Authors :
Presenting Author: Paloma Parra-Díaz, MD – Hospital Ruber Internacional; Fundación INCE. Madrid, Spain
Arnaud Monteil, PhD – Institut de Génomique Fonctionnelle, Montpellier, France; Isabel del Pino, PhD – Centro de Investigación Príncipe Felipe, Valencia, Spain; Álvaro Beltrán-Corbellini, MD – Neurology – Hospital Ruber Internacional, Madrid, Spain; Egidio Spinelli, MD – Children's Hospital at London Health Sciences Centre (LHSC), Ontario, Canada; Daniel Calame, MD, PhD – Baylor College of Medicine; Texas Children's Hospital; Houston, TX, USA; Rafael Vera-Medialdea, MD – Hospital Materno-Infantil, Complejo Hospitalario Carlos Haya, Málaga, Spain; Klaus Dieterich, MD, PhD – Grenoble Alpes University; CHU Grenoble Alpes, Grenoble, France; Hélène Tevissen, MD – Centre Hospitalier de Valence, Valence, France; Luca Soliani, MD – IRCCS Istituto delle Scienze Neurologiche di Bologna; University of Bologna, Bologna, Italy; Duccio Maria Cordelli, MD, PhD – IRCCS Istituto delle Scienze Neurologiche di Bologna; University of Bologna, Bologna, Italy; Stephan Waltz, MD – Children‘s Hospital Amsterdamer Strasse, Cologne, Germany; Kacie Riley, MS, CGC – Duke University Hospital, Durham, NC, USA; Amy Kritzer, MD – Boston Children’s Hospital, Boston, MA, USA; Elena Caron, MD – The University of Tennessee Health Sciences Center; Le Bonheur Children’s Hospital, Memphis, TN, USA; Antonio Gil-Nagel, MD, PhD – Neurology – Hospital Ruber Internacional; Fundación Iniciativa para las Neurociencias, Madrid, Spain
Rationale:
The sodium-leak channel NALCN plays a critical role in regulating the resting membrane potential in many cells, including neurons in the central nervous system. CLIFHADD syndrome (Congenital Contractures of Limbs and Face, Hypotonia and Developmental Delay), has been linked to gain-of-function mutations in NALCN, while IHPRF 1 and 2 syndromes (Infantile Hypotonia, Psychomotor Retardations and Facies), have been associated with loss-of-function mutations in either NALCN or its subunit UNC80, respectively. These disorders cause a range of symptoms, including developmental delay, hypotonia, and seizures. However, the type and severity of epilepsy in this population are still uncertain. Our objective is to characterize epilepsy in a large cohort of patients with NALCN or UNC80-related disorders.
Methods:
We identified patients with epilepsy from a larger cohort of individuals with NALCN/UNC80-related disorders participating in an ongoing study of deep phenotyping conducted by our group. Information on seizure semiology, age of onset, lifetime medication response, neurophysiological and neuroimaging tests were collected from medical reports and clinical interviews with families.
Results:
The full cohort consisted of 46 patients (30 CLIFAHDD, 8 IHPRF 1, 8 IHPRF 2 syndromes; 34.8% females; median age 6.5 years [3 months- 24 years]). Of these, 16 patients (34.8%) had a diagnosis of epilepsy. One patient with CLIFAHDD had febrile seizures in infancy and another patient had only one febrile seizure at the age of six. A higher frequency of epilepsy was observed in IHPRF 1 (62.5%) and IHPRF 2 (87.5%) syndromes, compared to those with CLIFAHDD (13.3%). The median age of seizure onset was 4.25 years (three months to 17 years). Overall, 62.5% patients were refractory to treatment, including all cases with onset before 12 months (43.75%), in which tonic seizures and epileptic spams were the predominant types of seizures. 33.3% of refractory patients met the criteria for Lennox-Gastaut syndrome, all of which had IHPRF syndromes. Six patients (1 CLIFAHDD, 1 IHPRF 1, and 4 IHPRF 2) were seizure-free on monotherapy at the time of evaluation, with three of them taking valproic acid and the rest taking levetiracetam, carbamazepine and lamotrigine. The median age of seizure onset in this group was 11 years and the most common seizure type was generalized tonic-clonic with unknown onset. At least one EEG was available in 10 patients, with variable results mostly showing diffuse slowing, bifrontal or multifocal spikes. Cranial MRI results were mostly normal, with cortical and cerebellar atrophy and ventriculomegaly observed in some cases.
Conclusions:
Epilepsy was highly prevalent in our cohort of patients with NALCN/UNC80-related disorders, especially in IHPRF 1 and 2 syndromes, which have previously been associated with loss-of-function mutations. Most patients had refractory seizures, particularly those with an earlier onset. Some patients were diagnosed with Lennox-Gastaut syndrome. This study emphasizes the importance of careful evaluation of these patients for proper diagnosis and treatment of epilepsy.
Funding: No specific funding received.