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Patient Clinical Information: The patient is a 13 year-old female reported to have tuberous sclerosis and seizures, slowly progressive loss of milestones over the last year, increased agitation and fevers, and decreased oral intake. The patient is confined to a wheelchair and has constant writhing and spastic movements accompanied by arching and intense muscle contraction and twitching.
Family History: The patient’s mother and two siblings are affected by tuberous sclerosis, and the father passed away four years ago from what was clinically diagnosed as “Huntington” disease.
Testing Ordered: Comprehensive Spinocerebellar Ataxia Repeat Expansion Panel
Genetic Findings: Previous testing performed on this patient included HTT trinucleotide repeat analysis based on the father’s Huntington disease diagnosis, resulting in both alleles within normal range, and whole exome sequencing that found a TSC1 splice-site variant, consistent with the TSC diagnosis already known. However, through additional repeat expansions analysis, we found an expansion in the ATN1 gene, causing Dentatorubral-pallidoluysian atrophy (DRPLA). The patient had one normal-range allele of 15 repeats, and one expanded allele at 67 repeats.
Outcome: The affected range for DRPLA is 36 or more repeats, with higher numbers of repeats correlating with earlier onset of disease, and with repeats over 65 being associated with infant and childhood-onset of symptoms. This is a rare autosomal dominant spinocerebellar ataxia with an estimated incidence of 2 to 7 per million people, and is primarily found in Japanese populations. Due to genetic anticipation, affected offspring are expected to have symptoms 26 to 29 years earlier than affected fathers and 14 to 15 years earlier than affected mothers, and a differential diagnosis for adult-onset DRPLA includes Huntington disease. The results explain the clinical presentation and early onset DRPLA in the patient, as well as the father’s previous diagnosis.
Figure 1: The top portion shows the patient’s allele profile for ATN1/DRPLA repeat expansion analysis with one allele at 15 repeats, considered normal, and the second expanded allele at 67 repeats. The bottom profile with control alleles shows what would be expected as normal repeat lengths at 9 and 15 repeats. The red line at 65 repeats shows the cut-off for early onset of Dentatorubral-pallidoluysian atrophy symptoms, consistent with the patient’s phenotype.
Reported by: Dimiter Kolev, Associate Reporting Specialist