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PubMed1993

Spine surgery in spinal muscular atrophy: long-term results.

Fifteen patients with spinal muscular atrophy operated on for scoliosis were reviewed and interviewed. Age at time of surgery averaged 16 yr. Follow-up averaged more than 5 yr. Eleven patients underwent posterior spinal fusion with Luque instrumentation. Four had Harrington instrumentation, with segmental wiring in three. Three out of the 15 also had anterior fusion with Dwyer instrumentation. Patients were immobilized in cast or brace for 6 months, on average, after surgery. The average curve correction was 50%. There was a loss of vital capacity after the operation, which in most cases was regained with time. In functional terms, there were improvements and deteriorations both in the short and long term. Esthetic appearance improved in all patients, as did the perceived well-being. Retrospectively all but one would have the operation again.

Adolescent↗
PubMed1995

Programmed cell death and the gene behind spinal muscular atrophy.

A gene involved in the development of spinal muscular atrophy (SMA) has been found on human chromosome 5 after a 4-year search. Named the neuronal apoptosis inhibitor protein (NAIP) gene, it is believed to inhibit the normal process of apoptosis--the disintegration of single cells that results from programmed cell death--in motor neurons. The researchers who found the NAIP gene also discovered that healthy people carry one complete copy of the gene along with many other partial copies. Many children with SMA have the partial copies but not the complete gene. This discovery facilitates the accurate genetic diagnosis of SMA. But gene therapy for SMA will not be possible until researchers find a suitable vector to stably introduce activated and intact copies of the gene into the motor neurons of children with SMA in time to stop motor neuron loss.

Apoptosis↗
PubMed1995

Noninvasive long-term ventilatory support for individuals with spinal muscular atrophy and functional bulbar musculature.

Ten individuals with spinal muscular atrophy (SMA) and chronic ventilatory insufficiency were trained in the use of assisted coughing techniques and received intermittent positive pressure ventilation (IPPV) via oral and/or nasal interfaces for a mean of 5.3 (range = 1 to 17) years. During this time they had significantly fewer respiratory complications than before introduction of noninvasive respiratory muscle aids despite the fact that 6 of the 10 went on to require more than 20 hours per day of ventilator use with less than 2 hours of ventilator-free breathing time (VFBT). All except two noninvasive IPPV users had vital capacities (VCs) less than 13% of predicted normal. They could, however, communicate verbally and take nutrition by mouth. All of the patients remained in the community. Five patients were gainfully employed and four were in school. We conclude that noninvasive respiratory muscle aids including noninvasive IPPV and assisted coughing techniques are effective and practical alternatives to tracheostomy for SMA patients with ventilatory failure but functional bulbar musculature.

Activities of Daily Living↗
PubMed1994

Complex repetitive arrangements of gene sequence in the candidate region of the spinal muscular atrophy gene in 5q13.

Childhood-onset proximal spinal muscular atrophy (SMA) is a heritable neurological disorder, which has been mapped by genetic linkage analysis to chromosome 5q13, in the interval between markers D5S435 and D5S557. Here, we present gene sequences that have been isolated from this interval, several of which show sequence homologies to exons of beta-glucuronidase. These gene sequences are repeated several times across the candidate region and are also present on chromosome 5p. The arrangement of these repetitive gene motifs is polymorphic between individuals. The high degree of variability observed may have some influence on the expression of the genes in the region. Since SMA is not inherited as a classical autosomal recessive disease, novel genomic rearrangements arising from aberrant recombination events between the complex repeats may be associated with the phenotype observed.

Amino Acid Sequence↗
PubMed2001

[Diagnostic progress in spinal muscular atrophy].

Progress of diagnostic methods in recognition of spinal muscular atrophy (SMA), the most common degenerative disease of the nervous system in children has been observed in the last years. It has been proved, that all types of SMA, phenotypically variable Werdnig-Hoffman and Kugelberg-Welander diseases are results of homozygous absence of the telomeric copy of SMN gene located on the long arm of chromosome 5; this discovery was very important for mechanisms investigation. Based on the evolution of SMA diagnostic, the results of diagnostic in 18 children hospitalized in the Department of Pediatric Neurology Collegium Medicum of Jagiellonian University are presented. In the years 1995-1997 the basic procedure for confirming the diagnosis of SMA has been muscle biopsy. Molecular studies introduced in 1998 were a chance for confirmation not only classical, but other than three main clinical SMA phenotypes. The molecular analysis performed in children allowed to confirm diagnosis in 7 patients, showing in 5 cases absence of exon 7 of the SMN gene and in 2 children detecting deletions involving SMN and NAIP genes. In the less typical cases the results of molecular analysis were less definite.

Adolescent↗
PubMedDate not supplied

Hip dislocation in spinal muscular atrophy.

Hip conditions in 49 patients affected with spinal muscular atrophy were studied: 35 of these were affected with the intermediate form of the disease (patients were able to sit but not walk), and 14 with the mild form (patients were able to walk). The Perkins method was used to measure the migration percentage of the femoral head. Thirty-one percent of the patients affected by the intermediate form of the disease had normal hips, 38% had unilateral or bilateral subluxation, 11% had hip dislocation. In the mild form of the disease, 50% of the patients had normal hips, 28% had unilateral or bilateral subluxation, and 22% had a hip dislocation. In the intermediate form of the disease there was a linear correlation between migration percentage and age, and between migration percentage and scoliosis. In the patients affected with the mild form of the disease who were able to walk, and in the patients affected with the intermediate form and fitted with orthoses who were able to stand, or to walk, there was no hip dislocation. Hence, walking with or without orthoses seems to be an important factor in preventing hip dislocation.

Child↗
PubMed1994

Genetic heterogeneity in spinal muscular atrophy: a linkage analysis-based assessment.

The spinal muscular atrophies (SMAs) are among the most common autosomal recessive disorders. The mapping of the gene responsible for SMA to chromosome 5 has allowed the assessment of genetic heterogeneity in kindreds with a putative diagnosis of SMA. We report linkage analysis of 71 Canadian SMA families (types 1, 2, and 3) using polymorphisms that both flank and are linked to SMA. Data demonstrating nonlinkage to 5q markers were initially obtained in five kindreds; reexamination of the clinical status of these families showed that one fulfilled all the SMA diagnostic criteria, two showed patterns for which a diagnosis of SMA was possible but not conclusive, and two showed patterns for which the diagnosis of SMA appeared unlikely. This results in a degree of genetic heterogeneity between 1.5% and 4.5%. The three kindreds for which SMA appeared either possible or likely were simplex (ie, contained only one affected individual), and therefore the possibility that they represented new mutations could not be discounted. Thus, the significant majority of classic SMA cases are caused by a mutation in the 5q13.1 locus. Low genetic heterogeneity has implications for both genetic counseling and the applicability of conventional and genetic therapies following cloning of the SMA gene.

Adult↗
PubMed1994

Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy.

Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explantation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (P = .09 +/- .06 for onset at 10-36 mo and .13 +/- .07 for onset at > 36 mo; and P = .09 +/- .07 for SMA IIIa and .12 +/- .07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given.

Adolescent↗
PubMed2004

Novel SCO2 mutation (G1521A) presenting as a spinal muscular atrophy type I phenotype.

Rare cases of suspected spinal muscular atrophy (SMA) have been found to have cytochrome c oxidase (COX) deficiency. To date, four cases with SMA features have been reported in children with mutations in the synthesis of cytochrome oxidase 2 (SCO2) gene. We report a male neonate who was born hypotonic, with persistent lactic acidosis, spontaneous activity with EMG testing, development of respiratory distress in the first few hours of life, and died at 30 days of age with progressive cardiomyopathy. Testing for survival motor neurone (smn) and NAIP deletions were negative and a skeletal muscle biopsy showed neurogenic features with severe reductions of COX enzymatic and histochemical staining intensity. Post-mortem muscle, heart, and liver biopsies showed severe, moderate, and mild reductions in COX activity, respectively, with parallel findings in the protein content for the mitochondrial DNA (COII) and nuclear DNA (COIV) encoded subunits. DNA sequencing of exon 2 of the SCO2 gene revealed compound heterozygosity with mutations at G1541A (common mutation, E140K) and also at a novel site in the copper binding region (G1521A in the current case (converting a highly conserved cysteine to tyrosine [corrected] (C133Y) [corrected]); mother heterozygous for G1521A; and father heterozygous for G1541A). This case provides strong support that SCO2 mutations can result in neonatal hypotonia with an SMA 1 phenotype. SCO2 mutations should be screened in suspected SMA cases with normal smn mutation analysis and any one of; cardiomyopathy, lactic acidosis, or COX deficiency in muscle.

Biopsy↗
PubMed2001

Nuclear gems and Cajal (coiled) bodies in fetal tissues: nucleolar distribution of the spinal muscular atrophy protein, SMN.

SMN, the affected protein in spinal muscular atrophy (SMA), is a cytoplasmic protein that also occurs in nuclear structures called "gems" and is involved in snRNP maturation. Coilin-p80 is a marker protein for nuclear Cajal bodies (coiled bodies; CBs) which are also involved in snRNP maturation, storage or transport. We now show that gems and CBs are present in all fetal tissues, even those that lack gems/CBs in the adult. Most gems and CBs occur as separate nuclear structures in fetal tissues, but their colocalization increases with fetal age and is almost complete in the adult. In adult tissues, up to half of all gems/CBs are inside the nucleolus, whereas in cultured cells they are almost exclusively nucleoplasmic. The nucleolar SMN is often more diffusely distributed, compared with nucleoplasmic gems. Up to 30% of cells in fetal tissues have SMN distributed throughout the nucleolus, instead of forming gems in the nucleoplasm. The results suggest a function for gems distinct from Cajal bodies in fetal nuclei and a nucleolar function for SMN. Spinal cord, the affected tissue in SMA, behaves differently in several respects. In both fetal and adult motor neurons, many gems/CBs occur as larger bodies closely associated with the nucleolar perimeter. Uniquely in motor neurons, gems/CBs are more numerous in adult than in fetal stages and colocalization of gems and CBs occurs earlier in development. These unusual features of motor neurons may relate to their special sensitivity to reduced SMN levels in SMA patients.

Adult↗
PubMed2005

SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder in humans which results in the loss of motor neurons. It is caused by reduced levels of the survival motor neuron (SMN) protein as a result of loss or mutation of the SMN1 gene. SMN is encoded by two genes, SMN1 and SMN2, which essentially differ by a single nucleotide in exon 7. As a result, the majority of the transcript from SMN2 lacks exon 7 (SMNDelta7). SMNDelta7 may be toxic and detrimental in SMA, which, if true, could lead to adverse effects with drugs that stimulate expression of SMN2. To determine the role of SMNDelta7 in SMA, we created transgenic mice expressing SMNDelta7 and crossed them onto a severe SMA background. We found that the SMNDelta7 is not detrimental in that it extends survival of SMA mice from 5.2 to 13.3 days. Unlike mice with selective deletion of SMN exon 7 in muscle, these mice with a small amount of full-length SMN (FL-SMN) did not show a dystrophic phenotype. This indicates that low levels of FL-SMN as found in SMA patients and absence of FL-SMN in muscle tissue have different effects and raises the question of the importance of high SMN levels in muscle in the presentation of SMA. SMN and SMNDelta7 can associate with each other and we suggest that this association stabilizes SMNDelta7 protein turnover and ameliorates the SMA phenotype by increasing the amount of oligomeric SMN. The increased survival of the SMNDelta7 SMA mice we report will facilitate testing of therapies and indicates the importance of considering co-complexes of SMN and SMNDelta7 when analyzing SMN function.

Animals↗
PubMed2002

Prenatal prediction of childhood-onset spinal muscular atrophy (SMA) in Turkish families.

Childhood-onset spinal muscular atrophy (SMA) is one of the most common neurodegenerative genetic disorders. SMN1 is the SMA-determining gene deleted or mutated in the majority of SMA cases. There is no effective cure or treatment for this disease yet. Thus, the availability of prenatal testing is important. Here we report prenatal prediction for 68 fetuses in 63 Turkish SMA families using direct deletion analysis of the SMN1 gene by restriction digestion. The genotype of the index case was known in 40 families (Group A) but unknown in the remaining 23 families (Group B). A total of ten fetuses were predicted to be affected. Eight of these fetuses were derived from Group A and two of these fetuses were from Group B families. Two fetuses from the same family in Group A had the SMNhyb1 gene in addition to homozygous deletion of the NAIP gene. One fetus from Group A was homozygously deleted for only exon 8 of the SMN2 gene, and further analysis showed the presence of both the SMN1 and SMNhyb1 genes but not the SMN2 gene. In addition, one carrier with a homozygous deletion of only exon 8 of the SMN1 gene was detected to have a SMNhyb2 gene, which was also found in the fetus. To our knowledge, these are the first prenatal cases with SMNhyb genes. Follow-up studies demonstrated that the prenatal predictions and the phenotype of the fetuses correlated well in 33 type I pregnancies demonstrating that a careful molecular analysis of the SMN genes is very useful in predicting the phenotype of the fetus in families at risk for SMA.

Cyclic AMP Response Element-Binding Protein↗
PubMedDate not supplied

[Clinical analysis of late infantile form of muscular atrophy].

Clinical analysis of 47 cases of late infantile spinal muscular atrophy is reported. In 25.5% of cases mothers reported weak fetal movements in pregnancy and low muscular tonus after birth, these signs predicted early manifestation of the disease. In 89,2% of cases the first signs of the disease appeared within the first 3 years of life. Delayed motor development in infancy was observed in 59.6%. Immobilization developed between the ages of 2 and 18 years, usually after 7 years of disease duration, and it was not correlated with the age of onset of the first signs of the disease. Mental development was normal in 81.5% of cases. Familial character of the disease was found in 51.1% of cases and in some of them intrafamilial variability was observed.

Adolescent↗
PubMed1989

Postpolio muscular atrophy. Diagnostic utility of macroelectromyography.

Muscles recovered from previous poliomyelitis may exhibit new weakness and wasting years after the original infection (postpolio muscular atrophy). Routine electrophysiological and morphological techniques may not differentiate weakening muscles from previously affected but stable muscles. We used quantitative motor unit potential analysis, single-fiber electromyography, and macroelectromyography (macro-EMG) to determine if these techniques could identify weakening muscles. We classified 18 previously affected muscles according to strength from 12 patients who had had poliomyelitis 18 to 50 years earlier. Muscles of normal strength had large-amplitude macro-EMG signals (1000 to 4110 microV; normal level, less than 390 microV). Muscles with new weakness and atrophy had smaller than expected macro-EMG amplitude (130 to 450 microV). Two muscles with weakness and atrophy unchanged since the original childhood infection had markedly increased macro-EMG amplitude (1710 and 1860 microV), suggesting the increased macro-EMG amplitude is due to stable reinnervation not strength. Mean motor unit potential duration and amplitude were lower in newly weakened muscles, but jitter, fiber density, and blocking were similar in all muscles regardless of strength. We conclude that low-amplitude macro-EMG signals may be useful in the identification of muscles weakened by postpolio muscular atrophy.

Adult↗
PubMed1983

Hand and ECG tremor in spinal muscular atrophy.

The presence of hand and electrocardiogram (ECG) tremor was studied in 31 children with severe, intermediate, or mild form of spinal muscular atrophy. Clinical tremor of the hands was seen in 16 (59%) of 27 patients, all with benign forms of the disease. Nineteen patients had ECG tremors, of whom 17 had the mild or intermediate form. With the exception of one, all patients in the mild or intermediate group had hand or ECG tremor. Hand and ECG tremor are valuable in the diagnosis of the benign forms of spinal muscular atrophy; they are of no value in diagnosis of the severe infantile type.

Adolescent↗
PubMedDate not supplied

A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: a preliminary report.

OBJECTIVE: To determine whether thyrotropin-releasing hormone (TRH) can increase muscle strength in children with spinal muscular atrophy types 2 and 3. DESIGN: A randomized, double-blinded, controlled, 5-wk drug trial of six subjects and three controls. Subjects and controls ranged from 4 to 8 yr of age and were randomly assigned to treatment and placebo groups in a ratio of 2:1. TRH (protirelin) or placebo was delivered intravenously through percutaneous intravenous catheters at a dose of 0.1 mg/kg (in 50 ml of normal saline) for a total of 29 days. Patients were evaluated using electromyography and handheld dynamometry of the deltoids, biceps, triceps, wrist extensors, hip flexors, quadriceps, hamstrings, and grip strength before and immediately after 5 wk of treatment. A unidirectional t test was used to compare mean values. RESULTS: Dynamometry improved significantly only for the six treated subjects (P < 0.02). Peroneal nerve conduction velocities were significantly faster in the treatment group (paired t test, P = 0.036). The parents of the treated children also provided anecdotal evidence of improvements in function. Improvements lasted 6-12 mo. CONCLUSIONS: TRH may be a useful treatment for spinal muscular atrophy. A larger, crossover design group comparison study is warranted.

Action Potentials↗
PubMed2005

Sleep-disordered breathing in spinal muscular atrophy types 1 and 2.

OBJECTIVE: Our aim was to assess the respiratory pattern during sleep in patients affected by spinal muscular atrophy types 1 and 2 and to compare their apnea-hypopnea indices with those of controls. DESIGN: All consecutively referred patients underwent polysomnography. Sleep stages were defined as either wake, quiet sleep (QS), or active sleep (AS). As measures of thoracoabdominal coordination, we measured: phase angle during QS and AS (Ph Angle QS and AS), phase relation during inspiration and expiration during QS and AS: (Ph RIB QS, Ph RIB AS, Ph REB QS; Ph REB AS) and the apnea-hypopnea index. RESULTS: The 14 consecutively referred infants and small children (age, 11.7 +/- 11.4 mos) showed a higher apnea-hypopnea index (P < 0.001), Ph Angle QS (P < 0.001), Ph Angle AS (P < 0.001), Ph RIB QS (P < 0.001), Ph RIB AS (P < 0.001), Ph REB QS (P < 0.001), and Ph REB AS (P < 0.001) compared with 28 healthy controls (age, 10.1 +/- 8.9 mos). CONCLUSIONS: Patients affected by types 1 and 2 spinal muscular atrophy had significantly higher apnea-hypopnea indices than controls. Thoracoabdominal asynchrony was present during the inspiratory and expiratory phases in both quiet and active sleep. Measures of thoracoabdominal coordination may be useful for the evaluation and monitoring of therapeutic interventions for these patients.

Case-Control Studies↗
PubMed1988

[Unusual complications at birth in a stillborn with spinal muscular atrophy].

A report is given on a premature stillborn with severe congenital spinal muscular atrophy, arthrogryposis multiplex congenita and hydrops fetalis. During delivery the head was spontaneously pulled off. The neuromuscular disease was the cause of this unusual complication. No alterations of collagenous fibres were found by light and electron microscopy in dermis, aorta or in the Achilles tendon. The hydrops fetalis was not of immunological nature.

Arthrogryposis↗