Grin1-Related Neurodevelopmental Disorder
Summary
Clinical characteristics.
GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior problems. To date, 72 individuals with GRIN1-NDD have been reported.
Diagnosis/testing.
The diagnosis of GRIN1-NDD is established in a proband who has either a heterozygous de novo GRIN1 pathogenic missense variant (64 individuals reported) or biallelic GRIN1 pathogenic missense or truncating variants (8 individuals from 4 families reported).
Management.
Treatment of manifestations: Standard treatment of DD/ID, seizures, feeding problems, and behavioral issues.
Surveillance: In infancy: regular assessment of swallowing, feeding, and nutritional status to determine safety of oral vs gastrostomy feeding. For all age groups: routine monitoring of developmental progress, educational needs, and behavioral issues.
Genetic counseling.
GRIN1-NDD is inherited in either an autosomal dominant or autosomal recessive manner:
- Autosomal dominant inheritance: All probands with a heterozygous GRIN1 pathogenic variant reported to date whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN1 pathogenic missense variant. When the GRIN1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism.
- Autosomal recessive inheritance: At conception, each sib of an individual with biallelic GRIN1 pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once the GRIN1-NDD pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Diagnosis
Formal diagnostic criteria for GRIN1-related neurodevelopmental disorder have not been established.
Suggestive Findings
GRIN1-neurodevelopmental disorder (GRIN1-NDD) should be considered in individuals with the following clinical and/or brain MRI findings.
Clinical findings
- Mild-to-profound developmental delay (DD) or intellectual disability (ID)AND
- Any of the following presenting in infancy or childhood:
- Epilepsy
- Muscular tone abnormalities such as hypotonia and spasticity
- Dystonic, dyskinetic, or choreiform movement disorder
- Autism spectrum disorder
- Microcephaly
- Cortical visual impairment
Brain MRI findings. A subset of individuals shows a malformation of cortical development consisting of extensive and diffuse bilateral polymicrogyria. See Figure 1.
Figure 1.
Brain MRI findings of polymicrogyria in children with GRIN1 neurodevelopmental disorder demonstrating bilateral extensive polymicrogyria (white arrows) that is more severe anteriorly Note in most images (except I): Increased extra-axial spaces and enlarged (more...)
Establishing the Diagnosis
The diagnosis of GRIN1-related neurodevelopmental disorder is established in a proband who has one of the following on molecular genetic testing (see Table 1):
- A heterozygous de novo pathogenic missense variant in GRIN1 (64 individuals have been reported)
- Biallelic pathogenic missense or truncating variants in GRIN1 (8 individuals from 4 families have been reported)
Because the phenotype of GRIN1-related neurodevelopmental disorder is often nonspecific and indistinguishable from many other inherited disorders, it is most likely to be diagnosed by either gene-targeted testing (i.e., a multigene panel) (see Option 1) or genomic testing (which does not require the clinician to determine which gene is likely involved) (see Option 2).
Option 1
A multigene panel that includes GRIN1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of GRIN1-related neurodevelopmental disorder, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, yields results similar to a multigene panel but has two advantages:
- A multigene panel may not include all rare genes recently identified as causing ID; and
- Comprehensive genomic testing may be able to detect pathogenic variants in genes that – for technical reasons – do not sequence well.
Exome sequencing is most commonly used; genome sequencing is also possible. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in GRIN1-Related Neurodevelopmental Disorder
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| GRIN1 | Sequence analysis 3 | 100% |
| Gene-targeted deletion/duplication analysis 4 | Unknown 5 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 5.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Epilepsy (seen in 65%), muscular hypotonia (66%), and movement disorders (48%) are common manifestations.
To date, 72 individuals with GRIN1-NDD have been reported, including 64 individuals with de novo heterozygous pathogenic missense variants and eight individuals from four families with biallelic pathogenic missense or truncating variants [Firth et al 2009, Hamdan et al 2011, Allen et al 2013, Redin et al 2014, Farwell et al 2015, Ohba et al 2015, Zhu et al 2015, Bosch et al 2016, Halvardson et al 2016, Helbig et al 2016, Kobayashi et al 2016, Lemke et al 2016, Retterer et al 2016, Vanderver et al 2016, Chen et al 2017, Ortega-Moreno et al 2017, Rossi et al 2017, Tan et al 2017, Zehavi et al 2017, Dillon et al 2018, Fry et al 2018, Paderova et al 2018, Papa et al 2018, Pironti et al 2018, Staněk et al 2018]. The following description of the phenotypic spectrum associated with GRIN1-NDD is based on these reports. In 62 of the 72 reported individuals, clinical information was sufficient to draw conclusions on the overall phenotype (54 individuals heterozygous for a de novo missense variant and 8 individuals with homozygous variants). Of note, phenotypic data on 11 individuals with a heterozygous de novo variant comes from the DECIPHER database.
Developmental delay (DD) and intellectual disability (ID). All affected individuals have a variable degree of DD or ID (profound in 17%, severe in 71%, moderate in 7%, mild in 5%). No active speech has been noted in 48% of individuals.
Epilepsy. Seizures occurred in 65% of individuals. Some affected individuals presented with different seizure types over time. Where specified, seizures have been classified as epileptic spasms (13%), generalized seizures (68%), and focal seizures (20%). Seizure types reported among generalized and focal seizures comprise tonic-, tonic-clonic-, atonic and/or myoclonic seizures, bilateral eyelid myoclonus, focal dyscognitive seizures, absence seizures, focal motor seizures, gelastic seizures, and status epilepticus.
Onset of seizures ranged from birth to 11 years with a median onset of 22.5 months. In 27 individuals on whom follow up or outcome on treatment with antiepileptic drugs was available, 17 had refractory seizures and ten were well controlled with standard antiepileptic drugs.
Other neurologic findings
- Muscular hypotonia (in 66%)
- Spasticity (40%)
- Movement disorders (48%) and where specified, affected individuals showed signs of dystonic (13%), dyskinetic (11%), and/or choreiform movements (15%).
- Cortical visual impairment (34%)
- Oculogyric crisis (11%)
Behavior problems. Signs of autism spectrum disorder were observed in 22%. Other behavior problems included stereotypic movements (32%), self-injurious behavior (7%), and sleep disorder (15%).
Feeding difficulties / gastrointestinal abnormalities. Feeding difficulties were reported in 31% of individuals. Severe muscular hypotonia, gastroesophageal reflux, or oral-pharyngeal dysphagia with chewing and swallowing difficulty caused persistent feeding problems, requiring G-tube insertion in a subset of individuals.
Growth. Growth restriction or short stature was seen in 11% while microcephaly was documented in 27%.
Neuroimaging. A malformation of cortical development (MCD) consisting of extensive diffuse bilateral polymicrogyria has been seen in 11 individuals [Fry et al 2018]. Polymicrogyria-affected brain regions comprised frontal, perisylvian, parietal, and temporal areas with some occipital sparing. Additional variable findings included increased extra-axial spaces, enlarged lateral ventricles, reduced white matter volume, thinning of the corpus callosum, and abnormal hippocampi. The MCD was similar in appearance to tubulinopathy-related or GRIN2B-related dysgyria [Platzer et al 2017]. See GRIN2B- Related Neurodevelopmental Disorder.
Other signs repeatedly noted in individuals without an MCD were generalized volume loss or cerebral atrophy (23%).
Signs of a leukoencephalopathy have been noted in two individuals with nonspecific hyperintensities of the white matter [Vanderver et al 2016, Pironti et al 2018].
Other
- Scoliosis has been seen in 11% of affected individuals.
- No specific dysmorphic facial features have been observed. If present, dysmorphic features are nonspecific.
Prognosis. Psychomotor regression or loss of acquired skills has specifically been noted in one individual starting at age 3.5 years with loss of speech, impaired social interaction, drooling, and loss of sphincter control [Papa et al 2018].
It is unknown if life span in GRIN1-NDD is abnormal. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
Genotype-Phenotype Correlations
De novo heterozygous pathogenic variants in individuals with a malformation of cortical development (MCD) are located in the domains S2 and M3 [Fry et al 2018]. As there are only a few individuals with causative GRIN1 variants in these regions who do not have an MCD, a genotype-phenotype correlation is possible.
All three children from a family with a homozygous nonsense GRIN1 variant displayed a fatal developmental epileptic encephalopathy leading to death between ages five days and five months [Lemke et al 2016]. A comparable clinical course has not been reported in the five individuals with homozygous GRIN1 missense variants located in the amino-terminal domain [Bosch et al 2016, Lemke et al 2016, Rossi et al 2017] or in any individual with a de novo variant. The heterozygous parents of children homozygous for GRIN1 variants did not show any manifestations of GRIN1-NDD.
Penetrance
Penetrance of GRIN1-related neurodevelopmental disorder is thought to be 100%.
Prevalence
The prevalence of GRIN1-NDD in the general population is unknown. To date, reports on fewer than 100 individuals have been published.
Differential Diagnosis
Because the phenotypic features associated with GRIN1-related neurodevelopmental disorder (GRIN1-NDD) are not sufficient to diagnose this condition, all disorders with the following features should be considered in the differential diagnosis:
- Intellectual disability (ID) without other distinctive findings; to date more than 180 such disorders have been identified (see OMIM Phenotypic Series: Autosomal dominant ID, Autosomal recessive ID, Nonsyndromic X-linked ID, and Syndromic X-linked ID).
- Early-onset epileptic encephalopathy (EIEE); to date, more than 70 disorders with EIEE have been identified (see EIEE OMIM Phenotypic Series).
- Polymicrogyria (see Polymicrogyria Overview)
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with GRIN1-NDD, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 2.
Recommended Evaluations Following Initial Diagnosis in Individuals with GRIN1-Related Neurodevelopmental Disorder
| System/Concern | Evaluation | Comment |
|---|---|---|
| Eyes | Ophthalmologic evaluation | Assessment for cortical visual impairment & oculogyric crisis |
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team evaluation | Assessment for feeding difficulties, nutrition, weight gain, constipation, & gastroesophageal reflux disease |
| Musculoskeletal | Orthopedics / physical medicine & rehabilitation / physical therapy (PT) / occupational therapy (OT) evaluation | Examination for muscular hypotonia, spasticity, & scoliosis To incl assessment of:
|
| Neurologic | Neurologic evaluation | Incl clinical evaluation for movement disorders, seizures, EEG, & brain MRI |
| Development | Developmental assessment | To incl:
|
| Psychiatric/ Behavioral | Neuropsychiatric evaluation | For individuals age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD |
| Miscellaneous/ Other | Family supports/resources | Assess:
|
| Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling |
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Treatment of Manifestations
Table 3.
Treatment of Manifestations in Individuals with GRIN1-Related Neurodevelopmental Disorder
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Developmental delay / Intellectual disability | See Developmental Delay - Intellectual Disability Educational Issues. | |
| Central visual impairment | No specific treatment; early intervention w/vision therapy may help to stimulate visual development. | |
| Seizures | Standardized treatment w/AEDs by experienced neurologist |
|
| Muscular hypotonia, spasticity, & movement disorder | Orthopedics / physical medicine & rehabilitation / PT / OT incl stretching to help prevent contractures & falls | Consider need for positioning & mobility devices, disability parking placard |
AED = antiepileptic drug; OT = occupational therapy; PT = physical therapy
- 1.
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states and provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; however, for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
- IEP services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine if any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
- Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
- For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech language pathologist who has AAC expertise. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and in many cases, can improve it.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
Table 4.
Recommended Surveillance for Individuals with GRIN1-Related Neurodevelopmental Disorder
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Eyes | Ophthalmologic evaluation | At time of diagnosis & then as clinically indicated |
| Gastrointestinal | Feeding, nutrition status, weight gain | As clinically indicated |
| Musculoskeletal | Examination for muscular hypotonia, spasticity, & scoliosis | As clinically indicated |
| Neurologic | Monitor those w/seizures. | As clinically indicated |
| Psychiatric | Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior | As clinically indicated |
| Miscellaneous/ Other | Monitor developmental progress & educational needs. | As clinically indicated |
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.