A Rare Case of Epileptic Encephalopathy Caused by X-Linked ALG13 Gene Mutation in a 6-Year-Old Girl
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Congenital disorder of glycosylation (CDG) type I is characterized by microcephaly, hepatomegaly, muscular hypotonia, and intractable epilepsy that develops early in life, often with infantile spasms, recurrent infections, and developmental delay. These features are caused by mutations in the asparagine-linked glycosylation 13 (ALG13) gene (Xq23) [1]. This rare mutation exhibits X-linked inheritance and is strongly associated with epileptic encephalopathy in females through mechanisms that remain unknown [2,3]. Here, we report the case of a girl with intractable seizures and infantile spasms who developed Lennox–Gastaut syndrome and was ultimately diagnosed with CDG due to a pathogenic variation in the ALG13 gene.
A 6-year-old girl presented to our hospital with intermittent epileptic spasms, with each cluster lasting about 1 hour per day. She also exhibited staring episodes and developmental regression that began at 4 months of age. She was born via cesarean section at a gestational age of 37+6 weeks, weighing 3.17 kg, and experienced no complications during or after birth. Neonatal screening tests for inborn errors of metabolism were negative. The patient’s mother had no significant medical history, and there was no family history of seizures or neurological disorders. The patient displayed a normal developmental pattern until the age of 4 months, when she experienced her first seizure and was diagnosed with infantile spasms. Her seizures initially improved with steroids but relapsed at 10 months of age. Following the relapse, she was treated for infantile spasms and remained stable for 18 months without seizures. Electroencephalography (EEG) revealed a hypsarrhythmia pattern, and screening for metabolic disorders at that time was negative. However, the patient’s seizures recurred at the age of 2 years, with a waxing and waning pattern. Initially manifesting as episodes of staring with spasms, the seizures later progressed to a myoclonic pattern affecting both limbs, beginning upon awakening in the morning. The patient was treated with a ketogenic diet, high-dose steroids, cannabidiol oil, and various anti-epileptic medications, none of which produced notable improvement. The developmental delays also progressed during this period.
At 6 years of age, the patient’s height, weight, and head circumference were 108.3 cm (<3rd percentile), 15.8 kg (<3rd percentile), and 48.4 cm (<3rd percentile), respectively. Physical examination revealed microcephaly and hypotonia in both lower limbs but no spasticity. Deep tendon reflexes displayed a normal response. The patient could only stand with support and exhibited mild dislocations of both hips. Global developmental delay was observed: her gross motor skills were at a 10 month level, fine motor skills at a 9 month level, social development at an 11 month level, language development at a 10 month level, and cognitive development at a 10 month level. At 6 years of age, an EEG displayed a Lennox–Gastaut pattern, characterized by generalized paroxysmal fast activity and generalized slow sharp wave discharges with frequent multifocal sharp wave discharges (Fig. 1). Magnetic resonance imaging performed at that time revealed diffuse cerebral atrophy. The patient also had cortical visual impairment (Fig. 2).
(A) Generalized sharp wave discharges. (B) Generalized paroxysmal fast activity (arrow) with multifocal spikes.
Magnetic resonance imaging revealing diffuse cerebral atrophy (T2-weighted image).
At 3 years of age, the patient underwent a targeted panel of next-generation sequencing at another hospital, which identified a pathogenic variant in ALG13 (NM_001099922.2:c.320A>G p.Asn107Ser) thought to be related to her condition. Other genes with variants of uncertain significance associated with neurological manifestations were also identified, but none fit her clinical presentation, as her symptoms had not yet fully evolved. At the time, sodium voltage-gated channel alpha subunit 1 (SCN1A) gene defect was considered more consistent with her clinical features, including severe convulsive seizures during fever and developmental delay. Therefore, the patient’s family was tested for SCN1A mutation, which yielded negative results. Consequently, a definitive diagnosis was not reached until the patient was 7 years old, when she underwent whole-exome sequencing (WES) at our hospital and the same ALG13 mutation was identified (Fig. 3). The patient and her family then underwent Sanger sequencing, upon which the patient was found to have a heterozygous mutation in ALG13 that was not observed in her parents. She was ultimately diagnosed with de novo ALG13-CDG.
(A) Asparagine-linked glycosylation 13 (ALG13) (NM_001099922.2:c.320A>G p.Asn107Ser) mutation, confirmed by Sanger sequencing (yellow box). (B) Family pedigree of the case. The patient’s father and mother were asymptomatic and negative for ALG13 mutation, respectively. The patient exhibited a de novo heterozygous ALG13 mutation (c.320A>G p.Asn107Ser). wt, wild-type.
In summary, our patient with CDG appeared normal at birth but developed early onset seizures beginning at 4 months of age. She initially responded to steroid therapy but continued to experience epileptic seizures, similar to previous reports [1,3,4]. As noted in the literature, although seizures may initially respond to antiepileptic drugs or a ketogenic diet [1,3], they eventually become refractory to all interventions. Phenotypically, CDG frequently affects girls with infantile spasms and is often accompanied by other types of seizures. EEG typically reveals hypsarrhythmia patterns along with, at times, a marked encephalopathic pattern of background slowing and fast activity with electrodecrement. Another hallmark of ALG13-CDG is intellectual disabilities, which exhibit diverse phenotypes. Consistent with our patient’s clinical characteristics, Shah et al. [5] reported that among six patients with ALG13 mutations, all eventually developed intellectual disability.
In the Online Mendelian Inheritance in Man (OMIM) database, ALG13-CDG is also categorized as ‘developmental and epileptic encephalopathy-36 (DEE36),’ characterized as an X-linked neurodevelopmental disorder with a mean age of seizure onset of 6.5 months [6]. According to previous reports, affected individuals exhibit various phenotypic anomalies such as a coarse face, low-set ears, micrognathia, and scoliosis. However, the primary co features of the disorder are seizures starting with infantile spasms and progressive intellectual disability. ALG13 is an early enzyme in the N-linked glycosylation pathway. The exact pathogenesis of ALG13 mutation regarding central nervous system developmental disorders has not been elucidated, but certain ‘loss of function’ or ‘gain of function’ variants are thought to lead to the pathological phenotype of this syndrome [7]. To date, 53 new variants of ALG13 have been reported [5]. Among them, ALG13 c.320A>G is a rare variation with an allele frequency of 0 in the gnomAD and Korean Variant Archive II (KOVA 2) databases [8]. In a mouse model, ALG13 expression in the central nervous system has demonstrated histological and cellular specificity, especially in cortical and hippocampal neurons, and ALG13 mutation appears to increase susceptibility to epileptic seizures [9]. ALG13 encodes an enzyme that catalyzes the second sugar addition in the highly conserved oligosaccharide precursor N-linked glycosylation reaction within the endoplasmic reticulum. N-linked glycosylation is a key modification that affects the structure and function of glycoproteins, including those interacting with proteins such as atrophin 1, mutations of which are also associated with progressive intellectual disability [9].
ALG13-CDG was first reported in 2012 in a boy with a de novo and likely pathogenic variant, c.280A>G p.Lys94Glu [10]. The patient presented with seizures, microcephaly, delayed visual maturation, extrapyramidal signs, hepatomegaly, and bleeding tendency, and he died at 1 year of age. Although this patient had abnormal transferrin glycosylation in the plasma, other reported cases [11] displayed normal glycosylation. In a study of 957 Asian patients with pediatric epilepsy, ALG13 variation was identified as a recurrent finding in pediatric epilepsy syndromes, marking the first mention of ALG13 in Korea [12].
Although ALG13 is located on the X chromosome, a strong female predilection for epileptic encephalopathy has been reported, and the mechanism of X inactivation or female disposition has not yet been elucidated [3,7,13]. Datta et al. [11] reviewed 38 patients with ALG13 defects, only one of whom was male. Male patients are rarely reported and usually exhibit more severe symptoms and clinical courses [2,10]. Berry et al. [13] suggested that ALG13 pathogenic variants lead to gain, rather than loss, of function. This may explain the higher prevalence in females as well as why most patients display normal transferrin glycosylation in biochemical tests. Ng et al. [3] studied 29 patients with ALG13 defects and found that female patients developed de novo mutations, and male patients with inherited mutations tended to respond to a ketogenic diet. Shah et al. [5] additionally reported that male patients exhibited severe phenotypes, with none surviving beyond 16 years. Many reports have attributed the female predominance of this condition to skewed X inactivation. If one of the two X chromosomes in females carries a mutant gene, selective advantages in cell proliferation can lead to the preferential expansion of cells carrying either the mutant or the normal X chromosome, resulting in a skewed pattern of X inactivation. The proliferation of cells favoring the normal X chromosome ultimately results in the elimination of cells with mutant X chromosomes [4]. In contrast, in patients with ALG13 mutations who underwent X inactivation, a random inactivation pattern was noted [4]. This random pattern in female patients with severe X-linked, female-limited diseases may ensure the expression of normal alleles in at least some cells. Assuming male lethality, the expression of the normal allele in some cells could promote the survival of affected females, although it does not protect them from major disabilities. Therefore, the ALG13 mutation represents a heavy burden for both males and females.
A limitation of this case is that an inactivation test for the X chromosome and a glycosylation test were not available; thus, we could not elucidate further details of the CDG inheritance characteristics and their effects on descendants.
ALG13-CDG is a rare syndrome characterized by a complex phenotype that includes early onset epileptic encephalopathy and intellectual delay, along with various anomalies. It can be diagnosed by detecting mutations of the ALG13 gene, a task for which targeted multigene panel sequencing or WES is used due to the syndrome’s rarity. However, these tests are unaffordable for most patients. Our patient was ultimately diagnosed because she participated in a study that employed WES for undiagnosed patients. We hope that these tests will eventually be widely commercialized and available at affordable prices. Although early detection is helpful for seizure control, most interventions do not alter the natural course of the disease. Further studies of the pathophysiology and treatment of this condition are required.
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Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Author contribution
Conceptualization: YJH. Data curation: HWC and KRJ. Formal analysis: HWC and YJH. Funding acquisition: HWC. Project administration: HWC and YJH. Visualization: HWC and YJH. Writing - original draft: HWC. Writing - review & editing: HWC, YJH, and KRJ.