GNAI1-Related Neurodevelopmental Disorder

Excerpt

Clinical characteristics: GNAI1-related neurodevelopmental disorder (GNAI1-NDD) is characterized by mild-to-profound developmental delay and intellectual disability, hypotonia, neurobehavioral and/or psychiatric manifestations, and epilepsy. The neurobehavioral and/or psychiatric manifestations include features of autism spectrum disorder such as stereotypic behaviors (hand flapping, head banging, hand wringing, repetitive noises, teeth grinding, mouthing behaviors), sensory sensitivities, and poor eye contact. Temper tantrums, anxiety, agitation, aggression, and attention-deficit/hyperactivity disorder are also reported. Seizure onset typically occurs within the first six months of life; seizure types include absence, generalized tonic-clonic, and focal-onset impaired awareness. Additional common features include scoliosis, hip dysplasia, feeding difficulties or obesity with insatiable appetite, constipation, and strabismus.

Diagnosis/testing: The diagnosis of GNAI1-NDD is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in GNAI1 identified by molecular genetic testing.

Management: Treatment of manifestations: Developmental and educational services; standard epilepsy treatment with anti-seizure medications by an experienced neurologist; physical medicine and rehabilitation, physical therapy, and occupational therapy to include stretching to help avoid contractures and falls; feeding therapy with gastrostomy tube placement as needed; standard treatments for constipation and strabismus; social work support and care coordination as needed.

Surveillance: At each visit, assess developmental progress, educational needs, mobility and self-help skills, growth, nutrition, and family needs, as well as for new seizures or changes in seizures, scoliosis, and constipation; behavioral assessment for autistic features, anxiety, attention-deficit/hyperactivity disorder, and aggressive or self-injurious behaviors as needed.

Genetic counseling: GNAI1-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. If the GNAI1 pathogenic variant identified in the proband is not identified in either parent, the recurrence risk to sibs is estimated to be 1%-8% because of the possibility of parental germline mosaicism. Once the GNAI1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.