Paroxysmal Nonkinesigenic Dyskinesia, 3, With Or Without Generalized Epilepsy

A number sign (#) is used with this entry because of evidence that paroxysmal nonkinesigenic dyskinesia-3 with or without generalized epilepsy (PNKD3) is caused by heterozygous mutation in the KCNMA1 gene (600150) on chromosome 10q22.

For a discussion of genetic heterogeneity of paroxysmal nonkinesigenic dyskinesia, see PNKD1 (118800).

Clinical Features

The coexistence of epilepsy and paroxysmal dyskinesia in the same individual or family had been described by Guerrini (2001), Guerrini et al. (2002), and others. Du et al. (2005) studied a large family of European descent with the combination of generalized epilepsy and paroxysmal dyskinesia (GEPD). Among 16 affected individuals, 4 developed isolated epileptic seizures, 7 had isolated paroxysmal nonkinesigenic dyskinesia, and 5 had both phenotypes. All patients except 1 had onset of symptoms in infancy or early childhood; 1 patient with isolated PNKD had onset in the early teens. Most patients had absence seizures, although 2 also had generalized tonic-clonic seizures. Interictal electroencephalography (EEG) showed generalized spike-wave complexes.

Clinical Variability

Zhang et al. (2015) reported 2 unrelated Chinese boys who presented with isolated paroxysmal nonkinesigenic dystonia in infancy. The clinical courses varied somewhat. One child first presented at 20 days of age, and the episodes lasted several minutes to 30 minutes. The episodes occurred once a week initially and 2 to 7 times per day after 1 year, and they were sometimes associated with nystagmus and strabismus. This patient also had sudden decreases in voluntary movement with hypotonia, occasional esotropia, and yawning, lasting as long as 1 hour and occurring once or twice a day. Medication was not beneficial. This patient had severe developmental delay, with sitting at almost 2 years of age and poor understanding of language. The second patient had onset of PNKD at age 7 months. The episodes lasted seconds to minutes and occurred 3 to 5 times a day to once per week. The episodes could be controlled by clonazepam. He had mild developmental delay and poor school performance later in childhood. Triggers of the episodes were not observed in either patient, and ictal and interictal EEG was normal in both patients, excluding a diagnosis of epilepsy, although Zhang et al. (2015) noted that the likelihood of these patients developing later-onset epilepsy could not be ruled out. Brain imaging in both patients was also normal. All parents were unaffected.

Inheritance

The transmission pattern of PNKD3 in the family reported by Du et al. (2005) was consistent with autosomal dominant inheritance.

Mapping

By genomewide linkage scan in a large 5-generation family of mixed European descent, Du et al. (2005) demonstrated a locus on 10q22 and narrowed the disease-associated interval to a region of 8.4 cM. The 10q22 locus associated with GEPD contained 40 genes.

Molecular Genetics

In all 13 affected members of a family with PNKD3, Du et al. (2005) identified a heterozygous missense mutation in the KCNMA1 gene (D434G; 600150.0001). Du et al. (2005) showed that the D434G mutant BK channel had a markedly greater macroscopic current. Single-channel recordings showed an increase in open-channel probability due to a 3- to 5-fold increase in Ca(2+) sensitivity. The authors proposed that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. The study suggested that BK channel-blocking agents might be used in therapy for epilepsy and paroxysmal dyskinesia.

In 2 unrelated Chinese boys with isolated PNKD3 and developmental delay but without seizures, Zhang et al. (2015) identified de novo heterozygous missense mutations in the KCNMA1 gene (E884K, 600150.0002 and N1053S, 600150.0003). The mutations were found by candidate gene screening and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed.