Juvenile myoclonic epilepsy phenotype in a family with Unverricht-Lundborg disease.

Unverricht-Lundborg disease (ULD), an autosomal recessive progressive myoclonus epilepsy, is due to an expansion, or less commonly a mutation, of the cystatin B (CSTB) gene. We report a clinical and molecular study of a Tunisian ULD family with five affected members presenting with a juvenile myoclonic epilepsy (JME)-like phenotype. The expansion of dodecamers was detected by a deamination/PCR assay. The expression profiles of CSTB and other candidate modifying genes, cathepsin B and cystatin C, were established by quantitative RT-PCR, and their respective transcription levels were compared with those from patients with a classic picture of ULD. Three patients had a fixed phenotype mimicking JME after 29 years of evolution. Only a discrete dysarthria was noticed in the two other patients. No correlation was observed between transcription level and severity of disease. Genetic screening should be performed in patients with a JME-like phenotype, when careful examination reveals discrete atypical signs of JME. This particular phenotype may be due to modifying genes and/or gene-environment interactions which require further clarification.

Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach.

IMPORTANCE: Huntington disease (HD), a prototypic monogenic disease, is caused by an expanded CAG repeat in the HTT gene exceeding 35 units. However, not all patients with an HD phenotype carry the pathological expansion in HTT, and the positive diagnosis rate is poor. OBJECTIVES: To examine patients with HD phenotypes to determine the frequency of HD phenocopies with typical features of HD but without pathological CAG repeat expansions in HTT in an attempt to improve the positive diagnosis rate. DESIGN, SETTING, AND PARTICIPANTS: Between January 1, 2004, and April 18, 2011, a total of 226 consecutive index patients with an HD phenotype were referred to specialized clinics of the French National Huntington Disease Reference Centre for Rare Diseases. They underwent detailed clinical examination and follow-up, as well as neuropsychological, biological, imaging, and genetic examinations. Nucleotide expansions in JPH3, ATN1, TBP, and C9ORF72 and mutations in PRNP, as well as acquired conditions commonly causing HD phenocopies, were first screened. MAIN OUTCOMES AND MEASURES: The diagnostic rate of HD phenocopies and frequency of other etiologies using deep clinical phenotyping and next generation sequencing. Our goal was to improve the genetic diagnosis of HD phenocopies and to identify new HD related genes. RESULTS: One hundred ninety-eight patients carried a pathological CAG repeat expansion in HTT, whereas 28 patients (12 women and 16 men) did not. Huntington disease phenocopies accounted for 12.4%, and their mean (SD) age at onset was similar to those of the HD-HTT group (47.3 [12.7] years vs 50.3 [16.4] years, P = .29). We first identified 3 patients with abnormal CTG expansions in JPH3, a fourth patient with an antiphospholipid syndrome, and a fifth patient with B12 avitaminosis. A custom-made 63-gene panel was generated based on clinical evolution and exome sequencing. It contained genes responsible for HD phenocopies and other neurodegenerative conditions, as well as candidate genes from exome sequencing in 3 index cases with imaging features of brain iron accumulation. We identified mutations in genes associated with neurodegeneration, including CACNA1A (n = 2), VPS13A (n = 1), UBQLN2 (n = 1), and VCP (n = 1). CONCLUSIONS AND RELEVANCE: Huntington disease phenocopies without CAG repeat expansions in HTT are not rare, occurring in 12.4% (28 of 226) herein, and should be considered in genetic counseling. We used next-generation sequencing combined with clinical data and disease evolution to explore multiple etiologies simultaneously. Our combined clinical and genetic exploration of 28 HD phenocopies identified the underlying cause in 35.7% (10 of 28). In conclusion, the etiologies of HD phenocopies are heterogeneous, and clinical evolution should be taken into account when searching for a genetic cause. The panel of candidate genes to be examined is larger than expected but can be guided by specific imaging and clinical features. Other neurodegenerative diseases with late onset in which variant segregation cannot be verified could be productively explored with the combined approach illustrated herein.