An Unusual Presentation of a <scp><i>DNMT1</i></scp> Mutation: Progressive Supranuclear Palsy Look‐Alike Disorder

Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a form of sporadic atypical parkinsonism with early postural instability, supranuclear vertical gaze palsy (VSGP), frontal cognitive and behavioral changes. PSP-RS may be mimicked by a number of disorders, known as PSP-look-alike syndromes.1 The “red flags” that indicate a diagnosis other than PSP-RS are an atypically early age at onset, “too long”/“too rapid” clinical course, a positive family history, or other neurological or non-neurological signs not typically associated with PSP-RS. Here we report a patient with the clinical presentation of a PSP-look-alike disorder, in whom slow symptom progression, deafness, and atypical crural ulcers were the leading “red flags” to seek an alternative diagnosis, resulting in the identification of a pathogenic DNMT1 variant. This 62-year-old man first started noticing shaking of the right hand in a resting position at the age of 52 years, together with gradually progressive difficulty in walking resulting in frequent falls (mainly backward) at the age of 55 years. Two years later, mood fluctuations were obvious, with restless behavior, social withdrawal, and emotional incontinence. After 10 years of disease evolution, he required assisted walking/standing. There was no response to high doses of levodopa (up to 1000 mg per day). His medical history revealed diabetes mellitus type 2 and progressive hearing loss since the age of 30 years. His 88-year-old mother, whose DNA sample was not available for genetic testing, had progressive hearing loss since the age of 50 years, with no other symptoms/diseases. No other relatives were reported as being affected. Examination upon referral to our clinic (Video 1), revealed signs of parkinsonism manifesting as bradykinetic-rigid syndrome, more prominent on the right, together with rest tremor of the right hand and severe postural instability with spontaneous backward falls. There were no cerebellar or pyramidal signs. Deep tendon reflexes were reduced in the lower limbs. Upon sensory examination, diminished perception of light touch and vibratory sensation distal to the calf was noted. Saccades were slow and the patient had a limited range of vertical eye movements, especially of his downgaze, which was overcome by activation of the vestibulo-ocular reflex, indicating a supranuclear origin of VSGP. Due to severe deafness, detailed neuropsychological testing could not be reliably performed, but bedside testing revealed failue to perform the Luria's sequence, positive applause sign, and other frontal-release signs (positive snout and glabellar reflexes, imitative and grasping behavior, pseudobulbar affect). The patient also experienced urinary incontinence, while the tilt table test was negative. Based on retrospective medical history data, his initial presentation resembled a PSP-parkinsonism phenotype, which eventually acquired some of the features of classic PSP-RS.2 Brain magnetic resonance imaging showed evidence of severe global atrophy, without signal alterations (Fig. 1). A “hummingbird sign” was also observed, but it could not be interpreted as significant in the presence of severe global atrophy. Brain 18-F-fluorodeoxyglucose-positron emission tomography showed a pattern of global hypometabolism in cortical and cerebellar regions (Fig. 1). In addition, the patient had electrophysiological signs of axonal sensory neuropathy, initially thought to be a part of diabetic complications. Another “red flag” was progressive deafness, observed both in the patient and his mother. After excluding repeat expansions associated with SCA1, 2,-3, 6, 7, Friedreich's ataxia and fragile X-associated tremor/ataxia syndrome, we performed whole-exome sequencing, which identified a heterozygous pathogenic variant in the DNMT1 gene (NM_001130823.3) c.1709C > T (p.Ala570Val). The DNMT1 gene (MIM: *126375) encodes an enzyme called DNA-methyltransferase-1, involved in DNA methylation.3 The penetrance of pathogenic variants in this gene is complete (100%) and they primarily result in two autosomal dominant phenotypes: autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN; MIM: #604121) and hereditary sensory and autonomic neuropathy type 1E (HSN1E; MIM: #614116).4 The typical presentation of HSN1E is a triad of hearing loss, sensory neuropathy, and cognitive decline. In ADCA-DN, deafness and narcolepsy are the diagnostic hallmarks, but their presence is not obligatory, making the diagnosis more challenging.4, 5 Our patient presented with a progressive parkinsonism of the PSP-RS phenotype, which has not been described within the DNMT1 spectrum so far. One could argue that the progressive instability was part of cerebellar ataxia. However, at the time of examination, signs of parkinsonism, together with VSGP and cognitive decline, were predominant. No signs of narcolepsy/cataplexy were present, but autosomal dominant deafness and slow saccades previously reported in an ADCA-DN patient, were the leading clues to the DNMT1-related disorder spectrum.5, 6 Although the signs of axonal sensory neuropathy in our patient could be attributed to diabetes, the distribution of the ulcers (more proximal than diabetic ulcers usually affecting the feet) drew our attention to a possible alternative etiology of neuropathy, such as the previously described axonal neuropathy in the DNMT1-spectrum disorders.7, 8 To date, 17 patients from several families with the p.Ala570Val DNMT1 variant have been reported (Table S1). They mostly presented with a typical ADCA-DN phenotype and without signs of parkinsonism. Nevertheless, DNMT1 variants may play a role in the pathogenesis of Parkinson's disease (PD). For instance, association analyses performed in Chinese PD patients and controls indicated DNMT1 variants/halotypes that may modulate PD susceptibility.9 In conclusion, our patient, together with the recently described patient with cerebellar ataxia with a hot-cross bun sign5 and PD susceptibility,9 highlights the need for careful consideration of DNMT1 mutations in atypical parkinsonism mimics. Additional clinical signs, such as deafness, neuropathy, crural ulcers, and falls with narcolepsy/cataplexy, pointed to a diagnosis other than “classic” atypical parkinsonism. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. M.J.-L.: 1A, 1C, 3A. A.M.: 1A, 1C, 3A. N.M.: 1C, 3A. A.W.: 1C, 3B. A.T. P.: 1C, 3A. I.P.: 1A, 3B. V.M.: 1A, 3B. N.K.: 1A, 3B. C.K.: 1A, 3B. V.S.K.: 1A, 3B. N.D.-M.: 1A, 1C, 3B. We thank the patient for his participation in this study. Ethical Compliance Statement: The patient signed an informed consent to participate in the study. The Ethics Committee of the Medical Faculty, University of Belgrade approved the study. 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. Funding Sources and Conflict of Interest: This study was supported by the German Research Foundation (DFG, FOR2488). AW provides consultancy services around research projects for CENTOGENE GmbH. Other authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months: CK received grants from the BMBF; MJFF and ASAP. Other authors declare that there are no additional disclosures to report. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Table S1. Clinical characteristics of patients carrying variant DNMT1 gene (NM_001130823.3) c.1709C>T (p.Ala570Val). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.