This report describes spastic paraplegia 78 (SPG78), which is a subtype of spastic paraplegia; SPG78 exhibits autosomal recessive inheritance. The human gene implicated in this disease, ATP13A2, is also implicated in a second neurodegenerative disease with some overlapping phenotypes, Kufor-Rakeb syndrome, aka Parkinson disease 9 (OMIM:606693, FBhh0000987). See the report for neurodegenerative disorders, ATP13A2-related (FBhh0000989) for information on experimental results using Drosophila models of this and related diseases.
[updated Mar. 2019 by FlyBase; FBrf0222196]
The hereditary spastic paraplegias (SPG, HSP) are a large group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'). [from OMIM:182600; 15.06.29]
[SPASTIC PARAPLEGIA 78, AUTOSOMAL RECESSIVE; SPG78](https://omim.org/entry/617225)
[ATPase 13A2; ATP13A2](https://omim.org/entry/610513)
Autosomal recessive spastic paraplegia-78 is an adult-onset neurodegenerative disorder characterized predominantly by spasticity and muscle weakness of the lower limbs, resulting in gait difficulties and loss of ambulation in some patients. Affected individuals also have cerebellar signs, such as dysarthria, oculomotor disturbances, and limb and gait ataxia; brain imaging shows cerebellar atrophy. Some patients may have mild cognitive impairment or frank dementia. The phenotype is highly variable (summary by Estrada-Cuzcano et al., 2017; pubmed:28137957). [from OMIM:617225; 2019.03.19]
ATP13A2 encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. The encoded ATPase plays a role in intracellular cation homeostasis and the maintenance of neuronal integrity; it is required for a proper lysosomal and mitochondrial maintenance. [Gene Cards, ATP13A2; 2019.03.19]
ATP13A2 encodes a lysosomal transmembrane P5B-type ATPase. ATP13A2 loss leads to lysosomal abnormalities, impaired mitochondrial function, increased metal sensitivity, and increased sensitivity to ER stress. It has been tied to autophagy and other cellular features of neurodegeneration (FBrf0241154 and references cited therein).