Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies.

OBJECTIVE: The term 'precision medicine' describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy. METHODS: A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management. RESULTS: We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%). SIGNIFICANCE: Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.

GNAQ/GNA11 Mosaicism Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification.

Mosaic mutations in genes GNAQ or GNA11 lead to a spectrum of diseases including Sturge-Weber syndrome and phakomatosis pigmentovascularis with dermal melanocytosis. The pathognomonic finding of localized "tramlining" on plain skull radiography, representing medium-sized neurovascular calcification and associated with postnatal neurological deterioration, led us to study calcium metabolism in a cohort of 42 children. In this study, we find that 74% of patients had at least one abnormal measurement of calcium metabolism, the commonest being moderately low serum ionized calcium (41%) or high parathyroid hormone (17%). Lower levels of ionized calcium even within the normal range were significantly associated with seizures, and with specific antiepileptics despite normal vitamin D levels. Successive measurements documented substantial intrapersonal fluctuation in indices over time, and DEXA scans were normal in patients with hypocalcemia. Neurohistology from epilepsy surgery in five patients revealed not only intravascular, but perivascular and intraparenchymal mineral deposition and intraparenchymal microvascular disease in addition to previously reported findings. Neuroradiology review clearly demonstrated progressive calcium deposition in individuals over time. These findings and those of the adjoining paper suggest that calcium deposition in the brain of patients with GNAQ/GNA11 mosaicism may not be a nonspecific sign of damage as was previously thought, but may instead reflect the central postnatal pathological process in this disease spectrum.

Late diagnoses of Dravet syndrome: How many individuals are we missing?

We report new genetic diagnoses of Dravet syndrome in a group of adults with complex epilepsy of unknown cause, under follow-up at a tertiary epilepsy center. Individuals with epilepsy and other features of unknown cause from our unit underwent whole-genome sequencing through the 100 000 Genomes Project. Virtual gene panels were applied to frequency-filtered variants based on phenotype summary. Of 1078 individuals recruited, 8 (0.74%) were identified to have a pathogenic or likely pathogenic variant in SCN1A. Variant types were as follows: nonsense (stopgain) in five (62.5%) and missense in three (37.5%). Detailed review of childhood history confirmed a phenotype compatible with Dravet syndrome. Median age at genetic diagnosis was 44.5 years (range 28-52 years). Tonic-clonic seizures were ongoing in all despite polytherapy including valproate. All had a history of fever sensitivity and myoclonic seizures, which were ongoing in two (25%) and three (37.5%) individuals, respectively. Salient features of Dravet syndrome may be less apparent in adulthood, making clinical diagnosis difficult. Regardless of age, benefits of a genetic diagnosis include access to syndrome-specific treatment options, avoidance of harmful drugs, and monitoring for common complications.

Moyamoya and progressive myoclonic epilepsy secondary to CLN6 bi-allelic mutations - A previously unreported association.

The neuronal ceroid lipofuscinoses (NCL) are a collection of lysosomal storage diseases characterised by the accumulation of characteristic inclusions containing lipofuscin in various tissues of the body and are one of the causes of progressive myoclonic epilepsy. Mutations in at least thirteen genes have been identified as causes of NCL, which can present as infantile, late-infantile, juvenile or adult forms. CLN6 codes for an endoplasmic reticulum transmembrane protein of unknown function. Homozygous and compound heterozygous mutations of the gene are associated with both late-infantile (LINCL) and adult onset (ANCL) forms of NCL, including Kufs disease, comprising ANCL without associated visual loss. Moyamoya, a rare vasculopathy of the circle of Willis, has been reported in conjunction with a number of inflammatory and other diseases, as well as a handful of lysosomal storage diseases. To our knowledge, this is the first reported case of Moyamoya in the context of the neuronal ceroid lipofuscinoses or a CLN6-related disease.

Congenital hyperinsulinism due to compound heterozygous mutations in ABCC8 responsive to diazoxide therapy.

Background Congenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic ß cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI. Case presentation A term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide. Conclusions Biallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.