#619814
Table of Contents
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-101 (DEE101) is caused by homozygous mutation in the GRIN1 gene (138249) on chromosome 9q34.
Homozygous mutation in the GRIN1 can also cause autosomal recessive neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSR; 617820).
Developmental and epileptic encephalopathy-101 (DEE101) is a severe autosomal recessive disorder characterized by early infantile epileptic encephalopathy and severe global developmental delay (summary by Blakes et al., 2022).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Lemke et al. (2016) reported 3 sibs, born of consanguineous parents (family 5), with severe neonatal epileptic encephalopathy. All developed intractable seizures on the first day of life and died between 5 days and 5 months of age. One patient was reported to have microcephaly; none had developmental progress.
Blakes et al. (2022) reported a Pakistani patient who presented on the second day of life with difficulty feeding, abnormal tone, and seizures associated with oxygen desaturation and apnea. Serial EEGs were consistent with myoclonic encephalopathy. At 35 days of life, he developed profound bradycardia with episodes of asystole, and an EKG showed episodic complete heart block. An echocardiogram was normal. He had abnormal oromotor coordination and required nasogastric feeding. At 12 months of age, he had multiple daily seizures and gastrointestinal reflux, and he required nasogastric feeding. He had axial hypotonia and limb contractures. He did not babble or smile, lacked head control, and had no purposeful limb movements.
The transmission pattern of DEE101 in the families reported by Lemke et al. (2016) and Blakes et al. (2022) was consistent with autosomal recessive inheritance.
In 3 infants (family 5) with DEE101, Lemke et al. (2016) identified a homozygous nonsense mutation in the GRIN1 gene (Q556X; 138249.0009). In vitro functional expression studies showed that the mutation rendered the channel nonfunctional, with no response to glycine or glutamate, resulting in a complete loss of function. The unaffected parents were heterozygous for the mutation, suggesting that heterozygous truncating mutations and haploinsufficiency for GRIN1 does not result in a neurologic phenotype.
In a Pakistani infant, born to consanguineous parents, with DEE101, Blakes et al. (2022) identified a homozygous splice site mutation in the GRIN1 gene (138249.0013). Functional studies were not reported.
Blakes, A. J. M., English, J., Banka, S., Basu, H. A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy. Am. J. Med. Genet. 188A: 595-599, 2022. [PubMed: 34611970, related citations] [Full Text]
Lemke, J. R., Geider, K., Helig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 46 others. Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy. Neurology 86: 2171-2178, 2016. [PubMed: 27164704, related citations] [Full Text]
ORPHA: 442835; DO: 0070387;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.3 | Developmental and epileptic encephalopathy 101 | 619814 | Autosomal recessive | 3 | GRIN1 | 138249 |
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-101 (DEE101) is caused by homozygous mutation in the GRIN1 gene (138249) on chromosome 9q34.
Homozygous mutation in the GRIN1 can also cause autosomal recessive neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSR; 617820).
Developmental and epileptic encephalopathy-101 (DEE101) is a severe autosomal recessive disorder characterized by early infantile epileptic encephalopathy and severe global developmental delay (summary by Blakes et al., 2022).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Lemke et al. (2016) reported 3 sibs, born of consanguineous parents (family 5), with severe neonatal epileptic encephalopathy. All developed intractable seizures on the first day of life and died between 5 days and 5 months of age. One patient was reported to have microcephaly; none had developmental progress.
Blakes et al. (2022) reported a Pakistani patient who presented on the second day of life with difficulty feeding, abnormal tone, and seizures associated with oxygen desaturation and apnea. Serial EEGs were consistent with myoclonic encephalopathy. At 35 days of life, he developed profound bradycardia with episodes of asystole, and an EKG showed episodic complete heart block. An echocardiogram was normal. He had abnormal oromotor coordination and required nasogastric feeding. At 12 months of age, he had multiple daily seizures and gastrointestinal reflux, and he required nasogastric feeding. He had axial hypotonia and limb contractures. He did not babble or smile, lacked head control, and had no purposeful limb movements.
The transmission pattern of DEE101 in the families reported by Lemke et al. (2016) and Blakes et al. (2022) was consistent with autosomal recessive inheritance.
In 3 infants (family 5) with DEE101, Lemke et al. (2016) identified a homozygous nonsense mutation in the GRIN1 gene (Q556X; 138249.0009). In vitro functional expression studies showed that the mutation rendered the channel nonfunctional, with no response to glycine or glutamate, resulting in a complete loss of function. The unaffected parents were heterozygous for the mutation, suggesting that heterozygous truncating mutations and haploinsufficiency for GRIN1 does not result in a neurologic phenotype.
In a Pakistani infant, born to consanguineous parents, with DEE101, Blakes et al. (2022) identified a homozygous splice site mutation in the GRIN1 gene (138249.0013). Functional studies were not reported.
Blakes, A. J. M., English, J., Banka, S., Basu, H. A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy. Am. J. Med. Genet. 188A: 595-599, 2022. [PubMed: 34611970] [Full Text: https://doi.org/10.1002/ajmg.a.62528]
Lemke, J. R., Geider, K., Helig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 46 others. Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy. Neurology 86: 2171-2178, 2016. [PubMed: 27164704] [Full Text: https://doi.org/10.1212/WNL.0000000000002740]
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