Neuropsychiatric‐Led Presentation of Late‐Onset Parkin‐Related Parkinson's Disease

Mutations in the Parkin (PRKN) gene represent the most common cause of autosomal‐recessive early‐onset Parkinson's Disease (PD). ¹ Typical age of onset is under 50 with a slowly progressive, ² symmetric, levodopa‐responsive parkinsonism. ¹ , ³ Cognitive function is typically preserved; ⁴ neuropsychiatric symptoms manifest as depression and anxiety are described in up to two‐thirds of patients, ¹ usually occurring as a complication of disease progression with additional motor features often limited to hyperreflexia and early dystonia. ¹ , ³ PRKN‐PD represents a distinct clinicopathologic entity from classical idiopathic‐PD, where dopaminergic neuronal loss occurs in the absence of Lewy body pathology. ⁵

A 62‐year‐old man presented with profound anxiety, somatic preoccupation and social withdrawal ultimately requiring hospital admission for management of agitated depression with electroconvulsive therapy and pharmacologic management with Olanzapine 5 mg BD. An asymmetric, levodopa‐responsive parkinsonism emerged aged 66. Cognitive testing (aged 66) revealed mild frontal‐dysexecutive and visuospatial deficits (MoCA 25/30). REM‐sleep‐behavior disorder, although an infrequent occurrence while on a selective‐serotonin‐reuptake‐inhibitor later in the disease course, was absent at presentation. There were no visual hallucinations or cognitive fluctuations. Low‐dose titrations of levodopa provoked dyskinesia and coincided with neuropsychiatric deterioration; ultimately a tolerable maintenance dose of 300 mg/daily was established.

Progressive evolution of parkinsonism and emergence of pyramidal features ensued over the following five years. Clinical examination aged 71 revealed severe bilateral parkinsonism, hyper‐reflexia, spasticity, clonus and a left extensor plantar response. Slow horizontal and hypometric vertical saccades were observed. Autonomic features (absent at presentation) emerged early in the eighth decade with urinary urgency, constipation and neurogenic orthostatic hypotension. Cognitive progression was characterized by behavioral rigidity and reduced verbal fluency. Neuropsychometry (aged 70) revealed an Addenbrooke's Cognitive Exam score of 70/100 (attention 15/18, memory 21/26, visuospatial 10/16, fluency 5/14, language 19/26) and a Frontal Assessment Battery score of 9/18. Neuropsychiatric symptoms of profound anxiety and somatic preoccupation persisted. There was no history of neurodegenerative disease in a four‐generation family history, with the exception of motor neuron disease in a maternal cousin.

MRI‐brain performed age 71 and 73 revealed mild generalized atrophy without lobar predilection and bilateral subcortical white matter change, without interval progression with normal midbrain volumes. Dopamine Transporter (DaT) scan demonstrated reduced uptake in the caudate and putamen bilaterally. Fluorodeoxyglucose‐Positron‐Emission Tomography (FDG‐PET) revealed bilateral, left greater than right, frontal and temporal hypometabolism. MRI of cervicothoracic and lumbar spine was non‐contributory, as were electromyography and nerve conduction studies. Next generation sequencing revealed a homozygous pathogenic missense variant in the PRKN gene (c.823C>T p.Arg275Trp).

Usual age of onset of PRKN‐PD is under 50, with only a small proportion of cases presenting over the age of 59 (<2%). ¹ Those with missense variants can have a later age‐at‐onset, higher UPDRS scores and demonstrate a phenotype more consistent with Idiopathic‐PD(IPD).¹ However, the clinical evolution in this case is novel for PRKN‐PD. A stark and debilitating neuropsychiatric onset is unusual with limited reports of behavioral‐ or psychiatric‐onset phenotypes; ⁶ one case is described also demonstrating bifrontal hypometabolism on FDG‐PET. ⁷ Cognition is typically preserved, ⁴ albeit a minority of patients demonstrate mild cognitive impairment, with a very small proportion (6%) with MMSE scores <25. ¹ This case demonstrates significant, domain‐specific, progressive cognitive impairment at odds with the typical phenotype. Interestingly, detailed neuropsychometry performed in two siblings with this variant, ⁸ uncovered deficits in executive and visuospatial function in one sibling in addition to significant generalized anxiety. This highlights the clinical heterogeneity of this condition even within families sharing the same variant, and underscores the importance of neurocognitive interrogation in this population. Whilst hyperreflexia is considered a typical finding in PRKN‐PD, additional pyramidal signs are unusual (~3% of cases). ⁴ Hypometric saccades have also been reported in parkin ⁹ although the degree of vertical saccadic impairment in this case is striking. Autonomic involvement is not uncommon ¹ and has been hypothesized to relate to mild involvement of the locus coeruleus and dorsal motor nucleus of the vagus nerve. ⁵

While p.Arg275Trp is a known pathogenic variant and is common in European ancestry populations in the heterozygous state, ¹ this case demonstrates biallelic carriage of a pathogenic mutation in an autosomal recessive disorder. A number of cases with distinct nucleotide variants resulting in the same amino acid substitution have been associated with neuropsychiatric features such as psychosis and paranoia. ⁶ Missense variants have been described as having a later age‐of‐onset ¹ (although typically still under 50, with one case description of onset‐age 68 ³ ) and cases associated with this specific mutation have also been reported with late disease onset. ¹⁰ The cognitive profile and autonomic features of this case raise the question of alpha‐synuclein co‐pathology which has been previously reported in PRKN‐PD, with one case demonstrating both central and cardiac sympathetic Lewy body deposition. ⁵ , ⁹ We report a neuropsychiatric led syndrome with atypical evolution, occurring in the context of a biallelic pathogenic Parkin mutation. This case highlights the importance of considering PRKN‐PD in the context of a neuropsychiatric led parkinsonian syndrome with atypical evolution.

Disclosures

Ethical compliance statement: Institutional review board or ethics committee approval was not required for this case report. Informed consent was obtained verbally from the participant in relation to submission and publication of this manuscript, this was recorded in the patient notes. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Financial Disclosures and Conflicts of Interest

Author disclosures are available in the Supporting Information.

Supporting information

Data S1. COI_disclosure.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.