The various types of SMA can be distinguished clinically by the distribution of weakness, by the pattern of inheritance, and by the age of onset.
There are two different forms of infantile SMA: an acute form or type I (MIM 253300) and a more chronic form or type II (MIM 253550). Both are inherited as autosomal recessive traits.
The acute or type I SMA, first described by Werdnig1,2 and by Hoffmann,3 is characterized by its severe generalized muscle involvement and fatal outcome. In about one-third of cases, the disease manifests before birth by diminished fetal movements in utero or by mild contractures. In the other cases, the onset occurs at birth or within the first 6 months of life. Generalized weakness associated with areflexia is the most common clinical features. Active movements are usually confined to the fingers and toes. Fasciculations can be detected in the tongue. The face is usually spared and the infant usually has a bright, normal expression. Intercostal paralysis with severe collapse of the chest is the rule. Breathing is almost entirely diaphragmatic, the diaphragmatic muscle being spared. The extraocular movements are normal. Feeding and breathing difficulties are usually responsible for death within 2 years of age. Some studies have presented survival statistics on type I SMA indicating that all patients with an age of onset in the first 6 months of life are deceased by 2 years of age.4,5 Another study showed a bad prognosis for patients with onset within the first 3 months of life; 50 percent died by 7 to 8 months and all were deceased before 5 years of age.6 However, life span of many patients with early SMA onset is often better than expected.
Type II SMA is a more slowly progressive generalized disease with a variable prognosis. Infants are able to sit unsupported but none are able to stand or walk unaided. Atrophy and fasciculations of the tongue are frequent and spontaneous tremor of the fingers may be evident. Tendon reflexes are diminished or absent. Clinical progression is slow or appears even to arrest. All children will develop, if untreated, severe scoliosis and respiratory ventilation defect. Life expectancy is highly variable, ranging up to adult life in some cases.
In juvenile SMA or type III or Kugelberg-Welander disease (MIM 253400),7 symptoms start from 18 months to 30 years of age. All patients are able to walk and proximal muscle weakness is progressive. Subsequently, the patients show difficulties in climbing stairs and gait becomes waddling. Muscle weakness associated with muscle atrophy is more proximal than distal. There is no evidence of sensory or upper motor neuron involvement. About one-fourth of the patients exhibit a hypertrophy of the calves, a feature similar to that observed in Duchenne or Becker muscular dystrophies.8 Finally, adult SMA is defined by an age of onset after 20 or 30 years of age. Aside from age of onset, the diagnostic criteria are identical to the other forms of SMA.9
In 1991, the international SMA consortium subdivided childhood SMA into three clinical groups based on the age of onset, age of death, and the achievement of certain motor milestones (Table 231-1).10 Clinical severity actually displays a continuous range from the severe to the mild forms of the disease.
Table 231-1: Classification of Childhood SMA |Favorite Table|Download (.pdf) Table 231-1: Classification of Childhood SMA
|Designation ||Symptoms (months) ||Course ||Death (years) |
|I ||0–6 ||Never sit ||< 2 |
|II ||< 18 ||Never stand ||> 2 |
|III ||> 18 ||Stands alone ||Adult |
Biochemical investigations of patients with proximal SMA reveal no specific abnormalities. Increased serum creatine phosphokinase (CK) activity is found in about half of the patients with type III SMA.11 The values can be 2 to 10 times higher than the normal upper limit.
Electromyographic (EMG) investigations reveal spontaneous discharge activity in resting muscle, increased amplitude, and prolonged duration of motor unit potentials during voluntary effort. Other EMG features of severe denervation are commonly found in older patients. Although nerve conduction velocity is generally considered normal, some decrease in velocity has been demonstrated in severe cases.12
Histologic studies of skeletal muscle show the typical changes of denervation with small groups of atrophic muscle fibers associated with markedly hypertrophied fibers.13,14 Small angular fibers randomly intermixed with normal-sized fibers are often observed. Atrophic fibers are arranged in groups that are usually of uniform fiber type based on the myosin ATPase reaction. This is considered as an extensive collateral reinnervation of previously denervated muscle fibers by sprouts from surviving motor neurons. In SMA type III, but not in infantile SMA (type I or II), one can observe markedly hypertrophic fibers, excessive variation in fiber size, and internal nuclei. Degenerative changes with necrosis and regenerative fibers associated with proliferative interstitial connective tissue can be observed.14 Because these changes are characteristic features of primary myopathies, they have been interpreted as “pseudomyopathic” changes. In addition, these myopathic changes are usually found in patients with high serum levels of CK activity and may suggest the presence of a myopathic process secondary to neurogenic process. However, these pseudomyopathic changes are not observed in other human neurogenic diseases, which suggests that they can be specific to the molecular mechanism resulting in or associated with juvenile SMA.
The most striking neuropathologic feature found at autopsy of SMA patients is a loss of the large anterior horn cells of the spinal cord. In the remaining surviving motor neurons, a severe degree of central chromatolysis is visible. These cells appear as large ballooned cells without stored substances. Other anterior horn cells are pyknotic. In addition, there are occasional figures of neuronophagia associated with astrogliosis and the anterior roots are very small.13
Although the signs of SMA type I, II, or III are more or less stereotyped, there are a number of conditions that must be considered by the clinician depending on the age of the patient.
Myopathies and Miscellaneous Diseases.
Diseases with a floppy infant syndrome, including congenital myotonic dystrophy, Prader-Willi syndrome (MIM 176270), myasthenia gravis (MIM 254200), congenital myopathies, and congenital muscular dystrophy, should be considered in the differential diagnosis of infantile SMA. Proximal muscle weakness of the upper and lower limbs associated with the presence of hypertrophic calves and the high level of CK activity found in one-fourth of type III SMA patients may lead to the consideration of Becker muscular dystrophy in the differential diagnosis. The X-linked inheritance pattern of Becker muscular dystrophy distinguishes it from SMA. The EMG is the most valuable diagnostic tool for differentiating the SMA from myopathies although muscle biopsy may sometimes be required for the diagnosis.
Other forms of SMA can be differentiated from proximal SMA based on the clinical features or the mode of inheritance.
Bulbar and spinal muscular atrophy or Kennedy syndrome is an X-linked recessive disease characterized by proximal muscle weakness with onset between 20 and 40 years of age (see Chap. 161). Muscle cramps are common. Dysphagia and dysarthria, due to bulbar involvement associated with gynecomastia and testicular atrophy, are specific to the Kennedy syndrome. The diagnosis is based on the detection of expansion of a (CAG) triplet in the androgen receptor gene.15
Distal SMA is a peroneal muscular atrophy similar to Charcot Marie Tooth disease (CMT; MIM 601472) type I or type II (see Chap. 227). The most important feature distinguishing distal SMA from CMT is the absence of sensory signs. Distal SMA is a clinically and genetically heterogeneous disease. The age of onset of symptoms varies from early childhood to adulthood. Recessive and dominant forms are observed. Genetic linkage studies showed that distal SMA is not linked to the SMA locus on chromosome 5q.16 Two genetic loci for distal SMA have been identified so far. The disease gene maps to chromosome 7p in a family showing a clinical phenotype starting in the upper limbs. In the classic phenotype, the disease gene has been mapped on chromosome 12q24.17,18 It remains to be established how frequent these loci are involved in distal SMA. No gene has been identified so far.