Horovitz et al. 2023

Quick Summary

This paper described four people with newly reported IRF2BPL variants. The individuals were very different from one another: two were children with developmental delay, one was an adult woman with long-standing balance problems and parkinsonism, and one was a teenager with progressive walking problems, cognitive decline, swallowing difficulty, and speech problems.

The article helps show how broad IRF2BPL-related disease can be. Some people with IRF2BPL-related NEDAMSS have early seizures, clear regression, and severe developmental disability. In this paper, however, some individuals had milder or less typical presentations, and one adult had symptoms that began with gait imbalance rather than childhood epilepsy.

The paper also raises an important caution: genetic results sometimes include more than one potentially important finding. In one child, the researchers found both an IRF2BPL variant and a likely disease-related variant in HCN1, another gene linked with epilepsy and neurodevelopment. Because of this, the authors could not say with certainty how much of that child's symptoms came from IRF2BPL alone.

Why This Paper Matters

IRF2BPL-related NEDAMSS was first described as a condition involving developmental delay, developmental regression, abnormal movements, loss of speech, and seizures. Early reports often focused on children with severe developmental epileptic encephalopathy or on people with prominent movement disorders. This paper added four new IRF2BPL variants and showed that the gene can be found in people with a wider set of symptoms.

The paper is especially useful because the four cases did not all follow the same pattern. Two children had developmental delay without reported seizures or regression at the time described. One adult woman had cerebellar ataxia and parkinsonism, with severe later loss of mobility but no clear childhood developmental history. One teenage boy had progressive walking impairment and cognitive decline, and the case description reports later tonic-clonic seizures.

The article also matters because the authors discussed adult-onset IRF2BPL presentations. They described Patient 2 as the oldest reported person with an IRF2BPL variant at the time of the article. Her symptoms included ataxia, parkinsonism, vertical gaze palsy, sleep disturbance, and eventual wheelchair dependence. This supports the idea that IRF2BPL should not be thought of only as an early-childhood epilepsy gene.

What The Researchers Studied

This was a case series of four people with novel IRF2BPL variants found by exome sequencing. Exome sequencing is a genetic test that looks at the protein-coding parts of the genome, where many disease-related variants are found.

The four people were being evaluated for different reasons: developmental delay, adult-onset cerebellar ataxia, or neurological decline. The researchers collected clinical histories, physical examination findings, neurological findings, brain MRI results, EEG results when available, other laboratory and genetic tests, and exome sequencing results.

The study did not include a large cohort, a treatment trial, or laboratory testing of the variants. Instead, it added detailed clinical descriptions of four individuals and compared them with what had already been reported about IRF2BPL. The discussion also placed the new variants into the broader map of known IRF2BPL variants, shown in Figure 4 of the paper.

What Was Learned About Symptoms

The four individuals had different symptom patterns, which is one of the main messages of the paper.

Patient 1 was an 18-month-old girl with global developmental delay. She had hip dysplasia in the newborn period and was treated with a Pavlik harness and body cast until 6 months of age. After the cast was removed, hypotonia, meaning low muscle tone, became clear. She stood without support at 13 months, walked without support at 2 years, and spoke simple words at 2 years. She was later diagnosed with speech apraxia, which means difficulty planning the movements needed for speech. She had no epilepsy and no developmental regression reported. Her EEG, brain MRI, hearing test, eye exam, echocardiogram, abdominal ultrasound, karyotype, and array-CGH were reported as normal.

Patient 2 was a woman with adult neurological disease. She had gait imbalance from about age 20 but remained able to manage daily activities for many years. She later developed cerebellar ataxia and parkinsonism. Levodopa was started at age 52 and gave mild improvement in bradykinesia, or slowness of movement. By age 55 she had severe speech impairment and disrupted sleep. At age 57 she needed help with all daily living activities and was wheelchair-bound. Her exam showed upper vertical gaze palsy, rigidity, bradykinesia, incoordination, hyperreflexia in the arms, absent reflexes in the legs, a Babinski sign on the right foot, and mild dysarthria. Her brain MRI and many metabolic and genetic tests for other ataxia conditions were normal. The authors noted that her childhood development was not documented, but her family denied childhood motor or cognitive problems, and she had graduated from university and worked as a school supervisor.

Patient 3 was a boy first described at age 5 with global developmental delay. He walked without support at 14 months, spoke simple words at 1 year, and used simple sentences after age 3. He had hypotonia and several physical features noted on exam, including upslanted palpebral fissures, hypertelorism, posteriorly rotated ears, synophrys, a high narrow palate, prominent fingertip pads, slender fingers, and joint laxity. At age 10, he had impaired social interactions. No seizures or regression had been observed. His EEG, brain MRI, echocardiogram, abdominal ultrasound, karyotype, and array-CGH were within the normal range.

Patient 4 was a boy who presented at age 13 with progressive walking impairment, gait instability, and cognitive decline. His family also reported behavioral problems and worsening school performance over time. The case description reports tonic-clonic seizures at age 16, treated with oxcarbazepine. At age 17, he developed dysphagia and dysarthria, meaning swallowing difficulty and speech difficulty. His early motor development was reported as normal, with no speech issues during infancy, although feeding was difficult until age 3 because of chewing problems. His exam showed ataxic gait and lower-limb weakness. Brain and spine MRI were normal, muscle enzymes were normal, and electroneuromyography showed proximal myopathy.

Overall, the paper supports that IRF2BPL-related disease can include developmental delay, low muscle tone, speech problems, ataxia, parkinsonism, gaze problems, swallowing difficulty, cognitive decline, and sometimes seizures. It also shows that MRI and EEG can be normal in some people, especially depending on the person and stage of illness.

One important source caution: the case description for Patient 4 reports tonic-clonic seizures, but the discussion later states that seizures were not a manifestation in the cases reported here. Because that is internally inconsistent, the safest reading is that the individual case descriptions should be followed closely and that seizure reporting in this paper is not perfectly clear.

What Was Learned About Genetics

The researchers reported four novel IRF2BPL variants. Three were frameshift variants and one was a nonsense variant. In plain language, both frameshift and nonsense variants are types of genetic changes that can cause the cell to make a shortened or disrupted protein.

The IRF2BPL variants reported were:

* Patient 1: c.2102del, p.Asn701ThrfsTer66 * Patient 2: c.590del, p.Asn197ThrfsTer15 * Patient 3: c.1099G>T, p.Glu367Ter * Patient 4: c.474\_504del, p.Ala161SerfsTer8

Patient 1 and Patient 3 had de novo IRF2BPL variants, meaning the variants were not found in either parent. Patient 2's parents were not available for testing, and the researchers could not test Patient 4's parents. This means the paper could confirm new occurrence in two people but not in all four.

Patient 1 also had a de novo HCN1 variant: c.1246C>T, p.Gln416Ter. HCN1 is a gene already associated with epilepsy and neurodevelopmental conditions. Because Patient 1 had both an IRF2BPL variant and an HCN1 variant, the authors were careful. They said they could not determine whether her developmental delay was due to the IRF2BPL variant, the HCN1 variant, or some combination of both. This is a helpful reminder that genetic interpretation can be complicated.

The authors discussed where the variants fall in the IRF2BPL protein. IRF2BPL has 796 amino acids and includes several regions, including a polyglutamine, or poly Q, tract and predicted PEST sequences. PEST sequences are protein regions that can help signal protein breakdown. The paper notes that many reported IRF2BPL variants are located in the poly Q tract or before the first PEST sequence.

Patient 2's adult-onset variant, p.Asn197ThrfsTer15, is located near the first PEST region. The authors observed that adult-onset cases reported so far appeared to have variants in this general part of the gene, but they were careful that it is still unknown whether this is truly an adult-onset cluster. More people would need to be reported before that could be established.

Patient And Cohort Details

This article was not a broad screening study. It was a four-person case series.

Two patients, Patients 1 and 3, were children whose main early issue was developmental delay. Both had hypotonia. Both had normal brain MRI and EEG results in the testing described. Neither had seizures or regression reported at the time of publication. Both had some physical features noted on exam, though the paper emphasizes that it is still not clear whether dysmorphic features are a consistent part of IRF2BPL-related disease.

Patient 2 was different from the childhood cases. She had adult-onset cerebellar ataxia and parkinsonism, with gait imbalance beginning around age 20 and major functional decline later in adulthood. Her cognitive history was not strongly suggestive of childhood disability, and her mini-mental test score was 27 out of 30. She developed severe motor disability and speech impairment, but the paper did not describe seizures for her.

Patient 4 had later childhood or adolescent neurological decline, with progressive walking impairment, cognitive decline, behavioral concerns, and school decline beginning before the reported seizure onset. He later developed dysphagia and dysarthria. His MRI was normal, but electroneuromyography suggested proximal myopathy.

Across the four cases, the shared theme was neurological involvement, but the details varied widely. The paper did not show one single IRF2BPL presentation. Instead, it added evidence that IRF2BPL can appear as developmental delay, adult movement disorder, progressive motor problems, or a mixed neurological picture.

What Families Can Take Away

This paper supports the idea that IRF2BPL-related conditions can look different from person to person. Some people have seizures and regression early in life, but others may have developmental delay without seizures, or movement symptoms that become more obvious later.

A normal MRI or EEG does not necessarily rule out an IRF2BPL-related condition. In several of the cases described here, brain MRI was normal. Some other tests were also normal before exome sequencing identified the IRF2BPL variant.

The paper also shows why careful genetic counseling is important. A genetic result may be new in the child, inherited, or uncertain if parents are not available for testing. Sometimes, as in Patient 1, more than one potentially important gene finding may be present. In that situation, families need help from genetics and neurology teams to understand what can and cannot be concluded.

For families, the practical message is not that every person with an IRF2BPL variant will develop the same symptoms. Rather, this paper supports broad awareness: IRF2BPL may be worth considering in children with unexplained developmental delay, people with developmental or neurological regression, and adults with unexplained ataxia, parkinsonism, dystonia, or related movement symptoms. Medical decisions, testing choices, therapies, seizure care, swallowing evaluations, and mobility supports should always be guided by the person's own care team.

Limits Of The Paper

This was a small case series with four people. It cannot tell families how common each symptom is, predict the future for a newly diagnosed child, or prove that a particular variant will always cause a particular pattern.

Two of the four cases did not have parental testing available, so the researchers could not confirm whether those variants were de novo or inherited. That limits what can be said about recurrence risk or inheritance in those families.

Patient 1 had both an IRF2BPL variant and an HCN1 variant. The authors clearly state that they could not determine which variant explained her symptoms. This makes Patient 1 important but also harder to interpret as a pure IRF2BPL case.

The paper did not include functional laboratory studies of the four variants. The variants were interpreted using clinical information, exome sequencing, inheritance when available, and comparison with prior reports, but the study did not directly test how each variant affects cells or neurons.

Some clinical details were limited. For Patient 2, childhood developmental milestones were not available. For Patient 4, the case text describes seizures and progressive decline, while parts of the discussion describe the cases as if seizures and regression were not present. That inconsistency means readers should be careful when using this article to summarize seizure frequency or regression patterns.

The article also did not test treatments. It described clinical features and diagnostic findings, but it does not show that any specific therapy changes the course of IRF2BPL-related disease.

Source Notes

* Uploaded PDF: full article text and figures. * Main text: Abstract, Introduction, Case 1, Case 2, Case 3, Case 4, Discussion. * Case 1: developmental delay, hip dysplasia, hypotonia, speech apraxia, normal MRI/EEG, IRF2BPL and HCN1 variants. * Case 2: adult-onset cerebellar ataxia, parkinsonism, sleep disturbance, neurological exam, normal MRI, IRF2BPL variant. * Case 3: developmental delay, hypotonia, social interaction concerns, normal MRI/EEG, de novo IRF2BPL variant. * Case 4: progressive walking impairment, cognitive decline, tonic-clonic seizures in the case description, dysphagia, dysarthria, normal MRI, proximal myopathy on electroneuromyography, IRF2BPL variant. * Figures 1-3: patient photographs illustrating physical features described for Patients 1 and 3. * Figure 4: schematic map of IRF2BPL protein regions and previously reported variants, with the four variants from this study shown in bold.