Parkinsonism With Spasticity, X-Linked

A number sign (#) is used with this entry because of evidence that X-linked parkinsonism with spasticity (XPDS) is caused by hemizygous mutation in the ATP6AP2 gene (300556) on chromosome Xp11. One such family has been reported.

Mutation in the ATP6AP2 gene can also cause a form of syndromic X-linked mental retardation (MRXSH; 300423) that has overlapping features.

Clinical Features

Poorkaj et al. (2010) reported a multigenerational family of Danish and German descent in which 5 males in 3 generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity. The age at symptom onset ranged from 14 to 50 years, with the most recent generation showing an earlier age of onset than the older generations. Two individuals had only a parkinsonian syndrome, with classic features of cogwheel rigidity, resting tremor, and bradykinesia. Three other patients first showed spasticity with hyperreflexia and extensor plantar responses followed by the development of parkinsonian features. The disorder was slowly progressive. The most severely affected individual had onset of spastic paraparesis at age 14 years followed by resting tremor and bradykinesia. Fluoro-DOPA PET scan showed decreased uptake in the putamen. He had a mild response to L-DOPA, but developed dystonic dyskinesias. Postmortem examination of 1 of the patients with only parkinsonism showed neuronal loss in the substantia nigra without Lewy body deposition. However, there was some Alzheimer disease-like pathology in the striatum and 4-repeat tau (MAPT; 157140)-positive plaques. Carrier females were unaffected.

Inheritance

The transmission pattern of XPDS in the family reported by Poorkaj et al. (2010) was consistent with X-linked recessive inheritance.

Mapping

By linkage analysis of a family with X-linked parkinsonism and spasticity, Poorkaj et al. (2010) found linkage to a 28-Mb region on chromosome Xp11.2-q13.3 (multipoint lod score of 2.068 was obtained between markers DXS991 and DXS993). Sequencing of several candidate genes in this interval failed to identify any pathogenic mutations.

Molecular Genetics

In affected members of a family with X-linked parkinsonism with spasticity, originally reported by Poorkaj et al. (2010), Korvatska et al. (2013) identified a c.345C-T transition in the ATP6AP2 gene (S115S; 300556.0002) that was shown to increase the skipping of exon 4, resulting in significant overexpression (about 50%) of a 150-bp minor splice isoform that produces a protein with internal deletion of 32 amino acids. The increase in this abnormal isoform was associated with a reduction in normal isoforms containing exon 4. The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Postmortem brain tissue from 1 affected individual showed decreased ATP6AP2 immunostaining in the frontal cortex and striatum. In addition, there was massive accumulation of SQSTM1 (601530) in the striatum, suggesting impaired autophagy and a defect in lysosome-mediated protein degradation.