A number sign (#) is used with this entry because of evidence that X-linked epilepsy-1 with variable learning disabilities and behavior disorders (EPILX1) is caused by hemizygous mutation in the SYN1 gene (313440) on chromosome Xp11.

Hemizygous mutation in the SYN1 gene can also cause X-linked intellectual developmental disorder-50 (MRX50; 300115).

X-linked epilepsy-1 with variable learning disabilities and behavior disorders (EPILX1) is an X-linked neurologic disorder characterized by the onset of complex partial seizures in the first or second decades. The seizures are often triggered by showering or water-related hygiene activities, consistent with reflex bathing epilepsy. Additional spontaneous seizures and secondary generalization may also occur. Most patients have associated developmental defects, including learning disabilities, behavioral problems, or autistic features. The pathophysiology of the reflex seizures is thought to be hyperexcitability of the cortical or subcortical neuronal areas that respond to physiologic stimulus in an exaggerated manner, possibly due to aberrant synaptic maturation (summary by Nguyen et al., 2015; Sirsi et al., 2017; Accogli et al., 2021).

Garcia et al. (2004) reported a novel X-linked recessive syndrome in a 4-generation kindred in which some males of normal intelligence had epilepsy and others had various combinations of epilepsy, learning difficulties, macrocephaly, and aggressive behavior. One patient had a diagnosis of autism. The natural history of seizures was variable, occurring only during childhood in some and developing at age 27 in 1. Some patients had seizures appearing only in association with specific stimuli, including bathing.

Fassio et al. (2011) reported a large French Canadian family in which 7 males had X-linked partial epilepsy with variable learning disabilities and behavioral disorders. Two patients also had autism. Nguyen et al. (2015) provided follow-up of the large multigenerational family reported by Fassio et al. (2011), noting that epilepsy was diagnosed in 10 male individuals, 4 of whom were deceased. Two female carriers had a single febrile seizure without subsequent epilepsy. In the 10 male patients with seizures, the age at onset ranged from 20 months to 20 years, although 1 less characterized deceased individual had onset at 50 years of age. One male patient had a febrile seizure. All 10 had rare or occasional nonreflex complex partial seizures, but 7 clearly had reflex seizures triggered by bathing, showering, other water-related hygiene habits, or by fingernail clipping. Some patients had secondary generalization of seizures. Of the 6 living male patients with seizures, 2 had a pervasive developmental disorder, language deficits, and impaired intellectual development. Another 3 had mixed dyslexia with borderline IQ. There was intrafamilial variability in seizure severity, but response to treatment was generally good. One of 2 carrier females showed mild mixed dyslexia, but both had normal IQ. The authors proposed that reflex seizures may be due to a hyperexcitable temporoinsular network, as evidenced by ictal scalp EEG and SPECT studies and structural hippocampal defects, which were observed in 2 male patients.

Vignoli et al. (2014) reported an 8-year-old Italian boy with bathing epilepsy who experienced complex partial seizures during contact with hot water. Psychomotor development was noted to be normal, but he had clumsiness, dyspraxia, and learning difficulties. IQ was 80. Ictal EEG was characterized by bilateral rhythmic theta activity over the frontocentral and vertex regions. He later presented with complex partial spontaneous nonreflex seizures which responded to treatment. Family history revealed a maternal uncle with the same reflex epilepsy manifest as complex partial seizures with secondary generalization; he also had mild intellectual disability. Peron et al. (2018) reported follow-up of this family.

Sirsi et al. (2017) reported a 7-year-old Latino boy who presented with refractory seizures at 3 years of age. After age 5, the seizures were triggered by showering or when water was poured over his face and shoulders. EEG showed left temporal spikes, and brain imaging was normal. He developed spontaneous nocturnal seizures and unprovoked seizures. A vagal nerve stimulator was placed at age 10 years, which resulted in some seizures control. He also had cognitive impairment and autism spectrum disorder. Family history was significant for epilepsy through the maternal relatives.

Accogli et al. (2021) reported 12 individuals from 10 unrelated families with bathing epilepsy associated with hemizygous (10 males) or heterozygous (2 females) mutations in the SYN1 gene. The patients had focal epilepsy with impaired awareness triggered by bathing or showering, regardless of water temperature. Seizures were typically triggered by water pouring over the head and consisted of behavioral arrest associated with pallor, cyanotic lips, buccal automatisms, and transient hypotonia. Seizures could also be induced by water immersion, towel rubbing, fingernail clipping, hair cutting, watching someone take a shower, or even by the thought of bathing or showering. Some patients showed evolution to generalized tonic-clonic seizures. The age at onset of provoked seizures ranged from 8 months to 15 years. Ictal EEG showed theta activity over the frontal-temporal areas; brain imaging was unremarkable. Three had a history of febrile seizures, and 9 patients developed unprovoked seizures. The seizures tended to respond well to antiseizure medication. Most patients had global developmental delay with impaired intellectual development, speech delay, and behavioral abnormalities, including ADHD, autistic features, and aggression. Accogli et al. (2021) noted that 2 female mutation carriers with bathing epilepsy also showed developmental delay, which may have been due to skewed X-inactivation.

Xiong et al. (2021) reported 2 unrelated Han Chinese boys with EPILX1. The patient in family A was a 6-year-old boy with profound global developmental delay since infancy, nonverbal expression, esotropia, and 2 febrile convulsions. In patient in family B was an 8.5-year-old boy with intellectual disability, focal epilepsy, abnormal social behavior, short temper, attention deficit, hyperactivity, and ametropia. A distant uncle had intellectual disability and a female cousin had mood disorder.

The transmission pattern of EPILX1 in the family reported by Fassio et al. (2011) and Nguyen et al. (2015) was consistent with X-linked recessive inheritance with incomplete penetrance.

By genetic linkage analysis, Garcia et al. (2004) mapped an X-linked epilepsy disorder in a 4-generation kindred to Xp11.3-q12, between the MAOB gene and marker DXS1275. A maximum 2-point lod score of 4.06 at theta = 0.0 was found with DXS1039.

By direct sequencing of the SYN1 gene, Garcia et al. (2004) identified a nonsense mutation (W356X; 313440.0001) in all 10 affected males and in obligate carrier females of a family with X-linked epilepsy and learning disabilities.

In 6 males from a large French Canadian family with X-linked partial epilepsy and learning disabilities, Fassio et al. (2011) identified a truncating mutation in the SYN1 gene (Q555X; 313440.0002). Investigation of this gene in several large cohorts of patients with epilepsy and/or autism identified 3 additional variants in the SYN1 gene (see, e.g., 313440.0003 and 313440.0004) in 1% of patients with autism spectrum disorders and 3.5% of patients with epilepsy. Three of the 4 mutations affected the D-domain, which is important for protein function. When expressed in Syn1-null neurons, these 3 mutant proteins were unable to rescue impairments in the size and trafficking of synaptic vesicle pools. The findings demonstrated that SYN1 is a predisposing gene to epilepsy and autism spectrum disorders and strengthened the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both disorders.

In an Italian boy with EPILX1 originally reported by Vignoli et al. (2014), Peron et al. (2018) identified a hemizygous splice site mutation in the SYN1 gene (313440.0007). The mutation, which was found by whole-exome sequencing, was inherited from the proband's unaffected mother. A maternal uncle with a similar disorder also carried the mutation, consistent with X-linked recessive inheritance. Functional studies of the variant and studies of patient cells were not performed. Both the proband and his uncle had bathing reflex epilepsy followed by nonreflex seizures. Peron et al. (2018) suggested that truncating SYN1 mutations tend to be associated with reflex seizures triggered by water, whereas missense variants tend to be associated with intellectual disability and autism without seizures.

In a 7-year-old Latino boy with EPILX1, Sirsi et al. (2017) identified a hemizygous nonsense mutation in the SYN1 gene (R422X; 313440.0008). The mutation was found through a gene panel test. The patient had a family history of the disorder on the maternal side, but further genetic studies were not performed on the family. Functional studies of the variant and studies of patient cells were not performed.

In 12 patients from 10 unrelated families with EPILX1 manifest as reflex bathing epilepsy, Accogli et al. (2021) identified mutations in the SYN1 gene (see, e.g., 313440.0008-313440.0010). The mutations, which were found by various exome sequencing methods and confirmed by Sanger sequencing, were all absent from the gnomAD database. Ten of the patients were males and carried a hemizygous mutation, and 2 were females with a heterozygous mutation. All but 1 were maternal inherited; the mutation in family 1 occurred de novo. All but 1 of the mutations were nonsense, frameshift, or splice site variants and predicted to result in premature termination; there was 1 missense variant. Functional studies of the variants and studies of patient cells were not performed. SYN1 mutations were not found in 12 additional patients with hot water epilepsy, suggesting that they are distinct genetic disorders.

In an 8.5-year-old Han Chinese boy (family B) with EPILX1, Xiong et al. (2021) identified a hemizygous nonsense mutation in the SYN1 gene (Q482X; 313440.0011). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.