Alexandra Dürr

Chapter 4 Clinical and Genetic Aspects of Spinocerebellar Ataxias with Emphasis on Polyglutamine Expansions

Publisher Summary This chapter discusses the clinical and genetical aspects of spinocerebellar ataxias with emphasis on polyglutamine expansions. Autosomal dominant cerebellar ataxias (ADCAs), alternatively called spinocerebellar ataxias (SCAs), are a highly heterogeneous group of neurodegenerative disorders characterized by cerebellar ataxia variably associated with other neurological signs. Seven of these disorders are often referred to as polyglutamine diseases caused by translated CAG repeat expansions. Clinically, these disorders are characterized by a wide range of phenotypes depending on the responsible locus, the size of the expansion, and disease duration. These disorders manifest above a threshold of CAG repeats that varies according to the gene. When large and not interrupted, the CAG repeats are unstable upon transmission, mostly resulting in expansions particularly during paternal transmissions. This observation and the strong negative correlation between the size of the expansion and the age at onset account for the phenomenon of anticipation often observed in families. The relative frequency of the responsible genes varies according to geographical origin, and polyglutamine diseases account for 40–80% of ADCAs. Genetic diagnosis, now possible in several of these disorders, does not yet permit specific treatment but allows accurate genetic counseling and offers the possibility of presymptomatic and prenatal testing.

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

Publisher Summary 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.