This is one of the most detailed clinical studies to combine neurologic, neuropsychological, and psychiatric investigations to establish phenotype–genotype correlation in early-onset parkinsonism. We expected to find particular behavioral or psychiatric pattern and maybe cognitive disorders in parkin mutation carriers because neuropathologic studies of these patients have shown severe generalized loss of dopaminergic neurons in the substantia nigra pars compacta13
that would greatly decrease dopaminergic efferents to the limbic and subcortical-frontal and sensory-motor systems. The 21 patients with and 23 patients without parkin mutations were appropriately matched for age at onset (31.1 years ± 8.3 vs 34.9 years ± 6.2) and disease duration (17.4 years ± 7.8 vs 12.9 years ± 7.7). Detailed clinical evaluations including UPDRS I–VI, with and without treatment, did not detect any significant differences between the two groups. The daily doses of levodopa were also similar in parkin mutation and non-mutation carriers (528 mg ± 439 vs 778 mg ± 343), but after calculation of the daily levodopa dose equivalents,12
a significant difference between the groups was observed: parkin mutation carriers improved to the same extent as noncarriers (68.4% ± 13.1 vs 70.2% ± 18.6, data not shown) with significantly lower daily levodopa dose equivalents (636 mg ± 462 vs 1,139 mg ± 451).
Previous studies have already shown in large cohorts of patients that parkin carriers had more levodopa induced dyskinesias, brisk reflexes, onset with foot dystonia,3,15–17
and a better response to low doses of medication, even after a long evolution of the disease,4,5
although none of these studies compared patients matched for age and disease duration. Our study confirms that parkin patients have very good responses to low doses of antiparkinsonian treatment. Furthermore, our parkin mutation carriers did not have more levodopa-induced complications than noncarriers, but the delay before the appearance of fluctuations after initiation of treatment was significantly longer in parkin mutation carriers than in patients without parkin mutations (14 years ± 5.1 vs 5 years ± 1.4). This delay in the development of levodopa-related dyskinesia was probably a result of the significantly lower doses of medication, but, curiously, the delay between the development of levodopa-related dyskinesias and dystonia did not differ between the two groups (10 vs 12 years and 13 vs 17 years, ). Interestingly, we show that dysautonomia, orthostatic hypotension, and urinary incontinence, which are absent in patients with parkin mutations, are also rare in the other early-onset PD cases.
All unaffected single heterozygous mutation carriers, with ages ranging from 28 to 68, had normal detailed neurologic examinations. Statistically significant reductions in [18
F]fluorodopa uptake have been observed in carriers of a single heterozygous parkin mutation15,18
compared to controls, and some were reported to have subtle extrapyramidal signs, such as resting tremor, reduced arm swing, or a mask-like face.3,4,15,18
It cannot be excluded that these healthy single heterozygous mutation carriers will develop parkinsonian symptoms in the future, but six of them are already more than 15 years older than the age at onset of their affected sibs. This observation supports the hypothesis that a single, even truncating, mutation may not be sufficient to trigger PD. These unaffected sibs of affected parkin mutation carriers are useful controls, however, for neuropsychological and psychiatric evaluations, because they share genetic and environmental factors but not the disease with their affected sib.
Neuropsychological examinations did not reveal major differences in general cognitive efficiency (MMSE, Mattis DRS, episodic memory, Grober and Buschke test) or executive functions (frontal score and FAB) in patients with and without parkin mutations and unaffected heterozygous parkin carriers. This is consistent with and confirms, with more detailed neuropsychological evaluations than in previous studies, that cognitive function remains normal in the majority of patients with parkin mutations,4,5,19
even after 45 years of evolution.4
Additionally, we showed that patients with early-onset PD without parkin mutations do not have cognitive decline even after more than 30 years of disease evolution. However, it is interesting to note that only one patient without a parkin mutation, who also has epilepsy, four patients with parkin mutations, and one healthy single heterozygous parkin carrier had abnormal results on the MDRS (<136), although the groups did not differ significantly after the Sidak correction for multiple testing. Functional or structural abnormalities in the caudate nucleus have been postulated to play a role in frontal-subcortical cognitive impairment or dementia in patients with basal ganglia disease. Interestingly, several studies3,15,17,18,20–22
reported that the decrease in [18
F]fluorodopa uptake in nigrostriatal terminals in the caudate nucleus is generally greater in patients with parkin mutations than in patients without this mutation. This pattern of nigrostriatal dysfunction might result in a different neuropsychological profile. However, this discussion remains speculative and the results must be confirmed by further studies with larger patient groups.
Behavioral disorders, including anxiety and psychosis, panic attacks, depression, disturbed sexual behavior, and obsessive-compulsive disorders, have been reported with variable frequency in patients with parkin mutations,4,5,7–9
and were suggested to be a distinctive feature of parkin disease.4
Dopaminergic dysfunction in cortical areas which might contribute to the psychiatric disorders, as postulated for patients with idiopathic PD,23
has been demonstrated in 13 homozygous or compound heterozygous parkin mutation carriers using PET with 11
However, our detailed psychiatric examinations including MINI, MADRS, and CPRS did not detect any significant qualitative or quantitative differences between parkin mutation carriers and noncarriers. Psychiatric manifestations were present in both groups of patients, but at a similar rate. They were less frequent, however, in the unaffected heterozygous parkin carriers, supporting the hypothesis that dopaminergic dysfunction or antiparkinsonian drugs might account for their greater frequency in patients. Nevertheless, they do not appear to be more frequent in parkin-related parkinsonism than in other early-onset patients.
The large spectrum of parkin gene defects, which differ in their predicted consequences on the function of the protein, also raises the question of their role in the variability of the phenotype. Despite the large number of parkin mutation carriers included, the number of cases in each of the genotype specific groups was too small for a specific neurologic, neuropsychological, or psychiatric pattern to emerge.
The results of this detailed clinical study indicate that patients with PD with parkin mutations are clinically indistinguishable from other early-onset patients. Severe generalized loss of dopaminergic neurons in the substantia nigra pars compacta in these patients is associated with an excellent response to low doses of levodopa-equivalent and delayed fluctuations. Their neuropsychological performance is not distinctive. Interestingly, behavioral problems and psychiatric symptoms, which have been considered to be markers of parkin disease, are observed at similar rates in both groups of early-onset patients and are more frequent in these patients than in unaffected heterozygous parkin mutation carriers.