Objective: To describe a unique Greek family with a Dentatorubral-pallidoluysian atrophy (DRPLA) like clinical presentation and a distinctive neuropathological phenotype.

Background: DRPLA is a cause of spinocerebellar ataxia classified as a CAG repeat disorder. It presents with variable phenotypes depending on the age of onset. Patients who present in adulthood manifest with cerebellar ataxia and dementia, whereas juvenile onset disease presents with progressive myoclonus, mental retardation and seizures.  Neuropathology shows combined dentatorubral and pallidoluysian systems degeneration (1).  DRPLA mostly presents in individuals of Asian origin, particularly those who are Japanese, and is rarely seen outside of this population (2). A study of spinocerebellar ataxias in the Greek population found no cases of DRPLA (3).

Method: Clinicopathological and genetic report of two siblings of Greek origin.

Results: Both patients presented with a clinical phenotype of ataxia and seizures. The brother had an earlier onset in his 20’s, presented with myoclonic seizures, ataxia, and cognitive impairment. The older sister presented in her 50s with tremors and ataxia, then developed generalized tonic-clonic seizures, absent myoclonus. Her son, who passed away at the age of 14, who was given a clinical diagnosis of “Friedreich’s ataxia” without genetic confirmation. [VN1] Neuropathological evaluation of the two cases showed a similar pattern of neuronal loss and gliosis, predominating in the dentate nucleus, inferior olive nucleus, and subthalamic nucleus with relative preservation of the substantia nigra and globus pallidus. The younger case had neuronal loss in the medial nucleus of the thalamus due to a previous thalamotomy.  P62 positive intranuclear inclusions were found only in preserved nigral neurons of the older case. Both cases showed Primary Age-Related Tauopathy (PART, Braak stage I and II, respectively) but lack of other tauopathy, α-synucleinopathy or TDP-43 proteinopathy. Genetic testing is currently being performed.

Conclusion: These two cases from a single Greek family manifested DRPLA-like clinical presentations associated with an atypical, Dentato-Olivo-Luysian, neuronal degeneration pattern. The nearly complete lack of neurons in affected regions might be a reason why we could not detect intraneuronal inclusions.  The anticipation phenomenon argues for a repeat disorder in this family and the genetic background is under study

References: 1. Yamada M. Dentatorubral‐pallidoluysian atrophy (DRPLA) The 50th Anniversary of Japanese Society of Neuropathology. Neuropathology. 2010 Oct;30(5):453-7. 2. Tsuji S. Dentatorubral–pallidoluysian atrophy. In Handbook of clinical neurology 2012 Jan 1 (Vol. 103, pp. 587-594). Elsevier. 3. Koutsis G, Pemble S, Sweeney MG, Paudel R, Wood NW, Panas M, Kladi A, Houlden H. Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia. Journal of the neurological sciences. 2012 Jul 15;318(1-2):178-80.

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