HSPs are among the most heterogeneous Mendelian diseases and can be inherited following autosomal-dominant, autosomal-recessive, and X-chromosomal modes of inheritance. Additionally almost half of all cases are apparently sporadic, and it is currently unknown whether these forms are also monogenetic in origin or whether they have more complex disease etiologies.

Currently there are at least 83 HSP loci and 68 HSP genes known, about three quarters of which have been identified within the past 5 years (Fig. 16.1) [6]. HSP loci are termed SPG 1–72 (SPG = spastic paraplegia gene) according to the HUGO gene nomenclature committee; however, not all HSP genes have received an SPG number.

About 40 % of HSP cases report an autosomal-dominant family history with affected family members in at least two generations. Mutations in any of the known 13 autosomal-dominant HSP genes explain about 70 % of dominant cases (Table 16.2).

SPG4, caused by mutations in the SPAST gene, accounts for roughly 50 % of autosomal-dominant HSP families and is by far the most common subtype of HSP. SPG4 is characterized by a variable age at onset ranging from early childhood to the 8th decade even within families sharing the same mutation, with a mean age at onset of just over 30 years of age. The majority of SPG4 cases have pure HSP with rather frequent neurogenic bladder disturbance (~70 %) and affection of the dorsal columns (~50 %). Motor evoked potentials are often normal even when there is clinically definite involvement of the corticospinal tracts [1]. Some cases with complicated SPG4 have been reported that feature cognitive deficits, upper limb involvement, thin corpus callosum, or other complicating signs and symptoms. Mutation types in SPG4 included missense, nonsense and splice site mutations, small insertions and deletions, and large genomic deletions. It is important to note that the latter mutations, which account for about one fifth of SPG4 cases, cannot usually be detected by Sanger sequencing. State-of-the-art diagnostic testing in SPG4 therefore needs to include a method to screen for macro-deletions like multiplex ligation-dependent probe amplification (MLPA) [9].

SPG3 typically presents as childhood-onset (<10 years) pure HSP with very slow progression and may be equally common as SPG4 in this age group. However cases with an onset as late as the 5th decade have been reported [21]. In adult-onset cases, SPG3 contributes less than 10 %. The phenotypic spectrum of SPG3 is broad and also involves very severe childhood-onset cases with pseudobulbar palsy, severe tetraparesis, motor axonal neuropathy and variably cognitive impairment, TCC, or optic atrophy. Furthermore ATL1 mutation also causes hereditary sensory neuropathy I (HSN1D), a severe mutilating sensory axonal neuropathy. Missense mutations in ATL1 are the predominant mutation type in both SPG3 and HSN1D.

SPG10 (KIF5A) and SPG31 (REEP1) both contribute about 5–10 % to SPG4-negative autosomal-dominant HSPs. With a broad age-at-onset spectrum reaching from childhood to late adulthood, they can both manifest as pure or variably complicated HSP. In SPG10, amyotrophy and cognitive deficits are the most frequent complicating features, and most patients with complicated SPG10 feature an axonal sensorimotor peripheral neuropathy. Additionally parkinsonism, deafness, and retinitis pigmentosa have been described in single cases. SPG31 can present with a Silver syndrome-like phenotype with severe hand muscle atrophy and axonal peripheral neuropathy; occurrence of both pure and complicated phenotypes within the same family has been reported.

With at least 52 known genes, autosomal-recessive HSP are extremely genetically heterogeneous, and most recessive HSP genes explain less than 1 % of cases (Table 16.3). Among the autosomal-recessive HSP subtypes that can present as pure HSP, SPG5 and SPG7 are the most common although both forms can also be complicated by additional symptoms.