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

Importance: 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.

Design, setting, and participants: 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.

Main outcomes and measures: 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 and relevance: 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.

Figure 1. Cases 1 and 2 With Hemizygous 22q11.2 Deletions and Diagnosed Parkinson Disease Show Loss of Dopamine Cells and α-Synuclein Pathology

Results of immunohistochemical studies for tyrosine hydroxylase in the striatum (A and D) and substantia nigra (B, C, E, and F) are shown from a representative case of 22q11.2 deletion syndrome with Parkinson disease (case 1; A–C) and a case of 22q11.2 deletion syndrome without Parkinson disease (D–F). C and F, Density of tyrosine hydroxylase–positive neurons in the substantia nigra at low power (upper panels) and high power (lower panels). Insets in C, Example of a Lewy body visualized with hematoxylin-eosin staining (*) and an α-synuclein–positive Lewy body and neurites (**) in the substantia nigra pars compacta. CP indicates cerebral peduncle; GPe, external segment of globus pallidus; GPi, internal segment of globus pallidus; IC, internal capsule; Put, putamen; RN, red nucleus; and SN, substantia nigra (original magnification ×1 in A, B, D, E, and insets in B and E; ×10 in upper panels of C and F; ×25 in lower panels of C and F; and ×40 in insets in C).

Figure 2. Details of Pathological Changes in Case 3

A, Case 3 showed a smaller midbrain with gross depigmentation of the substantia nigra (left) compared with a control case without either 22q11.2 deletion syndrome or parkinsonism (right). Hematoxylin-eosin–Luxol fast blue staining of the substantia nigra pars compacta (SNc) revealed decreased density of pigmented cells in case 3 (B) compared with a control (C). D, Extensive gliosis and microglial activation in the substantia nigra as visualized with glial fibrillary acidic protein (brown chromogen) and Iba-1 (red chromogen, arrow), respectively. The amygdala (E) and thalamus (F) also showed gliosis and neuronal loss (hematoxylin-eosin–Luxol fast blue). Severe depletion of tyrosine hydroxylase–positive axons was visible in the dorsal putamen (Put) (G) and the dorsolateral aspect of the rostral putamen (H). Acc indicates accumbens; CD, caudate; GPe, external segment of globus pallidus; GPi, internal segment of globus pallidus; and IC, internal capsule. Tyrosine hydroxylase immunoreactivity was preserved in the CD and Acc (H) and was more abundant in the matrix (M) compared with the patches (P) (inset in H). I, Tyrosine hydroxylase–positive neurons were severely depleted in the ventrolateral aspect of the substantia nigra (SN) (inset). CP indicates cerebral peduncle; RN, red nucleus (original magnification ×25 in B–F; ×1 in G–I; and ×25 in insets in H and I).