Medical Biology - Research Publications

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Author: Bahlo, Melanie × Author: Berkovic, Samuel × Author: Broderick, Karen × Author: Damiano, John × Author: Hildebrand, Michael × End date: 2019 × Start date: 2015 × Type: Journal Article ×

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    Evidence of linkage to chromosome 5p13.2-q11.1 in a large inbred family with genetic generalized epilepsy
    Kinay, D ; Oliver, KL ; Tuzun, E ; Damiano, JA ; Ulusoy, C ; Andermann, E ; Hildebrand, MS ; Bahlo, M ; Berkovic, SF (WILEY, 2018-08)
    The clinical genetics of genetic generalized epilepsy suggests complex inheritance; large pedigrees, with multiple affected individuals, are rare exceptions. We studied a large consanguineous family from Turkey where extensive electroclinical phenotyping revealed a familial phenotype most closely resembling juvenile myoclonic epilepsy. For a subject to be considered affected (n = 14), a diagnostic electroencephalogram was required. Seizure onset ranged between 6 and 19 years (mean = 12 years). Thirteen of 14 experienced myoclonic jerks; in 11, this was associated with eyelid blinking, and in 10 it was interspersed with absences. Generalized tonic-clonic seizures were seen in 11. One individual had generalized tonic-clonic seizures alone. Electroencephalograms demonstrated generalized polyspike and wave discharges that were not associated with photoparoxysmal response. Intellect was normal. Nineteen family members were subsequently chosen for nonparametric multipoint linkage analyses, which identified a 39.5 Mb region on chromosome 5 (P < 0.0001). Iterative analysis, including discovery of a subtly affected individual, narrowed the critical region to 15.4 Mb and possibly to 5.5 Mb. Homozygous versus heterozygous state of the refined 5p13.2-q11.1 haplotype was not associated with phenotypic severity or onset age, suggesting that one versus two pathogenic variants may result in similar phenotypes. Whole exome sequencing (n = 3) failed to detect any rare, protein-coding variants within the highly significant linkage region that includes HCN1 as a promising candidate.
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    Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease)
    Berkovic, SF ; Staropoli, JF ; Carpenter, S ; Oliver, KL ; Kmoch, S ; Anderson, GW ; Damiano, JA ; Hildebrand, MS ; Sims, KB ; Cotman, SL ; Bahlo, M ; Smith, KR ; Cadieux-Dion, M ; Cossette, P ; Jedlickova, I ; Pristoupilova, A ; Mole, SE (LIPPINCOTT WILLIAMS & WILKINS, 2016-08-09)
    OBJECTIVE: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery. METHODS: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL. RESULTS: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis. CONCLUSIONS: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes.