Knowledge on rare diseases and orphan drugs

Prevalence of Young onset Parkinson disease (YOPD) in Europe is estimated to be 1/5,000-8,000 (5-10 % of all PD patients). Males are more affected than females (1.7:1). Women develop the disease 2 years later than men.

The age at onset of motor symptoms lies between 21-45 years. The predominant initial motor symptoms include rigidity and painful cramps which may be followed by tremor, bradykinesia, gait complaints and falls. Compared to PD, a lower risk of developing falls and freezing of gait but a higher risk of dystonia, motor fluctuations, and levodopa induced dyskinesia (LID) have been reported. YOPD patients report higher prevalence of non-motor symptoms including apathy, anxiety disorders (including panic disorders, generalized anxiety disorder, and social phobia), depression, psychosis (hallucinations), behavioral disturbances (agitation or impulse control disorder), dementia, and higher concentration difficulties than patients with sporadic or more typical form of PD. Women are more likely to present with tremor or to develop apathy, anxiety, depression, or LID. Likewise, untreated YOPD patients may present with cramps and dystonic postures more often than older PD patients.

The exact etiology of YOPD is still unknown. Symptoms of YOPD are thought to result from degeneration of the dopamine producing neurons in the substantia nigra secondary to infectious diseases, pharmacotherapy, or genetic. Mutations in PRKN (6q25.2-q27), PINK1 (1p36.12), PARK7 (1p36.23), and VPS13C (15q22.2), (21q22.11) genes have also been implicated in some cases of YOPD. The genes PODXL (7q32.3), DNAJC6 (1p31.3) and SYNJ1 (21q22.11) have been implicated in both YOPD and Atypical juvenile parkinsonism.

Diagnosis relies on presence of the clinical symptoms with tremor present in 85% of YOPD patients, an early age at onset, a family history of PD and a positive response to dopaminergic therapy. Diagnosis is confirmed by genetic analysis and cerebral scintigraphy of the dopamine transporters. Final diagnosis is usually made by the presence of lewy bodies in the brain during autopsy.

Differential diagnosis includes atypical juvenile parkinsonism, late onset PD, hereditary essential tremor, Wilson disease, Gaucher disease type 3, Pantothenate kinase-associated neurodegeneration, juvenile Huntington disease and central basal ganglia lesions.

In most cases, YOPD is sporadic. However, familial cases have been reported in which an autosomal recessive mode of inheritance have been suggested.

For symptomatic therapy, an initial treatment with a dopamine receptor agonist maintained at a very low threshold is advised. A switch to or addition of levodopa (L-DOPA) is recommended in cases where treatment response is suboptimal or if problematic adverse effects develop. However, after 5 years of treatment with L-DOPA, 30-40% of patients (59-100% by 10 years) develop dyskinesias and motor fluctuations. Some dopamine receptor agonists may also have antidepressive efficacy. Additional treatments include subthalamic nucleus deep brain stimulation and stereotactic surgery (fetal transplantation, pallidal stimulation, pallidotomy, thalamotomy or both).

The survival rate is favorable, with a median survival age of 30 years. YOPD is also associated with slower disease progression and less cognitive decline until later ages. However, YOPD patients are more likely to have earlier motor complications such as violent and disabling dyskinesias, painful dystonia, and unpredictable and severe motor fluctuations with a greater frequency of occurrence. Poorer quality of life has also been noted resulting from social and psychosocial disturbances.

Last update: July 2020 - Expert reviewer(s): Dr Coro PAISAN-RUIZ