The spinal muscular atrophies (SMAs) have been historically conceptualized as hereditary disorders preferentially affecting anterior horn cells and selected motor cranial nerve nuclei.1 As in all disorders caused or influenced by genetics, molecular biology has served to confound as much as clarify the nosology. We have become very aware that the historical boundaries of hereditary neuromuscular disease are inaccurate. Part of this confusion arises from phenotypic overlap. For example, although lower motor neuron (LMN) morbidity dominates most SMA phenotypes, upper motor neuron (UMN) features may occur in some forms of distal SMA. Conversely, hereditary spastic paraplegia is a predominantly UMN disorder but may have notable LMN features in some genotypes. Even more damaging to the historical nosology of hereditary neuromuscular disease is the discovery that mutations of a single gene may produce variable phenotypes that have been historically represented as two or more diseases (Table 8-1).
TABLE 8-1.SMA MUTATIONS ALLELIC WITH OTHER NEUROMUSCULAR PHENOTYPES |Favorite Table|Download (.pdf) TABLE 8-1.SMA MUTATIONS ALLELIC WITH OTHER NEUROMUSCULAR PHENOTYPES
|Locus (Gene) ||SMA ||ALS ||CMT ||HSP ||Other |
|20q13.32 (VAPB) || |
|fALS 8 || || || |
|12q24.3 (heat-shock protein 8) ||HMN IIA || ||CMT 2L || ||Desmin-related myopathy |
|7q11.23 (heat-shock protein B1) ||HMN IIB || ||CMT 2F || || |
|7p14,3 (GARS) ||HMN VA || ||CMT 2D || || |
|11q12.3 (BSCL2) ||HMN VA (Silver syndrome) || ||CMT 2D ||SPG17 || |
|4p16–p15 ||Silver syndrome || || ||SPG38 || |
|2p22–23 (spastin) ||Silver syndrome || || ||SPG4 || |
|6q21 (FIG4) || ||ALS 11 ||CMT 4J || || |
|12q24.1 (TRPV4) ||Scapuloperoneal SMA or dSMA or severe congenital form of SMA || ||CMT 2C || || |
|17p11.2 (PMP22) ||Scapuloperoneal SMA || ||HNPP || || |
|9q34 (senataxin) ||HMN with UMN signs ||ALS4 || ||May look phenotypically identical to HSP || |
|2p13.1 (dynactin) ||HMN VII ||AR form of ALS1 || || || |
|1q22 (lamin A/C) ||SMA IV || ||CMT 2B1 || ||Emery–Dreifuss MD, LGMD 1B, congenital MD |
|14q32.31 (dynein) ||HMN I or SMA-lower leg predominant || ||CMT 2O || ||This is allelic SMA-LED (lower leg predominant) |
In this chapter, we will discuss the SMAs related to mutations of the survival motor neuron (SMN) gene, the non-SMN infantile forms of the disease, the rare childhood bulbar forms of motor neuron disease (MND), Hirayama disease, Kennedy disease, the distal SMAs, the scapuloperoneal forms of SMA, and the uncommon SMA phenotypes that occur in association with multisystem disorders (Tables 8-2 and 8-3).2–6 We emphasize this predominantly phenotypic classification as this remains, for the most part, the most practical means by which these disorders are recognized if not diagnosed.
TABLE 8-2.SMA CLASSIFICATION—PROXIMAL OR GENERALIZED WEAKNESS |Favorite Table|Download (.pdf) TABLE 8-2.SMA CLASSIFICATION—PROXIMAL OR GENERALIZED WEAKNESS
|Category ||Eponym ||Acronym ||Gene/Locus ||Weakness Pattern ||Other Features |
|Infantile onset ||Werdnig–Hoffman ||SMA I ||SMN ||Proximally predominant bulbar ||Ventilatory failure |
| || |
Pop-up div Successfully Displayed
This div only appears when the trigger link is hovered over.
Otherwise it is hidden from view.