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Table 1 Migraine-related monogenic neurological and vascular disorders and their causal genes and mechanism of mutations

From: Advances in genetics of migraine

Disorder Symptoms/Key Clinical Findings Causal gene/s Mutations and mechanisms
With mostly neurological symptoms and signs:
 Familial Hemiplegic Migraine (FHM) • Migraine
• Visual disturbances
• Motor weakness (e.g. hemiplegia, ataxia, nystagmus)
• Sensory Loss (e.g. numbness)
• Difficulty with speech (e.g. dysphasia, aphasia)
• Additional neurological symptoms (e.g. confusion, seizures, memory loss, coma)
CACNA1A Missense, gain-of-function ↑ Ca 2+ influx into the presynaptic terminal resulting in excessive neurotransmission.
ATP1A2 Missense, partial-to-complete loss-of- function ↑synaptic K + and glutamate triggering neuronal hyperexcitability.
SCN1A Spectrum of FHM3 mutations is highly complex, biological mechanisms remain unclear – however mutations result in a ↓ in inhibitory transmission which triggers a ↑ in excitatory transmission.
 Mendelian Migraine with Aura • Typical Migraine with Aura KCNK18 Frameshift mutation in TRESK potassium channnel, but has dominant negative effect due to alternatively translated TRESK fragment which downregulates TREK1 and TREK2 potassium channels.
 Episodic Ataxia type 2 (EA2) • Migraine
• Nystagmus
• Muscle weakness
• Paraesthesia
• Progressive cerebellar ataxia (e.g. imbalance and incoordination)
• Vertigo
CACNA1A Loss-of-function mutations result in decreased channel function and thereby a ↓ in intracellular Ca 2+ ; how this triggers EA2 disease mechanisms remains unclear.
 Spinocerebellar Ataxia type 6 (SCA6) • Migraine
• Cerebellar atrophy
• Dysarthria
• Nystagmus
• Progressive cerebellar ataxia
• Sensory neuropathy (e.g. pins and needles, tingling and burning)
CACNA1A Expansion of ‘CAG’ polyglutamine repeats in COOH tail of CACNA1A protein, toxic gain-of-function affecting channel regulation s → selective degeneration of cerebellar Purkinje cells
 Familial Advanced Sleep-Phase Syndrome (FASPS) 2 • Disrupted circadian rhythms (e.g. early onset and offset sleep-wake cycles)
• Migraine with Aura
CSNK1D Loss-of-function (partial). Casein kinase Iδ phosphorylates mammalian clock protein PER2. CKIδ also phosphorylates and regulates GJA1/Connexin43, an astrocytic gap junction protein and a migraine GWAS loci.
 ROSAH syndrome • Ocular (e.g. retinal dystrophy, optic nerve edema, low-grade inflammation),
• Splenomegaly
• Anhidrosis
• Migraine headache
ALPK1 Possible gain-of-function. May affect ciliary formation, regulation of apical transport. Etiology of migraine unclear, but kinase function may affect CGRP activity.
 Paroxysmal dyskinesia disorders • Recurrent and brief attacks of involuntary movement (can be induced by voluntary movements, [PKD], coffee, alcohol, strong emotion [PNKD] or exercise [PED]
• Can present with, or have, accompanying hemiplegic migraine
PRRT2 Missense or most frequently loss of function truncating mutations in PRRT2, result in ↑ presynaptic vesicle release and excitatory transmission, possibly a modifier gene for hemiplegic migraine.
PNKD Missense mutations affect protein cleavage and stability. PNKD interacts with synaptic active zone proteins and mutant protein is less effective at inhibiting exocytosis, resulting in ↑ neurotransmitter release. 
SLC1A3 Spectrum of FHM3 mutations is highly complex, biological mechanisms remain unclear – however mutations result in a ↓ in inhibitory transmission which triggers a ↑ in excitatory transmission.
With mostly vascular symptoms and signs:
 Cerebral Autosomal Dominant Arteriopathy Subcortical Infarcts with Leukoencephalopathy (CADASIL) • Premature stroke
• Cognitive disturbances (e.g. dementia,
• psychiatric issues varying from personality changes to severe depression, coma, confusion)
• Difficulty with speech (e.g. aphasia)
• Motor weakness (e.g. hemiplegia)
• Migraine with aura
• Seizures
NOTCH3 Usually gain-of-function cysteine residue mutations, which produces toxic NOTCH3 protein accumulation and progressive damage in neuronal blood vessels.
 COL4A1/A2 disorders • Stroke and small vessel disease (e.g. porencephaly, leukodystrophy
• Eye defects (e.g.retinal arterial tortuosity, Axenfeld-Rieger anomaly, cataract)
• Systemic effects (e.g. kidney, muscle cramps, Raynaud phenomenon, cardiac arrhythmia, and hemolytic anemia
• Migraine with and without Aura
COL4A1
COL4A2
Usually missense mutations of highly conserved glycine residues in the Gly-X-Y repeat of the collagen triple-helical domain, which impair collagen IV heterotrimer assembly. Some truncating mutations resulting in haploinsufficiency.
 Retinal vasculopathy with cerebral leukodystophy (RVCL) • Vascular retinopathy, visual loss
• Mini-strokes, cerebral leukodystrophy
• Cognitive disturbances (e.g. depression, seizures, mental impairment)
• Migraine (mainly without aura)
• Mild renal and liver dysfunction
• Raynaud’s phenomenon and gastro-
• intestinal bleeding in some individuals
TREX1 C-terminal truncations of TREX1 3′-5′ exonuclease which result in its mislocalisation in the cell, which causes dysregulation of the ER oligosaccharyltransferase (OST), release of free glycans and potentially glycosylation defects.
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