Table 2.

Allelic Disorders

GeneClinical Characteristics
ATP1A2 Alternating hemiplegia of childhood (OMIM 104290), characterized by intermittent recurrent prolonged hemiplegic episodes that mimic hemiplegic migraine
Polymicrogyric syndrome 1
CACNA1A Episodic ataxia type 2 (OMIM 108500). Episodes of ataxia & sometimes migrainous headache w/interictal nystagmus. In 1 family, affected members experienced hemiplegia; 1 family member had migraine during episodes of ataxia. 2 Assoc pathogenic variants: nonsense, frameshift, & splice site variants & multiexon deletions that disrupt the open reading frame
Progressive cerebellar ataxia. Severe progressive ataxia & cerebellar atrophy. Assoc pathogenic variants: missense variants incl p.Gly293Arg in P loop of 1st domain; p.Ala454Thr in I-II loop; p.Arg1664Gln
Spinocerebellar ataxia type 6 (SCA6). Adult-onset, slowly progressive cerebellar ataxia, dysarthria, & nystagmus. Assoc w/a CAG repeat expansion; this expansion has not been observed in families w/FHM 3 but some persons w/SCA6 may have migraine.
Developmental & epileptic encephalopathy 42 (OMIM 617106). De novo pathogenic variants in CACNA1A are recognized to be an important cause of epileptic encephalopathy. 4
SCN1A The vast majority of pathogenic variants in SCN1A cause epilepsy. SCN1A seizure disorders encompass a spectrum from simple febrile seizures & generalized epilepsy w/febrile seizures plus to Dravet syndrome & intractable childhood epilepsy w/generalized tonic-clonic seizures. Phenotypes w/intractable seizures incl Dravet syndrome are usually assoc w/progressive cognitive & motor decline.
Interstitial deletions of 2q24-q3 (incl a cluster of voltage-gated sodium channel genes: SCN1A, SCN2A, SCN3A, SCN7A, SCN9A) are assoc w/tonic focal & myoclonic jerks that tend to appear in infancy & are later followed by mixed-type seizures, which persist to late childhood & are drug resistant. 5
Larger deletions of 2q24.3 are assoc w/dysmorphic features (e.g., microcephaly, ptosis, downslanting palpebral fissures, long eyelashes, micrognathia), 6 & digit anomalies in persons w/2q24-q31 deletions. 7
Reported duplications of 2q24.2-q3 involving the cluster of voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN7A, & SCN9A vary in size. Reported persons presented w/focal seizures & epileptic spasms w/neonatal onset (as early as 3rd day of life). 8
Familial autism 9
Rasmussen encephalitis assoc w/pathogenic variant p.Arg1575Cys 10

From: Familial Hemiplegic Migraine

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