ALG13. This is the Epilepsiome page for ALG13, which is associated with nonsyndromic intellectual disability and X-linked early infantile epileptic encephalopathy (EIEE) [OMIM#300884]. ALG13-related EIEE is characterized by infantile onset of seizures and developmental delay. Thus far, disease-causing variants in ALG13 have been reported in fewer than 20 individuals, so the full disease spectrum is not yet understood.
Here are the most recent blogs that mention ALG13
- Publications of the week – GABRG2, CACNA1A, and ALG13
- Three novel aspects about epilepsy gene panels
In a nutshell. A de novo pathogenic variant in ALG13 was first discovered via exome sequencing in a boy with refractory epilepsy with polymorphic seizures, multisystem features and abnormal glycosylation of serum transferrin, consistent with a diagnosis of congenital disorders of glycosylation type 1 (CDG-1). Soon after this publication, a de novo disease-causing variant was reported in a girl with developmental delay, dysmorphic facies, severe intellectual disability, and seizures. Since the original reports in 2012, de novo ALG13 variants have been identified in a small number of boys and girls with early infantile epileptic encephalopathy or infantile spasms, as well as developmental delay, intellectual disability, and variable additional features. Although most reported cases of disease-causing ALG13 variants have been de novo, at least 1 inherited variant has been reported in multiple male siblings with nonsyndromic intellectual disability. Further studies are needed to fully elucidate the phenotypic and variant spectrum, as well as the disease mechanism, of ALG13-related epilepsy.
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ALG13-related epilepsy, also known as early infantile epileptic encephalopathy type 9 (EIEE36), is a genetic early infantile epileptic encephalopathy. Based on the presentation in the relatively small number of individuals described thus far, ALG13-related epilepsy is characterized by infantile onset of seizures, as well as developmental delay, intellectual disability and variable other features. Additional clinical features may include hypotonia, visual impairment, involuntary movements, behavioral problems, developmental regression, dysmorphic facies, such as hypertelorism, brain abnormalities, such as cerebral atrophy, and skeletal findings, such as scoliosis and joint contractures. EEG may show hypsarrhythmia, amongst other findings. Some patients have presented with features consistent with a diagnosis of infantile spasms, Lennox-Gastaut syndrome, or West syndrome. In addition, at least one patient has been reported to have abnormal isoelectric focusing of serum transferrin, which is consistent with a diagnosis of congenital disorders of glycosylation (CDG). This patient also had other multisystemic findings consistent with diagnosis of CDG, including hepatomegaly, optic nerve atrophy, recurrent infections, and increased bleeding tendency. An inherited ALG13 variant has also been identified in one family with multiple brothers with nonsyndromic intellectual disability.
Mutation spectrum. Fewer than 10 unique disease-causing ALG13 variants have been reported in the scientific literature. Thus far, all of the reported variants have been missense. Pathogenic variants have been identified in multiple exons and do not appear to be limited to one region of the gene. A single recurrent ALG13 variant (p.Asn107Ser) has been observed in at least 8 unrelated females with seizures, developmental delay and intellectual disability. Interestingly, all symptomatic females reported thus far have this same recurrent de novo variant, suggesting that this variant may have a unique disease mechanism. To view the variants that have been reported thus far, visit ClinVar.
Genotype-Phenotype Correlation. Pathogenic variants in ALG13 cause a phenotype with significant variable expressivity, ranging from non-syndromic intellectual disability to a complex multisystemic condition consistent with a diagnosis of congenital disorders of glycosylation. The majority of patients described thus far present with early onset epilepsy and developmental delay. Further studies are needed to define the full phenotypic spectrum of ALG13-related disorders.
General Considerations for Variant interpretation. When reviewing a genetic variant to determine its significance for a given patient, it is important to weigh multiple pieces of evidence:
Considerations for gene level interpretation. First, it is important to establish the strength of the evidence showing that the gene is associated with epilepsy. Some genes may only have one variant reported in a single individual with epilepsy, while other genes may have multiple variants reported in many large families with an autosomal dominant pattern of epilepsy. For ALG13, there is moderate evidence for its role in human epilepsy.
Considerations for variant level interpretation. When reviewing the significance of a variant, it is important to consider the impact on the gene and the presence of the variant in previously described patient and control populations. Many clinical genetic testing laboratories classify genetic variants into different categories, ranging from benign to pathogenic. Variants that are common in control populations and would not be predicted to have a major impact on the gene/protein are generally classified as benign. Variants are more likely to be classified as pathogenic if the variants are rare or not present in the control population, reported in multiple individuals or families with disease, and likely to have a higher impact on the gene/protein based on the type of mutation or functional studies. Variants with uncertain or limited available evidence may be classified as variants of uncertain significance (VUS), indicating that further information is required in order for the variant to be further defined. In some cases, testing additional family members can be helpful, as it allows the lab to determine whether or not the variant was inherited (versus de novo) and how the variant segregates with disease in the family. This is particularly true for ALG13 variants, as most disease-causing variants would be expected to be de novo. Sometimes further classification of a VUS requires waiting for the identification of additional patients or families with similar or nearby variants.
Inheritance, Penetrance & Prevalence. ALG13 is located on the X chromosome, and, therefore, ALG13-related conditions are inherited in an X-linked pattern. Thus far, all reported cases of the recurrent p.Asn107Ser variant in females have been confirmed (or suspected) to be de novo, while some variants identified in males have been inherited from healthy asymptomatic mothers, suggesting that some variants are not penetrant in carrier females. The exact prevalence of ALG13-related epilepsy is unknown; studies of large cohorts of patients with epilepsy or intellectual disability suggest that ALG13 is a relatively minor contributor to genetic forms of epilepsy and developmental delay.
Mechanism. The ALG13 gene encodes a subunit of a UDP-N-acetylglucosamine transferase, which is involved in catalyzing a step in endoplasmic reticulum N-glycosylation of proteins. Asparagine (N)-glycosylation is important for regulation of protein folding and stability. The mechanism underlying ALG13-related epilepsy and intellectual disability is not yet fully understood. One male patient with an ALG13 variant had abnormal isoelectric focusing of serum transferrin, suggesting an underlying glycosylation defect, but this finding has not been reported in other patients with ALG13-related conditions. The presence or lack of glycosylation defects in patients with ALG13 variants may be due to differences in the underlying disease mechanism (e.g. loss-of-function versus gain-of-function/dominant negative).
Recurrence risk & testing of family members. ALG13 variants can be de novo or inherited in an X-linked pattern. Each child of an individual with a disease-causing variant has a 50% (1 in 2) of inheriting the disease-causing variant. All female children of males who carry a disease-causing variant will inherit the variant. Few families with inherited ALG13 variants have been reported thus far, so the phenotypic spectrum of carrier females who have an affected male family member is not yet known. Although not yet reported, somatic or germline mosaicism of ALG13 variants is possible, making the recurrence risk for families with one child with a ALG13 variant higher than the general population risk.
Therapy. A specific therapy recommendation has not yet been proposed for ALG13-related epilepsy.
The current section on therapy is a brief overview, and, from the therapeutic perspective, does not represent a comprehensive review of the literature. It should therefore not be used for clinical decision-making without input from a health care provider with relevant expertise in the field.
Research studies, patient registries, and family connections. The Epilepsiome team is happy to facilitate if you have questions or a specific interest in this gene. There are a number of groups/websites that provide relevant information and support for individuals and families with ALG13-related conditions, including the groups listed below.
- American Epilepsy Society
- Epilepsy Foundation
- Epilepsy Action UK
- CLIMB: Children Living with Inherited Metabolic Diseases
- National Organization for Rare Disorders (NORD)CDG Care