Parkinson's Disease with a Homozygous <scp><i>PARK7</i></scp> Mutation and Clinical Onset at the Age of 5 Years

Mutations in the PARK7 gene, which encodes DJ-1, are a rare cause of autosomal recessive Parkinson's disease (PD).1 Only approximately 30 PARK7-linked PD cases have been reported.2 PARK7 mutations typically cause levodopa-responsive parkinsonism with early or even juvenile age at onset (AAO) (median AAO, 27 years) and slow progression.2 However, detailed phenotype descriptions are scarce. Here we provide a comprehensive clinical characterization of a PARK7-linked PD case with the youngest AAO ever reported. The proband was a Flemish man who presented to our clinic at the age of 27 years. At the age of 5 years he developed bilateral hand tremor, impaired dexterity, and less intelligible speech. The AAO was confirmed to us by his father and his sister, who was 9 years older, and was also documented in the report of the speech therapist who started treating him at the age of 7. The patient was seen by a child psychiatrist, and his symptoms were attributed to his nervous, anxious personality. His symptoms progressed very slowly as he grew up. At the age of 26, he was first examined by a neurologist, who found parkinsonism and referred him to our center. Clinical exam revealed aprosodic, hypophonic dysarthria, and hypomimia (Video 1). There was mild to moderate, somewhat jerky postural and kinetic tremor, mild bradykinesia, and mild rigidity in the upper limbs, more so on the left (Videos 2-5). Gait was normal except for bilaterally reduced arm swing (Video 6). There was no rest tremor or dystonia. He had no postural instability or pyramidal signs. Magnetic resonance imaging of the brain was normal. The [123I] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) single-photon emission computerized tomography (SPECT) showed almost absent uptake in the putamina and lower uptake in the caudate nuclei, especially on the left, confirming the diagnosis of PD (Fig. 1). A homozygous PARK7 mutation (c.471_473delGCC; p.Pro158del) was found, which results in deletion of a conserved proline residue and has been reported once before in a Dutch patient with PD.3 In the gnomAD database, this variant had an allele frequency of 0.0067%, and all carriers were European and heterozygous. He had no PRKN, PINK1, LRRK2, SNCA, VPS35, or GBA mutations. His 36-year-old sister, his only sibling, had isolated, very mild symmetric action tremor of the arms without other abnormalities. She had a normal 123I-FP-CIT SPECT and was heterozygous for the p.Pro158del mutation. There were no other relatives with neurological disorders. Pramipexole 2.1 mg every day (q.d.) had a favorable effect on his tremor, bradykinesia, and rigidity, but had to be stopped because of behavioral side effects. Levodopa 100 mg 3 times a day also improved his parkinsonism, but was withdrawn because of severe daytime somnolence. Rasagiline and amantadine induced nausea. Trihexyphenidyl up to 2 mg 4 times a day was ineffective and caused cognitive side effects. Propranolol 80 mg q.d. and primidone 250 mg q.d. had no effect. At the age of 30, his Movement Disorder Society–Unified Parkinson's Disease Rating Scale Part III score (under monotherapy with trihexyphenidyl 2 mg q.d.) was only 19. Montreal Cognitive Assessment score was normal (28/30). He responded positively on the Rapid Eye Movement Sleep Behavior Disorder Single-Question Screen. His score on the Parkinson Anxiety Scale was 18/48, with a subscore of 11 for persistent anxiety, compatible with generalized anxiety disorder. The Questionnaire for Impulsive-Compulsive Disorders in PD–Rating Scale did not reveal impulse control disorders. He had no sleep disorder based on Scales for Outcomes in PD (SCOPA)–Sleep, nor was there any autonomic dysfunction based on SCOPA–Autonomic Dysfunction. Beck Depression Inventory score was 11, indicating borderline depressive symptoms. His score on the University of Pennsylvania Smell Identification Test (UPSIT) was 29, consistent with moderate hyposmia. The main clinical manifestations of this patient were action tremor, hypokinesia, rigidity, anxiety, and hyposmia. Olfactory testing has previously been reported in only 2 patients with PD with PARK7 mutations. One of these had normal odor identification but abnormally poor odor discrimination based on the Sniffin' Sticks test,4 whereas the other patient was anosmic based on the UPSIT.5 Taken together with our case, these data suggest that olfactory impairment is a consistent feature in this form of PD. The most striking aspect of the patient's phenotype was his unusually young AAO. The majority (83%) of PARK7-linked PD cases have an AAO between 20 and 40 years, whereas only 13% have an AAO below 20.2 The youngest AAO reported in a patient with PARK7 mutations was 16 years.6 Intuitively, one would expect a neurodegenerative process that already manifests itself at such a young age to be more aggressive and more rapidly progressive. This is true for Huntington's disease, where long CAG repeat lengths cause both younger AAO and more rapid progression.7 Similarly, PD attributed to SNCA triplications has both a younger AAO and more aggressive course than PD with SNCA duplications.8 In contrast, autosomal recessive PD caused by PRKN, PINK1, and PARK7 mutations typically combines young AAO with very slow progression, as illustrated to an extreme degree by our current case. In autosomal recessive PD, the biological mechanisms that determine AAO are apparently distinct from those that drive disease progression. Further research is required to explain this paradox. We thank Dr. Sascha Vermeer (University Hospitals Leuven) for discussions. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. A.D.: 1A, 1B, 1C, 2A V.R.: 1C, 2B E.B.: 1C, 2B K.V.L.: 1A, 1B, 1C, 2B W.V.: 1A, 1B, 1C, 2A, 2B The authors confirm that the approval of an institutional review board was not required for this work. The patient provided written informed consent for publication of his case history and videos. We affirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report.

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