SMA I (acute spinal muscular atrophy; Werdnig-Hoffmann disease).
Incidence
Autosomal recessive inheritance.
Clinical Characteristics
SMA I (acute spinal muscular atrophy; Werdnig-Hoffmann disease). SMA I manifests as severe weakness before age six month. Affected children are not able to sit without support. Proximal, symmetric muscle weakness, lack of motor development, and poor muscle tone are the major clinical manifestations. Often mild contractures are noted at the knees and, rarely, at the elbows. In the neonatal period or during the first few months, the infants with the gravest prognosis have problems sucking or swallowing and often show abdominal breathing. The muscles of the face are spared completely; the ocular muscles and the diaphragm are not involved until late in the course of disease. The heart is normal. Of note, a peculiar tremor of the electrocardiographic baseline has been attributed to fasciculation of limb and chest wall muscles. Fasciculation of the tongue is seen in most but not all patients. A postural tremor of the fingers is seen only occasionally in SMA I. Most patients die before age two years. However, on occasion patients whose weakness was thought to have started before age six months are still walking in adolescence or adulthood. Dubowitz (1995) offered an explanation for this finding, suggesting that the prognosis for survival depends primarily on respiratory function. Diagnosis: The diagnosis of spinal muscular atrophy (SMA) is established in individuals with evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brainstem. Diagnostic criteria vary by age of onset. SMA I has very obvious clinical characteristics: Muscle weakness. Lack of motor development. Poor muscle tone. Onset 0-6 months. Facial weakness: minimal or absent. Fasciculation of the tongue: seen in most but not all patients. A postural tremor of the fingers: seen occasionally in patients with SMA I. No sensory loss. Normal cerebral function including intellect. The intellectual skills of this group of patients has been shown to be in the average range during the formative years; by adolescence the patients, as a group, have above average intellectual capabilities. Mild contractures; often at the knees, rarely at the elbows. Absence of tendon reflexes. Normal reaction to sensory stimuli. An alert appearance. Testing used in the past to establish the diagnosis of SMA currently has little role in the diagnosis of most patients and is used primarily if molecular genetic testing of the SMN1 gene is normal. These tests include: Electromyography (EMG). EMG reveals denervation and diminished motor action potential amplitude. The EMG shows regular spontaneous motor unit activity, a unique feature in SMA. This is seen most commonly in SMA I/and occasionally in SMA II, but not in SMA III. A reduced interference pattern is seen with maximal effort; polyphasic waves, positive sharp waves, and fibrillations are present in all patients with SMA. Nerve conduction velocities (NCV). Motor and sensory NCVs are normal.
Precipitants
none
Provocation Tests
none
Diagnostic Procedures
It is strongly clinically suspected. Testing used in the past to establish the diagnosis of SMA currently has little role in the diagnosis of most patients and is used primarily if molecular genetic testing of the SMN1 gene is normal. These tests include: Electromyography (EMG). EMG reveals denervation and diminished motor action potential amplitude. The EMG shows regular spontaneous motor unit activity, a unique feature in SMA. This is seen most commonly in SMA I/and occasionally in SMA II, but not in SMA III. A reduced interference pattern is seen with maximal effort; polyphasic waves, positive sharp waves, and fibrillations are present in all patients with SMA. Nerve conduction velocities (NCV). Motor and sensory NCVs are normal. Molecular Genetic Testing: SMN1 mutation analysis: Mutation analysis is used to detect deletion of exons 7 and 8 of SMN1. Approximately 95-98% of individuals with a clinical diagnosis of SMA lack exon 7 in both copies of SMN1 (i.e., they are homozygous). Approximately 2-5% of patients with a clinical diagnosis of SMA are compound heterozygotes for deletion of SMN1 exon 7 and an intragenic mutation of SMN1.
Other analysis method used is the SMN1 sequence analysis: Sequence analysis may be used to identify the intragenic SMN1 mutations present in the 2-5% of patients who are compound heterozygotes. Linkage analysis is available for families in which direct DNA testing (Mutation analysis and/or sequence analysis) is not informative. Genetic analysis is available on a clinical basis. For detailed information on these tests, please contact genetests.org.
Muscle biopsy is generally not indicated if genetic DNA testing is available.