Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications.

[22q11.2 deletion syndrome]

Clinical case reports of parkinsonism co -occurring with hemizygous 22 q 11 .2 deletions and the associated multisystem syndrome , 22 q 11 .2 deletion syndrome (22 q 11 .2 DS ), suggest that 22 q 11 .2 deletions may lead to increased risk of early -onset Parkinson disease (PD ). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition .To evaluate a possible association between 22 q 11 .2 deletions and PD .An observational study of the occurrence of PD in the world 's largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22 q 11 .2 DS (n = 159 [6 with postmortem tissue ]; age range , 18 .1 -68 .6 years ) was conducted in Toronto , Ontario , Canada . Rare postmortem brain tissue from individuals with 22 q 11 .2 DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder .A clinical diagnosis of PD made by a neurologist and neuropathological features of PD . RESULTS Adults with 22 q 11 .2 DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69 .7 ; 95 % CI , 19 .0 -178 .5 ). All cases showed early onset and typical PD symptom pattern , treatment response , and course . All were negative for family history of PD and known pathogenic PD-related mutations . The common use of antipsychotics in patients with 22 q 11 .2 DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years . Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22 q 11 .2 DS -PD cases . Typical α-synuclein-positive Lewy bodies were present in the expected distribution in 2 cases but absent in another .These findings suggest that 22 q 11 .2 deletions represent a novel genetic risk factor for early -onset PD with variable neuropathological presentation reminiscent of LRRK 2 -associated PD neuropathology . Individuals with early -onset PD and classic features of 22 q 11 .2 DS should be considered for genetic testing , and those with a known 22 q 11 .2 deletion should be monitored for the development of parkinsonian symptoms . Molecular studies of the implicated genes , including DGCR 8 , may help shed light on the underlying pathophysiology of PD in 22 q 11 .2 DS and idiopathic PD .