Spasticity is a common feature of so many neurologic conditions that even the inherited forms of spasticity are difficult to classify or categorize. Overall, 36 forms of inherited spastic paraplegia have been identified. The well-characterized subgroup of autosomal dominant and pure forms with only pyramidal signs in the lower limbs have already been associated with 15 loci at which 9 genes have been identified, and more unpure forms of the disease exist. This complicates things for neurologists, who do not know which gene to test first, and for molecular geneticists, who have to test multiple genes in the same patient. The horizon has become even wider, because in this issue of Neurology®, Dick et al. 1 describe another locus for an autosomal recessive, complex form of spastic paraplegia: SPG35 (table). In this disease, spastic paraplegia is not the sole sign. In the complex forms of the disease, there can be a plethora of other signs or symptoms, such as mental retardation or cognitive decline, deafness, cerebellar ataxia, epilepsy, dysarthria, ichthyosis, optic atrophy, peripheral neuropathy, retinitis pigmentosa, and cataract, and this is not the complete list. Despite a much lower prevalence of recessive forms in Western countries, the complex forms of spastic paraparesis encompass 18 different loci, but only 5 genes have been identified so far, most of which are associated with complicated forms. Homozygosity mapping in consanguineous families is a very powerful genetic tool. To localize SPG35, Dick and his collaborators took advantage of a large consanguineous family from Oman with 7 affected and 14 unaffected members. These are ideal conditions for mapping a gene. The onset was in early childhood; this facilitated ascertainment of unaffected individuals and increased the power of a linkage analysis. But finding the locus where the gene is located is only the first step in the identifying the disease gene. Does the phenotype help to identify the disease gene? Could the clinical picture in the family presented by Dick et al. give a clue to the identity of the SPG35 gene after its locus has been mapped? SPG35 is associated with mental retardation or cognitive deterioration, which runs far a field from spasticity. In addition, genes responsible for mental retardation are associated with varied cellular functions. Interestingly, several patients in this family also had seizures, suggesting the possibility of ion channel involvement, as in most familial forms of epilepsy. The authors chose the candidate gene approach. They selected two genes in the candidate interval and analyzed their sequence in the patients, but found no mutations. Presently, only the locus of SPG35 has been defined; identification of the disease gene would be facilitated if other families with the same phenotype and/or the same locus were identified. According to current knowledge, the spastic paraplegia genes (but we do not know if these are also responsible for mental deterioration and for epilepsy) can be prioritized according to the putative function of the encoded protein. Intracellular trafficking is thought to be impaired by mutations in spastin/SPG42 and the kinesin heavy chain/KIF5A/SPG103 but also in atlastin/SPG3A, 4 NIPA1/SPG65 Strümpellin/SPG8, 6 REEP1/SPG31, 7 and Protrudin/SPG33. 8 Mitochondrial dysfunction is the underlying cause of paraplegin/SPG7. 9 However, when a gene is finally identified, it might have no known function, as happened with recently identified genes in autosomal recessive forms of spastic paraplegias.

Discovering the mechanism of neuronal dysfunction/degeneration resulting from a gene defect is a difficult art, and translating the discovery into therapy …