Monogenic epilepsies: genotype-phenotype correlations and precision therapy

Publikation: Bog/antologi/afhandling/rapportPh.d.afhandlingpeer review


Epilepsy is one of the most prevalent neurological disorders and identifying the cause of seizures is instrumental for the proper diagnosis, management and follow-up, prognostic counselling and for estimating the recurrence risk of additional seizures. The etiologies can be divided into categories such as structural, genetic, infectious, metabolic, and immune. These are not mutually exclusive categories and the etiology in some patients can fall into more than one category. Genetic factors are considered to be a major contributor to childhood onset epilepsies. Monogenic epilepsies are believed to occur in 1 per 2120 live births and they are genetically very heterogeneous. Symptoms range from self-limiting (familial) epilepsies to devastating developmental and epileptic encephalopathies (DEEs). Patients suffering from rare monogenic epilepsies often endure a long diagnostic odyssey but timely genetic testing can ensure a precision diagnosis, accurate counseling and give access to the precision therapy ecosystem. A rare and still ill-defined subgroup of monogenic epilepsies are the glycosylphosphatidylinositol (GPI) anchoring disorders. GPI is a complex glycolipid that plays an essential role in embryogenesis and neurogenesis. It is synthesized through a complex multistep pathway and pathogenic variants in 22 of these genes have been linked to a neurodevelopmental disorder. Common symptoms include early-onset and treatment-resistant epilepsies, developmental and cognitive impairment, movement disorders, behavioral and psychiatric comorbidities and structural malformations of internal organs.

In the first part of this thesis, we investigated how common monogenic epilepsies are at a tertiary epilepsy center and how often genetic testing enables precision therapy approaches. Patients born from 2006-2011 and followed at the Danish Epilepsy Center in 2015 were offered stepwise genetic testing; whole exome sequencing followed by single nucleotide polymorphism array if patients remained genetically unsolved. The majority of the children had focal epilepsy or a multifocal DEE while 10% were diagnosed with a genetic generalized epilepsy. A genetic diagnosis could be reached in >50% and based on the genetic findings the treatment could potentially be tailored in 50% of the genetically diagnosed children. Treatment was adjusted in 34/56 (60%); > 50% reduction in seizure burden was reported in 30/32 (93%) while only 4/30 (12%) became seizure-free. Satisfactory seizure control with alternative treatments was obtained prior to genetic diagnosis in 12/56 (40%) patients which prevented further treatment adjustments. The diagnostic yield was particularly high amongst patients with onset of seizures before the second year of life. A GPI-anchoring disorder was detected in four patients (two males with a PIGA and two females with PIGN- and PIGT-related disorder, respectively).

The second part of this thesis, was based on patients diagnosed with a GPI anchoring disorder. The four patients identified in the first part of the thesis, together with those identified through different matchmaking strategies, were piled into gene specific study cohorts. These cohorts were used to further characterize the phenotypical spectrum including the epileptology, to explore the causes of early demise, to explore genotype-phenotype correlations and to investigate the role of vitamin B6 as precision therapy in genetically confirmed cases with a GPI anchoring disorder.

PIGA is involved in first step of the GPI anchor biosynthesis pathway and catalyzes the transfer of N-acetylglucosamin to a phospholipid. We studied a cohort of 76 patients with PIGA encephalopathy and expanded the phenotypical spectrum with a pure neurological phenotype to the mild end of the spectrum and a Fryns syndrome–like phenotype at the severe. Most had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. The median age at death was two years and more than half of them died of respiratory failure (15/30, 50 %) or possible sudden unexpected death in epilepsy (3/30, 10 %) in early childhood. The PIGA-specific mortality rate/1000 person-years was 44.9/1000 person-years (95 %, CI 31.4-64.3).

PIGN encodes phosphoethanolamine transferase I. We identified 26 unpublished patients with PIGN-related epilepsy. This encephalopathy was associated with a wide spectrum of epilepsy phenotypes ranging from (focal, generalized and combined focal and generalized) DEEs to intellectual disabilities with epilepsy (ID+E). Those with PIGN-related ID+E had a later age of seizure onset, were more likely to achieve seizure freedom and had a better cognitive outcome than the PIGN-related DEEs.

PIGT encodes the GPI transamidase, a pentameric complex that t...
ForlagSyddansk Universitet
Antal sider81
StatusUdgivet - 24 jun. 2022


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