Typical features of Parkinson disease and diagnostic challenges with microdeletion 22q11.2

Abstract

Objective: To delineate the natural history, diagnosis, and treatment response of Parkinson disease (PD) in individuals with 22q11.2 deletion syndrome (22q11.2DS), and to determine if these patients differ from those with idiopathic PD.

Methods: In this international observational study, we characterized the clinical and neuroimaging features of 45 individuals with 22q11.2DS and PD (mean follow-up 7.5 ± 4.1 years).

Results: 22q11.2DS PD had a typical male excess (32 male, 71.1%), presentation and progression of hallmark motor symptoms, reduced striatal dopamine transporter binding with molecular imaging, and initial positive response to levodopa (93.3%). Mean age at motor symptom onset was relatively young (39.5 ± 8.5 years); 71.4% of cases had early-onset PD (<45 years). Despite having a similar age at onset, the diagnosis of PD was delayed in patients with a history of antipsychotic treatment compared with antipsychotic-naive patients (median 5 vs 1 year, p = 0.001). Preexisting psychotic disorders (24.5%) and mood or anxiety disorders (31.1%) were common, as were early dystonia (19.4%) and a history of seizures (33.3%).

Conclusions: Major clinical characteristics and response to standard treatments appear comparable in 22q11.2DS-associated PD to those in idiopathic PD, although the average age at onset is earlier. Importantly, treatment of preexisting psychotic illness may delay diagnosis of PD in 22q11.DS patients. An index of suspicion and vigilance for complex comorbidity may assist in identifying patients to prioritize for genetic testing.

Figure 1. Study flow chart: Identification and characterization of patients with 22q11.2 deletion syndrome and Parkinson disease

^a Literature review performed on November 1, 2016. ^b One publication by our own group. ^c Two cases were reported during preparation of this article.^, 22q11.2DS IBBC = International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome.

Figure 2. Antipsychotic medication and delay in diagnosis of Parkinson disease (PD) in 22q11.2 deletion syndrome

*Complete data on age at motor symptom onset, age at PD diagnosis, and history of antipsychotic medication use were available for 33 cases (for n = 8 cases, antipsychotic status was uncertain). Two suspected PD cases receiving antipsychotic medication (see e-Methods, links.lww.com/WNL/A514) were excluded. (A) There was no difference in mean age at motor symptom onset (38.7 ± 8.9 vs 40.6 ± 6.9 years) between patients without and patients with a history of antipsychotic use. (B) However, the median time between motor symptom onset and a diagnosis of PD was shorter in antipsychotic-naive patients compared to those with a history of antipsychotic treatment. Triangle without fill = in the antipsychotic-naive group, the patient with the youngest age at motor symptom onset (18 years) had the longest time to diagnosis. Also, in this patient with reduced dopamine transporter (DAT) binding on imaging, bradykinesia could not be established formally due to cognitive impairment. Diamonds without fill = patients using clozapine before PD diagnosis. Diamond with black fill = in one patient, the neurologist deferred the PD diagnosis due to olanzapine use. Fourteen years after the onset of motor symptoms, DAT imaging showed the typical pattern of severely reduced striatal DAT binding. EOPD = early-onset (<45 years) PD.