Clinical Guidance

Many recurrent GNB1 variants have been associated with phenotypic variability among individuals with the same variant. Although not conclusive, the following genotype-phenotype correlations have been proposed:

• Fifty-five percent of individuals with dystonia had a p.Ile80 substitution ( or ). This possible genotype-phenotype correlation was initially suggested by .

• Three of the four individuals with cutaneous mastocytosis had the p.Ile80Thr variant .

• A genotype-phenotype correlation between the p.Ile80Thr variant and severe axial hypotonia or hypotonic quadriplegia has been suggested .

Source: GeneReviews — "GNB1 Encephalopathy"

Penetrance

Most probands reported to date with GNB1-E whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GNB1 pathogenic variant. Penetrance is expected to be 100%.

Source: GeneReviews — "GNB1 Encephalopathy"

Diagnostic Criteria

Formal diagnostic criteria for GNB1 encephalopathy have not been established.

Suggestive Findings

GNB1 encephalopathy (GNB1-E) should be considered in individuals with the following clinical findings.

Clinical findings

Source: GeneReviews — "GNB1 Encephalopathy"

Differential Diagnosis

Because the phenotypic features associated with GNB1 encephalopathy are not sufficient to diagnose this condition clinically, all disorders with intellectual disability and/or seizures without other distinctive findings should be considered in the differential diagnosis. See OMIM Phenotypic Series:

• Autosomal Dominant Intellectual Developmental Disorder

• Autosomal Recessive Intellectual Developmental Disorder

• Nonsyndromic X-Linked Intellectual Developmental Disorder

• Syndromic X-Linked Intellectual Developmental Disorder

• Epileptic Encephalopathy, Early Infantile

Source: GeneReviews — "GNB1 Encephalopathy"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with GNB1 encephalopathy, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with GNB1 Encephalopathy

Source: GeneReviews — "GNB1 Encephalopathy"

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.

Source: GeneReviews — "GNB1 Encephalopathy"

Surveillance Guidelines

Table 5.

Recommended Surveillance for Individuals with GNB1 Encephalopathy

System/Concern

|

Evaluation

|

Frequency

Feeding

| • Measurement of growth parameters

• Evaluation of nutritional status safety of oral intake

| At each visit

Gastrointestinal

| Monitor for recurrent constipation, cyclic vomiting, gastroesophageal reflux, distended abdomen w/cramps.

Neurologic

| • Monitor those w/seizures as clinically indicated.

• Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).

Development

| Monitor developmental progress educational needs.

Psychiatric/

Behavioral

| Behavioral assessment for anxiety, attention, aggressive or self-injurious behavior

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, self-help skills

Hematologic

| • CBC to monitor for hematologic malignancies

• Education of family re early clinical signs of hematologic malignancies (e.g., easy bruising due to thrombocytopenia)

| Every 6 mos - yr

Skin | Dermatologic evaluation to monitor for development of mastocytosis | At each visit

Miscellaneous/

Other

| Assess family need for social work support (e.g., palliative/respite care, home nursing; other local resources) care coordination.

CBC = complete blood count; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "GNB1 Encephalopathy"