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Spinal muscular atrophy (SMA) is one of the most common fatal autosomal recessive disorders, characterised by progressive degeneration of anterior horn cells. Before the advent of genetic testing, the diagnosis of SMA was based on clinical, histopathological, and electrophysiological features. In 1992, the International SMA Consortium defined diagnostic criteria of proximal SMA based on clinical findings.1 In SMA type I (severe; Werdnig-Hoffmann disease), affected persons have onset of symptoms before 6 months of age and are never able to sit without support. Electromyography demonstrates denervation features. In early 1995, the candidate gene, the survival motor neuron (SMN) gene, was identified, making the confirmation of SMA by DNA analysis possible.2
With the availability of a genetic test for SMA, many investigators are refining the diagnostic criteria published by the Consortium. Studies involving hundreds of patients with proximal SMA have disclosed a subset of patients who fulfill at least one exclusion criterion defined by the Consortium.3 We identified an infant with severe SMA who fulfilled two exclusion criteria and also showed inexcitability of all nerves as well as muscles. This report will further delineate the wide range of phenotypes for this particular gene mutation.
A 2945 g male infant was born at term. First fetal movements were noted at 13 weeks of gestation. Chorionic villus sampling at 10 weeks of gestation disclosed normal chromosomes. Decreased fetal movement and polyhydramnios were noted at about 34 weeks of gestation. At delivery, the infant was cyanotic with no respiratory effort and was subsequently intubated. On physical examination, the infant had no spontaneous movements. He opened his eyes with brief fixation but no following. Tongue fasciculations were present. Other cranial nerves seemed intact. Mild flexion contractures of both elbows, knees, and ankles were noted. Tone was flaccid in both upper and lower limbs, and there was no movement response to painful stimulus. Deep tendon reflexes were absent.
Brain MRI disclosed mild diffuse cortical and deep atrophy. His EMG was severely abnormal, with widespread fibrillations and absent voluntary motor units except in the genioglossus, where mildly neurogenic motor units with decreased recruitment were seen. Stimulation of the median, ulnar, tibial, and peroneal nerves with a maximal stimulus resulted in no clinical or electrical response. The biceps brachii and rectus femoris muscles were electrically inexcitable by direct needle stimulation. Median, ulnar, and sural sensory potentials were not obtainable. DNA testing showed a homozygous deletion of exons 7 and 8 in the telomeric SMN gene, confirming the diagnosis of SMA. The infant expired at 3 weeks of age, and the parents declined postmortem examination.
Typical EMG studies in those with SMA show fibrillations and fasciculations at rest and an increased mean duration and amplitude of motor units. Motor nerve conduction velocities may be slowed but are usually normal. Korinthenberg et al reported inexcitability of motor nerves in three siblings, each of whom died from SMA before 1 month of age.4 In addition to a homozygous deletion of exons 7 and 8 of the telomeric SMN gene, all three siblings showed a large deletion in the region that includes all alleles of the multicopy markers Ag1-CA and C212, localised at the 5′ end of the two SMN gene copies. It has been postulated that the severity of disease may be correlated to the extent of a deletion involving the SMN gene and the multicopy markers.3-5 The infant in our report with SMA type I showed electrical inexcitability of motor nerves as well as the characteristic alteration of the SMN gene.
Although it has been known for some time from histological studies that sensory systems are involved in SMA, electrophysiological sensory findings have been previously reported only once.4 Sensory nerve conduction velocity was tested in an infant with severe SMA and showed no recordable potential, but the infant in our report also exhibited universal absence of sensory potentials. In both cases, DNA analysis disclosed the 5q deletion. It is unclear whether this finding represents a distinct entity or merely the severe end of classic Werdnig-Hoffmann disease. The diagnostic criteria produced by the International SMA Consortium currently lists “abnormal sensory nerve action potentials” as an exclusion criterion.1 Our finding of absent sensory potentials in a 5q deletion established case of SMA indicates further need for revision of the Consortium criteria.
Studies involving large series of patients with SMA have identified cases of SMA variants.3 These patients were diagnosed as infantile SMA by the presence of proximal weakness and atrophy, hypotonia, and evidence of neurogenic alterations in EMG and muscle biopsy. In addition, these patients also exhibited one of the exclusion criteria defined by the Consortium—for example, diaphragmatic weakness, involvement of the CNS, or arthrogryposis. Although these patients did not show the typical SMN deletion and were therefore probably not linked to chromosome 5q, they could have had point mutations. The infant in our report showed no respiratory effort after birth, indicating diaphragmatic weakness. He did, however, possess the characteristic SMN gene alterations. This finding suggests that diaphragmatic weakness should be reconsidered as an exclusion criterion by the Consortium.
Review of the literature disclosed no previous reports of electrically inexcitable muscles in SMA. This phenomenon is known to occur in a few other neuromuscular conditions such as periodic paralysis and critical illness polyneuropathy. Fibrillations, as seen in the infant in our report, are commonly seen in acute denervation and are thought to be caused by perturbation of the sarcolemmal membrane, rendering it unstable. One possibility may be that the severe denervation in SMA type I can result in abnormal function of the membrane to make it electrically inexcitable. Further electrophysiological studies at the cellular level are required to delineate this interesting finding.