Lorena Travaglini1, Marta Nardella1, Emanuele Bellacchio2, Adele D'Amico1, Alessandro Capuano3, Roberto Frusciante3, Matteo Di Capua3, Raffaella Cusmai3, Sabina Barresi4, Silvia Morlino5, José M Fernández-Fernández6, Marina Trivisano3, Nicola Specchio3, Massimiliano Valeriani3, Federico Vigevano3, Enrico Bertini1, Ginevra Zanni7. 1. Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 2. Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 3. Department of Neurosciences, Unit of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 4. Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 5. Unit of Medical Genetics, San Camillo-Forlanini Hospital, Rome, Italy. 6. Laboratori de Fisiologia Molecular i Canalopaties, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. 7. Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address: ginevra.zanni@opbg.net.
Abstract
BACKGROUND: Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, localized at presynaptic terminals of brain and cerebellar neurons, result in clinically variable neurological disorders including hemiplegic migraine (HM) and episodic or progressive adult-onset ataxia (EA2, SCA6). Most recently, CACNA1A mutations have been identified in patients with nonprogressive congenital ataxia (NPCA). METHODS: We performed targeted resequencing of known genes involved in cerebellar dysfunction, in 48 patients with congenital or early onset ataxia associated with cerebellar and/or vermis atrophy. RESULTS: De novo missense mutations of CACNA1A were found in four patients (4/48, ∼8.3%). Three of them developed migraine before or after the onset of ataxia. Seizures were present in half of the cases. CONCLUSION: Our results expand the clinical and mutational spectrum of CACNA1A-related phenotype in childhood and suggest that CACNA1A screening should be implemented in this subgroup of ataxias.
BACKGROUND: Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, localized at presynaptic terminals of brain and cerebellar neurons, result in clinically variable neurological disorders including hemiplegic migraine (HM) and episodic or progressive adult-onset ataxia (EA2, SCA6). Most recently, CACNA1A mutations have been identified in patients with nonprogressive congenital ataxia (NPCA). METHODS: We performed targeted resequencing of known genes involved in cerebellar dysfunction, in 48 patients with congenital or early onset ataxia associated with cerebellar and/or vermis atrophy. RESULTS: De novo missense mutations of CACNA1A were found in four patients (4/48, ∼8.3%). Three of them developed migraine before or after the onset of ataxia. Seizures were present in half of the cases. CONCLUSION: Our results expand the clinical and mutational spectrum of CACNA1A-related phenotype in childhood and suggest that CACNA1A screening should be implemented in this subgroup of ataxias.
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