Neurodevelopmental Disorder With Regression, Abnormal Movements, Loss Of Speech, And Seizures

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS) is caused by heterozygous mutation in the IRF2BPL gene (611720) on chromosome 14q24.

Clinical Features

Marcogliese et al. (2018) reported 7 unrelated patients, ranging in age from 2.5 to 43 years, with a neurodevelopmental disorder. Five patients had a more severe disorder characterized by neurodevelopmental regression that became apparent between 2 and 10 years of age after normal early development in most patients, although a few had mild early delays. These patients presented with difficulties walking that progressed to loss of independent walking; all became wheelchair-bound. They also lost language skills and fine and gross motor skills, and developed severe dysphagia requiring tube feeding, facial weakness, and dysarthria. One patient died at age 15 years due to feeding intolerance. Additional features included ataxia, dystonia, choreoathetosis, spasticity, dysmetria, and variable types of seizures. Ocular abnormalities were observed in some patients; these included esotropia, gaze palsies, nystagmus, and decreased saccades. Brain imaging was normal in 2 patients, but showed progressive cerebral and/or cerebellar atrophy in the others. The oldest patient (patient 5) had cerebral, cerebellar, brainstem, and corpus callosum atrophy at age 34 years. These 5 patients had nonsense mutations. Two patients had a somewhat less severe phenotype associated with missense mutations. One was an 11-year-old boy with gross motor and speech delay since infancy. He had refractory myoclonic seizures and was nonverbal with autistic features. The other was a 16-month-old girl who developed transient seizures in infancy, and thereafter showed hypotonia and mild developmental delay with no speech. She had subtle dysmorphic facial features. These patients did not show neurologic regression, were able to walk, and did not have movement abnormalities. Brain imaging was essentially normal in these 2 patients.

Tran Mau-Them et al. (2019) identified 11 unrelated individuals with findings consistent with NEDAMSS. Most patients had normal initial psychomotor development, followed by severe global neurologic regression and epilepsy and variable central nervous system anomalies. Onset of regression varied, before age 7 years in most patients, but after age 10 and 17 years in 2. Patients with early-onset regression had more severe outcomes. Only 1 patient was without regression, although that patient was only 3.5 years old when last examined. Epilepsy was seen in 7 of the 11 patients, beginning from the age of 6 months to 26 years, with nonspecific EEG findings, and was severe and often intractable. Other neurologic features were variable, ranging from severe tetraparesis to a cerebellar syndrome with ataxia, dysarthria, and nystagmus. Brain imaging was normal in 4 of 10 cases, but with variable anomalies in 6, including diffuse or focal brain or cerebellar atrophy.

Molecular Genetics

In 7 unrelated patients with NEDAMSS, Marcogliese et al. (2018) identified heterozygous mutations in the IRF2BPL gene (see, e.g., 611720.0001-611720.0005). The mutations were found by exome sequencing and confirmed by Sanger sequencing. The mutations occurred de novo in all patients from whom parental DNA was available for analysis. Five patients carried nonsense mutations, whereas 2 patients with a slightly less severe phenotype carried missense mutations. Overexpression of nonsense mutations in Drosophila failed to induce lethality, as was observed with overexpression of the wildtype gene, suggesting that the nonsense mutations resulted in a loss of function. Expression of the K418N mutation (611720.0005) resulted in lethality at higher temperatures, suggesting that it causes a partial loss of function, whereas expression of the P372R variant (611720.0004) resulted in lethality, similar to wildtype. Partial knockdown of the pits gene in Drosophila using RNAi resulted in progressive neurologic motor and learning dysfunction, and specific knockdown of the gene in photoreceptors of the eye caused progressive abnormalities. Complete disruption of the pits gene was toxic to the fly, resulting in lethality, as was overexpression of both pits and IRF2BPL. The findings suggested that the IRF2BPL gene is involved in both neurologic development and neuronal maintenance.

Using exome sequencing, Tran Mau-Them et al. (2019) identified different de novo heterozygous nonsense or frameshift mutations in the IRF2BPL gene (see, e.g., 611720.0006 and 611720.0007) in 11 unrelated patients with NEDAMSS. All of the mutations were absent from the gnomAD database and were expected to encode a shortened protein lacking the C-terminal RING-finger domain.

Animal Model

Marcogliese et al. (2018) found that the closest ortholog to the IRF2BPL gene in Drosophila, called 'pits,' was broadly detected, including in the nervous system. Expression was detected in various regions of the brain, including in the mushroom body and in the nuclei, cell bodies, and axons of neurons. Disruption of the pits gene was toxic to the fly, resulting in lethality, as was overexpression of both pits and IRF2BPL. The pits gene is located on the X chromosome in Drosophila.