The portal for rare diseases and orphan drugs

The prevalence of hereditary spastic paraplegia (HSP) is highly variable, ranging from 1/11,000-77,000 in Europe.

Clinically, HSPs can be divided into the pure and complex form. Pure HSPs are characterized by slowly progressive lower extremity spasticity and weakness, often associated with urinary disturbances, and deep sensory abnormalities (reduction of lower extremity vibration sense). Complex forms of HSP forms are characterized by the presence of additional neurological or non-neurological features. Neurological features may include cerebellar dysfunction (ataxia, nystagmus, tremor), axonal or demyelinating peripheral neuropathy (sensory and/or motor disturbances), cognitive impairment (dysexecutive syndrome, dementia), sensory impairment (optic, auditive neuropathy), epilepsy, myopathic features (ptosis, opthalmoparesis), extrapyramidal features (Parkinsonism, chorea, dystonia), psychiatric disturbances, and brain and spine imaging abnormalities (brain white matter alterations, thin corpus callosum, brain iron accumulation, cerebellar atrophy) which may be suggestive of a genetic subtype. Non-neurological manifestations may include ophthalmological abnormalities (cataracts, retinitis pigmentosa, macular degeneration), and orthopedic abnormalities (scoliosis, joint dislocation, and different foot deformities).

The disease is due to the dysfunction of the upper motor neurons of the corticospinal tract. To date, more than 80 genes have been linked. The encoded proteins are involved in many processes, including axonal transport, myelination, endo-membrane trafficking, mitochondria functions, complex lipid and nucleotide metabolism. The most common causative genes include SPAST (2p22.3), ATL1 (14q22.1), REEP1 (2p11.2) and KIF5A (12q.13.3)SPG7 (16q24.3), SPG11 (15q21.1), and CYP7B1 (8q12.3) for autosomal recessive HSP. However, a significant number of patients are without a genetic diagnosis after systematic testing.

Diagnosis is based on the clinical symptoms, neurological examination, progressive course of the disease, biomarker dosages, brain and spine MRI, family history, molecular genetic testing, and exclusion of the differential diagnoses.

Differential diagnosis includes multiple sclerosis, spinal vascular abnormality, vitamin B12 deficiency, HTLVI infection, primary lateral sclerosis, diplegic cerebral palsy, metabolic genetic diseases (dopa-responsive dystonia, leukodystrophies, brain metal accumulation disorders).

Genetic testing is possible where a mutation has previously been identified in a family.

Patterns of inheritance include mostly autosomal dominant and autosomal recessive, and rarely X-linked and mitochondrial. In addition, multiple recessive and dominant forms exist for the genes KIF1C (17p13.2), REEP2 (5q31.2), ALDH18A1 (10q24.1), ERLIN2 (8p11.23). SPAST (2p22.3), ATL1 (14q22.1), REEP1 (2p11.2) are usually associated with the pure form, autosomal recessive forms often lead to more complicated phenotypes, while some genes are associated with both phenotypes. High intrafamilial variability and incomplete penetrance are frequent.

Management is symptomatic with physiotherapy, anti-spasticity drugs (baclofen, tizanidine, diazepam, botulinum toxin), and orthoses.

Prognosis depends on the phenotype (pure/complex form), genotype, and is highly variable due to incomplete penetrance and variable gene expression.