This report describes Kufor-Rakeb syndrome (KRS), which is a subtype of Parkinson disease; it is also called Parkinson disease 9 (PARK9). KRS exhibits autosomal recessive inheritance. The human gene implicated in this disease, ATP13A2, is also implicated in a second neurodegenerative disease with some overlapping phenotypes, spastic paraplegia 78 (OMIM:617225, FBhh0000988). 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]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from OMIM:168600; 2013.07.23]
[KUFOR-RAKEB SYNDROME; KRS](https://omim.org/entry/606693)
[ATPase 13A2; ATP13A2](https://omim.org/entry/610513)
Kufor-Rakeb syndrome is a rare autosomal recessive form of juvenile-onset atypical Parkinson disease (PARK9) associated with supranuclear gaze palsy, spasticity, and dementia (summary by Bruggemann et al., 2010; pubmed:21060012). Biallelic mutation in the ATP13A2 gene also causes autosomal recessive spastic paraplegia-78 (SPG78; 617225), an adult-onset neurodegenerative disorder with overlapping features. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism.[from OMIM:606693; 2019.03.19]
Some patients have neuroradiologic evidence of iron deposition in the basal ganglia, indicating that the pathogenesis of PARK9 can be considered among the syndromes of neurodegeneration with brain iron accumulation (NBIA) (summary by Bruggemann et al., 2010; pubmed:21060012). [from OMIM:606693; 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).
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]