Familial
spastic paraplegia (FSP or SPG) is a genetically heterogeneous group of upper motor neuron syndromes. To date, two distinct loci for X-linked recessive type (
SPG1 and SPG2), three loci for autosomal dominant type (FSP1, FSP2 and
FSP3), and one locus for autosomal recessive type have been reported.
SPG1 and SPG2 have been mapped to Xq28 and Xq21-q22, respectively.
SPG1 shows a mutation in the gene for
neural cell adhesion molecule L1 (LICAM), which is an axonal
glycoprotein involved in neuronal migration and differentiation. Different mutations of the same L1 gene also cause.
MASA (
mental retardation,
aphasia,
spastic paraplegia,
adducted thumbs) syndrome and X-linked hydrocephalus. SPG2 shows mutations in one of the major
myelin proteins, the proteolipid
protein (PLP) gene, and is allelic to
Pelizaeus-Merzbacher disease. Thus, mutations in two functionally distinct genes manifest the phenotype of X-linked
spastic paraparesis. Three dominantly inherited
spastic paraplegia genes have been genetically mapped to regions of chromosomes, yet no specific genes or mutations have been identified. FSP1 is mapped to a region of 7 cM on chromosome 14q12-q23 (approximately 20% of dominant FSP families) and FSP2 to 4 cM on chromosome 2p21-p24 (approximately 70% of dominant FSP families). Anticipation (increasing clinical severity in successive generations) has been observed in both FSP1 and FSP2 families. Another autosomal dominant FSP (
FSP3) has been mapped in the centromeric region of chromosome 15q (< 10% of dominant FSP families). An autosomal recessive FSP has been mapped to chromosome 8q. The definite genetic heterogeneity in FSP indicates that a multitude of genes/
proteins can cause
spastic paraplegia. Clinical features of each of the loci which may permit differential diagnosis are discussed. We also present pedigrees of two new FSP families.