5. Hereditary spastic paraplegia with developmental delay or dementia Many of the children with progressive spastic paraplegia either have been developmentally delayed since early life or have appeared to regress mentally as other neurologic symptoms developed. Examples of this syndrome and its variants are too numerous to be considered here but are contained in the review by
Gilman and Romanul. The autosomal recessive syndrome of Sjögren-Larsson, with the onset in infancy of spastic weakness of the legs in association with developmental delay, stands somewhat apart from the others in this large group because of the associated ichthyosis. The mutation for the latter is in ALDH3A2 that codes for fatty aldehyde dehydrogenase. This relates to both dry skin, itchy and discolored skin, and the myelinopathy that characterize Sjögren-Larsson syndrome.
6. Hereditary spastic paraplegia with polyneuropathy Our colleagues had observed several patients in whom a sensorimotor polyneuropathy was combined with unmistakable signs of corticospinal disease. The age of onset was in childhood or adolescence, and the disability progressed to the point where the patient was chairbound by early adult life. In 2 of the cases, a sural nerve biopsy revealed a typical hypertrophic polyneuropathy; in a third case there was only a depletion of large myelinated fibers. The syndrome resembles the myeloneuropathy of adrenoleukodystrophy.
7. Spastic paraparesis with distal muscle wasting (Troyer syndrome, SPG20 mutation) This disorder is transmitted as an autosomal recessive trait in the Amish population. Onset is in childhood with amyotrophy of the hands, followed by spasticity and contractures of the lower limbs. Cerebellar signs (mild), athetosis, and deafness may be added. The mutation is in SPG20.
SYNDROME OF BLINDNESS DUE TO DEGENERATIVE DISORDERS (SEE CHAP. 12)
There are 2 main classes of progressive blindness in children, adolescents, and adults: progressive optic neuropathy and retinal degenerations (retinitis pigmentosa and tapetoretinal macular degeneration). Of course, there are many congenital anomalies and retinal diseases beginning in infancy that result in blindness and microphthalmia. Some of those of neurologic interest were described briefly in connection with the hereditary spastic paraplegias and in Chap. 12.
History Although familial amaurosis was known in the early 18th century, it was Leber, in 1871, who gave the definitive description of this disease and traced it through many genealogies. The family studies of Nikoskelainen and coworkers indicate that all daughters of carrier mothers become carriers themselves, a type of transmission that is determined by inheritance of defective mitochondrial DNA from the mother (Wallace et al). Common to all cases is the presence of a pathogenic mitochondrial DNA abnormality (Riordan-Eva et al), but the defect may occur at one of several sites as discussed in Chap. 36. Thus, Leber optic atrophy has been added to the growing list of mitochondrial diseases. Variants in approximately 20 genes have been detected, together accounting for about half of cases.
This mitochondrial disease should not be mistaken for Leber’s congenital amaurosis, a retinal degeneration with a mutation in RPE65 that affects photoreceptors and causes infantile blindness. The latter disease assumes importance in part because it has an established gene therapy with some efficacy.