The literature contains a large number of descriptions of familial spastic paraplegia combined with other neurologic abnormalities. Some of the syndromes had developed early in life in conjunction with moderate degrees of developmental delay. In these, the rest of the neurologic picture appeared many years after birth and was progressive. Some idea of the number of these “hereditary paraplegia-plus” syndromes and the diverse combinations in which they may be present is conveyed in the review by Gout and colleagues. Again, it is hardly possible to describe each of these symptoms in any degree of detail. The list below includes the best-known entities but all are rare. But if the term hereditary spastic paraplegia is to have any neurologic significance, it should be applied only to the pure form of the progressive syndrome. The more common “atypical” or “syndromic” cases—with amyotrophy, cerebellar ataxia, tremors, dystonia, athetosis, optic atrophy, retinal degeneration, amentia, and dementia—should be put in separate categories and their identity retained for nosologic purposes until such time as additional biochemical and genetic data related to pathogenesis are forthcoming. The gene mutations found in some of the variant types were summarized by Fink, but—as with all types of uncomplicated and complicated hereditary spastic paraplegia—the mechanisms of neuronal loss are not known. To be separated from these cases are all the congenital nonprogressive types of spastic diplegia and athetosis. The following list includes the best-known entities: 1. Hereditary spastic paraplegia with ataxia (Ferguson-Critchley syndrome, SAX1 mutation) This syndrome is one of a collection of leg spasticity and generalized ataxia syndrome that may also be characterized by a disorder of gaze, or optic atrophy. Most impressive are the manifestations of spinocerebellar ataxia beginning during the fourth and fifth decades of life, accompanied by weakness of the legs, alterations of mood, pathologic crying and laughing, dysarthria and diplopia, dysesthesias of limbs, and poor bladder control. The tendon reflexes are lively, with bilateral Babinski signs. Sensation is diminished distally in the limbs. The whole picture resembles a chronic progressive form of multiple sclerosis. In other cases, running through several generations of a family, the extrapyramidal features were more striking; such cases overlap with the following syndromes. A dominant form of the disease is due to a mutation in SAX1.
2. Hereditary spastic paraplegia with extrapyramidal features Action and static tremors, parkinsonian rigidity, dystonic tongue movement, and athetosis of the limbs have all been conjoined with spastic paraplegia. Gilman and Romanul have reviewed the literature on this subject. In the authors’ experience, the picture of parkinsonism with spastic weakness and other corticospinal signs has been the most frequent combination.
3. Hereditary spastic paraplegia with optic atrophy (OPA3 mutation) This is known as Behr syndrome or optic atrophy-ataxia syndrome, since cerebellar signs are usually conjoined. Some patients also have athetosis. The syndrome is transmitted as an autosomal recessive trait, with onset in infancy and slow progression. The mutation is in OPA3. There may be a relationship to decreased excretion of 3-methylglutaconic aciduria of an optic atrophy and cataract syndrome (Costeff syndrome).
4. Hereditary spastic paraplegia with macular degeneration (Kjellin syndrome, SPG11 and SPG15 mutations) Spastic paraplegia with amyotrophy, oligophrenia, and central retinal degeneration constitutes the syndrome described in 1959 by Kjellin. Although the developmental delay is stationary, the spastic weakness and retinal changes are of late onset and progressive. Mutations have been found in SPG11 and SPG15.