Familial Hemiplegic Migraine with an ATP1A4 Mutation: Clinical Spectrum and Carbamazepine Efficacy

Abstract

An Italian family with familial hemiplegic migraine (FHM) with the absence of mutations in the known genes associated with this disorder, namely ATP1A2, ATP1A3, CACNA1A, and SCN1A, has recently been reported. Soon afterward, whole exome sequencing allowed the identification of the carrier status of a heterozygous ATP1A4 mutation c.1798 C >T, in four affected members of this family. Here we compare the clinical symptoms of the affected family members with those from the other FHM families linked to mutations in the known genes associated with this disorder. A further two-year follow-up, including clinical response to carbamazepine administered to the proband and the maternal grandmother due to a worsening of the migraine symptoms, is reported. The clinical condition of the proband’s brother, carrying the same mutation and suffering from congenital ventricular and supraventricular extrasystoles, isdiscussed as well.

Migraine and Its Equivalents: What Do They Share? A Narrative Review on Common Pathophysiological Patterns

“…The same mutation was also found in the subjects with absence or episodic ataxia [66,67]. Other mutations involved in familial hemiplegic migraines are: ATP1A, encoding a sodium-potassiumtransporting ATPase subunit in FHM type 2 [68,69]; SCN1A, a voltage-gated sodium channel subunit, in FMH tipe 3 [70] while no mutation has been identified to date in FMH type 4. A PRRT2 mutation was described in a family with benign paroxysmal torticollis, hemiplegic migraine and paroxysmal kinesigenic dystonia [71].…”

“…CGRP and serotonin involved in the modulation of cortical spreading depression, cortical pain transmission and intestinal microbiota [50] hyperactivation of the parasympathetic and sympathetic nervous systems and alterations of adrenergic autonomic system [51] Abdominal migraine mitochondrial disease gene mutations and hypothalamic-pituitary-axis dysfunction [33] Infantile colic hypersensitivity influenced by circadian biology and CGRP modulates the sensory activity that, on its turn, is potentially involved in the pathogenesis of abdominal pain by inducing the neurogenic inflammation of sensory neurons in the gut [50] Benign paroxysmal vertigo defective neuronal channel activity [28] Benign paroxysmal torticollis mutation of calcium ion, sodium/potassium pump and sodium transporter (CACNA1A, ATP1A2 and SCN1A) [66][67][68][69][70] Motion sickness vestibular instability due to a defective calcium ion channel, involvement of vomiting center [77] Recurrent limb pains are recurrent short episodes of pain lasting until 72 h leading to an interruption of activities. Pain is localized deeply in the extremities of arms or legs.…”

Case Report: Migraine-Induced Dystonia of the Lower Extremities

“…However, CDS is not specific and may also be an accompanying phenomenon in the disease process ( 20 ). Previously reported channel genes associated with migraine include CACNA1A, ATP1A2, ATP1A3, ATP1A4, SCN1A, PRRT2, PNKD, SLC2A1, SLC1A3 and SLC4A4 ( 21 , 22 ). Different types of myotonia correspond to different pathogenic genes, such as the TOR1A gene mutation in DYT1, the TUBB4A gene mutation in DYT4, and the GNAL gene mutation in DYT25 ( 2 ).…”

“…The ATP1A2 and ATP1A3 genes, which are different isoforms encoding the Na+/K+-ATPase (NKA) alpha subunit, are associated with FHM2 ( ATP1A2 ), childhood alternating hemiplegia ( ATP1A2/A3 ), RDP ( ATP1A3 ), cerebellar ataxia-reflex loss-progressive optic atrophy ( ATP1A3 ), and recurrent encephalopathy with cerebellar ataxia ( ATP1A3 ), respectively ( 25 ). The ATP1A4 mutation is a novel gene mutation that was detected associated with FHM ( 22 ). PRRT2 mutations lead to dysregulation of transmembrane calcium and sodium channels, resulting in diseases such as FHM2 and PKD ( 17 ).…”

Embracing the Complexity of Neurodevelopmental Disorders

“…Finally, an interesting whole-exome sequencing case report describes an Italian family with familial hemiplegic migraine in which a heterozygous ATP1A4 mutation was identified in the absence of mutations in the genes known to be associated with familial hemiplegic migraine [ 7 ]. Four family members presented at least two migraine attacks preceded by visual symptoms and transient unilateral weakness and paresthesia.…”