By: Natalie L. Boehm, MBA, RBLP-T
West Syndrome
By: Natalie L. Boehm, MBA, RBLP-T
What is West Syndrome
According to the Genetic and Rare Diseases Information Center, West syndrome is caused by hypsarrhythmia (chaotic brain waves) that is seen in infantile spasms in infants and children. Infantile spasms start occurring between four to eight months of age. Less than 50,000 Americans are living with West Syndrome.
Causes of West Syndrome
West syndrome can develop due to one or more genes being mutated. West syndrome can be inherited in the following ways:
Autosomal dominant inheritance: the gene causing the condition is not located on the X or Y chromosome. Only one copy of the responsible gene has to pair with the pathological variant or mutated gene to cause the offspring to develop the condition. Can be caused by the parent having the condition or a gene mutates causing the condition when there is no family evidence of the condition being passed down.
X-linked recessive inheritance: the mutated gene is carried on the X chromosome. Mothers who carry this mutation may have mild symptoms of the condition. Any male children the mother has will have a fifty percent chance of developing the condition. For a daughter to develop the condition, both parents have to have the mutation on the x chromosome. For mothers who carry the mutation, there is a fifty percent chance that their daughters will become carriers. For fathers who have the mutation, any daughter that he has will be carriers of the mutation.
Autosomal recessive inheritance: the gene causing the condition is not located on the X or Y chromosomes. Both parents have to carry the recessive or mutated gene in order for their child to develop the condition. Carriers normally do not experience any symptoms of the condition but have a one in four chance of having a child with the condition.
(Genetic and Rare Diseases Information Center, 2021)
Genetic Mutations
The following genetic mutations are known to cause West Syndrome.
NTRK2: encodes a member of the neurotrophic tyrosine receptor kinase family. The kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates (combines) itself and members of the MAPK pathway, leading to cell differentiation. Mutations have been associated with obesity and mood disorders (National Library of Medicine, 2023).
WDR45: encodes a member of the WD repeat protein family. Members of the family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Mutations of WDR-45 are linked to a variety of neurodevelopmental and neurodegenerative conditions. (National Library of Medicine, 2022) (Children’s Hospital of Philadelphia, 2022).
SCN2A: encodes one member of the sodium channel alpha subunit gene family. Mutations are associated with seizure disorders and autism spectrum disorder (National Library of Medicine, 2022).
CDKL5: member of the Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations are associated with X-linked infantile spasm syndrome (West Syndrome) and Rett syndrome. (National Library of Medicine, 2022).
ARX: homeobox-containing gene expressed during development that is a member of the group-ii aristaless-related protein family whose members are expressed primarily in the central and/or peripheral nervous system. Gene is thought to be involved in CNS development. Mutations of this gene cause X-linked cognitive disability and epilepsy (National Library of Medicine, 2022).
PIGA: encodes protein required for synthesis of N-acetylglucosaminyl phosphatidylinositol, the first intermediate in the biosynthetic pathway of GPI anchor. GPI anchor is a glycolipid found on many blood cells which serve to anchor proteins in place. Mutations of this gene are known to develop paroxysmal nocturnal hemoglobinuria. Inherited variants of the PIGA gene causing a deficiency can lead to intellectual disability, infantile spasms, and other abnormalities of the brain and spinal cord ( National Library of Medicine, 2022) (MedlinePlus, 2022).
SPTAN1: encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell regulation. Mutations of this gene cause early infantile epileptic encephalopathy-5 (National Library of Medicine, 2023).
PLCB1: encodes protein that catalyzes the formation of inositol 1,4,5-triphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. The reaction uses calcium as a cofactor which plays an important role in the intracellular transduction of many extracellular signals (National Library of Medicine, 2023). Mutations of this gene can produce severe infantile epileptic encephalopathy (Ngoh et. al., 2014).
GRIN2B: encodes a member of the N-methyl-D-aspartate receptor family. The encoded protein is a subunit of the NMDA receptor ion channel which acts as an antagonist binding site for glutamate. Early expression of this gene in development suggests a role in brain development, circuit formation, synaptic plasticity, and cellular migration and differentiation. Mutations of this gene are associated with neurodevelopmental disorders, autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, and schizophrenia (National Library of Medicine, 2023).
ST3GAL3: encodes protein that is a type II membrane protein, which catalyzes the transfer of sialic acid from CMP-sialic acid to galactose-containing substrates. Normally found in the Golgi apparatus, can be proteolytically processed to a soluble form. Mutations have been associated with autosomal recessive nonsymdromic cognitive disability and infantile epileptic encephalopathy (National Library of Medicine, 2022).
SIK1: encodes a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. Encoded protein is a member of the adenosine monophosphate-activated kinase that plays a role in conserved signal transduction pathways. Mutations of this gene are associated with early infantile epileptic encephalopathy 30 (National Library of Medicine, 2022).
PHACTR1: protein encoded by this gene is a member of the phosphatase and actin regulator family of proteins. The protein can bind actin and regulate the reorganization of the actin cytoskeleton. The protein plays a role in tubule formation and in endothelial cell survival. (National Library of Medicine, 2022). Mutations of this gene are associated with multifocal epilepsy with infantile spasms and hypsarrhythmia (Marakhonov et. al., 2021).
GUF1: encodes a GTPase that triggers back-translocation of the elongating ribosome during mitochondrial protein synthesis. The encoded protein is thought to prevent misincorporation of amino acids in stressful, suboptimal conditions. A mutation of this gene is associated with early infantile epileptic encephalopathy-40 (National Library of Medicine, 2022).
CNPY3: encodes a protein that binds members of the toll-like receptor protein family and functions as a chaperone to aid in folding and export of these proteins (National Library of Medicine, 2022). Mutations of this gene are linked to early-onset epileptic encephalopathy, West syndrome, and hippocampal malrotation (Mutoh et. al., 2018).
Signs and Symptoms
Symptoms of West Syndrome can develop from birth up to 11 years of age (birth to childhood). Symptoms can vary from mild to severe and can affect each individual differently. Symptoms of West syndrome are:
Developmental regression: loss of developmental skills, psychomotor regression
Infantile spasms: epileptic spasms
Myoclonus: myoclonic jerks
Abnormality of skin morphology: abnormal skin structure
Abnormality of the nervous system: neurological abnormality
(Genetic and Rare Diseases Information Center, 2021)
Diagnosis
The first step in diagnosing West Syndrome is for a series of EEG’s to be conducted. Several will be done during the time the child is awake and asleep looking for any irregular brain activity and particularly signs of hypsarrhythmia. Additional tests that may be conducted include neuroimaging to look for brain abnormalities, blood tests to find if a metabolic condition is present, and genetic testing to see if any gene mutations linked to West syndrome is present (Children’s Hospital of Philadelphia, 2022).
Treatment Options
According to the Epilepsy Foundation, the following treatments are used for West Syndrome:
Steroid therapy with either prednisone/prednisolone or adrenocorticotropic hormone (ACTH)
Vigabatrin
If steroids and/or Vigabatrin do not work other antiseizure meds that are used include Valproate (Depakote), Topiramate (Topamax), Pyridoxine (Vitamin B6), Zonisamide (Zonegran), Clobazam (Onfi) or Clonazepam (Klonopin).
Conclusion
According to the Genetic and Rare Diseases Information Center, West syndrome is caused by hypsarrhythmia (chaotic brain waves) that is seen in infantile spasms in infants and children. West syndrome can be inherited or caused by a genetic mutation. West syndrome can develop from infancy to childhood (birth to 11 years of age). Steroids and anticonvulsant medication are common treatments for West syndrome.
Resources:
Children’s Hospital of Philadelphia (2022). WDR45-Related Disorders and BPAN. Children’s Hospital of Philadelphia. Retrieved from: https://www.chop.edu/conditions-diseases/wdr45-related-disorders-and-bpan
Children’s Hospital of Philadelphia (2022). West Syndrome. Children’s Hospital of Philadelphia. Retrieved from: https://www.chop.edu/conditions-diseases/west-syndrome
Genetic and Rare Diseases Information Center (2021). West syndrome, About the Disease. National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center. Retrieved from: https://rarediseases.info.nih.gov/diseases/7887/west-syndrome
Hernandez, A. and Wirrell, E. (2020). Infantile Spasms West Syndrome. Epilepsy Foundation. Retrieved from: https://www.epilepsy.com/what-is-epilepsy/syndromes/infantile-spasms-west-syndrome
Marakhonov, A. V., Přechová, M., Konovalov, F. A., Filatova, A. Y., Zamkova, M. A., Kanivets, I. V., Solonichenko, V. G., Semenova, N. A., Zinchenko, R. A., Treisman, R., & Skoblov, M. Y. (2021). Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia. Clinical genetics, 99(5), 673–683. https://doi.org/10.1111/cge.13926
Mutoh, H., Kato, M., Akita, T., Shibata, T., Wakamoto, H., Ikeda, H., Kitaura, H., Aoto, K., Nakashima, M., Wang, T., Ohba, C., Miyatake, S., Miyake, N., Kakita, A., Miyake, K., Fukuda, A., Matsumoto, N., & Saitsu, H. (2018). Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy. American journal of human genetics, 102(2), 321–329. https://doi.org/10.1016/j.ajhg.2018.01.004
MedlinePlus (2022). PIGA Gene, phosphatidylinositol glycan anchor biosynthesis class A. Medline Plus, National Library of Medicine. Retrieved from: https://medlineplus.gov/genetics/gene/piga/
National Library of Medicine (2022). ARX aristaless related homeobox [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/170302
National Library of Medicine (2022). CDKL5 cyclin dependent kinase like 5 [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/6792
National Library of Medicine (2023). GRIN2B glutamate ionotropic receptor NMDA type subunit 2B [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/2904
National Library of Medicine (2022).GUF1 GTP binding elongation factor GUF1 [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/60558
National Library of Medicine (2023). NTRK2 neurotrophic receptor tyrosine kinase 2 [ Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/4915
National Library of Medicine (2022). PHACTR1 phosphatase and actin regulator 1 [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/221692
National Library of Medicine (2022). PIGA phosphatidylinositol glycan anchor biosynthesis class A [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/5277
National Library of Medicine (2023). PLCB1 phospholipase C beta 1 [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/23236
National Library of Medicine (2022). SCN2A sodium voltage-gated channel alpha subunit 2 [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/6326
National Library of Medicine (2022). SIK 1 salt inducible kinase 1 [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/150094
National Library of Medicine (2023). SPTAN1 spectrin alpha, non-erythrocytic 1 [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/6709
National Library of Medicine (2022). ST3GAL3 St3 beta-galactoside alpha-2,3-sialyltransferase 3 [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/6487
National Library of Medicine (2022). WDR45 WD repeat domain 45 [Homo sapiens (human)]. National Library of Medicine, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/11152
Ngoh, A., McTague, A., Wentzensen, I. M., Meyer, E., Applegate, C., Kossoff, E. H., Batista, D. A., Wang, T., & Kurian, M. A. (2014). Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum. Developmental medicine and child neurology, 56(11), 1124–1128. https://doi.org/10.1111/dmcn.12450
