SCN1A – Familial Hemiplegic Migraine Type 3

Familial hemiplegic migraine type 3 (FHM3) is a rare autosomal dominant migraine subtype characterized by transient unilateral motor weakness and severe headache preceded by aura. The SCN1A gene encodes the neuronal voltage-gated NaV1.1 sodium channel, and heterozygous missense mutations in SCN1A have been implicated in FHM3. Affected individuals experience recurrent hemiplegic episodes often triggered by minor head trauma or stress, with possible neuropsychiatric manifestations.

Genetic evidence for SCN1A in FHM3 includes at least six unrelated families harboring segregating missense variants. In a three-generation FHM3 pedigree, c.4871T>C (p.Leu1624Pro) segregated with hemiplegic migraine in three affected members ([PMID:26763045]). A Chinese family exhibited the novel c.5009T>G (p.Leu1670Trp) variant in all five clinically affected relatives ([PMID:27919014]). Segregation across these and other pedigrees totals 14 affected relatives with co-segregation of pathogenic SCN1A alleles. De novo and familial occurrences across diverse ethnicities support a strong genetic link.

The variant spectrum in FHM3 is dominated by missense substitutions clustering in voltage-sensor and pore regions of NaV1.1. Reported variants include c.787C>G (p.Leu263Val), c.4495T>C (p.Phe1499Leu), and c.4946T>A (p.Leu1649Gln), each altering channel gating. No truncating or frameshift mutations have been associated with pure FHM3, underscoring a mechanism distinct from SCN1A-related epilepsy.

Functional studies in heterologous systems reveal both gain- and loss-of-function effects consistent with cortical hyper- and hypo-excitability. The p.Leu263Val and p.Leu1624Pro mutations induce delayed fast inactivation, increased persistent current, and accelerated recovery from inactivation ([PMID:18621678]). The p.Leu1670Trp and p.Leu1649Gln variants display folding/trafficking defects rescued at lower temperature and pronounced gain-of-function upon restoration of surface expression ([PMID:30038559]). These data concordantly link biophysical channel defects to FHM3 pathophysiology.

Although CACNA1A and ATP1A2 account for most familial hemiplegic migraine cases, SCN1A mutations constitute <5% of FHM families, indicating locus heterogeneity. Negative SCN1A screening in sporadic hemiplegic migraine cohorts highlights the need for comprehensive gene panels and supports a non-monogenic contribution in some pedigrees ([PMID:30498473]).

In summary, autosomal dominant SCN1A missense mutations cause FHM3 through mixed biophysical alterations of NaV1.1, with robust segregation in multiple families and concordant functional data. Genetic testing for SCN1A should be considered in FHM patients negative for CACNA1A/ATP1A2 variants. Identification of SCN1A mutations informs prognosis, guides management to avoid triggers, and enables genetic counseling.

References

• Cephalalgia • 2016 • Early-onset familial hemiplegic migraine due to a novel SCN1A mutation PMID:26763045
• Cephalalgia • 2017 • A novel SCN1A mutation identified in a Chinese family with familial hemiplegic migraine: A case report PMID:27919014
• Frontiers in Molecular Neuroscience • 2018 • Gain of Function for the SCN1A/hNav1.1-L1670W Mutation Responsible for Familial Hemiplegic Migraine PMID:30038559
• Frontiers in Neurology • 2018 • Familial Hemiplegic Migraine Type 3 (FHM3) With an SCN1A Mutation in a Chinese Family: A Case Report PMID:30498473
• Proceedings of the National Academy of Sciences of the United States of America • 2008 • Divergent effects of the L263V SCN1A mutation in familial hemiplegic migraine PMID:18621678

Evidence Based Scoring (AI generated)