Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant

Abstract

Previous reports have described a spectrum of clinical phenotypes in patients with MED25 pathogenic variants. One specific phenotype is the Basel-Vanagaite-Smirin-Yosef syndrome, which is a rare, autosomal recessive disorder characterized by a wide range of symptoms including eye abnormalities, cardiac abnormalities, palatal abnormalities, intellectual disability, and epilepsy. Although epilepsy appears to be common, the electroclinical phenotypes of patients with Basel-Vanagaite-Smirin-Yosef syndrome have not been well described. Here, we report 3 Basel-Vanagaite-Smirin-Yosef syndrome patients from 2 families of Lebanese descent with a homozygous MED25 founder variant from Alberta Children's Hospital, Calgary, Alberta. We describe in detail electroclinical phenotypes in each of these 3 patients. These patients developed seizures with onset between 2 and 3 years of age, multifocal and generalized discharges, as well as photoparoxysmal responses on electroencephalogram. We review the relevance of these epilepsy findings in the context of other published reports of Basel-Vanagaite-Smirin-Yosef syndrome.

The MED25 gene encodes a component of the Mediator (MED) complex. The Mediator interacts with transcriptional activators and repressors and is required for the regulated transcription of most RNA polymerase II–dependent genes. ¹ MED25 homozygous pathogenic variants were shown to cause Basel-Vanagaite-Smirin-Yosef syndrome, ² an exceedingly rare autosomal recessive conditions with currently only 22 patients described. ³ A MED25 homozygous variant was first linked to 7 individuals in a large family from 3 consanguineous unions presenting with intellectual disability, neuropsychological problems, and facial dysmorphia. ⁴ Subsequently, another MED25 homozygous variant was linked to 7 individuals in 4 unrelated Israeli families with autosomal recessive intellectual disability, eye and palatal abnormalities, cardiac abnormalities, microcephaly, and thin corpus callosum. Since then, several smaller case series and case reports have demonstrated that patients with MED25 homozygous pathogenic variants have a variety of systemic symptoms. ³ It is unclear whether there is any clear genotype-phenotype correlation. However, intellectual disability appears to be universal, and epilepsy was present in 10 of 21 patients. In mining our clinical epilepsy registry, we identified 3 patients with a MED25 homozygous pathogenic variant with a diagnosis of Basel-Vanagaite-Smirin-Yosef syndrome. This is a recurrent founder variant seen in several Lebanese families in the Alberta Children's Hospital. Our experience regarding this variant has previously been published.^5,6 Below, we report on their clinical phenotypes with an emphasis on the description of their epilepsies.

Methods

The Pediatric Epilepsy Outcome-Informatics Project was implemented on January 1, 2016, by the Children's Comprehensive Epilepsy Program at the Alberta Children's Hospital with a vision to provide comprehensive clinical care, quality improvement, and research that leads to improved outcome and education for all stakeholders in a manner that optimizes societal resources. ⁷ The project includes utilization of standardized clinical note with common clinical data elements, point of care data entry, near-time data analysis, and availability of outcome dashboards. The clinical note was used as standard of care by epileptologists and nurses in the Neurology service at the Alberta Children’s Hospital at clinical encounters as part of patient's electronic health records. Clinical data elements included seizure description (duration, frequency, semiology, epilepsy diagnoses), treatment (antiseizure medications, side effects, nonmedication therapies), and psychological comorbidities. The patient data are then aggregated, analyzed, and then presented as population- and patient-specific dashboards by Data and Analytics (Alberta Health Services) and is available to clinicians at the point of care.

Using the outcome dashboard, we identified 4 epilepsy patients with MED25 pathogenic variants. Two patients (N1, N2) from the same family and 1 patient (N3) from an unrelated family gave consent to have their clinical information published. One family did not provide consent to publication.

Interpretation of electroencephalography and report generation were performed by epileptologists from the Alberta Children's Hospital and is in accordance with the rigorous standards set forth by the Canadian Society of Clinical Neurophysiologists. Classification of seizure types was in keeping with the recent updated classification of epileptic seizures from the International League Against Epilepsy (ILAE). ⁸ Interpretation and classifying genetic variants were performed as per the American College of Medical Genetics and Genomics (ACMG) guidelines. ⁹

Case Series

Case 1 (N1)

Patient N1 is a 10-year-old female of Lebanese descent, and she was born to a 36-year-old mother via cesarean section at term. She was seen by pediatric neurology at 4 months of age, and her head circumference was around 40th to 50th percentile. General examination revealed bilateral scalloping of the temples, brittle hair, protuberant large tongue, and externally rotated and flat ears. Neurologic examination showed significant axial hypotonia, appendicular hypertonia, and normal deep tendon reflexes. Other medical conditions include bilateral Duane syndrome, sleep-disordered breathing, systemic hypertension, nephrocalcinosis, hypocalcemia, and gastroesophageal reflux. Developmentally, she did not speak any words and was nonambulatory. She is able to roll from prone to side, sit independently, and take steps with support. She can hold objects but does not have clear hand preference. She expresses discomfort with facial expression and sounds. Detailed neuropsychological assessment was not performed because of lack of patient's ability to engage with the testing. Research whole exome sequencing performed at the University of Calgary revealed a MED25 c.377A>T p.Asp126Val homozygous pathogenic variant. The patient was also found to have SLC34A1 p.Ser424Leu homozygous pathogenic variant of uncertain significance associated with hypophosphatemic nephrolithiasis and osteoporosis syndrome. She was given a diagnosis of Basel-Vanagaite-Smirin-Yosef syndrome. Magnetic response imaging (MRI) of the brain performed at 2 months of age was normal.

A surveillance routine electroencephalography (EEG) performed at the age of 13 months revealed rare right temporal spikes and intermittent right posterior slowing. EEG at 3 years of age showed independent spikes recorded in the left and right parietal head regions that were activated in sleep, as well as infrequent generalized epileptiform discharges. Photoparoxysmal response was detected, most prominently at 11-Hz stimulation inducing generalized spike wave discharges. This was blocked by orange, red, blue, and green filters. Her first epileptic seizure was at 3 years 5 months of age and was described as focal preserved consciousness seizure with clonic of the face. She later developed frequent generalized myoclonic seizures. Other event types included staring spells and laughing spells that were deemed nonepileptic (behavioral) because of lack of ictal correlate on the EEG. Semiologically, the laughing spells did not resemble gelastic seizures. She was started on levetiracetam and clonazepam. At 6 years of age, EEG showed frequent multifocal and generalized discharges with epochs of spike wave activation in sleep. The patient eventually developed side effects to both levetiracetam (withdrawn, hallucination) and clonazepam (sedation), and the family declined to continue antiseizure medication. EEG performed at 9 years of age showed frequent generalized epileptiform discharges with photoparoxysmal responses most prominently at 18-Hz stimulation.

Case 2 (N2)

Patient N2 is a 20-year-old girl, older sibling of N1. Neurologically, she has global developmental delay, and examination revealed dysmorphia, hypotonia, and normal deep tendon reflexes. Her medical diagnoses included closed ventricular septal defect, short stature, clubfeet, hypercalcinuria, nephrocalcinosis congenital cataracts, retinal detachments, and glaucoma. At 17 years of age, she sits independently and requires a walker to ambulate. She has no clear hand preference. She uses an eye-gaze, “yes-no” communication device. She understands 1-step commands. Her clinical findings are in keeping with Basel-Vanagaite-Smirin-Yosef syndrome, and she shares the same homozygous MED25 variant as her sister (N1). Brain MRI at 12 years of age demonstrated patchy periventricular T2 hyperintensities and mild ventricular dilatation (Figure 1A). Spine MRI revealed a stable small thoracic (T1-T11) syrinx.

Figure 1.

(A) Axial FLAIR Image Above the Level of the Basal Ganglia of Patient N2 Demonstrating Patchy Periventricular FLAIR Hyperintensity. (B) Epoch of EEG of Patient N2 at 11 Years of Age Demonstrating Robust Photoparoxysmal Response. Photic Stimulation at 10 Hz and 16 Hz Produced Occipital Predominant Diffusely Distributed Polyspikes and Spikes. Sensitivity 10 μV/mm; Time Base, 30 mm/s. FLAIR, Fluid-Attenuated Inversion Recovery.

Onset of epilepsy was at 3 years of age. Prolonged focal impaired consciousness seizures and generalized tonic-clonic seizures were documented. Other event types included episodic laughter and screaming that did not have EEG ictal correlate, and thus these were deemed nonepileptic (behavioral) in nature, similar to her sister (N1). The patient was started on levetiracetam. EEG demonstrated focal left and right parietal and generalized epileptiform discharges as well as a photoparoxysmal response at multiple frequencies (Figure 1B). Although the seizures were initially controlled on levetiracetam, the family declined to continue antiseizure medications after the age of 17 years because of adverse effects. This led to a recurrence of monthly generalized tonic-clonic seizures.

Case 3 (N3)

Patient N3 is a 5-year-old girl, born at term to a mother with gestational diabetes. Both parents are of Lebanese descent. She had a history of bilateral congenital cataracts, diagnosed at 9 months of age. She had a moderate atrial septal defect and bilateral metatarsus adductus type 1, which were managed conservatively. Developmentally, she is able to ambulate independently with bilateral ankle foot orthoses at 2.5 years of age. Fine motor skills were normal. She communicates by babbling and responds to her name. She appears social with adults.

At 2 years of age, she had a bilateral tonic-clonic seizure—unknown whether focal or generalized in the context of a urinary tract infection. EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters. Four months after her first seizure, she had an unprovoked focal impaired consciousness seizure. She was seizure-free since levetiracetam was started.

Brain MRI showed subtle T2 hyperintense signals within the subcortical white matter in the left frontal lobe and diffuse scattered prominent perivascular spaces bilaterally.

Patient N3 has a second cousin who has homozygous variants in the MED25 gene, identified by whole exome sequencing, but this cousin did not have epilepsy. A single-nucleotide polymorphism microarray identified at least 2.34% of haploid genome exhibiting an absence of heterozygosity, including a region of chromosome 19 encompassing the MED25 gene. A clinical diagnosis of Basel-Vanagaite-Smirin-Yosef syndrome was made, and targeted sequencing of the MED25 gene revealed that patient N3 is homozygous for the p.Asp126Val pathogenic variant.

Discussion

In this case series, we described 3 patients from 2 unrelated Lebanese families in Calgary, Alberta, with the same MED25 c.377A>T p.Asp126Val likely pathogenic variant. Their clinical phenotypes, specifically their craniofacial anomalies, match the phenotype of Basel-Vanagaite-Smirin-Yosef syndrome. ³ We provided detailed data on their epilepsies, which was unclear in previous series of patients with Basel-Vanagaite-Smirin-Yosef syndrome. We also provide a summary of our 3 patients and Basel-Vanagaite-Smirin-Yosef syndrome patients previously reported in the literature (Table 1).

Table 1.

A Comparison of the Clinical Features of the 3 Basel-Vanagaite-Smirin-Yosef Syndrome Patients in This Report and Those Previously Reported in the Literature.

	Patient 1	Patient 2	Patient 3	Figueiredo et al (2015)	Basel-Vanagaite et al (2015)	Nair et al (2018)	Nair et al (2019)	Haynes et al (2020) Patient 1	Haynes et al (2020) Patient 2	Haynes et al (2020) Patient 3	Maini et al (2021)
Number of patients				7	7	1	2				2
MED25 variant	c.377A>T p.D126V homozygous	c.377A>T p.D126V homozygous	c.377A>T p.D126V homozygous	c.418C $>$ T p.R140W homozygous	c.116A $>$ G p.Y39C homozygous	c. $518\mathrm{T}>\mathrm{C}$ p.I173T homozygous	c. $518\mathrm{T}>\mathrm{C}$ p.I173T homozygous	c.316G $>$ A p.G106R and c.1165delp.L389Sfs*35	c.394C $>$ T p.R132C homozygous	c.377A>T p.D126V homozygous	c. 1778 1779delAG p.Q593Rfs? Homozygous
Seizure types	Focal, myoclonic seizures	Focal, generalized tonic-clonic	Focal, bilateral tonic-clonic	NA	+, details NA	+, details NA	No seizures	+	Tonic, myoclonic seizures	Myoclonic seizures	Myoclonic seizures
Non epileptic events	Staring and laughing spells	Screaming, laughing spells	-	NA	NA	NA	-	NA	NA	NA	NA
Interictal EEG findings	Multifocal IED, generalized IED, generalized slowing	Focal IED, generalized IED, generalized slowing	Multifocal IED, generalized IED, generalized slowing	NA	NA	Focal IED	-	NA	NA	NA	NA
Photoparoxysmal response	+	+	$+$	NA	NA	NA	-	NA	NA	NA	NA
Antiseizure medication	Levetiracetam, clonazepam	Levetiracetam	Levetiracetam	NA	Valproate	NA, seizures well controlled	-	NA	NA	NA	Topiramate, oxcarbazepine, levetiracetam
Developmental delay/ID	+	+	+	+	+	+	+	+	+	+	+
Absent/delayed speech	+	+	$+$	$+$	+	+	+	+	+	+	+
Short stature	+	+	-	NA	+	+	-	+	-	-	+
Brain MRI	Normal	Patchy periventricular T2 hyperintensities and mild ventricular dilatation	Macrocephaly, prominent perivascular spaces, subtle T2 hyperintensities in the subcortical white matter in the left frontal lobe	NA	T2 hyperintensity in the frontal and occipital periventricular white matter, thin/absent corpus callosum in some patients	Frontotemporal predominant cerebral atrophy	Normal	Agenesis of corpus callosum, polymicrogyria, acute ischemia in the right frontal and parietal subcortical white matter, and corona radiata	Resolved cysts, otherwise normal	T2 hyperintensity in the right occipital lobe	Thin corpus callosum, perisylvian polymicrogyria, dilated lateral ventricles
Hypotonia	+	+	$+$	NA	+	+	+	+	-	-	+
Ocular abnormalities	Duane syndrome	Congenital cataracts, retinal detachments, glaucoma	Congenital cataracts	NA	Congenital cataract, ptosis	-	-	Mild microcornea, optic disc cupping, blepharophimosis	Cataracts, endophthalmos	Strabismus	Strabismus, hyperpigmented fundus oculi, macular abnormalities
Congenital heart disease	-	Ventricular septal defect	Atrial septal defect	NA	Atrial septal defect, ventricular septal defect	Atrial septal defect	Coarctation of aorta and ventricular septal defect in 1 patient	Patent ductus arteriosus, pulmonary hypertension, dilated, and hypertensive right ventricle	-	-	Patent foramen ovale, patent ductus arteriosus
Urogenital abnormalities	Nephrocalcinosis	Nephrocalcinosis, hypercalcemia	$-$	NA	Hypospadias, hydronephrosis, clitoromegaly	-	$-$	Hypospadias	Hypospadias, bifid scrotum	$-$	-
Skeletal anomalies	-	Bilateral hip subluxation, bilateral club feet, mild scoliosis	Bilateral metatarsus adductus type 1	NA	Kyphosis, scoliosis, pectus carinatum	-	-	Contractures of proximal interphalangeal joints	+, details NA	$-$	Scoliosis
Microcephaly	NA	NA	-	NA	+	+	-	$+$	+	-	-
Dysmorphia	Scalloping of temples, brittle hair, protuberant large tongue, externally rotated and flat ears	+, details NA	Hypertelorism, prominent epicanthal folds, wide and depressed nasal root, low-set ears, thin upper limb, nevus flammeus in the forehead and back of neck	Broad nasal tip, short philtrum, thin upper lip, high forehead	Nevus flammeus, hypertelorism, downslanting palpebral fissures, low-set ears, short philtrum, cleft palate, exaggerated cupid's bow	Sparse hair, high forehead, bilateral epicanthal folds, broad nasal tip, flat and short philtrum, thin upper limb, large mouth	High forehead, sparse scalp hair and eyebrows, flat nasal bridge with broad nasal tip, hypertelorism, short philtrum, large mouth with a thin upper lip, cleft palate, bilateral single palmar crease	Bilateral cleft lip and palate, micrognathia, small deep-set eyes, down-slanting palpebral fissures, broad nasal bridge, glossoptosis, decreased nasolabial folds, down-turned mouth	Cleft palate, mild micrognathia, telecanthus with borderline hypertelorism, single palmar flexion crease on the left	Cleft palate, frontal bossing, synophrys, triangular-shaped face, prominent nose with hypoplastic alae nasi, coarse facial features, small widely spaced teeth	High forehead, epicanthus, down-slanting palpebral fissures, broad and overhanging nasal tip, downturned corners of mouth, single palmar crease

Abbreviations: EEG, electroencephalography; ID, intellectual disability; IED, interictal epileptiform discharge; MRI, magnetic resonance imaging; NA, not available.

The epilepsy phenotypes between the 3 patients were remarkably similar. Onset of seizure was between 2 and 3 years of age, and seizures were both focal and generalized in onset. In terms of seizure control, levetiracetam seemed to be very effective in the case of N3, but unclear in the case of N1 and N2 because of lack of adherence to antiseizure medications. EEG in all 3 patients demonstrated multifocal and generalized discharges and photoparoxysmal responses. Photoparoxysmal response or photosensitivity refers to the occurrence of spikes or spike and wave discharges during intermittent photic stimulation. ¹⁰ Photoparoxysmal response is found in 0.6% to 30% of patients with epilepsies. ¹¹ However, the pathogenesis of photosensitivity is still poorly understood. ¹² Three susceptibility loci mapped to chromosome 6p21, 13q31, and 7q32, termed photoparoxysmal response 1-3, respectively, have been described. ¹² Given that all 3 patients with the same MED25 c.377A>T p.Asp126Val homozygous variant demonstrated photoparoxysmal response, it raises the possibility that the Mediator complex may shed light on the pathophysiology of photoparoxysmal response in patients with epilepsy. Photosensitivity can occur in epilepsy syndromes such as idiopathic generalized epilepsies, epilepsy with eyelid myoclonia, myoclonic epilepsy of infancy, and photosensitive occipital lobe epilepsy. In addition, photosensitivity is seen in patients with developmental and epileptic encephalopathies such as Lennox-Gastaut syndrome, Dravet syndrome, and various progressive myoclonus epilepsies. Photosensitivity has even been shown to provoke epileptic spasms. ¹³ Our patients, presenting with combined generalized and focal epilepsy, did not demonstrate any fixation-off phenomenon, and their EEGs showed a combination of multifocal and generalized epileptiform discharges, features that did not fit neatly in any of the aforementioned photosensitive epilepsy syndromes. ¹⁴

Epilepsy appears to be a common finding in the published literature cases of MED25 homozygous variants. In the Israeli case series of 7 individuals with MED25 c.116A>G p.(Tyr39Cys) variant described by Basel-Vanagiate, 4 of 7 patients had seizures. ² Valproate was effective in managing seizures in 1 patient. Seizures were not present in the Brazilian case series of 7 individuals in a large consanguineous family with MED25 c.418C>T p.Arg140Trp variants. ⁴ One patient with MED25 c.518T>C p.Ile173Thr homozygous variant and ADCK3 c.1534C>T p.Arg512Trp homozygous variant presented with seizures that were well controlled, and EEG showed left temporal epileptiform discharges. ¹⁵ However, the relative contribution of MED25 or ADCK3 variants to the epilepsy phenotype in this patient is unknown because variants in either gene are associated with epilepsy. Two siblings with the MED25 c.518T>C p.Ile173Thr variant did not present with seizures, but this may be due to young age at description (1 and 3 years of age). ¹⁶ Three patients with MED25 compound heterozygous variants c.1165delC and c.316G>A, c.394C>T homozygous variants, and c.377A>T homozygous variants presented with epilepsy, with at least 1 that was drug-resistant. ¹⁷ One patient with the MED25 c.1778_179delAG p.Gln593Argfs homozygous frameshift variant developed bilateral perisylvian polymicrogyria and myoclonic seizures that were controlled on levetiracetam. ³

Variants in other mediator complex subunits have been associated with genetic and neurologic diseases ¹⁸ These subunits include MED1, MED12, MED12L, MED13, MED13L, MED17, MED20, MED23, MED25, MED27, and CDK8. Intellectual disability appears to be a common feature among pathogenic variants in these genes. Pathogenic variants in MED12, MED12L, MED13, and MED13L, which encode for the CDK8-Kinase mediator module, are associated with heterogeneous clinical presentations including craniofacial and cardiac anomalies as well as brain malformations. ¹⁸ Epilepsy has been found in patients with pathogenic variants in the genes MED17 ¹⁹ and MED23. ²⁰ One report identified efficacy of the ketogenic diet in the treatment of drug-resistant epilepsy in a patient with MED23 pathogenic variant. Interestingly, MED23 may be a regulator of energy homeostasis, and liver-specific knockout of Med23 in mice led to reduced gluconeogenesis. ²¹ Thus, it is hypothesized that ketogenic diet may provide an alternative fuel source for the brain in patients with MED23 pathogenic variants.

Conclusion

Epilepsy is a common finding in patients with Basel-Vanagaite-Smirin-Yosef syndrome. We revealed that the electroclinical characteristics of their epilepsy demonstrated remarkable similarity, such as the presence of multifocal and generalized discharges and photoparoxysmal response. This is the first detailed description of the epilepsy phenotype of Basel-Vanagaite-Smirin-Yosef syndrome patients. Systemic features overlapped with patients described in previous reports.