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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↗
PubMed1996

Electrocardiographic findings in children with spinal muscular atrophy.

Most of the patients in this study with spinal muscular atrophy were found to have tremors of the isoelectric line in the electrocardiogram (ECG) tracings. There were a total of 47 cases of SMA (mean age 40.8 months). All three types of SMA had a similar incidence (about 80%) of tremors in the tracings (p = 0.885). In 7 cases the ECG tremors had an intermittent pattern. ECG tremors were commonly found in the majority of SMA patients and this finding, though non-specific, may suggest a possible SMA diagnosis.

Adolescent↗
PubMed2001

Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals.

Amino Acid Sequence↗
PubMed1975

Sensory system involvement in infantile spinal muscular atrophy.

Nine cases of infantile spinal muscular atrophy were studied post-mortem. Their ages at death ranged from 5 months to 10 years. In all cases severe loss of anterior horn cells in the spinal cord and neurogenic muscular atrophy were characteristic of this disease. In 6 cases there was also loss of myelin in the posterior columns particularly affecting the lumbar contribution. Sensory ganglia, especially from the lumbar region, contained nodules of Nageotte, indicating sensory neuron degeneration. These sensory abnormalities were more severe in the longer surviving cases. It seems possible that sensory neuron degeneration occurs more commonly in Werdnig-Hoffmann disease than has previously been supposed but that it is less severe and develops more slowly than motor neuron degeneration.

Anterior Horn Cells↗
PubMed1988

Electrophysiological findings in childhood spinal muscular atrophies.

The aim of this study was to evaluate in indirect way through electrical activity of muscles and nerves the state of motoneuron in different forms of childhood spinal proximal muscular atrophies (SMA). The material comprised 454 cases of SMA type Ia (Werdnig-Hoffmann) types Ib + II (intermediate form) and type III (Kugelberg-Welander form). The quantitative EMG revealed the differences between different forms of SMA's in respect to spontaneous and volitional activity. The most unique phenomenon is the occurrence in SMA Ia form of rhythmic firing of motor unit (MUF) persisting during sleep. The comparison of duration, shape and amplitude of action potentials in acute severe form Ia and mild long-standing form III indicates the inability to increase the motor unit territory in form Ia as opposed to form III where most motoneurons have ability to enlarge their field. It was also stated that in the early stage of SMA the EMG has not only diagnostic but also prognostic value.

Adolescent↗
PubMed2002

Stable motor and lung function throughout pregnancy in a patient with infantile spinal muscular atrophy type II.

Patients with infantile spinal muscular atrophy rarely decide to have their own children especially if there is major respiratory impairment. We studied prospectively the pregnancy course and outcome of a 34-year-old woman with spinal muscular atrophy type II who delivered a healthy boy. Pregnancy was entirely uneventful, except that for 1-2 weeks after the caesarean section, the patient was extremely weak with dyspnoea and bulbar involvement. Several weeks after delivery her motor function had returned to pre-pregnancy levels. Pulmonary function remained stable throughout pregnancy, and thereafter, at approximately 70% predicted levels for forced vital capacity and for forced expiratory volume in 1 s. Blood gases after midgestation revealed low normal PaO(2) values around 85 mmHg and concomitant hyperventilation resulting in PaCO(2) levels below 30 mmHg.

Adult↗
PubMed1988

Electromyographic and computed tomographic findings in five patients with monomelic spinal muscular atrophy.

Five patients with monomelic spinal muscular atrophy are described. Clinical features included insidious onset of wasting and weakness of one limb, lack of involvement of the cranial nerves, brain stem, pyramidal tracts and sensory system, and a stable condition over a period of 4-20 years. Clinical findings, electromyography and/or muscle biopsy were consistent with anterior horn cell lesion. Central cavities were excluded by magnetic resonance imaging studies of the spinal cord. Computed tomography of skeletal musculature and electromyography indicated more diffuse lower motor neuron involvement by revealing abnormalities in clinically unaffected muscles in 4 of the 5 patients. Myokymic discharges were found in the affected limb of 1 patient.

Adolescent↗
PubMed1996

[Childhood spinal muscular atrophies].

Current knowledge of infantile spinal muscular atrophies (ISA) is reviewed by analyzing cases seen by the neurology service at Hospital Sant Joan de Déu in Barcelona from 1978 through 1986. The assessment is mainly clinical. The total number of patients is 60, as follows: 24 with severe or type I forms, 24 with intermediate or type II forms and 12 with type III forms. All type I patients presented hypotonia and weakness before age four months and died before the age of two years. DNA genome tests were performed for eight, revealing that four had deletions in the seventh and eighth exons. One patient had a single deletion in exon 7, one had a deletion in the neuronal apoptosis inhibitory protein gene as well as in exon 7. No deletions were detected in two patients. Four type II patients died of respiratory complications. All except one acquired autonomous sedestation. Severe scoliosis presented in 14 patients, with most requiring corsets. Fourteen required arthrodesis of the spinal column by way of Luque's technique. DNA genome studies were performed for 19, revealing that 14 had deletions in both exons 7 and 8. Exon 7 deletion was present in two. Two also had deletions in exon 3, an abnormality known as the "Spanish mutation". Genetic conversion or an equivalent deletion in exon 7 was observed in the remaining patients. Five of the type III patients walked autonomously, although with pelvic balancing and Gower's maneuver upon rising from the floor. Braces were required for walking by four, whereas three walked so precariously that they only achieved partial autonomy inside the home. DNA genome studies were performed in seven, revealing exon 7 and 8 deletions in six patients. Only one presented a partial deletion in exon three.

Adolescent↗
PubMed1999

Prenatal onset spinal muscular atrophy.

Five patients with severe spinal muscular atrophy (SMA) type I, all of whom presented with reduced fetal movements in utero, severe weakness at birth, and short survival time were assessed to attempt to determine whether their phenotype could be explained by their genotype. The diagnosis was confirmed by clinical, electrophysiological and histopathological features. Polymerase chain reaction assays were used to define the molecular diagnosis. A gene-dosage assay was used to assess the quantity of centromeric survival motor neuron gene (SMNc) present. In all cases the telomeric survival motor neuron gene (SMNt) was absent. The SMNc gene was present but in reduced copy number compared with a control group of children with less severe type I SMA, so may be important in determining severity. In the differential diagnosis of reduced fetal movements, SMA should be considered. The clinical classification may in future be clarified by molecular genetic findings.

Cell Survival↗
PubMed2006

Descriptive epidemiology of spinal muscular atrophy type I in Estonia.

Spinal muscular atrophy is the second most frequent autosomal-recessive disorder in Europeans. There are no published epidemiological data on SMA in Estonia and other Baltic countries. The aim of this study was to estimate the incidence of SMA I in Estonia. All patients with SMA I diagnosed between January 1994 and December 2003 were included in the study. The diagnosis was established on the basis of neurological evaluation, ENMG findings, molecular studies and muscle biopsy. PCR and restriction enzyme analysis was used to detect the homozygous deletion of the SMN1 gene. A total of 9 cases of SMA I were identified during this 10-year period. The incidence of SMA I in Estonia is 1 in 14,400 live births, which is similar to the result from Hungary but lower than average incidence in the world. Only one of the patients was female. Typical SMN1 gene deletion was found in all cases.

Cyclic AMP Response Element-Binding Protein↗
PubMed1998

Spinal muscular atrophy.

The history of the spinal muscular atrophies (SMA) began in the 1890s with Guido Werdnig and Johann Hoffmann. Together, their papers present a rather complete picture of the clinical and pathologic aspects of infantile SMA: onset during the first year of life, occurrence in siblings with normal parents, progressive floppiness and weakness, hand tremor, and death from pneumonia in early childhood. Based on the work of an international collaboration, the following is current nomenclature: SMA type 1 (or I) for onset of symptoms before age 6 months, SMA type 2 (II) for onset between 6 and 18 months, and SMA type 3 (III) for onset after age 18 months. Linkage of autosomal recessive SMA to chromosome 5q11.2-13.3 was reported by Gilliam et al in 1990. A novel gene, whose function remains unknown, called the survival motor neuron gene (SMN) at 5q13, contains deletions in more than 98% of SMA patients. Some patients with atypical forms of SMA have been shown to have mutations in SMN. Because there is no effective therapy for SMA, management consists of preventing or treating the complications of severe weakness, such as restrictive lung disease, poor nutrition, orthopedic deformities, immobility, and psychosocial problems.

Child↗
PubMed2002

[Role of signs of fetal hypokinesia in the diagnosis of spinal muscular atrophy of neonatal onset].

INTRODUCTION: Spinal muscular atrophy (SMA) is characterized by early degeneration of anterior horn cells. The most frequent and severe type of neonatal onset is Werdnig-Hoffmann disease. The neurologic and genetic characteristics of SMA are well-known. The aim of this study was to analyze the dysmorphologic features of this disease. PATIENTS AND METHODS: We present an analysis of 10 cases of SMA identified among 27,864 infants with congenital defects registered by the Spanish Collaborative Study of Congenital Malformations (ECEMC) between April 1976 and December 1998. We also report a clinical case of neonatal SMA presenting the classical signs of fetal hypokinesia deformation sequence. RESULTS: The minimum estimation of the prevalence of SMA with congenital defects in our population is 0.32 per 100,000 live births. We found a male-to-female ratio of 3.5. The most frequently associated congenital defects in our population of neonatal SMA were located in the extremities (mainly arthrogryposis), face and thorax and could be explained by intrinsic fetal hypomobility secondary to the neuromuscular disorder. The characteristics of fetal hypokinesia deformation sequence are discussed in the case report presented herein: dystocic delivery, short umbilical cord, polyhydramnios, intrauterine growth retardation, craniofacial malformations, skeletal abnormalities with multiple articular contractures, pulmonary hypoplasia, etc. CONCLUSIONS: It is important to recognize the congenital defects associated with neuromuscular disorders, because dysmorphologic features are sometimes more marked than neurologic features in the neonatal period and because of the wide spectrum of congenital defects in neonatal SMA that result in a fetal hypokinesia deformation sequence.

Female↗
PubMed2006

In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate.

OBJECTIVE: Spinal muscular atrophy results from loss of the survival motor neuron 1 (SMN1) gene and malfunction of the remaining SMN2. We investigated whether valproic acid can elevate human SMN expression in vivo. METHODS: Blood was collected from 10 spinal muscular atrophy carriers and 20 spinal muscular atrophy patients treated with valproic acid. RESULTS: Seven of 10 carriers demonstrated increased SMN messenger RNA and protein levels. SMN2 messenger RNA levels were elevated in 7 patients and unchanged or decreased in 13 patients. INTERPRETATION: We provide first proof of the in vivo activation of a causative gene by valproic acid in an inherited disease and discuss strategies of monitoring drug response in patients.

Cyclic AMP Response Element-Binding Protein↗
PubMed1997

Degeneration of cocultures of spinal muscular atrophy muscle cells and rat spinal cord explants is not due to secreted factors and cannot be prevented by neurotrophins.

We have shown recently that cocultures of muscle cells from infantile spinal muscular atrophy (SMA) patients innervated by motoneurons of normal rat spinal cord explants undergo a degeneration process, suggesting that muscle may play a role in this atrophy, which previously has been considered to be a pure motoneuron disease. Conditional media of SMA cocultures did not affect control healthy nerve muscle cocultures. Conversely, conditioned media of control cocultures were unable to prevent degeneration of SMA cocultures. Moreover, neurotrophic factors, thought to be of help in motoneuron disease treatment, did not protect SMA cocultures from premature death. Our results suggest that the abnormal phenotype observed in nerve-muscle coculture (1) is not due to the release of a toxic factor nor to the lack of a secreted survival factor, and (2) does not respond to neurotrophin treatment.

Animals↗
PubMed1994

Biochemical and immunocytochemical analysis in chronic proximal spinal muscular atrophy.

Immunocytochemical and biochemical analyses were carried out on patients affected by chronic SMA. Three groups of patients were identified. In group I, the muscle presented a fascicular atrophy; a high percentage of atrophic type II fibers; and fibers expressing fast, slow, embryonic, and fetal myosin isoforms. In group II, the muscle was characterized by atrophic fibers and normal/hypertrophic fibers expressing only slow myosin isoforms. In group III, the muscle was characterized by fiber type grouping and fibers coexpressing fast and slow myosin isoforms but never embryonic or fetal MHC isoforms. The muscles of groups I and III contained both fast and slow myosins whereas group II muscles were predominantly slow by immunocytochemical analysis or only slow by biochemical analysis. In view of these results, immunocytochemical and histochemical analyses could help to classify chronic SMA and help to understand the different pathogenic processes which seem to be related to the maturational stage of the muscle at the age of onset of the disease.

Adolescent↗
PubMed1990

Chronic childhood spinal muscular atrophies in Algeria. A genetic study.

This paper describes a genetic study of the chronic spinal muscular atrophies of late infancy and early childhood in Algeria. There were 50 index patients occurring in 44 kindreds and fourteen secondary cases. Genetic and nosological studies indicated that 52% of the patients constitute a genetically homogeneous subgroup with an age of onset between 3 and 24 months and an autosomal recessive mode of transmission. They also indicated that a large subgroup of index patients (48%) had a late age of onset, between 3 and 14 years. Such a large number of late presenting cases has not been reported in previous series. The majority of these cases are probably due to an autosomal recessive gene. A small proportion may represent new dominant mutations or nongenetic phenocopies. A possible sex influence on disease manifestations is discussed. A trend toward later male onset has been noted, and the degree of disability is more marked in males at or after the age of 10. Finally, some empirical risks for use in genetic counselling are presented.

Adolescent↗
PubMedDate not supplied

Gene deletion patterns in spinal muscular atrophy patients with different clinical phenotypes.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of lower motor neurons. We have assayed deletions in two candidate genes, the survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes, in 108 samples, of which 46 were from SMA patients, and 62 were from unaffected subjects. The SMA patients included 3 from Bahrain, 9 from South Africa, 2 from India, 5 from Oman, 1 from Saudi Arabia, and 26 from Kuwait. SMN gene exons 7 and 8 were deleted in all type I SMA patients. NAIP gene exons 5 and 6 were deleted in 22 of 23 type I SMA patients. SMN gene exon 7 was deleted in all type II SMA patients while exon 8 was deleted in 19 of 21 type II patients. In 1 type II SMA patient, both centromeric and telomeric copies of SMN exon 8 were deleted. NAIP gene exons 5 and 6 were deleted in only 1 type II SMA patient. In 1 of the 2 type III SMA patients, SMN gene exons 7 and 8 were deleted with no deletion in the NAIP gene, while in the second patient, deletions were detected in both SMN and NAIP genes. None of the 62 unaffected subjects had deletions in either the SMN or NAIP gene. The incidence of biallelic polymorphism in SMN gene exon 7 (BsmAI) was found to be similar (97%) to that (98%) reported in a Spanish population but was significantly different from that reported from Taiwan (0%). The incidence of a second polymorphism in SMN gene exon 8 (presence of the sequence ATGGCCT) was markedly different in our population (97%) and those reported from Spain (50%) and Taiwan (0%).

Age of Onset↗