Molecular aspects of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower limbs spasticity and weakness. What was first thought to be a small group of rare Mendelian disorder has now become a large group that includes many complex syndromes. While large families with defined modes of inheritance were used for the initial HSP gene discovery, new sequencing technologies have recently allowed the study of small families, with the identification of many new disease causative genes. These discoveries are slowly leading to a better understanding of the molecular mechanisms underlying HSP with the identification of precise disease pathways. These insights may lead to new therapeutic strategies for what is a group of largely untreatable diseases. This review looks at the key players involved in HSP and where they act in their specific pathways.