title: Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications.
abstract: OBJECTIVE
  Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 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.
  
  
  OBJECTIVE
  To evaluate a possible association between 22q11.2 deletions and PD.
  
  
  METHODS
  An observational study of the occurrence of PD in the world's largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (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 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder.
  
  
  METHODS
  A clinical diagnosis of PD made by a neurologist and neuropathological features of PD. RESULTS Adults with 22q11.2DS 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 22q11.2DS 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 22q11.2DS-PD cases. Typical α-synuclein-positive Lewy bodies were present in the expected distribution in 2 cases but absent in another.
  
  
  CONCLUSIONS
  These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological presentation reminiscent of LRRK2-associated PD neuropathology. Individuals with early-onset PD and classic features of 22q11.2DS should be considered for genetic testing, and those with a known 22q11.2 deletion should be monitored for the development of parkinsonian symptoms. Molecular studies of the implicated genes, including DGCR8, may help shed light on the underlying pathophysiology of PD in 22q11.2DS and idiopathic PD.
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Butcher
authors.forename: Tim-Rasmus
authors.initials: TR
authors.lastname: Kiehl
authors.forename: Lili-Naz
authors.initials: LN
authors.lastname: Hazrati
authors.forename: Eva W C
authors.initials: EW
authors.lastname: Chow
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bassett
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins; D002170:Canada; D002872:Chromosome Deletion; D004268:DNA-Binding Proteins / Q000378:metabolism; D004062:DiGeorge Syndrome / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005260:Female; D005820:Genetic Testing; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009460:Neurologic Examination; D064887:Observational Studies as Topic; D010300:Parkinson Disease / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012720:Severity of Illness Index; D014446:Tyrosine 3-Monooxygenase; D055815:Young Adult; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
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