The abovementioned symptoms, especially in combination with a positive family anamnesis
Familial Hemiplegic Migraine Type 1, FHM1 - CACNA1A
Episodic Ataxia Type 2 (EA2)
According to diagnostic criteria, Familiar Hemiplegic Migraine (FHM) is a migraine with aura in conjunction with a positive family anamnesis (at least one first-degree relative with similar attacks), whereby the aura characteristically includes hemipareses of varying degrees. These pareses can be prolonged, even beyond the duration of the headache. Other focal neurological symptoms such as impaired vision (scintillating scotoma, hemianopsia), sensory disturbance (wandering paresthesia / hypesthesia), or speech disorders may occur in conjunction with aura. Vigilance problems (from light confusion to coma) or rare psychiatric abnormalities have also been described. Magnetic resonance imaging may also reveal cerebellar abnormalities (vermis atrophy in some FHM1 families). Recurrent migraine attacks may begin in a patient's childhood or teenage years. The severity of the symptoms can vary greatly in affected families.
Up to 50% of FHM1-affected families show cerebellar symptoms between attacks, ranging from nystagmus to a mild cerebellar ataxia (late onset).
Mutations in the CACNA1A gene (FHM1) are the most common cause of FHM and are found in approximately 50% of all patients and up to 90% of patients with accompanying cerebellar symptoms.
FHM2 is caused by mutations in the ATP1A2 gene; FHM3 by mutations in the SCN1A gene.
FHM1 is caused by mutation in the CACNA1A gene located on chromosome 19 (19p13). Males and females are equally affected. Penetrance is approximately 80%. The clinical phenotype can vary greatly both within and between families. CACNA1A codes for the alpha-1 subunit of the voltage-dependent P/Q-type calcium channel, which is primarily expressed in the brainstem and in cerebellar Purkinje cells. The alpha-1 subunit is comprised of four similar transmembrane domains, which make up the functionally important "ion pores" of the channel. Different mutations in the CACNA1A gene cause a wide spectrum of episodic and chronic, progressive central nervous system disorders; missense mutations lead to the clinical symptoms of FHM.
Two other clinical phenotypes are associated with mutations in the CACNA1A gene:
• Episodic Ataxia Type 2 (EA2)
Splice-site and frameshift mutations (premature stop codon)
• Spinocerebellar Ataxia Type 6 (SCA6)
Expansion of CAG polyglutamine triplets in the 3' untranslated region
< 1 : 10 000
All exons as well as their flanking regions are analyzed using DNA sequencing.
Deletions and/or duplications of one or more exons are captured using MLPA.
2 - 4 ml of EDTA blood
4 - 6 weeks