Progressive myoclonic epilepsies (PMEs) are a rare group of disorders with genetic and phenotypic heterogeneity. Pathogenic variants in SEMA6B were first implicated in PME in 20201 (EPM-11). SEMA6B encodes semaphorin 6B, part of the semaphorin family of molecules involved in nervous system development and axon guidance. 2 We report a case of SEMA6B-associated PME with an Angelman-like presentation, highlighting that this specific etiology should be considered in the differential diagnosis of similar neurodevelopmental clinical syndromes. A 28-year-old right-handed female presented to the movement disorders clinic for evaluation of disabling myoclonus. She was born at term to non-consanguineous parents of Romanian ancestry. Neonatal period was uncomplicated, but she had global developmental delay (walking from 24 months, speaking a few words from 7 years with limited vocabulary) and intellectual disability. Attention-deficit/hyperactivity disorder (ADHD) was diagnosed at age 4. She had recurrent ear infections in childhood with multiple tympanostomy tubes. At age 7, she developed episodes of staring, blinking, and loss of muscle tone, treated with valproic acid. At 9 years, she developed frequent head drop. EEG revealed hyperventilation-induced generalized spike-and-slow wave activity and photic stimulation-induced generalized slowing with spikes. At age 13, she developed generalized tonic–clonic (GTC) seizures and frequent jerky movements during wakefulness. Antiseizure medications initially controlled symptoms but were later stopped by the family and she continued to have about 3 GTCs/year. Motor and cognitive function gradually declined; she was dependent for daily activities and required wheelchair assistance due to loss of muscle tone with stance. She developed photosensitivity in teenage years and often wore sunglasses. Family history was non-contributory. On examination (Video 1), she had facial dysmorphism (low set ears, deep set eyes, large nose, wide mouth, prominent jaw) with a remarkably cheerful demeanor. She responded to simple questions and commands. Speech was dysarthric. Extraocular movements were dysmetric but full. Muscle tone and strength appeared normal but were difficult to examine due to frequent brief myoclonic jerks at rest and on action involving eyes and perioral region, upper and lower limbs, and neck. She had multiple clusters of myoclonic jerks followed by loss of tone and head drop. Muscle stretch reflexes were brisk and symmetric. She had truncal ataxia, wide-based stance and required assistance to stand. Previous genetic workup in childhood for Angelman syndrome, Rett syndrome, and chromosomal microarray had been negative. Targeted panel testing identified a heterozygous variant in exon 17 of SEMA6B (c. 1978C>T, p. Gln660*; NM₀32108. 4). This was classified as likely pathogenic, on the basis of being a truncating variant in a region critical to protein function and absence from population databases. Initiation of clonazepam and levetiracetam drastically improved myoclonus but resulted in irritability, prompting switch to brivaracetam. A repeat EEG showed frequent posterior predominant low amplitude spike–wave discharges, diffuse background slowing, and slow posterior dominant rhythm (Fig. S1). Brain MRI at age 29 showed mild left hippocampal internal architecture blurring, likely reflecting early mesial temporal sclerosis (Fig. S2). Given the duration of untreated seizures and absence of mesial temporal changes reported in the childhood MRI, we speculate that is a secondary seizure-related finding. Since the identification of SEMA6B in the pathogenesis of PME, 38 patients with PME and non-PME phenotypes have been reported. 3-5 Non-PME phenotypes include epilepsy, developmental and epileptic encephalopathy (DEE, including with sleep-wave activation during sleep DEE-SWAS) and neurodevelopmental disorders. 3, 4, 6 Almost all pathogenic variants occur de novo and variants in exon 17 result in truncated protein. 3 A wide spectrum of seizure types has been reported with SEMA6B, including GTCs, absence, atonic, myoclonic and tonic seizures, as well as focal seizures and nonconvulsive status epilepticus. 3 Seizures are typically childhood-onset, but adult onset in siblings around age 50 has been reported. 7 Non-epileptic myoclonus is also common, next to developmental delay (including motor and speech domains), regression, and intellectual disability. Though neuroimaging is often normal, non-specific findings such as cerebellar/cerebral atrophy have been reported in a few patients. 3 Seizure and myoclonus treatment regimens include valproate, levetiracetam, clonazepam, lamotrigine, and zonisamide, but results may vary. 3 In one case, refractory functionally impairing interictal myoclonus was treated successfully with zonisamide. 8 The phenotypes and genotypes reported in individuals with SEMA6B variants are summarized in Table 1. In line with previous descriptions, our patient had global developmental delay, intellectual disability with regression, and childhood onset-polymorphic seizures with predominance of myoclonus (including atonic episodes with head drops). These features together with facial features such as wide mouth, happy demeanor, ataxia, and frequent epileptic and non-epileptic (cortical) myoclonus invoked initial clinical suspicion for Angelman syndrome. 16 Though variable dysmorphic features in SEMA6B variants have been reported, phenotypic overlap with Angelman syndrome has not been highlighted before. 6 Defects in SEMA6B gene function interfere with axonal pathfinding during embryogenesis and can possibly explain the complex clinical phenotypes. 6 We speculate that convergence of clinical findings in Angelman syndrome and individuals with variants in SEMA6B could potentially be related to reduced dendritic spine density in both conditions. SEMA6B has also been included in the list of genes causing intellectual disability and Rett syndrome-like presentations. 6, 15 PMEs often straddle the borders of epilepsy and movement disorders subspecialties. With advances in genetic diagnostics, increasing causes for PMEs are identified. SEMA6B is a recently identified cause of PME with expanding phenotypic spectrum. We recommend that this gene be considered in the differential diagnosis of Angelman syndrome-like presentations. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. Y. M.: 1B, 1C, 2A, 2B, 3A. S. G.: 1A, 1C, 2A, 2C, 3B. C. G.: 1A, 2A, 2C, 3B. We thank the patient and her family for allowing publication for educational purposes. Ethical Compliance Statement: We confirm that approval of an institutional review board was not required for this work. Informed written consent from the patient's mother to publish details of this case report. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Author disclosures are available in the Supporting Information. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1. COI disclosure forms Figure S1. Awake EEG at age 29 years: Anteroposterior montage showing frequent posterior predominant low-amplitude spike–wave discharges, slowing of the posterior dominant rhythm (mostly in the theta frequency range), and diffuse background slowing. Figure S2. 3-Tesla Brain MRI at age 29 years, showing (A) sagittal T1 magnetization-prepared rapid gradient echo (MP-RAGE) ; (B) axial T2 fluid-attenuated inversion recovery (FLAIR) ; (C) coronal T2 and (D) coronal T2 FLAIR images. The midline structures, brainstem, cerebellum, and brain parenchyma are unremarkable (A, B). There is mild blurring of the internal architecture of the left hippocampus (red arrow, C), without any atrophy or FLAIR signal abnormality (D), felt to most likely represent early mesial temporal sclerosis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Mahjoub et al. (2026) studied this question.