Progressive myoclonic epilepsies (PMEs) are a rare group of clinically and genetically heterogeneous disorders characterized by symptoms such as action myoclonus, GTCS, and progressive neurological deterioration (Andermann, 1990), typical onset is in childhood or adolescence. The concept of PMEs was first introduced by Herman Lundborg (Genton et al., 2016), who studied several Swedish families with a common ancestor in 1903 and noticed a particular form of epilepsy associated with progressive myoclonus, with varying degrees of severity. PMEs are typically inherited in an autosomal recessive manner, while a small number of patients have mitochondrial or autosomal dominant inheritance patterns (Franceschetti et al., 2014; Kälviäinen, 2015).

PMEs can be divided into two broad clinical groups. In the first group, the patients present with severe, treatment-resistant, and physically disabling myoclonus, tonic-clonic seizures, and ataxia, with intact cognitive skills (Berkovic et al., 1986). In the second group, the patients experience significant cognitive impairment and degeneration. In the early stages of PMEs, the clinical and electroencephalogram (EEG) characteristics may be similar to those of idiopathic generalized epilepsy syndromes, particularly juvenile myoclonic epilepsy. However, treatment failure, progressive aggravation of neurological symptoms, and EEG manifestations indicate PMEs (Shahwan et al., 2005). As for the management, classical anti-myoclonic agents, including valproate, and levetiracetam, often have limited lasting efficacy in patients with PME. Clonazepam is often helpful, but it typically leads to considerable sedation and tolerance over time. Zonisamide has good anti-epileptic effectiveness, sometimes with a long-lasting effect, and has been shown to improve inter-ictal myoclonus (Vossler et al., 2008; Herzog et al., 2021). Gene modification and enzyme replacement therapies may help improve the condition in the near future (Minassian, 2014).

In recent years, the clinical application of next-generation sequencing technology has led to the discovery of multiple gene mutations related to PME (such as GOSR2, ASAH1, KCTD7, TBC1D24, SCARB2, PRICKLE1, CARS2, and SERPINI) (Li et al., 2021). Pathogenic variants of semaphorin 6B (SEMA6B) can also cause EPM-11 [OMIM#618876], as demonstrated in a few case studies (Hamanaka et al., 2020; Courage et al., 2021; Herzog et al., 2021; Li et al., 2021; Shu et al., 2021; Xiaozhen et al., 2021; Duan et al., 2022). To date, 13 cases of SEMA6B-related PME have been reported, all of whom presented with seizures, while three presented with myoclonic seizures. Adult-onset EPM-11 has rarely been reported in the previous literature, and herein, we report one case of adult-onset EPM-11 who presented with late-onset gait instability, seizures, and cognitive impairment.

PME has high genetic heterogeneity, and more than 40 genes are reportedly associated with this disorder. SEMA6B is one of the pathogenic genes that are related to PME and is located on chromosome 19p13; it contains 17 coding exons and a PPAR-binding site in the upstream sequence (Correa et al., 2001). SEMA6B is a member of the class-6 semaphorin family, which is involved in neural development, including neural crest cell migration, axon guidance, and cerebellar development (Andermatt et al., 2014). SEMA6B is highly expressed in multiple brain regions, including the cerebral cortex, cerebellar Purkinje cells, interneurons, and specific cell types, including excitatory and GABAergic inhibitory neurons (Hamanaka et al., 2020). Consequently, disruption of SEMA6B function in GABAergic neurons may contribute to epilepsy.

To the best of our knowledge, 13 cases of SEMA6B-associated PME, including the case described in the present study, have been reported. The first 12 had childhood-to-juvenile onset, and only our case presented as adult onset. The clinical characteristics and genetic detection of the EMP-11 patients are summarized in Table 1. Several reported cases identified patients harboring a truncating variant in the final exon of SEMA6B. Interestingly, a missense variant in exon 16 of SEMA6B (c.1834G > A/p. V612M) was found to be related to cerebellar hypoplasia, with symptoms including cerebellar ataxia and developmental delay (Aldinger et al., 2019). The SEMA6B c.432C>G (exon6) variant identified in this study is a novel mutation and is absent in the Genome Aggregation Database (gnomAD), Exome Aggregation Consortium (ExAC), and 1000 Genomes Project. This variant is predicted to be a damaging missense mutation by several missense prediction software packages, including Polythen2, MutationTaster, CADD, and ReVe, and p. C144W is highly conserved in other organisms (Figure 1D).

In this family, the proband and his sister have similar phenotypes and carry the same variant, which is absent in other siblings. Therefore, we assume that this variant might have originated from their mother, who died in an accident. The mechanism of SEMA6B-related disease remains unclear. Previous studies have shown that missense and nonsense variants can lead to protein function problems, resulting in clinical symptoms such as epilepsy (Xiaozhen et al., 2021). Further functional studies will help us clarify the mechanism.

In conclusion, we reported a family with adult-onset PME-11 harboring a novel heterozygous missense variant. The new genetic variation reported here strengthens the gene–disease relationship. This finding may expand the consideration of the age of onset for EPM-11 and extend the mutational spectrum. However, further functional studies are required to better elucidate the pathogenesis of this disease.