Medicine (Austin & Northern Health) - Research Publications

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Author: Grinton, Bronwyn × Author: Scheffer, Ingrid × End date: 2012 × Start date: 2012 × Type: Journal Article ×

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    PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures
    Scheffer, IE ; Grinton, BE ; Heron, SE ; Kivity, S ; Afawi, Z ; Iona, X ; Goldberg-Stern, H ; Kinali, M ; Andrews, I ; Guerrini, R ; Marini, C ; Sadleir, LG ; Berkovic, SF ; Dibbens, LM (LIPPINCOTT WILLIAMS & WILKINS, 2012-11)
    OBJECTIVE: Benign familial infantile epilepsy (BFIE) is an autosomal dominant epilepsy syndrome characterized by afebrile seizures beginning at about 6 months of age. Mutations in PRRT2, encoding the proline-rich transmembrane protein 2 gene, have recently been identified in the majority of families with BFIE and the associated syndrome of infantile convulsions and choreoathetosis (ICCA). We asked whether the phenotypic spectrum of PRRT2 was broader than initially recognized by studying patients with sporadic benign infantile seizures and non-BFIE familial infantile seizures for PRRT2 mutations. METHODS: Forty-four probands with infantile-onset seizures, infantile convulsions with mild gastroenteritis, and benign neonatal seizures underwent detailed phenotyping and PRRT2 sequencing. The familial segregation of mutations identified in probands was studied. RESULTS: The PRRT2 mutation c.649-650insC (p.R217fsX224) was identified in 11 probands. Nine probands had a family history of BFIE or ICCA. Two probands had no family history of infantile seizures or paroxysmal kinesigenic dyskinesia and had de novo PRRT2 mutations. Febrile seizures with or without afebrile seizures were observed in 2 families with PRRT2 mutations. CONCLUSIONS: PRRT2 mutations are present in >80% of BFIE and >90% ICCA families, but are not a common cause of other forms of infantile epilepsy. De novo mutations of PRRT2 can cause sporadic benign infantile seizures. Seizures with fever may occur in BFIE such that it may be difficult to distinguish BFIE from febrile seizures and febrile seizures plus in small families.
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    PRRT2 Mutations Cause Benign Familial Infantile Epilepsy and Infantile Convulsions with Choreoathetosis Syndrome
    Heron, SE ; Grinton, BE ; Kivity, S ; Afawi, Z ; Zuberi, SM ; Hughes, JN ; Pridmore, C ; Hodgson, BL ; Iona, X ; Sadleir, LG ; Pelekanos, J ; Herlenius, E ; Goldberg-Stern, H ; Bassan, H ; Haan, E ; Korczyn, AD ; Gardner, AE ; Corbett, MA ; Gecz, J ; Thomas, PQ ; Mulley, JC ; Berkovic, SF ; Scheffer, IE ; Dibbens, LM (CELL PRESS, 2012-01-13)
    Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).
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    In vivo loss of slow potassium channel activity in individuals with benign familial neonatal epilepsy in remission
    Tomlinson, SE ; Bostock, H ; Grinton, B ; Hanna, MG ; Kullmann, DM ; Kiernan, MC ; Scheffer, IE ; Berkovic, SF ; Burke, D (OXFORD UNIV PRESS, 2012-10)
    Benign familial neonatal epilepsy is a neuronal channelopathy most commonly caused by mutations in KCNQ2, which encodes the K(v)7.2 subunit of the slow K(+) channel. K(v)7.2 is expressed in both central and peripheral nervous systems. Seizures occur in the neonatal period, often in clusters within the first few days of life, and usually remit by 12 months of age. The mechanism of involvement of K(v)7.2 mutations in the process of seizure generation has not been established in vivo. In peripheral axons, K(v)7.2 contributes to the nodal slow K(+) current. The present study aimed to determine whether axonal excitability studies could detect changes in peripheral nerve function related to dysfunction or loss of slow potassium channel activity. Nerve excitability studies were performed on eight adults with KCNQ2 mutations and a history of benign familial neonatal epilepsy, now in remission. Studies detected distinctive changes in peripheral nerve, indicating a reduction in slow K(+) current. Specifically, accommodation to long-lasting depolarizing currents was reduced in mutation carriers by 24% compared with normal controls, and the threshold undershoot after 100 ms depolarizing currents was reduced by 22%. Additional changes in excitability included a reduction in the relative refractory period, an increase in superexcitability and a tendency towards reduced sub-excitability. Modelling of the nerve excitability changes suggested that peripheral nerve hyperexcitability may have been ameliorated by upregulation of other potassium channels. We conclude that subclinical dysfunction of K(v)7.2 in peripheral axons can be reliably detected non-invasively in adulthood. Related alterations in neuronal excitability may contribute to epilepsy associated with KCNQ2 mutations.