Recurrent coma and fever in familial hemiplegic migraine type 2. A prospective 15-year follow-up of a large family with a novelATP1A2mutation

Abstract

Background Familial hemiplegic migraine (FHM) is a rare monogenic migraine subtype characterised by attacks associated with transient motor weakness. Clinical information is mainly based on reports of small families with only short follow-up. Here, we document a prospective 15-year follow-up of an extended family with FHM type 2. Patients and methods After diagnosing FHM in a patient with severe attacks associated with coma and fever, we identified eight more family members with FHM and one with possible FHM. All family members were prospectively followed for 15 years. In total 13 clinically affected and 21 clinically non-affected family members were genetically tested and repeatedly investigated. Results A novel p.Arg348Pro ATP1A2 mutation was found in 14 family members: 12 with clinical FHM, one with psychomotor retardation and possible FHM, and one without FHM features. In 9/12 (75%) family members with genetically confirmed FHM, attacks were severe, long-lasting, and often associated with impaired consciousness and fever. Such attacks were frequently misdiagnosed and treated as viral meningitis or stroke. Epilepsy was reported in three family members with FHM and in the one with psychomotor retardation and possible FHM. Ataxia was not observed. Conclusion FHM should be considered in patients with recurrent coma and fever.

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

“…FHM-causing mutations have been identified in three genes encoding a calcium channel (FHM1), a sodium channel (FHM3) and the alpha2 subunit (FHM2) (De Fusco et al, 2003). At least 80 mutations in ATP1A2 have been described to cause FHM2 (Figure 4, reviewed in Bottger et al, 2012; Pelzer et al, 2016). In contrast to the ATP1A1 mutations that all target recurrent hotspots, many of the mutations in ATP1A2 have been reported just once, and they affect both the transmembrane and the cytoplasmic parts of the protein.…”

Familial Hemiplegic Migraine with Severe Attacks: A New Report withATP1A2Mutation

“…We present a table with the mutations described in the literature from 2003 to 2016 and their main phenotypic characteristics (Table 1). Some of the mutations produce long-lasting attacks of hemiplegic migraine, but they are related to other neurological pathologies such as seizures and mental retardation [1], coma, and fever [23]. The case we present had no other neurological diseases apart from FHM.…”

Early Treatment in Acute Severe Encephalopathy Caused by ATP1A2 Mutation of Familial Hemiplegic Migraine Type 2: Case Report and Literature Review

“…Moreover, the confusion, hemiplegia, hemiconvulsions, disturbances of consciousness, and extensive cytotoxic edema indicating severity of the disease are considered to be part of the same spectrum in FHM2, and CSD has been suggested as a possible underlying mechanism. 13 Furthermore, glutamate excitotoxicity can also produce secondary mitochondrial metabolic dysfunctions, and some studies about FHM2 have showed mild reduction in NAA and mild increase in lactate content in 1 H-MRS, cytotoxic edema such as an eosinophilic change of neurons, acute swelling of oligodendrocytes and astrocytes in the widespread cerebral cortex, and subcortical white matter in autopsy, suggesting some abnormalities with other metabolic diseases such as mitochondrial encephalopathy in FHM2. 14 In this case, the patient was diagnosed with severe encephalopathy of FHM2, presenting extensive cortical edema in neuroimaging, progressive symptoms, and neurological deficits, suggesting long-lasting duration of the disease.…”