Penetrance

The penetrance of PRRT2-related disorder ranges from 50% to 90% ; thus, individuals heterozygous for a known PRRT2 pathogenic variant may be clinically unaffected. Among the core phenotypes, penetrance is estimated to be 75%-95% for PRRT2-related SeLIE, 50%-61% for PRRT2-related PKD, and up to 87% for PRRT2-related HM .

Source: GeneReviews — "PRRT2-Related Disorder"

Diagnostic Criteria

Suggestive Findings

PRRT2-related disorder (PRRT2-RD) should be considered in individuals with any one of the following core phenotypes and/or in individuals with a paroxysmal movement disorder and a positive family history of any of the core phenotypes.

Self-Limited (Familial) Infantile Epilepsy (SeLIE)

SeLIE is characterized by the following clinical and supportive findings .

Source: GeneReviews — "PRRT2-Related Disorder"

Differential Diagnosis

PRRT2 pathogenic variants are found in the majority of individuals with paroxysmal kinesigenic dyskinesia (PKD), up to 70% of individuals with self-limited (familial) infantile epilepsy (SeLIE), and almost all individuals with PKD with infantile convulsions (PKD/IC) . It is proposed to be the fourth most common gene associated with familial hemiplegic migraines . PRRT2 pathogenic variants are rarely identified in individuals with childhood absence epilepsy , episodic ataxia , and paroxysmal torticollis . PRRT2-related paroxysmal hypnogenic dyskinesia has been reported in only two individuals to date . Other genes known to be associated with these phenotypes are listed in . Table 3. Genes of Interest in the Differential Diagnosis of PRRT2-Related Disorder

Management Guidelines

No clinical practice guidelines for PRRT2-related disorder have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PRRT2-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. PRRT2-Related Disorder: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "PRRT2-Related Disorder"

Clinical Guidance

SeLIE. Treat fevers promptly. PKD. Avoid stress, sleep deprivation, and anxiety (consistently reported as factors that increase the likelihood for PKD episodes) and other triggers to help prevent attacks and lower attack frequency. HM. Use triptans and dihydroergotamine with caution due to their associated increased risk of ischemic vascular events.

Source: GeneReviews — "PRRT2-Related Disorder"

Surveillance Guidelines

Monitoring existing manifestations, the individual's response to supportive care, and the emergence of new manifestations requires regularly scheduled follow up with the treating neurologist as well as educators and social services. The evaluations summarized in are recommended.

Table 6.

PRRT2-Related Disorder: Recommended Surveillance

System/Concern | Evaluation | Frequency

Seizures

| • Neurologic exam baseline EEG

• Imaging further workup per treating neurologist

| Per treating neurologist

Paroxysmal dyskinesias

| • Neurologic exam

• Imaging further workup per treating neurologist

| Once every 1-2 yrs

Hemiplegic events

| On 1st occurrence then 1x/yr

Development (young children)

| Monitor developmental progress educational needs. | At each visit

Cognition (older children/adults)

Family/Community

| Assess family need for social work support or follow-up genetic counseling if new questions arise (e.g., family planning).

Source: GeneReviews — "PRRT2-Related Disorder"