English Version
Sébastien Ponsonnard

Hereditary spastic paraplegia

Hereditary spastic paraplegia

Schlüsselwörter ICD 10: G11.4; Strumpell-Lorrain disease (designating one type of HSP called SPG4); familial spastic paraplegia
Keywords ICD 10: G11.4; Strumpell-Lorrain disease (designating one type of HSP called SPG4); familial spastic paraplegia
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Disease summary:  Strumpell-Lorrain disease or hereditary spastic paraplegia describes a group of rare and heterogeneous genetic neurological disorders [1]. In Europe, HSP is estimated to affect 1 to 9 per 100,000 individuals [2–6].

HSP is an inherited neurodegenerative group of disorders which affects primarily the corticospinal tract with a distal to proximal retrograde axonal degeneration. For this reason, in the so-called pure HSP cases, the clinical picture is characterised mainly by a progressive spasticity of the lower limbs leading to paraparesis or paraplegia affecting several members of the same family. Many patients experience only stiffness and weakening of the leg muscles; a few require the use of a wheelchair. The progression of the disease to the rest of the corticospinal tracts, to peripheral nerves, the cerebellum or the brain explains the other additional symptoms commonly found in complicated or complex HSP cases: cerebellar ataxia, dysarthria, extrapyramidal disorder, mental retardation, dementia, epilepsy, retinopathy, deafness, axonal or demyelinating neuropathy and eventually systemic signs. The clinical diagnosis is based on four criteria [7]: exclusion of differential diagnoses, compatible family history (although not obligatory), progressive disturbance of gait and corticospinal tract deficits in the lower limbs with hyperreflexia.

Spinal cord atrophy is a common finding in HSP [8]. Conventional brain magnetic resonance imaging findings are usually normal in patients with HSP, but multiple diffusion tensor indices can be disrupted [9]. It can disclose different findings in complicated or complex HSP, such as thin corpus callosum, leukoencephalopathy and hyperintensity sign in the corticospinal tract.

Diagnosis must be confirmed by DNA analysis. The most commonly involved genes are the SPG4 and SPG3A which encode for the proteins spastin and atlastin, respectively. Transmission of HSP can be autosomal dominant, autosomal recessive, X-linked or maternally inherited (mitochondrial inheritance) [10]. Mutations in more than 80 distinct loci and more than 50 mutated gene products have been identified in patients with HSP [11,12]. The main pathogenic mechanisms underlying the clinical phenotype include membrane trafficking disturbance, impairment of organelle transport, morphogenesis and distribution in neuronal cells, and mitochondrial dysfunction. Membrane trafficking and organelle morphogenesis and distribution are important for axonal development, maintenance and degeneration [1,13].

There is no specific pharmacological treatment. Treatment is symptomatic and includes physical therapy, benzodiazepines, oral or intrathecal baclofen [14] and injections of botulinum toxin [15] to reduce spasticity. By blocking potassium channels, prolonging action potentials and thereby increasing neurotransmitter release at the neuromuscular junction, dalfampridine may be useful in the treatment of HSP [16,17].