A number sign (#) is used with this entry because this form of adult-onset dystonia-parkinsonism, also known as Parkinson disease-14 (PARK14), is caused by homozygous or compound heterozygous mutation in the PLA2G6 gene (603604) on chromosome 22q13.

Mutations in the PLA2G6 gene can also cause early-onset forms of neurodegeneration with brain iron accumulation (NBIA): see NBIA2A (256600) and NBIA2B (610217).

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

Paisan-Ruiz et al. (2009) reported 2 unrelated consanguineous families in which a total of 3 individuals had young-adult onset of a rapidly progressive neurodegenerative disorder characterized by parkinsonism, dystonia, and severe cognitive decline. In the first family, a 34-year-old Indian woman developed rapid cognitive decline, slow movements, imbalance, hand tremor and dysarthria over 6 months. By age 27, she could not walk without assistance. Other features included depression, facial hypomimia, eyelid opening apraxia, supranuclear vertical gaze palsy, and hypometric vertical saccades. Kayser-Fleischer rings and pigmentary retinopathy were absent. She had generalized rigidity and dystonia in all limbs, as well as bradykinesia. Serum creatine kinase was increased. A cousin had a similar disorder, but had noted leg dragging and dystonia since age 10 years. L-DOPA treatment was beneficial in both, but caused prominent dyskinesias. Brain MRI showed generalized cerebral atrophy, but no evidence of brain iron accumulation. The second proband was a 21-year-old Pakistani man who developed dragging of the foot, cognitive decline, and personality changes with aggression at age 18. The disorder was rapidly progressive, and he had pyramidal and extrapyramidal features, including spasticity, hyperreflexia, bradykinesia, and rigidity. Brain MRI again excluded brain iron accumulation, and PET scan showed decreased dopamine transporter activity in the striatum. Paisan-Ruiz et al. (2009) noted some phenotypic overlap with Kufor-Rakeb syndrome (PARK9; 606693) and PKAN (NBIA1; 234200).

Although Paisan-Ruiz et al. (2009) noted that brain MRI in these patients showed no evidence of brain iron accumulation, Gregory et al. (2009) stated that this disorder could be considered under the umbrella designation of atypical neurodegeneration with brain iron accumulation (NBIA).

Yoshino et al. (2010) reported 3 Japanese patients, including 2 sibs, with very early-onset Parkinson disease. All 3 patients had onset before age 30 years of L-DOPA-responsive parkinsonism with varying degrees of dementia and frontotemporal lobar atrophy. Brain MRI of 1 patient showed iron accumulation in the substantia nigra and striatum.

Shi et al. (2011) reported a Chinese man, born of consanguineous parents, with PARK14. He developed foot dragging and difficulty walking at age 37 years. Symptoms progressed to include masked facies, bradykinesia, and rigidity, but no atypical features. He had initial good response to L-DOPA treatment, but developed dyskinesias. Brain MRI excluded iron deposition. PET scan showed significant reduction in DAT binding in the basal ganglia. The patient's clinically unaffected 34-year-old sister was also homozygous for the mutation, and PET scan showed some loss of binding.

Magrinelli et al. (2022) reported 14 new patients from 12 families with PARK14, and reviewed the findings in their patients and patients identified in a systematic literature search, for a total of 86 patients from 68 families. Median age of symptom onset was 23 years, with onset before age 31 years in 70/83 (84.3%). The most common manifestations at onset, either alone or in combination, were extrapyramidal features (48.1%), gait/balance problems (36.7%), and psychiatric/cognitive issues (31.6%). Psychiatric issues were the sole presenting symptoms in 20.2%. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6%. Cognitive impairment and psychiatric issues affected 76.1% and 87.1%, respectively. Parkinsonism responded to levodopa in 97.3%, with levodopa-induced dyskinesias in 80.7%. Brain MRI showed cerebral atrophy in 47.9% and cerebellar atrophy in 39.5%, with evidence of iron deposition in 25.6%.

By homozygosity mapping, followed by candidate gene sequencing, of 2 unrelated families with adult-onset dystonia-parkinsonism, Paisan-Ruiz et al. (2009) identified 2 different homozygous mutations in the PLA2G6 gene (R741Q; 603604.0009 and R747W; 603604.0010, respectively). Affected members of 3 additional families with a similar phenotype did not have PLA2G6 mutations.

In 3 Japanese patients, including 2 sibs, with onset of PARK14 before age 30 years, Yoshino et al. (2010) identified compound heterozygous mutations in the PLA2G6 gene (603604.0011-603604.0013). Haplotype analysis suggested a founder effect for 1 of the mutations (R635Q; 603604.0011). None of the parents with heterozygous mutations had signs of the disorder. The 2 probands represented 6.9% of 29 patients with very early-onset parkinsonism and cognitive decline in the overall study.

In a Chinese patient, born of consanguineous parents, with early-onset Parkinson disease, Shi et al. (2011) identified a homozygous mutation in the PLA2G6 gene (D331Y; 603604.0016). Heterozygous mutation carriers in the family were unaffected. The patient was identified in a cohort of 12 Chinese families with early-onset parkinsonism who were screened for PLA2G6 mutations; none of the other 11 families carried a PLA2G6 mutation.

Magrinelli et al. (2022) reviewed the mutations in 86 patients from 68 families with PARK14, including 14 new patients from 12 families and 72 patients from 56 families identified through a systematic search of the literature. Parental consanguinity was seen in 55% of the families. Homozygosity for mutations in the PLA2G6 gene was seen in 46/86 (53.5%), with compound heterozygosity in 40/86 (46.5%). A total of 54 mutations in PLA2G6 have been associated with parkinsonism, including 4 novel variants in the newly reported patients. Among these 54 mutations, 44 were missense, 2 were in-frame deletions, 4 were splicing, 2 were nonsense, and 2 were frameshift mutations. The most commonly observed mutations were D331Y (603604.0016), seen in 17 families, mainly from China and Taiwan, and R741Q (603604.0009), seen in 12 families from India, Pakistan, and Saudi Arabia.