VGKC複合体抗体関連脳症とその周辺疾患

Voltage-Gated Potassium Channel-Complex Antibodies Associated Encephalopathy and Related Diseases

VGKC複合体抗体は，アイザックス症候群の過剰興奮症候に加え，精神症状，不眠，自律神経障害を呈するモルヴァン症候群，さらに近時記憶障害とてんかんを主徴とする辺縁系脳炎でも陽性となる一群がある。VGKC複合体は，いくつかの蛋白により構成されているが，LGI1（leucine-rich glioma inactivated 1）とCaspr2（contactin-associated protein 2）が主たる抗原である。

Abstract

Voltage-gated potassium channel (VGKC) complex antibodies are auto-antibodies, initially identified in acquired neuromyotonia (aNMT; Isaacs' syndrome), which cause muscle cramps and difficulty in opening the palm of the hands. Subsequently, these antibodies were found in patients presenting with aNMT along with psychosis, insomnia, and dysautonomia, collectively termed Morvan's syndrome (MoS), and in a limbic encephalopathy (LE) patient with prominent amnesia and frequent seizures. Typical LE cases have a distinctive adult-onset, frequent, brief dystonic seizure semiology that predominantly affects the arms and ipsilateral face. It has now been termed faciobrachial dystonic seizures (FBDS). The VGKC complex is a group of proteins that are strongly associated in situ and after extraction in the mild detergent digitonin. Recent studies indicated that the VGKC complex antibodies are mainly directed toward associated proteins (for example LGI1, Caspr2) that complex with VGKCs themselves. Patients with aNMT or MoS are most likely to have Caspr2 antibodies, whereas LGI1 antibodies are found characteristically in patients with FBDS and LE. We systematically identified and quantified autoantibodies in patient sera with VGKC-complex antibody associated encephalopathy and showed the relationship between individual antibodies and patient's symptoms. Furthermore, we revealed how autoantibodies disrupt the physiological functions of target proteins. LGI1 antibodies neutralize the interaction between LGI1 and ADAM22, reducing the synaptic AMPA receptors.