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Atypical, Early‐Onset Dystonia‐ Parkinsonism with Oculogyric Crises and Anterior Horn Cell Disorder Due to a Novel DJ ‐1 Mutation

2021; Wiley; Volume: 8; Issue: S1 Linguagem: Inglês

10.1002/mdc3.13282

2330-1619

Karan Desai, Shruti Agrawal, Priyanka Walzade, Sangeeta Ravat, Pankaj Agarwal,

Genetic Neurodegenerative Diseases

Early-onset dystonia-parkinsonism can be caused by disorders including Wilson's disease, NBIAs, and inherited monogenic disorders causing dystonia, parkinsonism or both. Within the latter category, dystonia predominates over parkinsonism in the DYT-designated disorders that include dopa-responsive dystonia for example, due to GTP cyclohydrolase 1 (GCH1), tyrosine hydroxylase (TH) and sepiapterin reductase (SR) genes; rapid-onset dystonia parkinsonism (ATP1A3), X-linked dystonia-parkinsonism (TAF1) and DYT-PRKRA.1 Parkinsonism is more prominent in the early-onset PARK syndromes; these are caused by parkin mutation in 50%, PINK-1 in 3%–4% and DJ-1 in 1% of cases. An 18-year-old boy presented with three episodes of involuntary upward deviation of eyes with preserved consciousness, over the preceding 18 months, each lasting from 30–90 minutes. In one attack, tonic, fixed, upward conjugate eye deviation was documented. In the previous 12 months, he had noted excessive involuntary blinking, mouth opening, and hand jerking. He was born of a consanguineous union, parents being first cousins. He was doing averagely well as a 12th grade school student but had anxiety and periods of low mood. Medical, drug and family history were negative. Examination (Video 1) revealed atypical blepharospasm with apraxia of eyelid opening, jaw opening dystonia, mild intrinsic hand muscle wasting and dystonic posturing of fingers with polyminimyoclonus due to fasciculations. Mild bradykinesia and rigidity was present in both lower limbs. Tongue fasciculations were noted. Deep tendon reflexes were exaggerated. The rest of the examination was normal. Routine metabolic tests, MRI brain, CSF analysis, EEG and testing for Wilson's disease were negative. Tc99m-TroDAT scan (Fig. 1A) revealed severely reduced tracer uptake in the striatum. EMG study (Fig. 1B,C) showed active and chronic partial denervation in several cervicothoracic, lumbosacral and bulbar myotomes, confirming widespread AHC disease. Clinical Exome testing revealed a novel homozygous mutation C.136T>C (p.Cys46Arg) in exon 3 of the DJ-1 gene, that was also present in a heterozygous state in both unaffected parents. The results were later validated with Sanger sequencing. Levodopa trial (600 mg/day for 3 months) was unhelpful. Trihexyphenidyl and botulinum toxin for blepharospasm provided moderate relief from dystonia. While DJ-1 mutations typically produce a benign parkinsonian phenotype, a more complex progressive syndrome with dystonia and/or dementia has also been reported.1-3 In a Dutch report of 4 DJ-1 patients who had otherwise typical parkinsonism,2 2 also had dystonia including blepharospasm, laterocollis and foot dystonia. In another Indian study,4 5 of 100 early-onset typical PD cases were caused by DJ-1, and 3 subjects also had limb dystonia and depression. In our patient, while dystonia was clinically more prominent than parkinsonism, markedly abnormal DAT scan provided further evidence of nigrostriatal denervation, as has also been reported earlier in DJ-1.2 AHC disease is an increasingly recognized feature of DJ-1, and familial parkinsonism, dementia and amyotrophic lateral sclerosis (ALS) have been reported.3 In the superoxide dismutase 1 ALS mouse model, knocking out DJ-1 further reduces motor neuron survival via glutamate excitotoxicity, accelerating ALS disease course and death.5 In a case of early-onset dystonia-parkinsonism, the presence of AHC signs can be a valuable clinical clue to the diagnosis of DJ-1. OGC, the presenting feature in our case is often seen in conditions involving dopamine synthesis,6 and can also be produced by some genes causing early-onset dystonia-parkinsonism for example ATP1A3 and ATP13A2. OGC has not yet been reported in DJ-1 mutation. We are thankful to the patient and his family for their cooperation. (1) Research Project: A. Conception, B. Clinical Examination C. Data Collection D. Literature Review. (2) Video: A. Recording and B. Editing. (3) Manuscript: A. Writing of the First Draft B. Review and Critique C. Final Approval K.D.: 1B, 1C, 1D, 2A, 3A, 3B S.A.: 1B, 1C, 1D, 2A, 3A, 3B P.W.: 1B, 1C, 1D, 2A, 2B, 3A, 3B P.A.A.: 1A, 1B, 1D, 2A, 2B, 2C, 3A, 3B, 3C S.H.R.: 1A, 1B, 1D, 2B, 3B, 3C Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Written valid and informed consent was obtained from the patient for video recording, and both print and online publication of his videos. We also 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. Funding Sources and Conflicts of Interest: No authors report any sources of funding or any conflicts of interest. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.