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We present the 1st report of chronic segmental spinal muscular atrophy confined to the upper extremities in identical male twins. This occurrence in identical twins, together with reports of siblings and parent-child pairs of a disorder phenotypically similar to the more common sporadic form in the literature, suggests a genetic etiology in some cases.
Proximal spinal muscular atrophy is an autosomal recessive human disease of spinal motor neurons leading to muscular weakness with onset predominantly in infancy and childhood. With an estimated heterozygote frequency of 1/40 it is the most common monogenic disorder lethal to infants; milder forms represent the second most common pediatric neuromuscular disorder. Two candidate genes-survival motor neuron (SMN) and neuronal apoptosis inhibitory protein have been identified on chromosome 5q13 by positional cloning. However, the functional impact of these genes and the mechanism leading to a degeneration of motor neurons remain to be defined. To analyze the role of the SMN gene product in vivo we generated SMN-deficient mice. In contrast to the human genome, which contains two copies, the mouse genome contains only one SMN gene. Mice with homozygous SMN disruption display massive cell death during early embryonic development, indicating that the SMN gene product is necessary for cellular survival and function.
Spinal muscular atrophy (SMA) is a common disorder characterized by loss of lower motor neurones of the spinal cord. The disease is caused by mutations in the survival motor neurone ( SMN ) gene. SMN is ubiquitously expressed and evolutionarily conserved, and its role in RNA processing has been well established. However, these properties do not explain the observed specificity of motor neurone death. To gain further insight into the function of SMN, we have isolated and characterized the Caenorhabditis elegans orthologue of the SMN gene ( CeSMN ). Here we show that CeSMN is transmitted maternally as a predominantly nuclear factor, which remains present in all the blastomeres throughout embryonic development and onwards into adulthood. In adult nematodes, a CeSMN-green fluorescent protein fusion protein is expressed in a number of cell types including the germline. Both disruption of the endogenous CeSMN function and overexpression of the gene result in a severe decrease in the number of progeny and in locomotive defects. In addition, its transient knockdown leads to sterility caused by a defect in germ cell maturation. The expression pattern and functional properties so far observed for CeSMN, together with its unusual behaviour in the germline, indicate that SMN may be involved in specific gene expression events at these very early developmental stages. We have also identified a deletion in the CeSMN promoter region in egl-32. This mutant may become a useful genetic tool with which to explore regulation of CeSMN and hence provide possible clues for novel therapeutic strategies for SMA.
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, causing symmetric proximal muscle weakness. SMA is classified in three clinical types, SMA I, SMA II, and SMA III, based on the severity of the symptoms and the age of onset. About 95% of SMA cases are caused by homozygous deletion of the survival motor neuron 1 (SMN1) gene (5q13), or its conversion to SMN2. The molecular diagnosis of this disease is usually carried out by a polymerase chain reaction-restriction fragment length polymorphism approach able to evidence the absence of both SMN1 copies. However, this approach is not able to identify heterozygous healthy carriers, which show a very high frequency in general population (1:50). We used the multiple ligation-dependent probe amplification (MLPA) approach for the molecular diagnosis of SMA in 19 affected patient and in 57 individuals at risk to become healthy carriers. This analysis detected the absence of the homozygous SMN1 in all the investigated cases, and allowed to discriminate between SMN1 deletion and conversion to SMN2 on the basis of the size showed by the peaks specific for the different genes mapped within the SMA critical region. Moreover, MLPA analysis evidenced a condition of the absence of the heterozygous SMN1 in 33 out of the 57 relatives of the affected patients, demonstrating the usefulness of this approach in the identification of healthy carriers. Thus, the MLPA technique represents an easy, low cost, and high throughput system in the molecular diagnosis of SMA, both in affected patients and in healthy carriers.
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.
A 2-year 9-month-old male was referred for gait disturbances. Main complaints were abnormal gait with frequent falls observed as soon as he began to walk unaided, at 18 months of age. The first neurologic examination revealed symmetric and proximal weakness in the lower limbs with difficulty running and walking upstairs. Deep tendon reflexes were decreased, and generalized hypotonia was observed. Three months later, at 3 years of age, he had lost independent gait, and 1 month later he could not stand unaided. DNA analysis revealed homozygous deletion in exons 7 and 8 of SMN1 gene, confirming the diagnosis of spinal muscular atrophy. According to the current classification, this patient would be classified as spinal muscular atrophy type III. The distinctive feature of this case was the short time elapsed (18 months) between onset of spinal muscular atrophy and the age at which he lost ambulation. This patient reinforces the notion that late onset of symptoms in spinal muscular atrophy and acquisition of independent gait do not exclude a rapidly progressive motor deterioration, which is important when talking with families about outcome. In those rapidly progressive cases, when promptly available, testing for SMN1 gene will prevent unnecessary, invasive, or uncomfortable procedures such as lumbar puncture, electromyography, or spinal cord magnetic resonance imaging.
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.
We reported a 49-year-old mother and her 28-year-old son with autosomal dominantly inherited bulbar spinal muscular atrophy (AD-BSMA). They showed progressive bulbar paresis, muscle wasting and weakness dominant in the proximal groups of limb muscles, and finger tremor. Onset of illness was in adult life. In laboratory examinations, elevated creatine kinase in serum and neurogenic changes either in EMG or muscle biopsy were noted. The son had neither gynecomastia nor abnormal sexual hormone levels which were observed in the sex-linked recessive bulbar spinal muscular atrophy (SR-BSMA). Elongation due to the CAG repeats at the androgen receptor gene of the X chromosome in SR-BSMA was not detected. In conclusion, it is clear that AD-BSMA is different from SR-BSMA on the basis of clinical and genetical aspects.
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Scapuloperoneal (SP) syndromes are heterogeneous neuromuscular disorders which are characterized by weakness in the distribution of shoulder girdle and peroneal muscles. SP syndromes can resemble facioscapulohumeral muscular dystrophy (FSH) due to scapular weakness or Charcot-Marie-Tooth disease (CMT) due to atrophy of peroneal muscles. Both neurogenic and myopathic SP syndromes have been described. Locus for the myopathic form of SP syndrome (scapuloperoneal muscular dystrophy, SPMD) has recently been assigned to chromosome 12q. We previously described a large New England kindred exhibiting an autosomal dominant neurogenic SP syndrome (scapuloperoneal spinal muscular atrophy, SPSMA). Disease expression was more severe and progressive in successive generations, which suggested genetic anticipation. We performed genetic linkage analysis of this family with microsatellite markers and excluded the loci for FSH, CMT, SPMD and SMA (spinal muscular atrophy) in our family. Linkage in our SPSMA family (lod score > 3) was established to seven microsatellite markers that map to chromosome 12q24.1-q24.31. The highest lod score with two-point linkage analysis was 6.67 (theta = 0.00) with marker D12S353. Multipoint analysis gave maximum lod scores of 7.38 between D12S354 and D12S79, and also 7.38 between D12S369 and NOS1 (neuronal nitric oxide synthase). The gene for SPSMA lies within the 19 cM interval between D12S338 and D12S366. This report establishes a locus for the neurogenic form of SP syndrome approximately 20 cM telomeric to the one described for the myopathic form of SP syndrome.
Spinal and bulbar muscular atrophy (SBMA) 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. To study AR protein expression in normal and SBMA individuals, we used several antibodies that recognize AR protein, and analyzed neural and nonneural tissues by immunohistochemistry and western blotting. Both the normal and the mutant AR proteins were widely distributed, predominantly, but not exclusively, in the cytoplasm of neurons regardless of the pathological involvement, and predominantly in the nuclei of the nonneural tissues in both normal and SBMA individuals, with different expression levels of AR protein among different tissues. In the motor neurons of SBMA patients, there were AR-immunoreactive ubiquitinated nuclear inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein. Absence of other immunoreactive AR epitopes within the inclusion may be due to altered AR configuration, or masking of AR epitopes by other proteins, or proteolytic cleavage of the AR. Our data show that, in addition to the normal cellular distribution of the AR protein, mutant AR-bearing nuclear inclusions are present in SBMA.
With the evidence of deletions in the region responsible for autosomal recessive spinal muscular atrophy (SMA) on chromosome 5, it is now possible to further clarify the clinical and diagnostic findings in proximal SMA. Homozygous deletions of the survival motor neuron (SMN) gene can be detected in about 95% of patients with early onset SMA. In a series of more than 200 patients, we tested 31 patients with atypical features of SMA who fulfilled at least one exclusion criterion according to the diagnostic criteria of the International SMA Consortium for the presence of SMN gene deletions. The patients were subdivided into two groups: 1. Seven index patients being not deleted for the SMN gene who belonged to a well-defined SMA plus variant that has already been shown to be unlinked with chromosome 5q markers: diaphragmatic SMA, SMA plus olivopontocerebellar hypoplasia, SMA with congenital arthrogryposis and bone fractures. 2. Twenty-four patients with clinical signs of SMA and neurogenic findings in EMG/muscle biopsy who had unusual features or other organ involvement. In order to structure this heterogeneous group, each patient was assigned to a subgroup according to the leading atypical feature. In 5 out of 8 unrelated patients with a history of preterm birth and/or perinatal asphyxia leading to a picture of severe SMA in combination with respiratory distress and/or cerebral palsy, no deletion of the SMN gene could be detected. There were five unrelated patients with extended central nervous system involvement (cerebral atrophy, EEG abnormalities, pyramidal tract signs, evidence of cerebellar involvement). Most of these patients (4/5) proved to belong to SMA 5q on the basis of SMN gene deletion findings. The same applied to a group of three patients with classical SMA in association with congenital malformations (mainly heart defect). A fourth group of three patients was characterized mainly by an unusual improvement of the condition; in these patients no SMN gene deletions were present. In three index patients a more complex syndrome of the CNS and other organs was suggested, but the detection of SMN gene deletions in two of them made a coincidence of features more likely. In addition, SMN gene deletions were found in two patients with evidence of congenital fibre type dysproportion in one and extremely raised CK activity ( > 10fold) in the other. While the confirmation of SMN gene deletions is very useful in cases with diagnostic doubts, caution is required when offering prenatal prediction with regard to SMA 5q in families with atypical features. There is strong evidence that there are clinical entities resembling SMA which most likely have another pathogenetic background.
The purpose of this study was to further identify and quantify the fatty acid oxidation abnormalities in spinal muscular atrophy, correlate these with disease severity, and identify specific underlying defect(s). Fifteen children with spinal muscular atrophy (3 type I, 8 type II, 4 type III) were studied. Serum carnitine total/free ratios demonstrated a tendency toward an increased esterified fraction ranging 35-58% of total carnitine (normal: 25-30% of total) in younger children with types I and II. The remaining type II and III patients, older than 23 months of age at sampling, had normal esterified carnitine levels. Urinary organic acid analysis demonstrated mild to moderate medium-chain dicarboxylic aciduria in type I patients and normal, mild, or moderate increases in short-chain and medium-chain organic acids in type II patients. In the type III group, the organic acids were normal except for one patient with mild medium-chain dicarboxylic aciduria. Muscle intramitochondrial beta-oxidation was measured in 5 children (2 type I, 2 type II, and 1 type III) and a significant reduction in the activities of short-chain L-3-hydroxyacyl-CoA dehydrogenase, long-chain L-3-hydroxyacyl-CoA dehydrogenase, acetoacetyl-CoA thiolase, and 3-ketoacyl-CoA thiolase were found; however, normal crotonase activity was documented. Most strikingly, there was a marked increase (3- to 5-fold) in the activity ratios of crotonase to L-3-hydroxyacyl-CoA dehydrogenase and thiolase activities with both short- and long-chain substrates. The combined abnormalities suggest a defect in a mitochondrial multifunctional enzyme complex, distinct from the trifunctional enzyme. These abnormalities may be either primary or secondary and may respond to dietary measures to reduce the dependence on fatty acid oxidation.
Chronic childhood-onset spinal muscular atrophy (SMA) is, after Duchenne muscular dystrophy, the most common neuromuscular disorder in childhood. Recent linkage analyses have mapped this disease to 5q12-5q14. We show that chronic SMA (Types II and III) is tightly linked to the marker locus D5S39 (Zmax = 5.47 at theta = 0.02) in eight French Canadian families. In contrast to previously published results, we do not observe close linkage between chronic SMA and D5S6 (Zmax = 0.34 at theta = 0.18) or D5S78 (Zmax = 0.25 at theta = 0.21). Last, we present a family that appears to be discordant for this localization but may represent the first example of an incompletely penetrant individual.
With a prevalence of approximately 1/10 000, and a carrier frequency of 1/40-1/60 the proximal spinal muscular atrophies (SMAs) are among the most frequent autosomal recessive hereditary disorders. Patients can be classified clinically into four groups: acute, intermediate, mild, and adult (SMA types I, II, III, and IV, respectively). The complexity and instability of the genomic region at chromosome 5q13 harbouring the disease-causing survival motor neuron 1 (SMN1) gene hamper molecular diagnosis in SMA. In addition, affected individuals with SMA-like phenotypes not caused by SMN1, and asymptomatic individuals with two mutant alleles exist. The SMN gene is present in at least one telomeric (SMN1) and one centromeric copy (SMN2) per chromosome in normal (non-carrier) individuals, although chromosomes containing more copies of SMN1 and/or SMN2 exist. Moreover, the two SMN genes (SMN1 and SMN2) are highly homologous and contain only five base-pair differences within their 3' ends. Also, a relatively high de novo frequency is present in SMA. Guidelines for molecular analysis in diagnostic applications, carrier detection, and prenatal analysis using direct and indirect approaches are described. Overviews of materials used in the molecular diagnosis as well as Internet resources are included.
The efficacy of direct prenatal diagnosis for spinal muscular atrophy (SMA) is demonstrated, and the potential pitfalls with this type of analysis are highlighted in the largest prospective single-center prenatal series in the United States. The presence or absence of exons 7 and 8 of the SMN gene was determined from 66 fetuses from 51 families. Direct and cultured chorionic villus samples (CVS) and amniocytes were analyzed. DNA analysis to exclude maternal cell contamination was performed on all CVS. Follow-up was obtained for 48 cases; 13 pregnancies continue. One child predicted to be affected with SMA remains asymptomatic at 13 months. Thirty-three cases were confirmed to be clinically unaffected in agreement with the prenatal molecular results. Three of 24 CVS had maternal cell contamination. In conclusion, direct molecular analysis of either CVS or amniocytes is highly accurate in the prenatal diagnosis of SMA. However, maternal cell contamination of CVS samples can confound these analyses, and the possibility of contamination must be excluded routinely.
The gene for autosomal recessive forms of spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q13, within a 4-cM region between the blocks D5S465/D5S125 and MAP-1B/D5S112. We identified two new highly polymorphic microsatellite DNA markers--namely, AFM265wf5 (D5S629) and AFM281yh9 (D5S637)--which are the closest markers to the SMA locus. Multilocus analysis by the location-score method was used to establish the best estimate of the SMA gene location. Our data suggest that the most likely location for SMA is between locus D5S629 and the block D5S637/D5S351/MAP-1B/D5S112/D5S357. Genetic analysis of inbred SMA families, based on homozygosity by descent and physical mapping using mega-YACs, gave additional information for the loci order as follows: cen-D5S6-D5S125/D5S465-D5S435-D5S629-SMA-+ ++D5S637-D5S351-MAP-1B/D5S112-D5S357- D5S39-tel. These data give the direction for bidirectional walking in order to clone this interval and isolate the SMA gene.
A report on 89 cases of proximal Spinal Muscular Atrophy with observations on the clinical features, criteria of classification and modes of inheritance. The various forms into which SMA is divided probably represent a single disease that may begin at any age and may vary in severity, due, as a rule, to an autosomal recessive gene.