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PubMed2005

Respiratory management of the infant with type 1 spinal muscular atrophy.

A recent paper has highlighted the differences in the respiratory management offered to infants with type 1 spinal muscular atrophy (SMA-1). Current views appear polarised between those who would offer nothing, to those who would proceed as far even as tracheostomy and long term invasive ventilation for these infants. Here we offer a personal view, as a possible template for managing a vexed and emotional problem. The complex non-respiratory aspects of the holistic care of these infants will not be discussed.

Humans↗

PubMed1995

A new mutation in the HEXA gene associated with a spinal muscular atrophy phenotype.

We describe two adult siblings who had had mild GM2 gangliosidosis since childhood. They presented with spinal muscular atrophy and dysarthria, and one sibling also had mental disturbances. Laboratory studies established the diagnosis of the B1 variant of GM2 gangliosidosis, because the hexosaminidase (Hex) A deficiency was not present upon testing with the unsulfated synthetic substrate 4-methylumbelliferyl N-acetylglucosaminide. HEXA gene analysis proved that the patients are compound heterozygotes for the previously identified G533-->A mutation and for a new mutation, G1171-->A, at exon 11. This new mutation affects a conserved amino acid and results in a Val-->Met substitution at position 391 of the HEXA gene. Full sequence of the alpha-subunit cDNA of Hex A revealed no other mutation. Assays for Hex A activities in patients suspected of having GM2 gangliosidosis should be performed with the sulfated substrate 4-methylumbelliferyl N-acetylglucosamine 6-sulfate.

Adult↗

PubMed1993

Advanced EMG techniques in diagnostics of spinal muscular atrophies and motor neuron disease--magnetic stimulation, single fiber EMG and macro EMG.

Motor neuron disease (MND) and spinal muscular atrophies (SMA) are difficult to diagnose with classical EMG methods because significant findings appear relatively late and both groups of diseases show neurogenic type of record differing only in a relatively greater amount of fasciculations and higher amplitude of motor unit potential (MUP) in MND compared with SMA. We examined 12 patients with MND-amyotrophic lateral sclerosis and 7 patients with SMA type III and IV according to Swash with advanced EMG techniques-magnetic stimulation, single fiber and macro EMG. With transcranial magnetic stimulation, a significant prolongation of cortical latency was found in MND (P < 0.0001 right hand and P < 0.0005 left hand) against SMA, where it was almost normal. With single fiber EMG, mean jitter was less markedly increased in MND (P < 0.05 against SMA) and fiber density was lower in MND (P < 0.005). With macro EMG, no significant difference was found in either macro amplitude or area. Macro fiber density was also lower in MND (P < 0.005). Advanced EMG techniques proved to differentiate clearly the III. (Kugelberg-Welander) and IV. (adult) type of SMA from MND-amyotrophic lateral sclerosis.

Adult↗

PubMed1986

Long-term follow-up of spinal fusion in spinal muscular atrophy.

From 1966 to 1983, 11 females and eight males with spinal muscular atrophy were treated by arthrodesis. Seventeen of 19 patients were evaluated by follow-up physical examination, roentgenograms, and questionnaires. In order to compare long-term versus short-term results, changes in management, and factors contributing to morbidity and mortality, three groups were identified for study. Group I consisted of 11 patients operated between 1966 and 1983 and alive at follow-up evaluation. Group II consisted of five patients operated between 1980 and 1983. Group III consisted of three patients, all deceased at follow-up evaluation and operated before 1980. In Group I, the preoperative curve averaged 119 degrees and at final follow-up examination, 99 degrees. The average preoperative curve in Group II was 80 degrees and at follow-up examination, 49 degrees. Long-term follow-up vital capacities were obtained in nine patients. The average preoperative vital capacity was 1033 cm3, and the average vital capacity seven years postoperation was 860 cm3. Most patients reported improvement in sitting, balance, and comfort. All patients are wheelchair-bound, as they were before surgery. Few long-term respiratory problems were reported.

Adolescent↗

PubMed1991

[Enzyme-and immuno-histochemistry of muscle biopsies in severe infantile spinal muscular atrophy].

The basic lesions in the muscle biopsies of 11 cases of severe infantile spinal muscular atrophy showed typical neurogenic fascicular muscular atrophy. It was found through histochemistry staining that both types of muscle fibres were involved which were characterised by the presence of type grouping of the damaged fibers, anyhow, the original mosaic pattern of both types were still partially reserved. With anti-laminin immunofluorescence staining, it was demonstrated that the basal membrane of atrophied small muscle fibre was still intact. It is considered that the main manifestation of damage on spinal anterior horn neuron is denervation of the skeletal muscle; meanwhile, the function of the muscle fibre in regulations carbohydrate metabolism is not apparently obstructs. The pathologic process of this disease develops from denervation to renervation and then back to denervation again. Therefore the clinical feature of muscle atrophy in this disease is progressive and developmental.

Anterior Horn Cells↗

PubMed1989

[Progressive spinal muscular atrophy and parathyroid adenoma. Clinico-pathologic study of a case].

A 82 year-old man died 6 years after the onset of a progressive spinal muscular atrophy. Post-mortem examination disclosed a parathyroid adenoma. Weakness and wasting were prominent in the proximal lower limbs. There were no fasciculations. Involvement of the medulla was mild and late. These clinical features were also present in 16 reported cases, which were improved by treatment of primary or secondary hyperparathyroidism. Our patient differs by the involvement of the hand muscles and the loss of tendon reflexes. Neuropathological study, as in one other reported case, showed a loss of anterior horn cells. Such cases underline that calcium metabolism must be studied in syndromes of spinal muscular atrophy.

Adenoma↗

PubMed1995

Spinal muscular atrophy with oculomotor palsy, epilepsy, and cerebellar hypoperfusion.

We report a boy with spinal muscular atrophy (SMA) type 1, who developed novel clinical and neuroradiologic features, indicating the broad spectrum of this degenerative disease. Widespread lesions in the central nervous system were disclosed by magnetic resonance imaging and single photon emission computed tomography (SPECT) studies. In particular, scattered regions of hypoperfusion demonstrated by SPECT suggested multisystem involvement including the cerebellum. The novel features of this patient were complex partial seizures and oculomotor palsy.

Cerebellum↗

PubMed1986

Electromyographic findings in different forms of infantile and juvenile proximal spinal muscular atrophy.

Quantitative electromyography (EMG) was performed in 223 infantile and juvenile cases of spinal muscular atrophy (SMA), which were classified into 3 groups: (A) form Ia, Werdnig-Hoffmann disease; (B) forms Ib and II, intermediate forms; and (C) form III, Kugelberg-Welander disease. The groups differed in the occurrence of spontaneous activity; only groups A and B showed spontaneous rhythmic firing of motor units, whereas in long-standing cases, pseudomyotonic volleys appeared. The parameters of individual motor unit potentials (MUPs) differed in the different forms of the disease. Group A showed, in addition to long potentials of high amplitude, some short and low amplitude potentials, and the histograms of amplitudes and durations were bimodal. In the long-standing cases, the values of these parameters were shifted to longer durations and higher amplitudes of motor unit potentials. However, in long-standing cases of the benign group C, the short, low potentials appeared as well as so-called linked potentials. In the very early stage of the disease, the children who were found to be suffering from chronic forms of SMA--both malignant (form Ib and II or benign group C)--had an EMG record that was slightly different from that of acute form Ia. Their EMG record shows more so-called "spinal" signs, particularly in the benign group C (Kugelberg-Welander disease). These increasing features of chronic anterior horn cell involvement followed a pattern of reinnervation and hypertrophy of muscle fibers. These phenomena were particularly seen in the benign group C. These findings indicate that in the early stage of SMA, the EMG not only has diagnostic, but also prognostic, value.

Action Potentials↗

PubMed2005

Autonomic dysfunction in cases of spinal muscular atrophy type 1 with long survival.

In Japan, quite a few patients with spinal muscular atrophy type 1 (SMA type 1) survive with mechanical ventilation. Since a patient with SMA type 1 and continuous artificial ventilation exhibited excessive perspiration and tachycardia, we examined the autonomic functions in three cases of SMA type 1, undergoing mechanical ventilation. Two cases exhibited the common sympathetic-vagal imbalance on R-R interval analysis involving 24-h Holter ECG recordings in addition to an abnormality in finger cold-induced vasodilatation. Furthermore, one case showed blood pressure and heart rate fluctuation with the paroxysmal elevation, and a high plasma concentration of norepinephrine during tachycardia. These findings suggest that autonomic dysfunction should be examined in SMA type 1 patients with long survival, although the pathogenesis remains to be clarified.

Autonomic Nervous System↗

PubMed1976

Isoelectric focusing and electrophoresis of cerebrospinal fluid proteins in muscular dystrophies and spinal muscular atrophies.

In the very few previous investigations of the CSF-proteins in muscular dystrophies the results have generally been reported as normal. In spinal muscular atrophies a barrier-damage pattern of CSF-proteins has been found in amyotrophic lateral sclerosis (ALS). In the present investigation the CSF-proteins were examined by isoelectric focusing and quantitative paper electrophoresis in 13 patients with muscular dystrophies and in 11 patients with spinal muscular atrophies. On isoelectric focusing, CSF-protein abnormalities were found in 85% of the cases with muscular dystrophies and in all patients with spinal muscular atrophies. Differences in the CSF-protein patterns were observed within the group of muscular dystrophies and between these and the cases of spinal muscular atrophies. In ALS and in myotonic dystrophy, abnormal CSF-protein fractions occurred mainly in the alkaline pH-range, while in limb-girdle dystrophy and the patient with facioscapulohumeral dystrophy, aberrant fractions appeared mainly in the acidic region. CSF-protein abnormalities were found in both the alkaline fractions (HAFs) with pI 9.2-9.6 and a fraction with PI 7.1 were found in half of the patients with myotonic dystrophy. The CSF electrophoresis in myotonic dystrophy showed increased levels of beta1-globulin in all cases examined. Signs of barrier-damage were commonly encountered in ALS in contrast to the muscular dystrophies, except for myotonic dystrophy. The results are discussed in terms of possible diagnostic value and with regard to pathogenetic significance, particularly in relation to the current hypothesis of a neural involvement in muscular disorders.

Adult↗

PubMed2000

Spinal muscular atrophy type 1: A noninvasive respiratory management approach.

STUDY OBJECTIVE: To determine whether spinal muscular atrophy (SMA) type 1 can be managed without tracheostomy and to compare extubation outcomes using a respiratory muscle aid protocol vs conventional management. DESIGN: A retrospective cohort study. METHODS: Eleven SMA type 1 children were studied during episodes of respiratory failure. Nine children required multiple intubations. Along with standard treatments, these children received manually and mechanically assisted coughing to reverse airway mucus-associated decreases in oxyhemoglobin saturation. Extubation was not attempted until, most importantly, there was no oxygen requirement to maintain oxyhemoglobin saturation greater than 94%. After extubation, all patients received nasal ventilation with positive end-expiratory pressure. Successful extubation was defined by no need to reintubate during the current hospitalization. RESULTS: Two children have survived for 37 and 66 months and have never been intubated despite requiring 24-h nasal ventilation since 5 and 7 months of age, respectively. One other child underwent tracheostomy for persistent left lung collapse and inadequate home care, another for need for frequent readmission and intubation, and one child was lost to follow-up 3 months after successful extubation. The other six children have been managed at home for 15 to 59 (mean 30.4) months using nocturnal nasal ventilation after an episode of respiratory failure. The nine children were successfully extubated by our protocol 23 of 28 times. The same children managed conventionally were successfully extubated 2 of 20 times when not using this protocol (p < 0.001 by the two-tailed Fisher's Exact t Test). CONCLUSION: Although intercurrent chest colds may necessitate periods of hospitalization and intubation, tracheostomy can be avoided throughout early childhood for some children with SMA type 1.

Child, Preschool↗

PubMed1997

Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene.

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

Adult↗

PubMed1993

Refined mapping of the GM2 activator protein (GM2A) locus to 5q31.3-q33.1, distal to the spinal muscular atrophy locus.

The GM2 activator locus (GM2A) had previously been considered as a candidate gene for some forms of spinal muscular atrophy (SMA; mapped to 5q11.2-q13.3). It was eliminated as a possible candidate because PCR-based mapping failed to localize the gene to chromosome 5, as was previously reported using an ELISA-based methodology. However, we demonstrated that the PCR primers used preferentially amplified a processed pseudogene (GM2AP) that we mapped to chromosome 3 and that GM2A was located on chromosome 5. In this report, we reconsider the candidacy of GM2A by refining its localization on chromosome 5 using fluorescence in situ hybridization. We localize GM2A to 5q31.3-q33.1; thus, it is not a candidate gene for SMA.

Cells, Cultured↗

PubMed2000

Nuclear targeting defect of SMN lacking the C-terminus in a mouse model of spinal muscular atrophy.

Deletion of the murine survival of motor neuron gene (SMN) exon 7, the most frequent mutation found in spinal muscular atrophy (SMA) patients, directed to neurons but not to skeletal muscle, enabled generation of a mouse model of SMA providing evidence that motor neurons are the primary target of the gene defect. Moreover, the mutated SMN protein (SMNDeltaC15) is dramatically reduced in the motor neuron nuclei and causes a lack of gems associated with large aggregates of coilin, a coiled-body-specific protein. These results identify the lack of the nuclear targeting of SMN as the biochemical defect in SMA.

Animals↗

PubMed1992

Genotyping of spinal muscular atrophy families with linked DNA probes.

We report on linkage analysis and haplotype characterization in 40 Italian families with spinal muscular atrophy (SMA). The investigated loci included D5S6, D5S112, D5S39, and D5S76. No evidence of unlinked families was found. Thirty-two (80%) of the examined families were fully informative for prenatal diagnosis and carrier detection. The frequencies of individual alleles did not differ between SMA and normal chromosomes.

Adult↗

PubMed1995

Mapping of the spinal muscular atrophy (SMA) gene to a 750-kb interval flanked by two new microsatellites.

The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped between D5S629 and D5S557. We report here a new single-locus microsatellite A31 (D5S823) and two multicopy microsatellites 97T-CA and 95/23-CA. The marker A31 maps to the region of overlap between YACs y116, y55 and y122, distal to D5S629; 97T-CA originates from a cosmid corresponding to the STS 97T, localized distally to A31, while 95/23-CA derives from a cosmid corresponding to the STS 97U, localized proximally to D5S557. We tested all our key recombinant families with these markers. In one type I/II SMA family, a recombinant was found that placed the SMA locus distal to D5S823. Homozygosity mapping in a consanguineous type I SMA family indicates that the SMA gene lies proximal to 95/23-CA. Thus, the two new markers, A31 and 95/23-CA further refine the SMA gene to an approximately 750-kb interval.

Base Sequence↗

PubMed2000

[A case of spinal muscular atrophy with marked calf hypertrophy and adolescent onset].

We report on a 41-year-old male patient with spinal muscular atrophy (SMA). He had slowly progressive muscular weakness and hypertrophic calves since 14 years of age. The upper arms were slightly, and the thighs moderately atrophic, but the calves were remarkably hypertrophic. There was muscle weakness of both the upper and lower limbs, being more proximal in distribution. He had a positive Gowers' sign and his gait was slightly waddling. Serum creatine kinase level was elevated (518IU/l). Electromyogram revealed a neurogenic pattern. Muscle biopsy of the left biceps brachii showed chronic neurogenic changes. Immunohistochemical examination and Western blot analysis using anti-dystrophin antibodies showed no abnormality. DNA analysis with multiplex PCR proved no deletion in the dystrophin gene, while deletions of exons 7 and 8 of the telomeric copy of survival motor neuron gene were detected. In 1978, Pearn et al. described a new variant syndrome of SMA, characterized by adolescent onset, gross hypertrophy of calves, and a slowly progressive clinical course. The present case is compatible with this syndrome. Therefore, it is suggested that this syndrome, mimicking Becker muscular dystrophy, is not an independent clinical entity, although the phenotype of this syndrome is different from that of typical SMA.

Adolescent↗

PubMed2000

[Autosomal dominant adult-onset spinal muscular atrophy with vocal cord paralysis: a case report].

This report concerns a 41-year-old female case of spinal muscular atrophy (SMA) associated with vocal cord paralysis. Her parents were not consanguineous. Her maternal grandmother and younger brother were suspected of having SMA. At age 37, she first experienced gait disturbance and began to have slowly progressive dysarthria and weakness of the extremities. Neurological examination revealed that she had inspiratory stridor, dysarthria and proximal muscular weakness of the extremities. Achilles tendon reflexes were absent, while there were no pathological reflexes or sensory disturbances. She showed a waddling gait and Gowers' sign. The laboratory data indicated mild elevation of serum CK. The nerve conduction study was normal, while the electromyographic study and muscle biopsy revealed neurogenic changes. We diagnosed the case as adult onset SMA of the autosomal dominant type. Laryngoscopy revealed that the patient had vocal cord paralysis, which was predominant in abductor muscles and of the posterior paralysis type according to the categories established by Isozaki. Genetic analysis showed no mutations in the genes of the neuronal apoptosis inhibitory protein and of the survival motor neuron.

Adult↗