A number sign (#) is used with this entry because juvenile-onset Parkinson disease-19A (PARK19A) and early-onset Parkinson disease-19B (PARK19B) are caused by homozygous mutation in the DNAJC6 gene (608375) on chromosome 1p31.

Parkinson disease-19A is an autosomal recessive neurodegenerative disorder characterized by onset of parkinsonism in the first or second decade. Some patients may have additional neurologic features, including mental retardation and seizures (summary by Edvardson et al., 2012 and Koroglu et al., 2013).

Parkinson disease-19B is an autosomal recessive neurodegenerative disorder with onset of parkinsonism between the third and fifth decades. It is slowly progressive, shows features similar to classic late-onset Parkinson disease (PD), and has a beneficial response to dopaminergic therapy (Olgiati et al., 2016).

For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see PD (168600).

Parkinson Disease 19A

Edvardson et al. (2012) reported 2 brothers, born of Arab-Muslim parents of Palestinian origin, with juvenile-onset Parkinson disease. Both had normal early psychomotor development, but showed motor symptoms consistent with Parkinson disease at ages 11 and 7, respectively. Features included bradykinesia, rigidity, postural instability, hypomimia, dysarthria, and asymmetric resting tremor. L-DOPA treatment was ineffective, and 1 patient became wheelchair-bound at age 13. The second patient had a more insidious disease course, and was dependent with an inability to walk by age 18. One patient had hypometric saccades. Brain MRI in both patients was unremarkable. Cognition was intact.

Koroglu et al. (2013) reported 4 patients from a large consanguineous Turkish family with juvenile-onset, rapidly progressive parkinsonism and mild to moderate mental retardation. The patients had onset of tremor and bradykinesia at 10 to 11 years of age. Other features included postural instability, rigidity, intermittent dystonic symptoms, hypomimia, and pyramidal signs. Three patients had absence and generalized seizures that started at ages 1 to 5 years and were well controlled. Response to L-DOPA was good, but limited by severe side effects. Later features included dysarthria, anarthria, and akinesia. All were wheelchair-bound or bedridden 10 to 15 years after onset. Brain MRI was unremarkable except in 1 patient who had diffuse brain atrophy.

Elsayed et al. (2016) reported a girl, born of consanguineous parents of Yemeni origin, who had onset of PD at age 10.5 years. Her disease started with visual hallucinations followed by slowed movement and rapidly progressive cognitive deterioration. She had severe rigidity, bradykinesia, and postural instability, but no resting tremor. Additional features included pyramidal signs, spasticity, and hyperreflexia. Over the following year, she developed seizures and additional features of psychosis, rendering her almost akinetic 2 years after disease onset. EEG suggested a diffuse encephalopathy with focal epilepsy; brain MRI was normal. Treatment with levodopa resulted in only a mild response.

Parkinson Disease 19B

Olgiati et al. (2016) reported 2 sets of sibs from 2 unrelated Caucasian families with early-onset Parkinson disease between 21 and 42 years of age. One family (GPS-0313) was of Dutch descent and the other (PAL-50) was of Brazilian descent. The patients had typical features of PD, including bradykinesia, resting tremor, rigidity, postural instability, and good response to levodopa, although some developed levodopa-induced dyskinesias. Brain imaging in 1 family was normal, but PET imaging showed nigrostriatal abnormalities consistent with PD. A patient from the Brazilian family showed marked improvement after deep subthalamic brain stimulation.

The transmission pattern of PARK19A in the families reported by Edvardson et al. (2012) and Koroglu et al. (2013) was consistent with autosomal recessive inheritance.

The transmission pattern of PARK19B in the families reported by Olgiati et al. (2016) was consistent with autosomal recessive inheritance.

Parkinson Disease 19A

In 2 brothers, born of consanguineous Palestinian parents, with juvenile-onset Parkinson disease-19A, Edvardson et al. (2012) identified a homozygous loss-of-function mutation in the DNAJC6 gene (608375.0001). The mutation was found by homozygosity mapping combined with whole-exome sequencing. Because the DNAJC6 gene plays a role in clathrin-mediated endocytosis, the findings suggested that a defect in the neuronal endocytic/lysosomal pathway contributes to the pathogenesis of Parkinson disease.

Koroglu et al. (2013) identified a homozygous loss-of-function mutation in the DNAJC6 gene (608375.0002) in affected members of a consanguineous Turkish family with severe juvenile-onset Parkinson disease and mental retardation. The mutation was found by homozygosity mapping and whole-exome sequencing.

In a girl, born of consanguineous parents of Yemeni origin, with PARK19A, Elsayed et al. (2016) identified a homozygous nonsense mutation in the DNAJC6 gene (Q789X; 608375.0005). The mutation, which was found by targeted sequencing of a PD panel of genes and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay and a complete loss of protein function.

Parkinson Disease 19B

In affected members of 2 unrelated families with PARK19B, Olgiati et al. (2016) identified homozygous mutations in the DNAJC6 gene: a missense mutation (R927G; 608375.0003) and a putative splice site mutation (c.2223A-T; 608375.0004). Patient fibroblasts from both families showed significantly decreased, but detectable, levels of DNAJC6 compared to controls, suggesting a loss-of-function effect. Olgiati et al. (2016) noted that the phenotype in these patients was not as severe as that observed in patients with truncating mutations, suggesting that some residual activity may mitigate the phenotype and consistent with a genotype/phenotype correlation. The families accounted for 2 (2.2%) of 92 probands with autosomal recessive PD who underwent sequencing of the DNAJC6 gene.