Clinical characteristics: Individuals with biallelic PRICKLE1-related disorders typically present with progressive myoclonus epilepsy (PME) with ataxia characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, varying degrees of neurologic regression mainly presenting with ataxia, and mild cognitive impairment or normal cognition. Onset of symptoms is between ages five and ten years. Action myoclonus may affect the limbs or bulbar muscles, while spontaneous myoclonus may occasionally involve facial muscles. Dysarthria may also be an early feature of this condition. The main seizure types are myoclonic or tonic-clonic with frequent nocturnal occurrence.

Individuals with heterozygous PRICKLE1 pathogenic variants have presented with non-PME seizures (isolated myoclonic seizures, juvenile myoclonic epilepsy), myoclonic epilepsy, developmental delay, intellectual disability, autism spectrum disorder, and/or central nervous system malformations.

Diagnosis/testing: The diagnosis of a PRICKLE1-related disorder is established in a proband with suggestive findings and biallelic or heterozygous pathogenic variant(s) in PRICKLE1 identified by molecular genetic testing.

Management: Treatment of manifestations: Occupational therapy, psychomotricity/physical therapy, and speech therapy for ataxia and neurodevelopmental impairment; adaptive devices as needed to maintain or improve independence in mobility and feeding; anti-seizure medications as needed, such as valproic acid, clonazepam, zonisamide, and levetiracetam.

Surveillance: Neurologic examination every six months; developmental assessment and evaluation of school performance and emotional status every six to 12 months as needed based on age.

Agents/circumstances to avoid: Phenytoin, carbamezapine, oxycarbazpine, gabapentin, pregabalin, tiagabine, and vigabatrin may worsen myoclonic seizures.

Genetic counseling: PRICKLE1-related PME with ataxia is associated with biallelic homozygous or compound heterozygous PRICKLE1 pathogenic variants and inherited in an autosomal recessive manner. PRICKLE1-related phenotypes associated with a heterozygous PRICKLE1 pathogenic variant are inherited in an autosomal dominant manner.

1. Autosomal recessive inheritance. If both parents of a proband with PRICKLE1-related PME with ataxia are known to be heterozygous for a PRICKLE1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial PRICKLE1 pathogenic variants.

2. Autosomal dominant inheritance. An individual with an autosomal dominant PRICKLE1-related disorder may have the disorder as the result of a de novo pathogenic variant or a pathogenic variant inherited from a parent. Each child of an individual with a heterozygous PRICKLE1 pathogenic variant has a 50% chance of inheriting the pathogenic variant.

Once the PRICKLE1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for PRICKLE1-related disorders are possible.