ADEM is considered an autoinflammatory demyelinating disease of the CNS and is often secondary to infections [
1]. However, some cases have been associated with recurrent inflammation and absence of known infections [
3,
4], raising the question if autoinflammation could trigger CNS demyelination as has been previously reported in MS [
5]. It could be expected to be of genetic origin – probably with a monogenic basis – based on the common origin of both diseases (that is, autoinflammation and ADEM-ON) and the early onset of manifestations. Although none of the variants can be considered to be the sole cause of the disease, we hypothesize that the presence of polymorphisms in
NLRP12 and
SIAE (Table
1) trigger systemic autoinflammation, and such inflammation could influence the demyelination process in an unknown fashion. NLRP12AD, part of the cryopyrin-associated periodic syndromes (CAPS), has been associated with several autoinflammatory conditions that are similar to the immunological features of our patient [
9‐
12]. However, to the best of our knowledge, there are no cases of NLRP12AD and inflammatory diseases in the CNS of humans. Interestingly, the role of
NLRP12 in inflammasome activation in the brain of murine models, including a model of experimental autoimmune encephalomyelitis, has been recently described [
13‐
15]. In addition,
SIAE has also been associated with susceptibility to autoimmune diseases [
16]. However, this association has been questioned [
17]. Although we failed to find a candidate gene or a genetic link with the neurological manifestations, the variant in
POLR3A is important because bi-allelic mutations on this gene are associated with hypomyelinating leukodystrophy 7 (HLD7) [
18]. Interestingly, our patient presents hypogonadotropic hypogonadism, which is one of the hallmarks of HLD7; however, the other clinical features and the MRI pattern are barely compatible with HLD7. Although only one of the
POLR3A alleles is mutated, a new association between heterozygous mutations in
POLR3A and susceptibility to varicella-zoster virus (VZV) infection (including encephalitis) was described recently. However, our patient did not show any evidence of VZV infection. Furthermore, these cases presented incomplete penetrance in healthy carriers [
19]. Thus, we cannot rule out a possible influence of the
POLR3A in the clinical features presented by our patient. High doses of IVIG are broadly used for the treatment of autoimmune diseases of different etiologies, including ADEM [
20]. However, the use of low doses of IVIG in ADEM-ON has not been extensively documented. Recently, a cohort of patients with multiphasic disseminated encephalomyelitis (MDEM), of whom some received monthly IVIG treatment, was described [
21]. These patients showed improved clinical manifestations, similar to our case. Our patient has had recurrent autoinflammatory symptoms leading to neurologic episodes every 6 months on average. Since the treatment with low-dose IVIG and colchicine was started, he has not presented any autoinflammatory or neurologic symptoms. It is known that IVIG at high doses works as an immunosuppressant to treat several autoimmune diseases. This effect is probably mediated by scavenging of complement and blockade or modulation of Fc receptors. At low doses, it is used as a prophylactic treatment in patients with immunodeficiencies in part by neutralizing the antigens. This could be a possibility in this patient because it could be neutralizing the virus or antigens. Therefore, this treatment prevents potential infections that usually trigger the autoinflammation and neurological manifestations, as is broadly known in ADEM or MDEM [
1]. In any of these two scenarios, the IVIG and colchicine are preventing the inflammation that precedes the neurological manifestations. Typically, FCAS is treated with interleukin-1 (IL-1) inhibitors such as anakinra, rilonacept, or canakinumab [
22,
23]. However, given the difficulty of finding these drugs in Ecuador and our patient’s economic inability to acquire them, colchicine was prescribed. This medication has a widespread effect on autoinflammatory disorders and has been widely accepted as a treatment in other PFS, such as in familial Mediterranean fever (FMF) [
22]. Apart from some minor gastrointestinal side effects, the medication has been well tolerated by our patient, and he has not presented any autoinflammatory or neurological symptoms.