Spastic paraparesis [108 genes]

Anita Harding’s landmark description of paraparesis distinguishes pure and complicated forms (Harding, 1983).

• Pure forms present isolated pyramidal signs such as spasticity, hyperreflexia, Babinski sign, and motor deficits, which may be associated with sphincter disorders and alteration of deep sensitivity.
• Complex forms include various clinical entities that combine spastic paraparesis with other neurological/non-neurological signs such as cerebellar ataxia, optic atrophy, retinitis pigmentosa, narrowing of the corpus callosum, neuropathy or epilepsy, among others.

Hereditary spastic paraparesis has an estimated prevalence of 1.8/100,000. The genetic cause is identified in 33-55% of families with autosomal dominant inheritance (PE-AD) and 18-29% of families with autosomal recessive inheritance (PE-AR). The most common form of PE-AD is SPG4 (SPAST), representing 40% of PE-AD forms and 20% of sporadic cases (Ruano et al., 2014). SPG3A (ATL1) is the cause of 10-15% of PE-AD cases (up to 40% in SPG4-negative cohorts), being the most frequent form of onset in the first decade (Giudice et al., 2014). SPG11 is the most common cause of PE-AR (20-50%) (Stevanin et al., 2008).

Diagnosis, prognosis and genetic counseling in affected patients and family members.

• ABCD1: Adrenoleukodystrophy
• ADAR, IFIH1, RNASEH2B: Aicardi-Goutières syndrome
• ALS2, FIG4, SETX: Amyotrophic lateral sclerosis
• ALDH3A2: Sjögren-Larsson syndrome
• CCT5: Hereditary sensory neuropathy with spastic paraparesis
• CSF1R: Hereditary diffuse leukoencephalopathy with spheroids
• CYP27A1: Cerebrotendinous xanthomatosis
• DARS2: Brainstem and spinal cord leukoencephalopathy with elevated lactate
• GFAP: Alexander syndrome
• KIF1C, KCNA2, MARS2, VAMP1: Spastic ataxia
• SACS: Spastic ataxia type Charlevoix-Saguenay
• SLC2A1: GLUT1 deficiency

Patients with clinical suspicion of paraparesis.