Chapter 14 SPG4, the Most Frequent Hereditary Spastic Paraplegia: Clinical and Genetic Aspects

Abstract

The most common form of autosomal dominant (AD) hereditary spastic paraplegia (HSP) is caused by mutations in the spastic paraplegia type 4 (SPG4) gene encoding spastin, a member of the AAA family of adenosine triphosphatases (ATPases). The genetic characterization of spastin/SPG4 has allowed the development of molecular testing to detect mutations that account for approximately 15–40% of pure and, in some cases, complex HSP. This chapter discusses the clinical and genetic aspects of SPG4, the most frequent hereditary spastic paraplegia. SPG4 is often considered the prototypical example of pure HSP in which patients progressively develop gait disturbances and spasticity in the lower extremities. However, SPG4 HSP is a phenotypically heterogeneous disorder, characterized by both interfamilial and intrafamilial variation. The mean age at onset is between 29 and 35 years, depending on the study. Onset, thus, occurs most often in young adults, although symptoms may start as early as 1 year or as late as 76 years. Because onset is very insidious in approximately 10% of the patients, it is not possible to determine the age at onset with precision. Furthermore, penetrance is age dependent and incomplete even in older mutation carriers. Approximately 20% of patients present abnormal signs when examined but have no awareness of being affected, and more than 6% of mutation carriers are completely asymptomatic on examination.