Background: Familial Hemiplegic Migraine (FHM), characterized by a
prolonged unilateral hemiparesis, mainly results from mutations in the
alpha-1a subunit of the calcium channel gene CACNA1A that can also
cause two other dominantly inherited neurological disorders, Episodic
Ataxia type 2 (EA2, with sometimes migrainous headaches) and
Spinocerebellar Ataxia type 6 (SCA6, late-onset and progressive).
A same mutation can have different clinical expression in a family
(hemiplegic migraine, migraine-coma, cerebellar ataxia). CACNA1A
mutations in FHM are usually missense, leading to gain-of-function,
while truncating mutations leading to loss-of-function are usually
associated with EA2.
Case report: This 9-year-old girl was seen as a baby for hypotonia
and transient vertical nystagmus. Her first brain MRI was normal. She
evolved as a congenital ataxia, but since the age of two, she had
attacks of coma, hemiparesis (either side), partial seizures, dystonic
movements and fever. Attacks were initially triggered by minor head
bumps, subsequently spontaneous. Brain MRIs in the acute stage
always showed transient unilateral hemisphere swelling. Follow-up
images revealed atrophic lesions in the temporo-occipital regions and
cerebellar atrophy. A prophylactic trial with flunarizine was ineffective.
Acetazolamide was recently introduced.
Methods: Since our patient shared features of both FHM and EA2, we
studied the CACNA1A gene by direct sequencing in the patient's and
parents' DNA.
Results: We identified an unreported de novo heterozygous deletion
of three base pairs (c.4503_4505delCTT) predicting the deletion of
one amino acid (p.Phe1502del). The CACNA1A protein contains 4
domains, each formed by six transmembrane segments. The deletion
is located in a highly conserved region in segment 6 (S6) of the third
domain. Mutations in S6 segments of calcium channels change
single-channel conductance and channel selectivity, most resulting in
loss-of-function.
Outlook: In vitro expression studies of the identified mutation are
underway, aiming at understanding its functional consequences and
finding an efficient treatment.