Fixation-off sensitivity

Inspired by a patient

Wang X, Zhang Y, Zhang W, Shen C, Jin L, Chen B, Jiang Z, Tao JX, Liu Y. The electroclinical features of idiopathic generalized epilepsy patients presenting with fixation-off sensitivity. Epileptic Disord. 2018 Dec 1;20(6):479-489. doi: 10.1684/epd.2018.1021. PMID: 30530446.

Abstract

To determine the electroclinical features of fixation-off sensitivity (FOS) in patients with idiopathic generalized epilepsy (IGE). We searched the EEG database using the terms "fixation-off sensitivity" and "idiopathic generalized epilepsy" over a four-year period from March 2014 to April 2018 in the Xijing Hospital, Xi'an, China. FOS was evaluated according to the technique proposed by Panayiotopoulos. Photic stimulation procedure and neuropsychological testing were performed during video-EEG monitoring. FOS was observed in eight patients with several different IGE syndromes, including four with eyelid myoclonia/Jeavons syndrome, two with juvenile myoclonic epilepsy, one with photosensitivity epilepsy, and one with epilepsy with generalized tonic-clonic seizures only. FOS was associated with seizures in five patients manifesting with eyelid myoclonic, myoclonic, and myoclonic-tonic-clonic seizures, and eyelid myoclonic status. FOS coexisted with photosensitivity in six patients as independent EEG features. Neuropsychological testing revealed transitory cognitive impairments associated with FOS. FOS is associated with several different IGE syndromes and may coexist with photosensitivity in the same patient as independent EEG features. FOS may be associated with both clinical seizures and cognitive impairments. Intermittent photic stimulation and registration of different eye conditions with and without fixation will aid the study of the dynamics of the visual system in epilepsy patients. [Published with video sequences on www.epilepticdisorders.com].

Das Pektezel L, Tezer FI, Saygi S. Electroclinical Presentations of Fixation-off Sensitivity in Adults With Symptomatic Epilepsy. J Clin Neurophysiol. 2021 Jul 6. doi: 10.1097/WNP.0000000000000880. Epub ahead of print. PMID: 34280943.

Abstract

Purpose: Fixation-off sensitivity (FOS) is a discharge pattern on EEG that occurs owing to the loss of central vision or fixation. Knowledge regarding the relationship between FOS and symptomatic epilepsy is limited. Therefore, we aimed to evaluate the electroclinical features of FOS in adult patients with symptomatic epilepsy. 

Methods: Outpatient video-EEG records of the Hacettepe University Faculty of Medicine were reviewed from 2009 to 2019. Patients aged >18 years with symptomatic epilepsy with a FOS pattern were included. Demographic, clinical, EEG, and neuroimaging data were retrospectively evaluated from an electronic database and patient files. 

Results: Eight patients (50% female) were included in this study; seven (87%) had refractory epilepsy. Prominent risk factors were family history of epilepsy in five patients and prenatal/natal insult in four patients. Notable MRI signs included cortical developmental malformation, posterior gliosis, and frontoparietal porencephalic cyst. The FOS pattern was generalized with posterior emphasis in two patients and lateralized or localized in six patients: frontocentroparietal (n = 1) and temporoparietooccipital (n = 5). Fixation-off sensitivity discharges were found to be increased by hyperventilation and decreased by drowsiness and sleep in 50% of patients. Fixation-off sensitivity disappeared in one patient with good seizure control. 

Conclusions: In this study, the disappearance of FOS in an epileptic patient with a structural lesion and detection of FOS activity related to a frontoparietal porencephalic cyst were remarkable. Family history of epilepsy was also substantially high. Our results indicate that the underlying mechanism of FOS is much more complicated than previously thought.

Dede HÖ, Bebek N, Emekli S, Baykan B, Yapıcı Z, Gökyiğit A. The clinical significance and electrophysiologic findings of fixation-off and closure of the eyes sensitivity: Data from a prospective unselected population. Epilepsy Res. 2021 Feb;170:106541. doi: 10.1016/j.eplepsyres.2020.106541. Epub 2020 Dec 25. PMID: 33387799.

Abstract

Purpose: Electroencephalography (EEG) findings related to the eye-closing motion can be defined in two ways: 'sensitivity to eyes closed' (SEC) and 'eye closure sensitivity (ECS).' Fixation-off sensitivity (FOS) is a different phenomenon induced by the elimination of central vision/fixation. The purpose of our study was to determine the frequencies of SEC, ESC, and FOS, and to analyze the relationship between eyes closure and the fixation-off phenomenon and clinical importance in an unselected population. 

Methods: We prospectively evaluated 200 routine interictal EEGs by adding a standardized FOS examination protocol between June and September 2015. Goggles covered with semitransparent tape were used to evaluate FOS. We determined SEC when the epileptiform discharges appeared during eye closure and continued during the eye closed state, whereas ECS was defined as transient epileptic abnormalities following the closure of the eyes lasting for 1-4 sec. The patients were evaluated in terms of demographic characteristics, clinical features, and the relationship between SEC, ECS, and FOS. 

Results: We detected SEC in 9 (4.4 %) and ECS in 11 (5.4 %) patients. FOS was detected in four (44.4 %) of the patients who showed SEC, all of whom had occipital epileptiform discharges. A statistically significant correlation was found between FOS and treatment resistance in the SEC group (p < 0.001). In logistic regression analysis, occipital lobe epilepsy (p < 0.001) and age under 20 years (p = 0.004) were found as risk factors for SEC. Another interesting finding was the suppression of epileptic discharges with fixation-off in three of 11 patients with ECS. 

Conclusions: According to the results of our study, FOS is related to treatment resistance. Therefore, FOS should be evaluated in patients with SEC.

Lo Barco T, Kaminska A, Solazzi R, Cancés C, Barcia G, Chemaly N, Fontana E, Desguerre I, Canafoglia L, Hachon Le Camus C, Losito E, Villard L, Eisermann M, Dalla Bernardina B, Villeneuve N, Nabbout R. SYNGAP1-DEE: A visual sensitive epilepsy. Clin Neurophysiol. 2021 Apr;132(4):841-850. doi: 10.1016/j.clinph.2021.01.014. Epub 2021 Feb 3. PMID: 33639450.

Abstract

Objective: To further delineate the electroclinical features of individuals with SYNGAP1 pathogenic variants.

Methods: Participants with pathogenic SYNGAP1 variants and available video-electroencephalogram (EEG) recordings were recruited within five European epilepsy reference centers. We obtained molecular and clinical data, analyzed EEG recordings and archived video-EEGs of seizures and detailed characteristics of interictal and ictal EEG patterns for every patient.

Results: We recruited 15 previously unreported patients and analyzed 72 EEGs. Two distinct EEG patterns emerged, both triggered by eye closure. Pattern 1 (14/15 individuals) consisted of rhythmic posterior/diffuse delta waves appearing with eye-closure and persisting until eye opening (strongly suggestive of fixation-off sensitivity). Pattern 2 (9/15 individuals) consisted of diffuse polyspike-and-wave discharges triggered by eye closure (eye-closure sensitivity). Both patterns presented in 8/15. Including archived video-EEG clips of seizures from 9/15 patients, we analyzed 254 seizures. Of 224 seizures experienced while awake, 161 (72%) occurred at or following eye closure. In 119/161, pattern 1 preceded an atypical absence, myoclonic seizure or myoclonic absence; in 42/161, pattern 2 was associated with eyelid myoclonia, absences and myoclonic or atonic seizures.

Conclusions: Fixation-off and eye closure were the main triggers for seizures in this SYNGAP1 cohort.

Significance: Combining these clinical and electroencephalographic features could help guide genetic diagnosis.

Nagele EP, Gutierrez CA, Achieng E, Hopp JL. Fixation-off sensitivity in focal epilepsy due to posterior quadrantic dysplasia. Neurology. 2020 Sep 29;95(13):597-598. doi: 10.1212/WNL.0000000000010621. Epub 2020 Aug 11. PMID: 32788240.

Lee S, Oh DA, Bae EK. Fixation-off sensitivity in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Seizure. 2019 Jan;64:6-7. doi: 10.1016/j.seizure.2018.11.010. Epub 2018 Nov 22. PMID: 30500480.

 

Mal de debarquement

Inspired by a patient's mother

General Discussion

Mal de debarquement (MDD) is a rare and poorly understood disorder of the vestibular system that results in a phantom perception of self- motion typically described as rocking, bobbing or swaying. The symptoms tend to be exacerbated when a patient is not moving, for example, when sleeping or standing still. Studies have shown that a brief period of these symptoms is common in healthy individuals after prolonged episodes of passive motion, normally lasting seconds to three days. However, in MDD, significant balance impairment can persist for months to years. Symptoms may diminish in time or may reappear spontaneously or after another exposure. The most common triggers are water-based activities such as ocean cruising. Less common triggers include airplane travel, extended landing travel and sleeping on water beds. Other common complaints of patients with MDD include a sensation of uneven ground below their feet while walking, or feeling as if they are still on a boat. It is rare for MDD patients to have true rotational vertigo or motion sickness.

Signs & Symptoms

The primary symptom is the persistence of a sense of motion and rocking. Some patients may experience fatigue, mood changes and confusion. Imbalance is a common complaint. Symptoms often increase when exposed to fast movements, flickering lights and grocery store aisles. There may be transient improvement in symptoms with re-exposure to passive motion, for example, riding in cars or trains. After completion of the trip, however, the symptoms tend to recur. 

Studies have shown that the length of time one is exposed to a motion experience does not determine the severity or duration of the syndrome, but most typical cases are triggered by day trips lasting several days.

Causes

The true cause behind MDD is still unknown. MDD likely results from the body’s balance system inadequately processing and adapting to multiple sensory inputs (visual, vestibular, proprioceptive and cognitive) from the environment once the stimulus (trigger) has ended. It is as yet undetermined as to the cause of the balance system’s inability to appropriately compensate and adapt. How or why this happens remains a mystery.

Affected Populations

The majority of people affected are adult females, although there have been reports of males having the diagnosis. Patients with migraine may have any increased susceptibility through unknown mechanisms.

Related Disorders

Benign paroxysmal positional vertigo (BPPV) is a common cause of dizziness, especially among the elderly. It comes about as a result of a movement of the head. Under normal conditions, calcium particles are attached to a specific location within the inner ear. As a result of injury or degeneration, these calcium particles clump together causing a sudden and brief episode of dizziness. (For more information on this disorder, choose “BPPV” as your search term in the Rare Disease Database.)

Meniere’s disease is a disorder characterized by periodic episodes of vertigo or dizziness; fluctuating, progressive hearing loss; tinnitus; and a sensation of fullness or pressure in the ear.

Diagnosis

The diagnosis of MDD still remains mostly clinical. As such, the history is very important. Persistent “dizziness” after an ocean cruise, a sailing trip, a prolonged airplane flight or a cross-country road trip is highly suggestive of MDD. Vestibular function tests in patients with MDD have been normal or nonspecific in their abnormality. These tests are important in excluding other etiologies for the patient’s symptoms.

Standard Therapies

Treatment

MDD is very difficult to treat, with little effectiveness of most treatments. Clonazepam at low doses once or twice a day has shown improvement in patients. Higher doses were not proven to be effective. Vestibular rehabilitation has shown effectiveness in a small number of patients.

Investigational Therapies

A small study from Dai et, al. (see References below) reported that using a full-field visual stimulus while the head was rolled resulted in >50% improvement in both subjective and objective symptoms. These findings are encouraging but need to be reproduced. Patients who do recover may be susceptible to recurrences of increased duration.

https://rarediseases.org/rare-diseases/mal-de-debarquement/

Chen Y, Cha YH, Gleghorn D, Doudican BC, Shou G, Ding L, Yuan H. Brain network effects by continuous theta burst stimulation in Mal de Débarquement Syndrome: simultaneous EEG and fMRI study. J Neural Eng. 2021 Oct 20. doi: 10.1088/1741-2552/ac314b. Epub ahead of print. PMID: 34670201.

Abstract

Objective: Heterogeneous clinical responses to treatment with non-invasive brain stimulation are commonly observed, making it necessary to determine personally optimized stimulation parameters. We investigated neuroimaging markers of effective brain targets of treatment with continuous theta burst stimulation (cTBS) in Mal de Débarquement Syndrome (MdDS), a balance disorder of persistent oscillating vertigo previously shown to exhibit abnormal intrinsic functional connectivity.

Approach: Twenty-four right-handed, cTBS-naive individuals with MdDS received single administrations of cTBS over one of three stimulation targets in randomized order. The optimal target was determined based on the assessment of acute changes after the administration of cTBS over each target. Repetitive cTBS sessions were delivered on three consecutive days with the optimal target chosen by the participant. EEG was recorded at single-administration test sessions of cTBS. Simultaneous EEG and fMRI data were acquired at baseline and after completion of 10-12 sessions. Network connectivity changes after single and repetitive stimulations of cTBS were analyzed.

Main results: Using electrophysiological source imaging and a data-driven method, we identified network-level connectivity changes in EEG that correlated with symptom responses after completion of multiple sessions of cTBS. We further determined that connectivity changes demonstrated by EEG during test sessions of single administrations of cTBS were signatures that could predict optimal targets.

Significance: Our findings demonstrate the effect of cTBS on resting state brain networks and suggest an imaging-based, closed-loop stimulation paradigm that can identify optimal targets during short-term test sessions of stimulation.

Riley J, Gleghorn D, Doudican BC, Cha YH. Psychological assessment of individuals with Mal de Débarquement Syndrome. J Neurol. 2021 Sep 19. doi: 10.1007/s00415-021-10767-4. Epub ahead of print. PMID: 34541614.

Abstract

Objective: To report on the psychological, personality, and behavioral profiles of individuals with persistent Mal de Débarquement Syndrome (MdDS).

Materials and methods: Individuals with MdDS who participated in neuromodulation clinical trials between May 2013 and June 2019 completed a series of standardized psychological questionnaires and underwent the Structural Clinical Interview for DSM-IV-TR (SCID) for specific psychiatric diagnoses. All data reported are from baseline assessments prior to any study interventions. Scores were compared to population norms for adult women.

Results: Complete datasets were available for 55 women. Mean age of onset of MdDS was 49.0 ± 11.9 years (range 22-69 years) and median duration of illness of 22 months (6 months-20 years). SCID results were as follows: healthy (48.1%), any lifetime Major Depressive Disorder (35.2%, 7.4% current); any lifetime history of anxiety disorder (11.1%); any lifetime substance use disorders (18.5%, 0% current). Compared to population norms, the MdDS group scored significantly higher on the Patient Health Questionnaire-9 depression scale and the Generalized Anxiety Disorder 7 (GAD-7) anxiety scale, but only the GAD-7 correlated with symptom severity. The NEO-Five Factor Inventory for personality, Positive and Negative Affect Schedule, Behavioral Inhibition System/Behavioral Activation System Scale, and the Empathy Quotient metrics did not correlate with duration of illness. Disability assessed by the 12-item World Health Organization Disability Assessment Schedule 2.0 was 25.7 ± 6.7, comparable to reports for concussion. Disability correlated with severity of depression, anxiety, neuroticism, and affect but not to severity of MdDS.

Conclusions: Psychological profiles of MdDS relate to disability but not to duration of illness.

Cha YH, Ding L, Yuan H. Neuroimaging Markers of Mal de Débarquement Syndrome. Front Neurol. 2021 Mar 4;12:636224. doi: 10.3389/fneur.2021.636224. PMID: 33746890; PMCID: PMC7970001.

Abstract

Mal de débarquement syndrome (MdDS) is a motion-induced disorder of oscillating vertigo that persists after the motion has ceased. The neuroimaging characteristics of the MdDS brain state have been investigated with studies on brain metabolism, structure, functional connectivity, and measurements of synchronicity. Baseline metabolism and resting-state functional connectivity studies indicate that a limbic focus in the left entorhinal cortex and amygdala may be important in the pathology of MdDS, as these structures are hypermetabolic in MdDS and exhibit increased functional connectivity to posterior sensory processing areas and reduced connectivity to the frontal and temporal cortices. Both structures are tunable with periodic stimulation, with neurons in the entorhinal cortex required for spatial navigation, acting as a critical efferent pathway to the hippocampus, and sending and receiving projections from much of the neocortex. Voxel-based morphometry measurements have revealed volume differences between MdDS and healthy controls in hubs of multiple resting-state networks including the default mode, salience, and executive control networks. In particular, volume in the bilateral anterior cingulate cortices decreases and volume in the bilateral inferior frontal gyri/anterior insulas increases with longer duration of illness. Paired with noninvasive neuromodulation interventions, functional neuroimaging with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and simultaneous fMRI-EEG have shown changes in resting-state functional connectivity that correlate with symptom modulation, particularly in the posterior default mode network. Reduced parieto-occipital connectivity with the entorhinal cortex and reduced long-range fronto-parieto-occipital connectivity correlate with symptom improvement. Though there is a general theme of desynchronization correlating with reduced MdDS symptoms, the prediction of optimal stimulation parameters for noninvasive brain stimulation in individuals with MdDS remains a challenge due to the large parameter space. However, the pairing of functional neuroimaging and noninvasive brain stimulation can serve as a probe into the biological underpinnings of MdDS and iteratively lead to optimal parameter space identification.

 

 

 

MED13L-related intellectual disability

Inspired by a patient

Smol T, Petit F, Piton A, Keren B, Sanlaville D, Afenjar A, Baker S, Bedoukian EC, Bhoj EJ, Bonneau D, Boudry-Labis E, Bouquillon S, Boute-Benejean O, Caumes R, Chatron N, Colson C, Coubes C, Coutton C, Devillard F, Dieux-Coeslier A, Doco-Fenzy M, Ewans LJ, Faivre L, Fassi E, Field M, Fournier C, Francannet C, Genevieve D, Giurgea I, Goldenberg A, Green AK, Guerrot AM, Heron D, Isidor B, Keena BA, Krock BL, Kuentz P, Lapi E, Le Meur N, Lesca G, Li D, Marey I, Mignot C, Nava C, Nesbitt A, Nicolas G, Roche-Lestienne C, Roscioli T, Satre V, Santani A, Stefanova M, Steinwall Larsen S, Saugier-Veber P, Picker-Minh S, Thuillier C, Verloes A, Vieville G, Wenzel M, Willems M, Whalen S, Zarate YA, Ziegler A, Manouvrier-Hanu S, Kalscheuer VM, Gerard B, Ghoumid J. MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype. Neurogenetics. 2018 May;19(2):93-103. doi: 10.1007/s10048-018-0541-0. Epub 2018 Mar 6. PMID: 29511999. 

Abstract 

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition. 

Tørring PM, Larsen MJ, Brasch-Andersen C, Krogh LN, Kibæk M, Laulund L, Illum N, Dunkhase-Heinl U, Wiesener A, Popp B, Marangi G, Hjortshøj TD, Ek J, Vogel I, Becher N, Roos L, Zollino M, Fagerberg CR. Is MED13L-related intellectual disability a recognizable syndrome? Eur J Med Genet. 2019 Feb;62(2):129-136. doi: 10.1016/j.ejmg.2018.06.014. Epub 2018 Jun 27. PMID: 29959045. 

Abstract 

Introduction: MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients. 

Materials and methods: In the search for genetic aberrations in individuals with ID, two of the patients were identified by chromosomal microarray analysis, and five by exome sequencing. One of the individuals, suspected of MED13L-related intellectual disability, based on clinical features, was identified by Sanger sequencing. 

Results: All 8 individuals had de novo MED13L aberrations, including two intragenic microdeletions, two frameshift, three nonsense variants, and one missense variant. Phenotypically, they all had intellectual disability, speech and motor delay, and features of the mouth (open mouth appearance, macroglossia, and/or macrostomia). Two individuals were diagnosed with autism, and one had autistic features. One had complex congenital heart defect, and one had persistent foramen ovale. The literature was reviewed with respect to clinical and dysmorphic features, and genetic aberrations. 

Conclusions: Even if most clinical features of MED13L-related intellectual disability are rather non-specific, the syndrome may be suspected in some individuals based on the association of developmental delay, speech impairment, bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance. 

Yi Z, Zhang Y, Song Z, Pan H, Yang C, Li F, Xue J, Qu Z. Report of a de novo c.2605C > T (p.Pro869Ser) change in the MED13L gene and review of the literature for MED13L-related intellectual disability. Ital J Pediatr. 2020 Jul 9;46(1):95. doi: 10.1186/s13052-020-00847-y. PMID: 32646507; PMCID: PMC7350599. 

Abstract 

Background: MED13L-related intellectual disability is a new syndrome that is characterized by intellectual disability (ID), motor developmental delay, speech impairment, hypotonia and facial dysmorphism. Both the MED13L haploinsufficiency mutation and missense mutation were reported to be causative. It has also been reported that patients carrying missense mutations have more frequent epilepsy and show a more severe phenotype. 

Case presentation: We report a child with ID, speech impairment, severe motor developmental delay, facial deformity, hypotonia, muscular atrophy, scoliosis, odontoprisis, abnormal electroencephalogram (EEG), and congenital ureteropelvic junction obstruction (UPJO) combined with high ureter attachment. We used whole-exome sequencing (WES) to detect the genetic aberration of the child and found a de novo mutation, c.2605C > T (p.Pro869Ser), in the MED13L gene. Neither of her parents carried the mutation. Additionally, we review the literature and summarize the phenotypes and features of reported missense mutations. After reviewing the literature, approximately 17 missense mutations in 20 patients have been reported thus far. For 18 patients (including our case) whose clinical manifestations were provided, 100% of the patients had ID or developmental delay (DD). A total of 88.9, 83.3 and 66.7% of the patients had speech impairment, delayed milestones and hypotonia, respectively. A total of 83.3% of the patients exhibited craniofacial deformity or other dysmorphic features. Behavioral difficulties and autistic features were observed in 55.6% of the patients. Cardiac anomalies were seen in only 27.8% of the patients. Of these patients, 44.4% had epileptic seizures. Of the 17 mutations, 2 were located in the N-terminal domain, 8 were located in the C-terminal domain, and 1 was located in an α-helical sequence stretch. One of them was located in the MID domain of the MedPIWI module. 

Conclusions: We report a new patient with a reported missense mutation, c.2605C > T (p.Pro869Ser), who exhibited some infrequent manifestations except common phenotypes, which may broaden the known clinical spectrum. Additionally, by reviewing the literature, we also found that patients with missense mutations have a higher incidence of seizures, MRI abnormalities, autistic features and cardiac anomalies. They also have more severe ID and hypotonia. Our case further demonstrates that Pro869Ser is a hotspot mutation of the MED13L gene. 

Snijders Blok L, Hiatt SM, Bowling KM, Prokop JW, Engel KL, Cochran JN, Bebin EM, Bijlsma EK, Ruivenkamp CAL, Terhal P, Simon MEH, Smith R, Hurst JA; DDD study, McLaughlin H, Person R, Crunk A, Wangler MF, Streff H, Symonds JD, Zuberi SM, Elliott KS, Sanders VR, Masunga A, Hopkin RJ, Dubbs HA, Ortiz-Gonzalez XR, Pfundt R, Brunner HG, Fisher SE, Kleefstra T, Cooper GM. De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder. Hum Genet. 2018 May;137(5):375-388. doi: 10.1007/s00439-018-1887-y. Epub 2018 May 8. PMID: 29740699; PMCID: PMC5973976. 

Abstract 

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes. 

Bessenyei B, Balogh I, Mokanszki A, Ujfalusi A, Pfundt R, Szakszon K. MED13L-related intellectual disability due to paternal germinal mosaicism. Cold Spring Harb Mol Case Stud. 2021 Oct 15:mcs.a006124. doi: 10.1101/mcs.a006124. Epub ahead of print. PMID: 34654706. 

Abstract 

The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common form of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications or sequence variants has been identified deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and be the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. 32 subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.