# 618443

NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT VARIABLE BRAIN ABNORMALITIES; NEDBA


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
16p13.3 Neurodevelopmental disorder with or without variable brain abnormalities 618443 AD 3 MAPK8IP3 605431
Clinical Synopsis
 

INHERITANCE
- Autosomal dominant
GROWTH
Height
- Short stature (in some patients)
Weight
- Obesity (in some patients)
HEAD & NECK
Head
- Small head circumference (in some patients)
Face
- Dysmorphic facial features, nonspecific (in some patients)
- Round face
- Short philtrum
- Long philtrum
Ears
- Low-set ears
Eyes
- Cortical visual impairment (in some patients)
- Deep-set eyes
- Strabismus
- Hypertelorism
- Upslanting palpebral fissures
Nose
- Prominent nasal bridge
- High nasal bridge
- Anteverted nares
Mouth
- Thin upper lip
- Small mouth
Teeth
- Abnormal teeth
SKELETAL
Spine
- Kyphosis
- Scoliosis
Hands
- Fifth finger clinodactyly
- Thin fingers
- Small hands
Feet
- Foot deformities
- Small feet
MUSCLE, SOFT TISSUES
- Hypotonia
NEUROLOGIC
Central Nervous System
- Global developmental delay
- Delayed walking
- Inability to walk
- Impaired intellectual development, variable severity
- Poor or absent speech
- Spasticity
- Gait instability
- Ataxia
- Dyspraxia
- Seizures (less common)
- Cerebral atrophy
- Cerebellar hypoplasia
- Thin corpus callosum
- Decreased white matter volume
- Perisylvian polymicrogyria
- Delayed myelination
Peripheral Nervous System
- Loss of myelinated fibers seen on sural nerve biopsy (1 patient)
- Neurogenic pattern seen on EMG
- Axonal neuropathy seen on nerve conduction studies
Behavioral Psychiatric Manifestations
- Autism spectrum disorder (in some patients)
- Behavioral abnormalities (in some patients)
MISCELLANEOUS
- De novo mutation
- Variable severity
MOLECULAR BASIS
- Caused by mutation in the mitogen-activated protein kinase 8-interacting protein 3 gene (MAPK8IP3, 605431.0001)

TEXT

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) is caused by heterozygous mutation in the MAPK8IP3 gene (605431) on chromosome 16p13.


Description

Neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) is characterized by global developmental delay apparent from infancy or early childhood, resulting in mildly delayed walking, variably impaired intellectual development, and poor or absent speech. Additional features may include hypotonia, spasticity, or ataxia. About half of patients have abnormal findings on brain imaging, including cerebral or cerebellar atrophy, loss of white matter volume, thin corpus callosum, and perisylvian polymicrogyria. Seizures are not a prominent finding, and although some patients may have nonspecific dysmorphic facial features, there is no common or consistent gestalt (summary by Platzer et al., 2019).


Clinical Features

Platzer et al. (2019) reported 13 unrelated patients, ranging in age from 3 to 19 years, with a neurodevelopmental disorder. All were noted to have delayed psychomotor development apparent in infancy or early childhood, as well variable degrees of intellectual disability (31% mild, 46% moderate, and 23% severe), often with speech delay or minimal speech; IQ was 48 to 49 in 3 patients tested. Two patients had autistic features. Most had abnormal muscle tone, including 9 with hypotonia, 4 with spasticity, and 2 with both, and 3 patients had ataxia or unsteady gait. Only 3 patients had a single generalized seizure in childhood; a fourth patient (individual 10) with earlier onset of more severe seizures also carried a likely pathogenic mutation in the SLC6A1 gene (137165). Less common features included cortical visual impairment (in 2), scoliosis (in 3), short stature (in 2), small head (in 3), and tapering fingers/fifth finger clinodactyly/small hands and feet. A few patients had nonspecific dysmorphic facial features, such as hypertelorism, low-set ears, deep-set eyes, strabismus, high nasal bridge, and abnormal teeth, but most did not have dysmorphic features and there was no consistent gestalt. Brain imaging was normal in 4 patients, but showed variable abnormalities in 8 others, including perisylvian polymicrogyria (in 2), cerebral atrophy, abnormal corpus callosum, white matter volume loss, and hypomyelination. The patients were ascertained through GeneMatcher and international collaborative efforts, including centers in Brazil, Germany, Israel, Italy, the United States, and the Netherlands.

Iwasawa et al. (2019) reported 5 Japanese patients, including 2 sibs, with NEDBA. The patients, who ranged in age from 5 to 29 years, were severely affected. They had hypotonia in infancy, and only a 5-year-old girl (individual 5) was able to walk at age 2 years; the other 5-year-old could 'cruise,' but the 3 older patients had spastic diplegia, never acquired walking, and were wheelchair-bound. Most were nonverbal or had only a few words; intellectual disability was severe or profound in all patients (DQ of 27-34), and the younger patients had autistic features. Two patients had epilepsy, and 3 had abnormal spikes on EEG. Brain imaging was abnormal in all patients, showing cerebral atrophy and hypoplasia of the corpus callosum; 3 patients had delayed myelination. There were some dysmorphic features in most patients, including round face, prominent nasal bridge, and thin upper lip. One patient also had upslanting palpebral fissures, anteverted nares, and a short philtrum. Two had short stature, 3 had obesity, and the 2 sibs, a brother and sister, had precocious puberty. Sural nerve biopsy in 1 patient (individual 2) showed loss of myelinated fibers; EMG indicated a neurogenic pattern, and nerve conduction studies indicated an axonal neuropathy.


Inheritance

The heterozygous mutations in the MAPK8IP3 gene that were identified in patients with NEDBA by Platzer et al. (2019) occurred de novo.


Molecular Genetics

In 13 unrelated patients with NEDBA, Platzer et al. (2019) identified 9 different de novo heterozygous mutations in the MAPK8IP3 gene (see, e.g., 605431.0001-605431.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. Three of the mutations were nonsense or frameshift and predicted to result in nonsense-mediated mRNA decay, whereas 6 were missense variants at highly conserved residues. Engineering of mutations corresponding to 1 nonsense (Y37X; 605431.0002) and 5 of the missense variants in C. elegans showed that only Y37X and L444P (605431.0003) resulted in increased axonal lysosome density compared to wildtype (about 88-fold increase for Y37X and 15-fold increase for L444P), consistent with a loss of protein function and impaired axonal transport. Further studies showed that 5 of the 6 investigated C. elegans unc16 mutants had variably decreased swimming cycle rates compared to controls, particularly for the Y37X and L444P variants. These defects could be rescued by expression of wildtype unc16. Platzer et al. (2019) interpreted these findings as evidence of disrupted axonal transport resulting from MAPK8IP3 mutations, but also noted that other functions of the gene may be disturbed by the mutations. Studies of patient cells were not performed. The patients were ascertained from a total cohort of 27,232 individuals with neurodevelopmental disorders.

In 5 Japanese patients, including 2 sibs, with NEDBA, Iwasawa et al. (2019) identified 2 different de novo heterozygous missense mutations in the MAPK8IP3 gene (R578C, 605431.0004 and R1146C, 605431.0005). The mutations were found by exome sequencing; the mutation in the sibs was suggested to have resulted from germline mosaicism. Expression of the variants in zebrafish resulted in axonal abnormalities, suggesting defects in neural development.


REFERENCES

  1. Iwasawa, S., Yanagi, K., Kikuchi, A., Kobayashi, Y., Haginoya, K., Matsumoto, H., Kurosawa, K., Ochiai, M., Sakai, Y., Fujita, A., Miyake, N., Niihori, T., Shirota, M., and 11 others. Recurrent de novo MAPK8IP3 variants cause neurological phenotypes. Ann. Neurol. 85: 927-933, 2019. [PubMed: 30945334, related citations] [Full Text]

  2. Platzer, K., Sticht, H., Edwards, S. L., Allen, W., Angione, K. M., Bonati, M. T., Brasington, C., Cho, M. T., Demmer, L. A., Falik-Zaccai, T., Gamble, C. N., Hellenbroich, Y., and 20 others. De novo variants in MAPK8IP3 cause intellectual disability with variable brain anomalies. Am. J. Hum. Genet. 104: 203-212, 2019. [PubMed: 30612693, images, related citations] [Full Text]


Creation Date:
Cassandra L. Kniffin : 05/22/2019
carol : 12/27/2021
carol : 05/24/2019
carol : 05/23/2019
ckniffin : 05/22/2019

# 618443

NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT VARIABLE BRAIN ABNORMALITIES; NEDBA


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
16p13.3 Neurodevelopmental disorder with or without variable brain abnormalities 618443 Autosomal dominant 3 MAPK8IP3 605431

TEXT

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) is caused by heterozygous mutation in the MAPK8IP3 gene (605431) on chromosome 16p13.


Description

Neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) is characterized by global developmental delay apparent from infancy or early childhood, resulting in mildly delayed walking, variably impaired intellectual development, and poor or absent speech. Additional features may include hypotonia, spasticity, or ataxia. About half of patients have abnormal findings on brain imaging, including cerebral or cerebellar atrophy, loss of white matter volume, thin corpus callosum, and perisylvian polymicrogyria. Seizures are not a prominent finding, and although some patients may have nonspecific dysmorphic facial features, there is no common or consistent gestalt (summary by Platzer et al., 2019).


Clinical Features

Platzer et al. (2019) reported 13 unrelated patients, ranging in age from 3 to 19 years, with a neurodevelopmental disorder. All were noted to have delayed psychomotor development apparent in infancy or early childhood, as well variable degrees of intellectual disability (31% mild, 46% moderate, and 23% severe), often with speech delay or minimal speech; IQ was 48 to 49 in 3 patients tested. Two patients had autistic features. Most had abnormal muscle tone, including 9 with hypotonia, 4 with spasticity, and 2 with both, and 3 patients had ataxia or unsteady gait. Only 3 patients had a single generalized seizure in childhood; a fourth patient (individual 10) with earlier onset of more severe seizures also carried a likely pathogenic mutation in the SLC6A1 gene (137165). Less common features included cortical visual impairment (in 2), scoliosis (in 3), short stature (in 2), small head (in 3), and tapering fingers/fifth finger clinodactyly/small hands and feet. A few patients had nonspecific dysmorphic facial features, such as hypertelorism, low-set ears, deep-set eyes, strabismus, high nasal bridge, and abnormal teeth, but most did not have dysmorphic features and there was no consistent gestalt. Brain imaging was normal in 4 patients, but showed variable abnormalities in 8 others, including perisylvian polymicrogyria (in 2), cerebral atrophy, abnormal corpus callosum, white matter volume loss, and hypomyelination. The patients were ascertained through GeneMatcher and international collaborative efforts, including centers in Brazil, Germany, Israel, Italy, the United States, and the Netherlands.

Iwasawa et al. (2019) reported 5 Japanese patients, including 2 sibs, with NEDBA. The patients, who ranged in age from 5 to 29 years, were severely affected. They had hypotonia in infancy, and only a 5-year-old girl (individual 5) was able to walk at age 2 years; the other 5-year-old could 'cruise,' but the 3 older patients had spastic diplegia, never acquired walking, and were wheelchair-bound. Most were nonverbal or had only a few words; intellectual disability was severe or profound in all patients (DQ of 27-34), and the younger patients had autistic features. Two patients had epilepsy, and 3 had abnormal spikes on EEG. Brain imaging was abnormal in all patients, showing cerebral atrophy and hypoplasia of the corpus callosum; 3 patients had delayed myelination. There were some dysmorphic features in most patients, including round face, prominent nasal bridge, and thin upper lip. One patient also had upslanting palpebral fissures, anteverted nares, and a short philtrum. Two had short stature, 3 had obesity, and the 2 sibs, a brother and sister, had precocious puberty. Sural nerve biopsy in 1 patient (individual 2) showed loss of myelinated fibers; EMG indicated a neurogenic pattern, and nerve conduction studies indicated an axonal neuropathy.


Inheritance

The heterozygous mutations in the MAPK8IP3 gene that were identified in patients with NEDBA by Platzer et al. (2019) occurred de novo.


Molecular Genetics

In 13 unrelated patients with NEDBA, Platzer et al. (2019) identified 9 different de novo heterozygous mutations in the MAPK8IP3 gene (see, e.g., 605431.0001-605431.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. Three of the mutations were nonsense or frameshift and predicted to result in nonsense-mediated mRNA decay, whereas 6 were missense variants at highly conserved residues. Engineering of mutations corresponding to 1 nonsense (Y37X; 605431.0002) and 5 of the missense variants in C. elegans showed that only Y37X and L444P (605431.0003) resulted in increased axonal lysosome density compared to wildtype (about 88-fold increase for Y37X and 15-fold increase for L444P), consistent with a loss of protein function and impaired axonal transport. Further studies showed that 5 of the 6 investigated C. elegans unc16 mutants had variably decreased swimming cycle rates compared to controls, particularly for the Y37X and L444P variants. These defects could be rescued by expression of wildtype unc16. Platzer et al. (2019) interpreted these findings as evidence of disrupted axonal transport resulting from MAPK8IP3 mutations, but also noted that other functions of the gene may be disturbed by the mutations. Studies of patient cells were not performed. The patients were ascertained from a total cohort of 27,232 individuals with neurodevelopmental disorders.

In 5 Japanese patients, including 2 sibs, with NEDBA, Iwasawa et al. (2019) identified 2 different de novo heterozygous missense mutations in the MAPK8IP3 gene (R578C, 605431.0004 and R1146C, 605431.0005). The mutations were found by exome sequencing; the mutation in the sibs was suggested to have resulted from germline mosaicism. Expression of the variants in zebrafish resulted in axonal abnormalities, suggesting defects in neural development.


REFERENCES

  1. Iwasawa, S., Yanagi, K., Kikuchi, A., Kobayashi, Y., Haginoya, K., Matsumoto, H., Kurosawa, K., Ochiai, M., Sakai, Y., Fujita, A., Miyake, N., Niihori, T., Shirota, M., and 11 others. Recurrent de novo MAPK8IP3 variants cause neurological phenotypes. Ann. Neurol. 85: 927-933, 2019. [PubMed: 30945334] [Full Text: https://doi.org/10.1002/ana.25481]

  2. Platzer, K., Sticht, H., Edwards, S. L., Allen, W., Angione, K. M., Bonati, M. T., Brasington, C., Cho, M. T., Demmer, L. A., Falik-Zaccai, T., Gamble, C. N., Hellenbroich, Y., and 20 others. De novo variants in MAPK8IP3 cause intellectual disability with variable brain anomalies. Am. J. Hum. Genet. 104: 203-212, 2019. [PubMed: 30612693] [Full Text: https://doi.org/10.1016/j.ajhg.2018.12.008]


Creation Date:
Cassandra L. Kniffin : 05/22/2019

Edit History:
carol : 12/27/2021
carol : 05/24/2019
carol : 05/23/2019
ckniffin : 05/22/2019