MOTOR NEURON DISORDERS

Predominantly Proximal Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a term used to describe a varied group of inherited disorders characterized by weakness and muscle wasting, secondary to degeneration of both anterior horn cells of the spinal cord and brainstem motor nuclei without pyramidal tract involvement. Three subtypes of autosomal-recessive predominantly proximal SMA have been described, all linked to chromosome 5q. A common nomenclature subdivides SMA into types I, II, and III, based on the age of onset and the age of death, whereas the other approach classifies cases as severe, intermediate, and mild, based on the ability to achieve independent sitting, independent standing, and walking. The International Consortium on SMA attempted to standardize the classification of childhood SMA to provide a rational basis for linkage studies and therapeutic trials (Table 18.4) (166).

SMA type I (Werdnig-Hoffmann, severe form) was defined by the International Consortium on SMA as follows: Onset from birth to 6 months, no achievement of sitting without support, and death usually prior to age 2 years. In SMA type II (intermediate form), onset is before 18 months, sitting is usually obtained, but standing and ambulation are never obtained and death occurs above the age of 2 years, usually much later in adulthood. In SMA type III (Kugelberg-Welander, mild form), the onset is after the age of 18 months, patients develop the ability to stand and walk, and death is in adulthood. There is considerable variability and severity within each of the three groups and occasionally some overlap exists. For example, patients with onset prior to 6 months may exhibit prolonged survival well past 4 years of age. Patients with onset between 6 and 18 months may ultimately achieve standing and independent ambulation. An adult-onset type of SMA with mild disease phenotype presenting usually in the second or third decade, has been recognized. These patients usually are able to ambulate with minor motor impairments. Although the adult-onset SMA is not classified formally by criteria set forth by the consortium, among clinicians, SMA type IV has been used widely to classify later-onset patients with mild disease features. A modified classification has been proposed by Zerres and Rudnik-Schoneborn which defines adult SMA as type IV (167).

The carrier frequency for SMA in the general population is estimated at about 1 in 40 to 50 individuals. Autosomal-recessive inheritance has long been documented in proximal SMA with childhood onset. In 1990, all three forms of SMA were mapped to chromosomal

TABLE 18.4 CHILDHOOD ONSET PROXIMAL SPINAL MUSCULAR ATROPHY

region 5ql3, indicating that allelic variance of the same disease locus accounts for the clinical heterogeneity (99,100). During the past two decades, tremendous advances have been made in our understanding of the genetic basis for SMA (168-176). A detailed analysis of the 5ql3 region revealed that this chromosomal region in humans contained a large inverted duplication, with at least two genes present in telomeric and centromeric copies.

Further studies have identified the SMA causative gene as the survival motor neuron (SMN) 1 gene (SMN1, telomeric copy), along with a disease modifying gene (SMN2, centromeric copy) (168-170). Briefly, the two SMN genes are nearly identical except for a difference of only five nucleotides in their 3' regions, without any alteration of the amino acid sequence of the protein. However, the critical difference between the SMN1 and SMN2 genes is a C-T transition located within the exon-splicing region of the SMN2 that affects the splicing of exon 7. This change results in frequent exon 7 skipping during the splicing of SMN2 transcripts (174,175)._It is thought that the resulting truncated SMN protein, without its exon 7 contribution, is a less stable form of SMN protein, and therefore, rapidly degraded. In about 95% of SMA patients, both copies of SMN1 exon 7 are absent because of mutations. In the remaining SMA-affected patients, other small or subtle mutations have been identified (169).

Genetic studies have now established that SMA is caused by mutations in the telomeric SMN1 gene, with all patients having at least one copy of the centromeric SMN2 gene. At least one copy of the SMN2 must be present in the setting of homozygous SMN1 mutations; otherwise, embryonic lethality occurs. The disease severity is primarily determined by the copy number of the SMN2 gene which produces a protein with similar function to the SMN1 gene but in much smaller quantities (176). The copy number of SMN2 varies in the population, and this variation appears to have some important modifying effects on SMA disease severity (177-179). All SMA patients have more than two SMN2 genes. It appears that a higher number of SMN2 copies in the setting of SMN1 mutations is associated with a less severe clinical SMA phenotype: SMA I (severe): two or three gene copies of SMN2; SMA II: three copies of SMN2; SMA III: four to eight copies of SMN2. However, substantial variations in SMA phenotype and disease severity can exist with a given SMN2 copy number, so it is not recommended that disease severity be predicted based solely on SMN2 copy numbers. Although we now know that SMN protein is expressed widely in many tissues throughout the body, its function is still not completely understood at this time.