The first symptom of PRICKLE1-related PME with ataxia syndrome (or EPM-1B) is usually ataxia, around 4 years of age, but it has been reported even before (up to 15 months of age), being characterized mainly by gait disturbances and action tremor. Action or other stimuli-induced myoclonus is also often present, together with ataxic tremor.
Seizures onset is usually between 5 and 10 years of age (mean around 7 years). The most common seizure types are myoclonic and generalized tonic-clonic seizures, but also atonic and focal motor seizures have been reported. Myoclonic and generalized seizures are often photosensitive.
Other clinical features may include dysarthria (with or without dysphagia), axonal neuropathy with absent limb reflexes, impaired vibration sense and proprioception, extensor plantar responses. Upward gaze palsy has also been reported in some patients.
With regard to the outcome, progressive ataxia has been reported, so that in some cases patients become wheelchair-bound. In contrast with other types of PME, which are associated with early and severe cognitive decline, in PRICKLE1-related PME with ataxia usually there is no cognitive impairment or only mild intellectual disability.
In patients with this syndrome brain MRI is usually normal, while EEG may show unspecific generalized or paroxysmal sharp/slow-wave activity with or without background slowing.
Notably, it has been reported one case of homozygous mutation of PRICKLE1 with developmental and epileptic encephalopathy characterized by very early-onset (10 months) drug-resistant epilepsy, associated with ataxia, developmental arrest and intellectual disability.
A case of sudden unexpected death due to status epilepticus in an adult individual has also been reported. This patient had no previous history of medical attention and presented a compound heterozygous mutation of PRICKLE1.
The broad phenotypic spectrum of PRICKLE1-related conditions include also several neural tube defects and other CNS malformations associated with heterozygous mutation, such as the following: myelomeningocele, tethered cord, hydrocephalus, diastematomyelia, caudal agenesis, Chiari type II malformation, agenesis of the corpus callosum, ventriculomegaly, and polymicrogyria.
Some other patients with different heterozygous variants of PRICKLE1 show myoclonic seizures without ataxia nor pathological findings at neuroimaging studies.
Remarkably it has also been reported one case of a de novo mutation in PRICKLE1-associated with myoclonic seizures, mild intellectual disability and autism spectrum disorder with normal MRI.
PRICKLE1