Gardella et al. 2023

Quick Summary

This paper described three unrelated people with IRF2BPL-related disease whose symptoms matched progressive myoclonus epilepsy, often shortened to PME. PME is a group of rare genetic conditions in which people develop seizures, worsening myoclonic jerks, balance problems, and gradual neurological decline.

The three people in this study were adults, ages 28 to 40, who had epilepsy beginning in late childhood, adolescence, or young adulthood. Their seizures included generalized tonic-clonic seizures, absences, and myoclonic seizures. Their myoclonus was often triggered by light, eye closure, or movement. Over time, they developed worsening walking problems, speech problems, cognitive decline, and cerebellar signs such as ataxia and poor coordination.

All three had de novo nonsense variants in IRF2BPL, meaning the genetic changes were new in the person and were not found in the parents. The variants were clustered near the beginning of the IRF2BPL protein, around a highly conserved coiled-coil region. The authors proposed that IRF2BPL should be considered a cause of progressive myoclonus epilepsy.

Why This Paper Matters

Before this paper, IRF2BPL was already known to cause a neurodevelopmental condition involving regression, seizures, movement disorders, loss of speech, ataxia, dystonia, pyramidal signs, and swallowing problems. However, the condition had usually been described under the broader IRF2BPL/NEDAMSS spectrum, not specifically as progressive myoclonus epilepsy.

This article was important because it identified a recognizable PME pattern in three unrelated people with IRF2BPL variants. Their symptoms were not just "seizures plus developmental problems." They had classic PME features: action myoclonus, light sensitivity, generalized seizures, ataxia, progressive motor and cognitive decline, and supportive EEG findings.

The paper also reviewed 31 previously published people with IRF2BPL-related disorders. When the authors combined those earlier cases with their three new patients, they noticed that some previously reported people may also have had unrecognized PME or might have developed PME features later. This helped broaden the IRF2BPL story from early developmental epileptic encephalopathy and movement disorders to include a later-onset progressive epilepsy syndrome.

Another new piece was the skin biopsy finding in one patient. The biopsy showed large intracellular glycogen-like inclusions in sweat gland cells, described as Lafora body-like. This did not prove the disease mechanism, but it suggested a possible link between IRF2BPL-related PME and cellular storage or protein-processing pathways that are also important in some other forms of PME.

What The Researchers Studied

This was a brief clinical case series with a literature review. The researchers described three unrelated people with a PME-like presentation and de novo IRF2BPL variants. The patients were 28, 37, and 40 years old at the time of the report.

The researchers collected detailed clinical information, including seizure history, movement symptoms, developmental and cognitive history, neurological examination, EEG and polygraphic EEG-EMG recordings, brain MRI, nerve studies, and biopsy findings in selected patients. Genetic testing was done using either a targeted epilepsy/intellectual disability gene panel or trio genome sequencing. The researchers also checked for other known PME genes and reported that those were negative.

The literature-review part searched PubMed for IRF2BPL reports available by January 1, 2023. The authors identified 14 clinical papers including 31 previously reported people. Combining those with the three new patients, they analyzed 34 total individuals with pathogenic IRF2BPL variants.

What Was Learned About Symptoms

The three new patients shared a PME pattern, but their exact histories were different.

Patient 1 was a 40-year-old man. He had hearing loss, umbilical hernia, and thoracic kyphosis from infancy. His motor milestones were normal, but speech delay was noticed at age 4, and he attended a school for children with special needs. At age 11.5, he began having generalized tonic-clonic seizures, with the first seizure occurring while he was playing video games. A few months later, erratic myoclonus and myoclonic seizures appeared. By age 17, he had action myoclonus, ataxic gait, rest "tremor," muscle cramps, frequent myoclonic jerks or seizures, and short absences triggered by eye closure. His IQ was reported as 60. Over time, his motor and cognitive abilities slowed, and myoclonus became severe enough to cause falls. As an adult, he was institutionalized and wheelchair-bound. His myoclonus, especially with action, light, or eye closure, severely affected voluntary movement, swallowing, and speech. He also had dysarthria, dysmetria, dysdiadochokinesia, panic attacks, hypogonadotropic hypogonadism, and some dysmorphic features.

Patient 2 was a 28-year-old woman. She had mild motor and cognitive delay and right-sided hemiparesis from early childhood and attended a special needs class. At age 8, she developed light-induced eyelid myoclonias and absences. At age 15, she began having abrupt falls, often triggered by intense environmental lights, and also had a few generalized tonic-clonic seizures. Over time, her myoclonic jerks and cognition worsened. She developed gait instability, mild hypotonia, and ataxia. At the time of the report, she still had light-sensitive myoclonus, falls, and absences. Her neurological exam showed strabismus, dysarthria, dysmetria, tetraparesis, myoclonus at rest, action myoclonus, ataxia, and dystonia. She used a wheelchair for longer distances, lived in a residence for people with special needs, and worked in a protected job.

Patient 3 was a 37-year-old man. His early history was described as uneventful until age 19, when he had his first generalized tonic-clonic seizure. Around the same time, myoclonic jerks appeared, triggered by environmental light and by movement. At age 23, he began to show gait imbalance and dysarthria. At age 25, his cognition was described as grossly normal, but he had action and light-sensitive myoclonus, gait ataxia, and dysmetria. He also had marked obesity and abnormal glucose-insulin findings. For several years, his course was relatively stable, and his myoclonus improved with a ketogenic diet. From age 33, myoclonus and walking worsened significantly, and by age 34 he was bedridden with marked action- and light-sensitive myoclonus, brisk reflexes, extension plantar responses, and cognitive impairment.

The EEG and neurophysiology findings supported the PME diagnosis. EEG showed background slowing in Patients 1 and 2, generalized spike or polyspike-wave bursts, and multifocal fast spike discharges. These abnormalities were strongly increased by eye closure and photic stimulation. EEG-EMG recordings showed that the myoclonic jerks were linked in time to cortical spike discharges, supporting a cortical source for the myoclonus. Overnight sleep recordings in Patients 1 and 3 showed abnormal sleep structure without recognizable sleep stages.

Brain MRI findings varied. Patient 1's MRI was unremarkable. Patient 2's MRI showed nonspecific findings, including cysts of the pineal gland and infundibulum. Patient 3's MRI showed marked cerebellar and brainstem atrophy. Nerve conduction studies in Patients 1 and 3 showed findings consistent with mixed sensory-motor neuropathy.

Across the broader combined group of 34 people with IRF2BPL-related disorders, motor and/or cognitive deterioration was described in all but one very young child. At latest follow-up, all had cerebellar signs when reported, 88% had moderate-to-profound intellectual disability, and 71% had epilepsy. MRI was normal in some people but showed atrophy or other nonspecific findings in others.

What Was Learned About Genetics

All three new patients had de novo nonsense variants in IRF2BPL. A nonsense variant creates an early stop signal in the gene's instructions. In plain language, this means the cell is expected to make a shortened IRF2BPL protein instead of the full-length protein.

The variants were:

* Patient 1: `c.370C>T`, `p.Gln124Ter` * Patient 2: `c.364C>T`, `p.Gln122Ter` * Patient 3: `c.364C>T`, `p.Gln122Ter`

The two variants are extremely close to each other in the protein, at amino acids 122 and 124. The authors noted that they sit in a proximal, highly conserved region of IRF2BPL around the coiled-coil domain. This clustering was one of the key genetic observations in the paper.

The full IRF2BPL protein has 796 amino acids. Variants at positions 122 or 124 are predicted to stop the protein very early. The authors suggested that these early truncating variants may disrupt the coiled-coil domain and remove the later C-terminal RING finger domain. The RING finger domain is important because IRF2BPL may act as an E3 ubiquitin ligase, a type of protein involved in tagging other proteins for processing or removal.

In the literature-combined analysis, 24 different pathogenic IRF2BPL variants were identified among 34 people. Twenty-one of the 24 variants were protein-truncating, and three were missense variants. Most were de novo, although two variants had been reported in families. The authors found that variants associated with the later-onset myoclonic or PME-like phenotype clustered around amino acids 119-166, near the coiled-coil region.

Patient And Cohort Details

The three new patients were adults with progressive myoclonus epilepsy features, but they differed in age at onset and severity.

Patient 1 had early speech delay, then seizures beginning at age 11.5, followed by progressive myoclonus, ataxia, cognitive slowing, speech and swallowing impairment, and wheelchair dependence. Patient 2 had early mild motor and cognitive delay, then light-induced eyelid myoclonias and absences beginning at age 8, followed by falls, worsening myoclonus, ataxia, dystonia, and increasing functional limitations. Patient 3 had no major early developmental history described, with generalized tonic-clonic seizures and myoclonus beginning at age 19, later gait and speech problems, and major decline in his 30s.

The literature review helped place these three people into a wider IRF2BPL pattern. Of the 34 total people reviewed, 29 could be placed into clinical subgroups. Nine had not had epilepsy. Six had epilepsy beginning in infancy, with a median onset of 6 months, often including spasms followed by other seizure types. These children developed severe hypotonia, cerebellar signs, and pyramidal signs; five of six were bedridden by latest follow-up.

Another 14 people had later epilepsy onset, with a median onset around 10 years. This later-onset group had generalized seizures such as myoclonic seizures, generalized tonic-clonic seizures, and absences, along with progressive cognitive and motor regression. Most had intellectual disability, gait problems, speech problems, action myoclonus, and cerebellar signs. Dystonia or dyskinesia, pyramidal signs, and eye movement abnormalities were present in some people.

The authors noted that only the three people in this paper had been explicitly diagnosed with PME, even though several previously published people had overlapping features. This suggests that PME may have been under-recognized within the IRF2BPL spectrum.

What Families Can Take Away

This paper supports IRF2BPL as a gene that can cause progressive myoclonus epilepsy. For families, this means IRF2BPL may be relevant not only when a child has infantile seizures and early developmental regression, but also when a person has later-onset myoclonus, generalized seizures, light sensitivity, ataxia, speech decline, swallowing difficulty, or gradual neurological worsening.

The paper also shows that IRF2BPL-related symptoms can change over time. Some people may begin with developmental delay or mild learning differences; others may have a more typical early history before seizures and movement symptoms appear. In the three people reported here, myoclonus and movement problems became more disabling over the years.

Light sensitivity and action-triggered myoclonus were major clues in these cases. The authors described myoclonus triggered by photic stimulation, eye closure, environmental lights, and voluntary movement. These observations may help families describe symptoms clearly to their neurology team, especially when jerks, falls, or sudden interruptions in movement are hard to explain.

The article mentions that several treatments partly helped myoclonus in individual patients, including valproic acid, clonazepam, perampanel, high-dose piracetam, and ketogenic diet. These were observations from a few people, not proof that any treatment will work for everyone. Medication choices, diet therapies, seizure care, swallowing support, mobility planning, and safety decisions should always be made with the person's own care team.

Limits Of The Paper

The main clinical report included only three new patients. That is meaningful for a rare disorder, but it is too small to predict the course for every person with an IRF2BPL variant.

The literature review combined cases from many earlier papers. Those papers did not all report the same details, and some people were still young when reported. This means some symptoms may have been missed, not yet developed, or described differently across studies.

The genotype-phenotype pattern is suggestive but not final. The authors observed that PME-like cases clustered around amino acids 119-166, near the coiled-coil region, but more cases are needed to know how strong that pattern is.

The skin biopsy finding came from one patient. The glycogen-like inclusions are interesting because they suggest possible overlap with storage-related pathways, but this finding cannot prove the disease mechanism by itself.

The treatment information was not from a clinical trial. The paper describes partial benefit from some anti-seizure and anti-myoclonus treatments in individual patients, but it cannot prove which therapy is best or predict response in another person.

Source Notes

* Uploaded PDF: full article text, figures, and figure legends. * Main text: Abstract, Introduction, New Patients, Neurophysiological assessment, Biopsies, Neuroimaging, Genetic testing, IRF2BPL Landscape, Discussion, Conclusions. * Figure 1: EEG-polygraphic findings showing epileptiform discharges, photic and eye-closure sensitivity, and EEG-EMG correlation with myoclonus. * Figure 2A: Axillary skin biopsy in Patient 3 showing glycogen-like intracellular inclusions. * Figure 2B: Brain MRI in Patient 3 showing cerebellar and brainstem atrophy. * Figure 2C: Clinical subgroup comparison of IRF2BPL cases, including DEE and PME-like groups. * Figure 2D: IRF2BPL protein map showing clustering of later-onset myoclonic/PME-associated variants around the proximal coiled-coil region. * Literature review section: summary of 31 previously reported IRF2BPL patients combined with the three new patients.