicles was reduced to 71%, 23% and 83% of control values, respectively. The percentage reduction of large myelinated fibres for each case was significantly correlated with duration of illness, biceps muscle power and histochemical atrophy factors. Histograms of large intramuscular nerve fascicles showed unimodal distributions and shifts to the left with single peak increases at 1 micron. The densities of small myelinated fibres in large fascicles correlated with counts of 'enclosed' muscle fibres in ATPase preparations. Compared with amyotrophic lateral sclerosis, a lesser reduction of large myelinated fibres, but a greater increase in small myelinated fibres, was noted in adult-onset chronic proximal spinal muscular atrophy. These findings imply that there is a less marked loss of myelinated nerve fibres with more effective reinnervation in adult-onset chronic proximal spinal muscular atrophy than in amyotrophic lateral sclerosis.

Adult↗
PubMed1995

Scoliosis and lung function in spinal muscular atrophy.

The notes and radiographs of 43 patients with a confirmed diagnosis of spinal muscular atrophy were reviewed. A significant inverse linear relationship between the severity of scoliosis and the percentage of predicted vital capacity and peak flow was found. The patients who stood had a significantly better lung function than patients who were confined to a wheelchair, and their scoliosis deteriorated significantly more slowly. Sixteen patients underwent surgical spinal stabilisation, 4 with Harrington instrumentation and 12 with segmental spinal instrumentation, at an average age of 12 years and 11 months. The average curve correction achieved was 40%. The decline in lung function seen pre-operatively was not only reversed, but a significant improvement was found at final follow-up.

Adolescent↗
PubMed1998

Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of nuclear inclusions of spinal and bulbar muscular atrophy. Nuclear inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar nuclear inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural inclusions. These findings indicate that nuclear inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural nuclear inclusions.

Aged↗
PubMed1992

Linkage analysis of spinal muscular atrophy.

Linkage data between four markers on chromosome 5 confirm and extend our previous studies that localized the mutation in spinal muscular atrophy to 5q11.2-q13.3. Localization of D5S6 by in situ hybridization refines the mapping of the defective gene to the region 5q12.2-q13. We also report the use of a highly informative PCR-based polymorphism with five alleles. This RFLP will be particularly useful for prenatal diagnosis where only old tissue samples from affected individuals are available. The high heterozygosity of this locus should also assist in identifying recombinants that will refine the genetic mapping of the mutation.

Chromosome Mapping↗
PubMed2003

Use of power mobility for a young child with spinal muscular atrophy.

BACKGROUND AND PURPOSE: Young children with severe motor impairments, such as spinal muscular atrophy, are often unable to move around their environment independently; therefore, they may be at risk for delays in areas of development not directly related to their motor limitations. Power mobility is an intervention that provides young children a means of independent movement and enables them to independently explore their environment. CASE DESCRIPTION: The participant was a 20-month-old girl with type II spinal muscular atrophy. INTERVENTION: The authors provided the child with a power wheelchair and gave her mother and physical therapist general guidelines to encourage her use of the power wheelchair. OUTCOMES: Within 6 weeks after receiving the power wheelchair, the child operated the wheelchair independently. She showed developmental gains in all domains of the Battelle Developmental Inventory and the Pediatric Evaluation of Disability Inventory over 6 months. The authors conducted an interview with the child's mother before and after intervention. She reported that the child was more independent after receiving the power wheelchair. DISCUSSION: The power wheelchair may have been associated with the changes in the child's mobility and her developmental changes over 6 months.

Child Development↗
PubMed1997

Spinal muscular atrophy gene wobbler of the mouse: evidence from chimeric spinal cord and testis for cell-autonomous function.

Human hereditary neurodegenerative diseases are genetically and mechanistically very heterogeneous and so are spinal muscular atrophies and cerebellar ataxias in the mouse, despite the common phenomenon of neuronal death. In this species, a number of mutations impair spermiogenesis in addition to neuron survival. Among these, the wobbler mutation on proximal chromosome 11 of the mouse leads to motoneuron degeneration in brain stem and spinal cord and to a defect of spermiogenesis. Chimeric mice of the type wr?/wr? <--> +/+ were produced, and their allelic status at the wr locus was determined by PCR diagnosis of a closely linked marker. Two overt chimeras, one female (XX <--> XX) and one male (XY <--> XY) were identified as wr/wr <--> +/+ and analyzed with respect to their pathological phenotype. Although there was patchy astrogliosis in the spinal cords of both chimeras, their motor performances were overtly normal and muscles were without signs of denervation. The male's testes revealed a mosaic pattern of normal and pathological spermatids. As no progeny was derived from wr spermatids, the spermatocytes appear as a primary target of the wr mutation in testis. Our results argue against a humoral mechanism of the wobbler disease and indicate a cell-autonomous action of the wr gene both in testis and in spinal cord.

Animals↗
PubMed1994

First-trimester prenatal diagnosis of spinal muscular atrophy using microsatellite markers.

Twenty-five pregnancies at risk for spinal muscular atrophy I (SMA I) have been monitored by first-trimester prenatal diagnosis. Microsatellite markers were used in all cases to amplify polymorphic regions at the D5S125, D5S435, D5S39, D5S127, and D5S112 loci. All families, including 12 SMA I pedigrees with a decreased index child, were fully informative for DNA analysis. Three fetuses were predicted to be affected and 22 fetuses were predicted to be unaffected. Twenty-two newborns were unaffected by clinical examination at birth. These results support the accuracy of SMA I prenatal diagnosis based on linkage analysis.

Base Sequence↗
PubMed1993

Fine mapping and narrowing of the genetic interval of the spinal muscular atrophy region by linkage studies.

The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q12.2-q13, within a genetic distance of about 6 cM, and is proximally flanked by the locus D5S6 and distally by D5S112. Here, we report linkage analyses in 64 SMA families with nine polymorphic markers closely linked to the SMA gene, which allowed us to narrow the SMA region to about 4 cM and to define a new proximal genetic border by the locus D5S125 (EF(TG/AG)n. Based on haplotype analysis and specific recombination events, the following order of the loci was determined: 5cen-D5S76-D5S6-D5S125-SMA-(5'MAP-1B-3'MAP- 1B)/D5S112-JK53CA1/2-(D5S39-D5S127)-5qter. The location of the SMA gene between D5S125 and MAP-1B is further supported by multipoint linkage analysis.

Cell Line, Transformed↗
PubMed1995

Hypoglycaemia in spinal muscular atrophy.

Repeated episodes of hypoglycaemia were observed in two girls with spinal muscular atrophy. During a 12 h fast blood glucose fell to 3.4 and 2.7 mmol/L, respectively. One girl developed hypoglycaemia and ketonuria. Reduced gluconeogenesis was probably the cause of hypoglycaemia in these patients who had a muscle mass of about 10% of bodyweight (normal 30-40%). Hypoglycaemia must be suspected and treated when patients with severe muscle wasting due to chronic neuromuscular disorders are admitted comatose. In our experience this condition is often regarded as respiratory insufficiency.

Adolescent↗