Familial hemiplegic migraine is a subtype of migraine with aura (see 157300). FHM was first described by Clarke (1910) in a family in which attacks of hemicranial pain and associated hemiparesis occurred in 4 generations. Rosenbaum (1960) described ... Familial hemiplegic migraine is a subtype of migraine with aura (see 157300). FHM was first described by Clarke (1910) in a family in which attacks of hemicranial pain and associated hemiparesis occurred in 4 generations. Rosenbaum (1960) described a family. Vasoconstriction, followed by focal edema, was thought to be responsible for the neurologic manifestations. Subsequent authors have reported additional associated features: persistent cerebellar dysfunction (Ohta et al., 1967); retinal degeneration, deafness, and nystagmus (Young et al., 1970); coma, fever, and meningismus (Munte and Muller-Vahl, 1990). The pattern of inheritance in these and other reported families was autosomal dominant. Also see Blau and Whitty (1955) and Glista et al. (1975). As Bradshaw and Parsons (1965) and Young et al. (1970) pointed out, hemiplegic and 'ordinary' migraine can occur in the same family, which suggests that they are basically the same entity. Joutel et al. (1993) noted that familial hemiplegic migraine had been reported in approximately 40 families. The age of onset varies from 5 to 30 years with a predominance during youth. Minor head trauma and cerebral angiography are well established triggering factors. Attacks are characterized by the presence of hemiparesis or hemiplegia, either isolated or associated with other aura symptoms such as hemianopic blurring of vision, unilateral paresthesias or numbness, and dysphasia. These symptoms usually last 30 to 60 minutes and are followed by a severe pulsatile headache lasting a few hours or days. In severe attacks, hemiplegia is often associated with fever, drowsiness, confusion, or coma, which usually also resolve within a few hours, days, or sometimes weeks. Marchioni et al. (1995) reported an affected mother with 2 affected sons and 1 affected daughter with prolonged episodes of hemiplegia lasting from 3 to 120 hours. Interictal electroencephalography demonstrated theta abnormalities contralateral to the side of the hemiparesis. Three of these individuals demonstrated minor neuropsychiatric difficulties such as dyscalculia, attention disturbances, and impaired long-term verbal memory when tested 2 months after their most recent attack. Marchioni et al. (1995) pointed out the difficulty of distinguishing between the diagnostic criteria of hemiplegic migraine versus migraine with prolonged aura, as promulgated by the International Headache Society. Spranger et al. (1999) reported a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks. The family consisted of 3 generations in which 3 members were affected with hemiplegic migraine associated with cerebellar ataxia and 2 additional members suffered only from cerebellar ataxia. In 2 patients, the migrainous headache was followed by an episode of paranoid psychosis within 24 hours. Both patients initially presented with acute panic attacks with anxiety, severe psychomotor agitation, and a perplexed facial expression. Retrospectively, the patients reported visual and auditory hallucinations. Based on the clinical and haplotype evidence indicating linkage to chromosome 19 in this family, they hypothesized that a dysfunction of the CACNL1A4 channel may be involved not only in the development of hemiplegic migraine but also in the acute psychotic episodes observed in these patients. Riant et al. (2010) identified putative pathogenic de novo mutations in the CACNA1A gene in 8 (32%) of 25 patients with onset of sporadic hemiplegic migraine before age 16 years. Only 1 patient had pure hemiplegic migraine. The 7 other patients had various associated neurologic features, including permanent cerebellar ataxia in 5, seizures in 4, and severe learning and motor delay in 4. Four patients had a particularly severe phenotype, with early presentation of hypotonia, ataxia, and delayed development, but only developing hemiplegic migraine episodes in later in childhood. All 4 of these patients later had mental retardation and marked ataxia. Three patients had episodes of unconsciousness or prolonged coma. Among the remaining patients with sporadic disease, 11 (44%) had de novo mutations in the ATP1A2 gene, resulting in an overall mutation frequency of 76% among patients with early-onset sporadic hemiplegic migraine. Overall, the phenotype was more severe in patients with CACNA1A mutations.
Ophoff et al. (1996) demonstrated 4 different missense mutations in conserved functional domains of the CACNL1A4 gene (601011.0001-601011.0004) in 5 unrelated families with familial hemiplegic migraine. Ducros et al. (1999) screened 16 families and 3 nonfamilial cases with ... Ophoff et al. (1996) demonstrated 4 different missense mutations in conserved functional domains of the CACNL1A4 gene (601011.0001-601011.0004) in 5 unrelated families with familial hemiplegic migraine. Ducros et al. (1999) screened 16 families and 3 nonfamilial cases with hemiplegic migraine associated with progressive cerebellar ataxia. They found the T666M mutation in the CACNA1A gene (601011.0002) in 9 families and 1 nonfamilial case. The T666M mutation was absent in 12 probands belonging to pure MHP families whose disease appeared to be linked to CACNA1A. In 2 of 27 patients with sporadic hemiplegic migraine, Terwindt et al. (2002) identified 2 mutations in the CACNA1A gene: T666M and arg583 to gln (R583Q; 601011.0018). Both mutations had previously been found in patients with FHM and progressive cerebellar ataxia. In a retrospective Finnish study, Majamaa et al. (1998) found mitochondrial DNA haplogroup U to be a significant risk factor for occipital strokes associated with migraine, although not with migraine itself.