FHM1/SHM1
Apart from CACNA1A there are two other genes (ATP1A2 and SCN1A) that can cause familial/ sporadic hemiplegic migraine, respectively FHM2/SHM2 and FHM3/SHM3. Diagnosis can be confirmed by genetic testing. Diagnostic testing should include sequence analysis and deletion/duplication analysis. However, not all individuals with hemiplegic migraine have a mutation in one of these genes. Depending on the clinical features, there is a higher or lower chance of finding a mutation. Generally speaking, patients with a mutation have a more severe phenotype. With FHM1/SHM1 there is reduced penetrance, meaning that not all individuals who carry a mutation in CACNA1A will develop FHM1/SHM1.
In order to exclude other causes of disease it is advised to perform a cerebral MRI in every new hemiplegic migraine patient. Permanent MRI abnormalities are not common in FHM1/SHM1, although cortical cerebral atrophy has been reported.
Due to the fact that FHM1/SHM1 is a rare disorder with a low attack frequency no large clinical treatment trails are available. Therefore, prophylactic treatment of FHM1/SHM1 generally follows guidelines of common forms of migraine. Consequently, treatment is only targeted on headache instead of the (often more debilitating) aura symptoms. Pharmacological agents that suggest some prophylactic effect in FHM1/SHM1 are: flunarizine, verapamil, sodium valproate and acetazolamide. Lamotrigine might have an effect on aura symptoms.
(Minor) Head trauma has been described as a trigger factor for attacks (attacks occur usually within 10 minutes). In some cases, head trauma leads to delayed oedema, which might lead to loss of consciousness, coma and in rare cases even death has been described in patients carrying a S218L CACNA1A mutation. Thus, patients might be advised not to practice contact sports.
Episodic ataxia type 2 (EA2)
CACNA1A together with one other gene (KCNA1) account for the majority of the episodic ataxia cases.There are no formal clinical diagnostic criteria for episodic ataxia type 2 (EA2). A prerequisite for diagnosis is a mutation in CACNA1A. Diagnostic testing of CACNA1A should include sequence analysis and deletion/duplication analysis.
Acetazolamide is able to effectively reduce the frequency of attacks.
Spinocerebellar ataxia type 6 (SC6)
Diagnosis of SCA6 is based on clinical characteristics together with a repeat expansion in CACNA1A. A brain MRI is advised as it is able to visualize the atrophy of the cerebellum. The degree of atrophy can be correlated to the clinical dysfunction of the patient. Furthermore, treatment of SCA6 is based on the treatment of symptoms as thus far no cure exists.
Early infantile epileptic encephalopathy type 42 (EIEE42)
Early infantile epileptic encephalopathy type 42 (EIEE42). Diagnosis is based on clinical characteristics, electroencephalographic findings and a mutation in CACNA1A. Typically the EEG shows a burst suppression pattern comprised of bursts of high voltage spikes alternated by low voltage basic rhythm with no sleep-wake differentiation.
A cerebral MRI of the brain is indicated as many cases with EIEE have structural abnormalities. There is no cure for EIEE42 and treatment is mainly focussed on reduction of seizures. However, traditional anti-epileptic drugs show limited results.