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. |