SCIENTIFIC BACKGROUND

ATP1A2, CACNA1A, SCN1A

Familial Hemiplegic Migraine (FHM) is a rare (prevalence approximately 1:10,000) monogenic form of migraine. Since 2004, the criteria of the International Headache Society have included FHM with forms of migraine with aura. The aura can include visual, sensory and speech disorders, but FHM is accompanied by a motor disorder in the form of reversible hemiparesis, which can last longer. In 20-40% of families, additional cerebellar symptoms such as progressive mild ataxia and/or nystagmus have been reported. By definition, the familial form requires at least one other first-degree relative with the disease.

 

The aura is presumably caused by CSD (cortical spreading depression), a depression wave that spreads slowly through the cerebral cortex and temporarily inhibits other neuronal activity. The actual headache is said to be caused by an activation of the so-called trigeminal vascular system (TGVS). Therapeutically and prophylactically, drugs can be used in the same way as for migraine. Triptans and other vasoconstrictive substances should be avoided.

 

So far, pathogenic variants associated with familial hemiplegic migraine have been identified in three genes. These genes (CACNA1A, ATP1A2 and SCN1A) encode either components of ion channels (CACNA1A and SCN1A) or a Na+-K+-ATPase (ATP1A2). Thus, FHM belongs to the group of ion channel diseases. Since pathogenic variants in these genes have not been detected in all families, it is suspected that there exist other rarer forms (FHM4-6). The sporadic form (SHM) is explained by dominant new mutations or reduced penetrance. Depending on the population studied, either no or only very rarely were pathogenic variants identified in the known FHM-causing genes in SHM. Since the forms do not differ much clinically, the molecular genetic clarification of these three genes using next generation sequencing (NGS) allows the investigation of the three genes in one sequence run.

 

FHM shows clinical, genetic and pathophysiological overlaps with epilepsy and other neurological diseases. Pathogenic variants in the three genes have also been described as the cause of epilepsy, for example, the SCN1A gene as the cause of Dravet syndrome or generalized epilepsy with febrile seizures plus (GEFS+). Due to autosomal dominant inheritance, there is a 50% risk of recurrence for offspring of carriers of pathogenic variants.

 

References

Pelzer et al. 2018, Neurology 90:e575 / Huang et al. 2017, Neuropsychiatr Dis Treat 13:1175 / Zameel Cader 2013, Hum Mol Genet Oct 15;22(R1):R39-44 / Di Lorenzo et al. 2012, J Headache Pain 13:571 / Weir et al. 2011, BMC Med 9:16 / Russel 2011, Lancet Neurol 10, 5:457 / Pietrobon 2010, J Physiol 588.11:1871 / de Vries et al. 2009, Hum Genet 126:115 / Haan et al. 2007, Cephalalgia 28:105 / Kubisch 2007, Med Gen 19:330

GENES

ATP1A2, CACNA1A, SCN1A

ASSOCIATED TESTS

How to order

LATEST ARTICLES

Cancer is a group of genetic diseases that can develop almost anywhere in the body. Many people in the world are affected by cancer every year. Follo...

Read more

Aiming to evaluate the role of chromosomal aneuploidy in pregnancy loss, a 2023 study 35 years in the making evaluated the genomic landscape of first...

Read more

Cancer is a complex genetic disease that affects millions of people in the world. It is one of the leading causes of death worldwide, with about ten ...

Read more

Researchers created a detailed map of the placenta during labor. By studying how maternal and fetal cells communicate, they discovered signals in the...

Read more

A recent paper published in Nature Medicine (1) aimed to identify genes and genomic biomarkers which can better predict outcomes and personalized the...

Read more

In honor of the international day of women and girls in science, we interviewed one of our very own, Dr. Evelina Papaioannou. Dr. Evelina Pa...

Read more

Aneuploidies, such as translocations, whole or segmental chromosomal duplications, and deletions, are examples of chromosomal abnormalities that are ...

Read more

Here you can read the winning essays from the first, annual DNA essay competition on the subject of "How unfolding the DNA code can help with precisi...

Read more

Introduction Our voices are as unique as our fingerprints! Although there are people whose voices might sound alike, there are no two voices exact...

Read more

Not everyone likes winter. For people who do not enjoy the cold weather, or having to put on a thick coat to go outside, a winter can be a source of ...

Read more