Juvenile Dentatorubral-Pallidoluysian Atrophy (DRPLA) in a Patient From Northeastern Mexico: Whole-Genome Sequencing With ExpansionHunter as a Key Diagnostic Tool

Dentatorubral-Pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide-repeat expansion in the ATN1 gene.DRPLA affects the dentate, red, pallid, and subthalamic nuclei.It is considered a form of spinocerebellar ataxia or progressive myoclonic epilepsy, usually characterized by ataxia, epilepsy, myoclonus, choreoathetosis, progressive cognitive decline, and neuropsychiatric symptoms.DRPLA is commonly classified into juvenile-onset disease (symptom onset before 20 years of age), which frequently presents with epilepsy and myoclonus, and adult-onset disease (symptom onset at 20 years of age or later), in which ataxia, choreoathetosis, and cognitive or neuropsychiatric manifestations are more prominent.In general, larger CAG repeat expansions are associated with an earlier age at onset, although considerable phenotypic variability exists.Molecular analysis is performed via repeat-primed PCR or Southern blot; both techniques are complex and not easily accessible.Particularly in Mexico, there are few laboratories that perform these tests.Therefore, wholegenome sequencing (WGS) using the ExpansionHunter (EH) methodology has shown good performance in detecting various classes of pathogenic tandem repeats relevant to human diseases, such as DRPLA, while also encompassing the analysis of differential diagnoses.We report a 24-year-old woman from Northeastern Mexico with behavioral and learning difficulties reported during childhood, epilepsy beginning at 16 years of age, nocturnal myoclonus, and progressive gait ataxia beginning at 20 years.Neurological examination revealed dyscalculia, dysarthria, ocular and dressing apraxia, left eye ptosis and esotropia, impaired coordination, dystonic movements, patellar hyperreflexia, resting tremor, gait instability, and dysdiadochokinesia.Brain magnetic resonance imaging (MRI) was reported to show cerebral white-matter signal abnormalities and generalized volume loss involving the cerebellum and brainstem.WGS data analyzed with EH identified a candidate repeat expansion in the pathogenic range of complete penetrance at ATN1.An orthogonal molecular assay was reported to identify alleles with 13 and 64 CAG repeats, respectively, supporting the molecular diagnosis of DRPLA.DRPLA is an infrequent polyglutamine disorder that should be considered in young patients with neurodevelopmental disorders, epilepsy, and progressive ataxia.The present case illustrates the feasibility of combining short-read WGS-based repeat-expansion screening with orthogonal molecular testing in the diagnostic evaluation of a patient with epilepsy, myoclonus, progressive ataxia, and cognitive/behavioral concerns.Therefore, the approach to these patients requires a multidisciplinary team and appropriate genetic counseling for confirmatory diagnosis, follow-up, prevention of possible complications, and recurrence risk management.