Parkinson Disease 23, Autosomal Recessive Early-Onset

A number sign (#) is used with this entry because of evidence that autosomal recessive early-onset Parkinson disease-23 (PARK23) is caused by homozygous or compound heterozygous mutation in the VPS13C gene (608879) on chromosome 15q22.

Description

Parkinson disease-23 is a progressive neurodegenerative disorder characterized by young-adult onset of parkinsonism associated with progressive cognitive impairment leading to dementia and dysautonomia. Some individuals have additional motor abnormalities. Affected individuals become severely disabled within a few decades (summary by Lesage et al., 2016).

Clinical Features

Lesage et al. (2016) reported 3 unrelated patients, 1 of Turkish descent and 2 of French descent, with onset of rapidly progressive Parkinson disease between 25 and 46 years of age. Early in the disease, the patients showed typical signs of the disorder, including a kineto-rigid syndrome, resting tremor, and good response to levodopa. However, the disease progressed rapidly, and all became bedridden within 15 years of onset. Additional features included early cognitive decline, loss of response to treatment, axial symptoms, and dysautonomia. Two patients had pyramidal signs and motor deficits. Brain MRI later in the disease course showed cerebral atrophy. Neuropathologic examination of 1 patient showed neuronal loss in the substantia nigra and alpha-synuclein (SNCA; 163890)- and ubiquitin (UBB; 191339)-positive Lewy bodies in multiple brain regions, reminiscent of diffuse Lewy body disease (DLB; 127750). MAPT (157140)-immunoreactive neurofibrillary tangles and neurites were present in the brainstem, hippocampus, and primary motor cortex. TDP43 (605078)-immunoreactive inclusions were not observed.

Inheritance

The transmission pattern of PARK23 in the families reported by Lesage et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 unrelated patients with PARK23, Lesage et al. (2016) identified biallelic mutations in the VPS13C gene (608879.0001-608879.0005). The mutations were found by homozygosity mapping and exome sequencing and confirmed by Sanger sequencing. Four of the 5 mutations were truncating mutations; direct functional studies of the mutations were not performed. However, in vitro cellular studies showed that knockdown of VPS13C resulted in abnormal mitochondrial morphology and function.