Table 1.
Phenotypic clues in select neurogenetic syndromes associated with paroxysmal neurological symptoms [modified from Silveira-Moriyama et al. (1)].
| Gene | Paroxysmal dyskinesia | Episodic ataxia | Epilepsy | Inheritance | Phenotype summary |
|---|---|---|---|---|---|
| PRRT2 | ✓ | ✓ | ✓ | AD | Most commonly: Classic PKD, benign familial infantile seizures, hemiplegic migraine, episodic ataxia. PKD has short duration (<1 min), high frequency (>daily), often asymmetric or unilateral, but also bilateral; may be chorea/dystonia/mix; may present sensory aura before attack; excellent response to low dose antiepileptic (carbamazepine and phenytoin are the most used, in this order); onset in the second decade of life and improvement or remission in the fourth decade of life. Family history of epilepsy or migraine is common. |
| SCN8A | ✓ | ✓ | AD | Most commonly developmental epileptic encephalopathy with onset < 2 years old; interictal movement disorders, tremor and hyperekplexia. Milder phenotypes exist combining BFIS, PKD. | |
| DEPDC5 | ✓ | ✓ | AD | Most commonly: Focal family epilepsy with variable foci. Has been reported in the “typical” PKD phenotype, with abnormal interictal EEG. | |
| CHRNA4 | ✓ | ✓ | AD | Most commonly: Autosomal dominant nocturnal frontal lobe epilepsy. Anecdotal reports of individuals with paroxysmal dyskinesia | |
| SLC16A2 | ✓ | XL | Allan Herndon-Dudley syndrome: Intellectual disability, choreoathetosis, spastic paraparesis, and thyroid hormone abnormalities. May have associated paroxysmal dyskinesia sometimes triggered by passive movements. | ||
| PNKD | ✓ | AD | Most common phenotype: PNKD starting in infancy or childhood; mix of chorea and dystonia; attacks lasting between min and 1 h, not triggered by sudden movement or exercise, but triggered by caffeine or alcohol intake, as well as emotional stress; response to benzodiazepines; not associated with epilepsy. May have migraine. | ||
| ATP1A3 | ✓ | ✓ | ✓ | AD | Most common phenotypes: AHC, RDP, CAPOS, D-DEMØ. AHC starts in infancy and presents with episodes of hemiplegia and often hemidystonia. It usually evolves with epilepsy and loss of developmental milestones, and often persistent movement disorder. The RDP phenotype does not usually cause paroxysmal dystonia, but persistent dystonia and/or parkinsonism of subacute onset. Paroxysmal ataxia, later becoming persistent, is also described in ATP1A3 mutations. Epilepsy is most consistently associated with AHC and has infantile onset in most. |
| ATP1A2 | ✓ | ✓ | AD | Alternating hemiplegia of childhood; Hemiplegic migraine. Some cases described with epilepsyand exacerbations including encephalopathy and paroxysmal dystonia. | |
| KCNMA1 | ✓ | ✓ | AD, AR* | In AD state, may resemble “classic” PNKD, but with associated epilepsy and developmental delay. May respond to stimulant. Phenotype is more severe in AR mutations with epilepsy, intellectual disability and cerebellar atrophy. | |
| SLC2A1 | ✓ | ✓ | ✓ | AD, AR* | Most common phenotypes: Infantile epilepsy, classic PED, PED associated with epilepsy. PED often in lower limbs; dystonia>chorea; low glucose CSF in some but not all patients; usually does not respond well to antiepileptic drugs. Age at onset is quite variable from childhood to adulthood. Family history of epilepsy is common. Variable penetrance and expressivity. Very rare homozyogous/compound heterozygous cases. |
| ECHS1 | ✓ | ✓ | AR | Leigh-disease like phenotype with clinical and imaging characteristics. Some patients may have paroxysmal exertional dyskinesia, either as an isolated finding or as an intermediate phenotype. | |
| TBC1D24 | ✓ | ✓ | ✓ | AR | Expanding phenotype including developmental delay, hearing impairment, DOORS syndrome, epilepsy, myoclonus, and paroxysmal neurological symptoms including PKD, PED and EA |
| GCH1 | ✓ | AD, AR* | Most common phenotypes: Dopa responsive dystonia. PED with dystonic features is a rare initial presentation in children, usually in the lower limbs, with excellent response to levodopa; GCH1 has AD inheritance but recessive forms are possible with usually with more severe phenotype and infantile onset. | ||
| PARKIN | ✓ | AR | Most common phenotypes: levodopa responsive Parkinsonism. PED with dystonic features is rarely seen, usually in the lower limbs, with excellent response to levodopa, usually starts in young adulthood. Family history of consanguinity can be a clue since AR inheritance. | ||
| ACDY5 | ✓ | AD | Most common phenotypes: Familial dyskinesia with facial myokymia. Paroxysmal dyskinesia brought on by stress or sleep may be the initial presentation, some patients have history of developmental delay or hypotonia. Older family members may present with persistent dyskinesias; dyskinesias may also improve in adult life. | ||
| KCNA1 | ✓ | ✓ | ✓ | AD | Most common phenotype: Episodic ataxia with interictal myokymia. A subset may have epilepsy with partial or generalized seizures, rarely epileptic encephalopathy. |
| CACNA1A | ✓ | ✓ | AD | Most common phenotype: Episodic ataxia with interictal nystagmus; some may have cerebellar atrophy and progressive interictal ataxia. Can respond to acetazolamide. Other paroxysmal disorders include hemiplegic migraine, epilepsy and possibly paroxysmal torticollis and paroxysmal tonic upgaze. Emerging evidence of role in neurodevelopmental disabilities. | |
| CACNB4 | ✓ | ✓ | AD, AR* | AD inheritance with episodic ataxia, predisposition to epilepsy. In recessive state can have severe phenotype. | |
| SLC1A3 | ✓ | ✓ | AD | Phenotype similar to CACNA1A (EA2), some reported cases with seizures, migraine, alternating hemiplegia and chronic ataxia. | |
| SCN2A | ✓ | ✓ | AD | Wide phenotypic variability with epileptic encephalopathy, benign familial neonatal seizures, interictal hyperkinetic movement disorder, and episodic ataxia. | |
| KCNA2 | ✓ | ✓ | AD | Epileptic encephalopathy and chronic ataxia, some patients reported episodic attacksa and infantile-onset seizures |
AD, Autosomal Dominant; AR, Autosomal Recessive: XL, X-Linked, DOORS, Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation Syndrome; EA, Episodic Ataxia.
The * indicates a possible but less common mode of inheritance.