Hereditary spastic paraplegia linked to chromosome 15q

Hereditary spastic paraplegia (HSP; also known as familial spastic paraplegia and Strumpell-Lorrain syndrome) is a heterogeneous group of disorders that share the primary feature of progressive, severe, lower extremity weakness and spasticity (see reference 1 for review). Autosomal dominant uncomplicated HSP is genetically heterogeneous. The disorder has been linked to loci on chromosomes 2p, 14q, and 15q in unrelated HSP kindreds. ^[2-4] Recently, we performed genetic linkage analysis in a kindred with autosomal dominant uncomplicated HSP. ^[5] Affected subjects developed progressive gait disturbance between ages 12 and 35 years and exhibited lower extremity hyperreflexia, spasticity, and weakness; extensor plantar response; diminished vibratory sense; and pes cavus. We found close linkage between the disorder and microsatellite polymorphisms on chromosome 15q (e.g., D15S128 LOD equals 9.70, theta equals 0.05). ^[4] Multipoint linkage analysis reached a maximum LOD score (10.16) between D15S128 and D15S156, a region that includes genes encoding alpha 5 and beta 3 subunits of GABA_A receptor. GABA receptors are important mediators of inhibitory neurotransmission in brain and spinal cord. In theory, abnormal GABA-mediated neurotransmission could produce spasticity and possibly other changes of HSP. There is precedent for GABA-neuron involvement in neurologic disease. For example, selective loss of intrastriatal GABA-ergic medium spiny neurons is one of the earliest changes of Huntington's chorea. In addition, we are aware of one example in which a GABA receptor gene mutation …