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Three patients from a large pedigree are described who had autosomal dominant spinal muscular atrophy that became manifest between the end of the fourth and the sixth decade. The disease progressed rapidly without evidence of corticospinal tract dysfunction, and within 3 years the patients died from respiratory failure.
Our previous experience with abnormal fatty acid metabolism in several children with spinal muscular atrophy (SMA) prompted evaluation of fatty acid metabolism in a larger cohort. Thirty-three infants with severe infantile SMA were shown to have a significantly increased ratio of dodecanoic to tetradecanoic acid in plasma compared with normal infants and 6 infants affected with equally debilitating, non-SMA denervating disorders. Seventeen children with milder forms of SMA had normal fatty acid profiles. In addition, all 5 infants with severe SMA evaluated in a fasting state developed a distinctive and marked dicarboxylic aciduria, including saturated, unsaturated, and 3-hydroxy forms, comparable in severity with the dicarboxylic aciduria of children with primary defects of mitochondrial fatty acid beta-oxidation. Nine children with chronic SMA and 23 control patients did not develop an abnormal dicarboxylic aciduria during fasting. No known disorder of fatty acid metabolism explains all of the abnormalities we find in SMA. Our data suggest, however, that the abnormalities are not a consequence of SMA-related immobility, systemic illness, muscle denervation, or muscle atrophy. These abnormalities in fatty acid metabolism may be caused by changes in cellular physiology related to the molecular defects of the SMA-pathogenic survival motor neuron gene or neighboring genes.
Fasciculation of the eyelids was observed in five of eleven children with spinal muscular atrophy (SMA); two had severe SMA and three were of intermediate severity. Three other children with intermediate SMA and the two children with mild SMA did not show eyelid fasciculations. This could provide an additional clinical sign to tongue fasciculation and hand tremor in the diagnosis of SMA in childhood.
A family with a hypertrophic form of peroneal muscular atrophy (PMA) was studied with typical clinical and electrophysiological abnormalities in the propositus and her child. The propositus' father was asymptomatic and slowing of nerve conduction velocities was limited to the peroneal nerves. Actual parentage was confirmed by 22 different serologic and electrophoretic marker systems.
Seven children with spinal muscular atrophy aged between 20 months and four years, none of whom had ever walked, were fitted with knee-ankle-foot orthoses. All the children could sit unsupported and therefore were at point 9 on the Vignos functional scale. Two children achieved autonomous walking, three assisted walking and the remaining two could stand without aid. During the follow-up period there was no progression of weakness and neither scoliosis nor contractures developed.
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.
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Late-childhood-onset spinal muscular atrophy (SMA) with rapid progression from proximal to distal muscle groups and leading to severe incapacity or death in adolescence or early adult life, was studied in two Melanesian families in Papua New Guinea. Probable SMA with cardiomyopathy was observed in a 12-year-old boy in a related family. The pattern of inheritance in the study group did not conform to any of the conventional Mendelian modes and it was conjectured that the disease was expressed in heterozygote carriers of the SMA gene only when an allelomorphic activator gene was present.
We report on a case of genetically proven X-linked spinal and bulbar muscular atrophy (X-SBMA) with prominent distal muscle atrophy and without proximal muscle involvement. The patient was a 35-year-old man who had a history of slow progressive hand and distal leg muscle weakness and wasting for 10 years. Motor nerve conduction velocities were normal with reduced compound muscle action potential amplitudes of hand and foot muscles. Sensory action potential amplitudes were small. Needle EMG revealed a chronic partial denervation with reduced interference in hand and distal leg muscles but with normal heading in all tested proximal muscles. Genetic studied showed an expansion of CAG repeat in the first exon of the androgen receptor gene, which suggests diagnosis of X-SBMA. The importance of genetic studies in this patient with unusual clinical presentation is emphasized.
Spinal muscular atrophy (SMA) is a neurodegenerative disease in humans and the most common genetic cause of infant mortality. The disease results in motor neuron loss and skeletal muscle atrophy. Despite a range of disease phenotypes, SMA is caused by mutations in a single gene, the Survival of Motor Neuron 1 (SMN1) gene. Recent advances have shed light on functions of the protein product of this gene and the pathophysiology of the disease, yet, fundamental questions remain. This review attempts to highlight some of the recent advances made in the understanding of the disease and how loss of the ubiquitously expressed survival of motor neurons (SMN) protein results in the SMA phenotype. Answers to some of the questions raised may ultimately result in a viable treatment for SMA.
To clarify the role of the orthopaedic surgeon in the management of spinal muscular atrophy, the records of 130 patients were reviewed. Seventy-three had died. Of the remaining fifty-seven, fifty were re-examined. The clinical manifestations of the disease, particularly those giving rise to orthopaedic problems, were studied. At the time of review the average age of the patients was 11.5 years. Thirty-five could not walk and all had some degree of muscle weakness, more marked proximally and in the lower limbs. The most common medical problem was repeated respiratory infection and the major orthopaedic problem was scoliosis, often severe. Nine of the thirty-five patients with scoliosis had had spine fusion. Most of them suffered some functional loss in attaining spinal stability.
The hereditary neurodegenerative disease spinal muscular atrophy (SMA) with childhood onset is one of the most common genetic causes of infant mortality. The disease is characterized by selective loss of spinal cord motor neurons leading to muscle atrophy and is the result of mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated in diverse nuclear processes including splicing, ribosome formation and gene transcription. Even though the genetic basis of SMA is well understood, it is not clear how defects in these ubiquitous processes result in motor neuron degeneration leaving other tissues unaffected. Recent evidence from animal and cell culture models of SMA points to roles for SMN in neurite outgrowth and axonal transport. Disruption of these functions might be particularly detrimental to motor neurons given their high metabolic demands and precise connectivity requirements, thus providing a possible explanation for the specificity of motor neuron susceptibility in SMA. Understanding the molecular mechanisms of SMN activity in neuronal processes may generate new targets for future therapeutic strategies.
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.
Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal peripheral neuropathies inherited in an autosomal dominant fashion. Our previous genetic and physical mapping efforts localized the responsible gene(s) to a well-defined region on human chromosome 7p. Here, we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V. This is the first example of an aminoacyl tRNA synthetase being implicated in a human genetic disease, which makes genes that encode these enzymes relevant candidates for other inherited neuropathies and motor neuron diseases.
We report the case of an 18-month-old girl with spinal muscular atrophy (SMA) that received 1 mg x kg(-1) rapacuronium for laryngospasm during induction of anaesthesia. Within 15 min, we observed some diaphragmatic recovery and, after emergence from anaesthesia, the child demonstrated adequate respiratory efforts. However, the child showed diminished strength of the upper extremity muscles. Since the preoperative workup had revealed bulbar symptoms and laryngeal function could not be easily assessed, the patient was kept intubated until upper extremity strength had returned to preoperative levels. Small doses of midazolam had been given to reduce the patient's anxiety but the patient was extubated within 5 h without any complications. Train of four (TOF) monitoring of the right adductor pollicis muscle, performed during anaesthetic recovery, was equivocal. In SMA, muscle groups are differentially affected so that TOF responses may be inconclusive and not reflect the state of the upper airway muscles. To our knowledge, this is the first report of use of a nondepolarizing neuromuscular blocking agent in a child with SMA.
Myelography was performed in 16 male patients with juvenile muscular atrophy of unilateral upper extremity. The age at onset ranged from 11 to 19 years (average, 16 years), and the age at study ranged from 15 to 38 years (average, 25 years). The most remarkable finding was an anterior shift of lower cervical dural canal during neck flexion, particularly of its posterior wall at around 6th vertebral level. The above finding was clearly shown in 12 patients whose duration of illness was under 20 years but not in 4 patients whose duration of illness was 20 years or over. And the rates of anterior shift of posterior lower cervical dura mater was inversely proportional to the duration of illness. There was a tendency that the greater the degree of the anterior dural shift and compression of the spinal cord, the greater the severity of the disease. We thought that the anterior shift of the posterior lower cervical dura mater provides the clue to understanding of its etiology and methods of arresting the progression of the disease.
Sixty patients with spinal muscular atrophy (SMA) are presented. Although the life span with Type I SMA (Werdnig-Hoffmann disease) may be short, children with the disease can be made more comfortable with appropriate medical care and parental support. Despite electrodiagnostic findings which are not always pathognomonic and muscle biopsies which can be difficult to interpret, the clinical presentation of these infants is so typical and the natural course of the disease so predictable that management can be telescopically designed. findings and muscle biopsies are more definitive. In these more benign forms of SMA, anticipatory medical management focuses on possible In SMA-II (Childhood) and SMA-III (Kugelberg-Welander), electrodiagnostic findings and muscle biopsies are more definitive. In these more benign forms of SMA, anticipatory medical management focuses on possible dislocating hips, scoliosis, pulmonary compromise, and sudden increase in weakness associated with intercurrent illness or prolonged immobilization due to fractures or surgery. Further considerations include maintenance of strength and endurance, independence in self-care, psychosocial, educational, and vocational endeavors. These more chronically affected children are eminently habilitable.
Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama's disease) occurs predominantly in men in the second decade with unilateral weakness of the fingers and hand, and atrophy of the hand and forearm. The symptoms generally progress for 3-4 years after onset and then stop. Since the second decade is a very important period starting one's career, early stopping of the progression and possibly the improvement are essential. On the bases of the neuroradiological studies, a forward displacement of the posterior wall of the dural canal at the lower cervical level on neck flexion is presumed to be the main pathogenetic mechanism in this disease. On neck flexion, the spinal cord is compressed anteroposteriorly at C7 and C8 segmental levels. Pathological studies suggested that chronic microcirculatory disturbances in the spinal cord as the result of repeated flexion of the neck might produce necrosis of the anterior horns. We used a cervical collar for the prevention of neck flexion in 14 patients in the early stage and compared the results with those of 18 patients who had natural courses. In the therapy group, muscle weakness of the affected hand improved in 5 patients and the progression of the disease was stopped in 8 patients with the duration of 1.8 +/- 1.2 years, whereas the duration of progression of the natural course group was 2.9 +/- 1.6 years. Only one patient who could not tolerate the use of collar showed a slight progression. These results suggest that the cervical collar is a useful therapeutic tool in this disease.