Objective: To report the postmortem findings in a case of early onset genetically confirmed DJ-1 (PARK7) PD.

Background: As a very rare cause (1-2%) of early onset Parkinson’s disease (EOPD), pathological descriptions are scarce. To date, only one other case has linked DJ-1 mutations with Lewy body and alpha-synuclein pathology.(2)

Method: A brain autopsy was conducted at the time of death and correlated with clinical features and genotype.

Results: Our patient presented at the age of 24 with levodopa responsive parkinsonism including left hand tremor, bradykinesia-rigidity, hyposmia, dysarthria, dysphagia. He had a history of cataracts and sensorineural hearing loss, type II diabetes, and hypertriglyceridemia. Mild cognitive impairment was an early feature of his condition.  Brain MRI revealed no secondary causes of parkinsonism. Dopamine transporter SPECT imaging showed bilateral nigrostriatal dopaminergic deficit, confirming the diagnosis of PD. There was no family history of similar neurological disorders. Genetic testing revealed compound heterozygous DJ-1 variants, including a novel Exon 4 deletion (maternally inherited) and a c.105dupT; A36Cfs*12 mutation (paternally inherited). His final year of life was marked by psychosis, progressive loss of mobility, dysphagia leading to gastrostomy, and decubitus ulcers. He died from complications of the disease, 15 years after symptom onset, at the age of 39. Please note, the clinical history and genotype were previously reported (3).

Gross examination and light microscopy confirmed the primary diagnosis of PD. There was hypopigmentation, degeneration, and gliosis of the substantia nigra and locus ceruleus. There was no evidence of Alzheimer’s disease, Frontotemporal dementia, or other tauopathies using beta-amyloid, tau, and TDP-43 immunohistochemistry. Multiple cortical and subcortical regions of the brain were stained with alpha-synuclein revealing widespread Lewy body and neurite pathology in brainstem, basal ganglia, and amygdala.

Conclusion: Our case is the second reported case linking alpha-synuclein brain pathology and DJ-1 mutations. Our patient had other atypical features include cataracts, sensorineural hearing loss, type 2 diabetes, and hypertriglyceridemia that may help to define the DJ-1 phenotype. DJ-1 is a deglycase that is believed to modulate mitochondrial responses to oxidative stress and may behave as a chaperone for alpha-synuclein.

References: 1. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003 Jan 10;299(5604):256-9. doi: 10.1126/science.1077209. Epub 2002 Nov 21. PMID: 12446870.

2. Taipa R, Pereira C, Reis I, Alonso I, Bastos-Lima A, Melo-Pires M, Magalhães M. DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology. Brain. 2016 Jun;139(Pt 6):1680-7. doi: 10.1093/brain/aww080. Epub 2016 Apr 16. Erratum in: Brain. 2016 Dec;139(Pt 12):e71. PMID: 27085187.

3. Narendra DP, Isonaka R, Nguyen D, Schindler AB, Kokkinis AD, Ehrlich D, Bardakjian TM, Goldstein DS, Liang TW, Gonzalez-Alegre P. Peripheral synucleinopathy in a DJ1 patient with Parkinson disease, cataracts, and hearing loss. Neurology. 2019 Jun 4;92(23):1113-1115. doi: 10.1212/WNL.0000000000007614. Epub 2019 Apr 26. PMID: 31028127; PMCID: PMC6556091.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pathological-findings-in-a-case-of-dj-1-early-onset-parkinsons-disease/