Other genetic associations
A fourth gene associated with this condition is the proline-rich transmembrane protein 2 (PRRT2 gene) - an axonal protein associated with the exocytosis complex.A fifth gene associated with this condition is SLC4A4, which encodes the electrogenic NaHCO3 cotransporter NBCe1. Diagnosis
Diagnosis of FHM is made according to these criteria:
Two attacks of each of:Aura with motor weakness accompanied by either reversible visual symptoms (flickering lights, spots, lines, etc. ), reversible sensory symptoms (pins and needles, numbness, etc.) or speech symptoms
At least two occurrences of:One or more aura symptoms that develop over at least 5 minutes
These symptoms lasting more than 5 minutes and less than 24 hours
Headache beginning within 60 minutes of aura onset: These headaches can last 4–72 hours, occur on only one side of the head, pulsate, be of moderate to severe intensity, and may be aggravated by common physical activities such as walking. These headaches must also be accompanied by nausea/vomiting, phonophobia (avoidance of sound due to hypersensitivity), and/or photophobia (avoidance of light due to hypersensitivity).At least one close (first- or second-degree) relative with FHM
No other likely causeSporadic forms follow the same diagnostic criteria, with the exception of family history. In all cases, family and patient histories are used for diagnosis. Brain-imaging techniques, such as MRI, CAT scan, and SPECT, are used to look for signs of other familial conditions such as CADASIL or mitochondrial disease, and for evidence of cerebellar degeneration. With the discovery of causative genes, genetic sequencing can also be used to verify diagnosis (though not all genetic loci are known).
Pathophysiology
FHM1 (CACNA1A)
The first discovered FHM locus was the CACNA1A gene (originally named CACNL1A4), which encodes the P/Q-type calcium channel CaV2.1. Currently, 17  mutations in this channel are known (table 1), and these mutations are distributed throughout the channel. Some of these mutations result in patients with notable cerebellar degeneration or other dysfunction, including one mutation (S218L), which may be related to severe responses to mild concussion, up to and including delayed cerebral edema, coma, and death. Fifteen of these mutants have received at least some further analysis at the electrophysiological level to attempt to determine how they might lead to the FHM1 phenotype. Contradiction in the literature is increasing as to the end result of these mutations on channel kinetics and neuronal excitability.A good example of this contradiction can be seen in the literature regarding the R192Q mutation. The first investigation of this mutation, using the rabbit isoform of the channel expressed in oocytes, found that it did not alter any measured channel properties. A subsequent report, using human channels expressed in HEK293 cells, found a small, hyperpolarizing shift in the midpoint for activation, a result common among FHM1 mutants. This shift results in channels that open at more negative potentials, thus have a higher open probability than wild-type channels at most potentials. This report also found that the R192Q mutant produced almost twice as much whole-cell current compared to wild-type channels. This is not due to a change in single channel conductance, but to an equivalent increase in channel density.