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 Î±-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 .

Diseases
Validation

Diseases presenting "brain tissue" symptom

22q11.2 deletion syndrome

alexander disease

cadasil

classical phenylketonuria

congenital toxoplasmosis

gm1 gangliosidosis

hereditary cerebral hemorrhage with amyloidosis

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

phenylketonuria

pyruvate dehydrogenase deficiency

sneddon syndrome

wolf-hirschhorn syndrome

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