Two Novel Mutations in 2 Families With Benign Familial Neonatal Convulsions

Benign familial neonatal convulsion is a rare autosomal dominant inherited epilepsy syndrome characterized by unprovoked seizures in the first few days of life, normal psychomotor development, and a positive intergenerational family history of neonatal seizures. Over 90% of the affected individuals have inherited causal mutations in KCNQ2 , which encodes for the potassium voltage-gated channel subfamily Q, member 2. Mutations in KCNQ2 are also associated with a severe neonatal encephalopathy phenotype associated with poor seizure control and neurodevelopmental deficits. The authors report the clinical presentations, response to medication, and intrafamilial phenotypic variability in 2 families with benign familial neonatal convulsions, carrying previously unreported heterozygous missense mutations, c.1066C>G (p.Leu356Val) and c.1721G < A (p.Gly574Asp), in KCNQ2 . The cases reported herein suggest that inherited missense mutations in KCNQ2 can be associated with an intermediate phenotype and illustrate the challenges associated with prognosis and counselling for individuals with inherited missense mutations in KCNQ2

Dystonia in RNA Polymerase III-Related Leukodystrophy

Objectives: To identify the prevalence of dystonia in a RNA Polymerase III (POLR3)-related leukodystrophy patient cohort and to further characterize their dystonic features. Background: POLR3-related leukodystrophy is a hypomyelinating leukodystrophy characterized by neurological and non-neurological features. Dystonia remains a challenging and under-recognized feature. Methods: A retrospective chart review was performed in a cohort of 20 patients for whom videos of a standardized neurological examination were available. Patients were recruited at the Montreal Children's Hospital of the McGill University Health Center and the Myelin Disorders Bioregistry Project. Families were consented at the initial assessment and the following data was recorded: age and symptoms at clinical presentation, investigations, causal gene and mutation(s), type and severity of dystonia, and treatment response when needed. Standardized examination videos were reviewed by three independent reviewers and scored using the Global Dystonia Scale. Results: 10 males and 10 females were included in this study; 12/20 had POLR3A mutations, while 8/20 had POLR3B mutations; 19/20 patients had documented dystonia, with 3/19 requiring therapy. There was a good response in two patients to a single agent, and a poor response in one patient to three agents; the majority had mild-to-moderate multifocal dystonia without a functional impact. Conclusions: Dystonia is a common, yet underdiagnosed, slowly progressive manifestation of POLR3-related leukodystrophy, and in most cases has limited-to-no functional impact. When treatment is needed, good response to typically used medication may occur. Further studies are needed to assess evolution of dystonia over time, patients’ functional outcome, and response to therapy (when needed)