About walker warburg syndrome

What is walker warburg syndrome?

Walker-Warburg syndrome (WWS) is a rare multisystem disorder characterized by muscle, brain and eye abnormalities, often leading to death in the first weeks of life. However, the specific symptoms and severity of WWS can vary greatly from case to case. The most consistent features are (1) a smooth appearance of the surface of the brain due to lack of normal folding pattern (lissencephaly or agyria), often with malformations of other brain structures including the cerebellum and brain stem, (2) various developmental abnormalities of the eye and (3) progressive degeneration and weakness of the voluntary muscles which is called congenital muscular dystrophy. WWS demonstrates autosomal recessive inheritance, with a recurrence risk of 1 in 4 or 25% for a couple who has previously had a child diagnosed with this genetic condition.

WWS is a severe form of the broader spectrum of conditions referred to as CMD (congenital muscular dystrophy), which is a group of disorders characterized by weakness and atrophy of various voluntary muscles of the body. Approximately 30 different disorders make up the muscular dystrophies. These disorders affect different muscles, may or may not have other body systems involved, and have different ages of onset, severity and inheritance patterns. The disorder was first reported in the medical literature in 1942.

What are the symptoms for walker warburg syndrome?

The main symptoms of WWS are Muscular dystrophy (progressive Degeneration and Weakness of the voluntary muscles) and abnormalities of the brain and eyes. Symptoms of WWS are congenital (present at birth), and some of the brain abnormalities can be detected by prenatal ultrasound and/or fetal MRI in the later stages of pregnancy.

Individuals with WWS have congenital muscular dystrophy, or a weakening and loss of muscle at birth. Muscular dystrophy causes affected infants to have severe Hypotonia (low muscle tone), muscle weakness, and atrophy (wasting away) which typically get worse over time. Some affected individuals develop contractures (abnormally fixed joints) that occur when thickening and shortening of tissue, such as muscle fibers, deform and restrict movement of an affected area.

Affected infants usually have a variety of serious brain findings, including type II lissencephaly (smooth brain), hydrocephalus (enlarged ventricles) and malformations in the back of the brain. Type II lissencephaly is also called cobblestone lissencephaly because the surface of the brain has a cobblestone appearance due to the collection of clumps of neurons (brain cells) at the surface. (For more information on this, choose “Lissencephaly” as your search term in the Rare Disease Database.) Hydrocephalus, which is characterized by having too much cerebrospinal fluid in the ventricles of the brain causing an enlargement, can be quite severe and lead to an abnormally large head. Malformations of the back portions of the brain can include hypoplasia (underdevelopment) of the cerebellum and brainstem. The cerebellum helps coordinate voluntary muscle movements, while the brainstem helps control basic functions such as breathing, salivation and heart rate. These posterior malformations can involve an abnormally enlarged space at the back of the brain, sometimes referred to as Dandy-Walker malformation. In some individuals with WWS, there is an encephalocele, which is a protrusion of part of the brain through the skull bone. Individuals with WWS may also have absence of the corpus callosum, which is the band of white matter that normally connects the two brain hemispheres.

The combined brain and muscle abnormalities lead to significant delays in reAching developmental milestones (e.g., sitting up, grabbing objects, crawling, talking) and can be so severe as to cause difficulties in breathing and swallowing. Children born with WWS display Intellectual disability and often have seizures.

The Eye abnormalities associated with WWS vary widely from person to person and can include any of the following: microphthalmia (abnormally small eyes), optic nerve hypoplasia (absent or underdeveloped optic nerves), retinal dysplasia (malformation of the retina which could cause the retina to become detached) and malformations of the fluid-filled space within the eyes behind the cornea and in front of the iris. Additional eye symptoms can include cataracts, coloboma (a cleft or loss of tissue of the retina or iris), buphthalmos (large and protruding eyes) or glauComa (increased pressure within the eyes). Most of these abnormalities lead to partial or complete blindness.

Occasionally, additional symptoms in different body systems can also be present. In some affected children, genitourinary abnormalities can occur, causing urinary tract blockage and kidney pelvic dilation (hydronephrosis) or failure of the testes to descend into the scrotum in males (cryptorchidism). Some affected children have other features, such as low-set or prominent ears, cleft lip or palate or cochlear hypoplasia (inner ear malformation).

What are the causes for walker warburg syndrome?

WWS is due to abnormally functioning or non-working genes that are important in muscle, brain and eye development. It is inherited in an autosomal recessive manner and occurs in an individual who inherits two abnormal copies of a gene, one from each parent. An individual that has one normally functioning copy of the gene and one non-working copy of the gene is a carrier for WWS but usually does not have any symptoms. The risk for two carrier parents who have children together to both pass on the abnormal or non-working gene and therefore have an affected child is 25%, or 1 in 4, with each pregnancy. The risk for these parents to have a child who is a carrier only (unaffected) is 50%, or 1 in 2, with each pregnancy. Their chance to have a child with two normally functioning copies of the gene (unaffected and not a carrier) is 25%, 1 in 4, with each pregnancy. These risks are the same for male and female offspring.

WWS results when certain genes involved in the development and function of the muscle, brain and eyes are not working properly. These WWS-associated genes are required for making proteins that are involved in a process known as glycosylation, which is the adding of sugar molecules to other proteins such that they can function correctly. The genes involved with WWS are required for the proper glycosylation of a protein called α-dystroglycan, as discussed in the Introduction. α-dystroglycan normally functions to stabilize muscle cells and aid in the migration of nerve cells in the brain during development. When these WWS-associated genes are unable to make proteins that normally glycosylate α-dystroglycan, it can lead to issues in the development of the muscle, brain and eyes that are seen in individuals affected by WWS and related dystroglycanopathies.

WWS has been associated with at least 14 different genes that are responsible for making proteins involved in the glycosylation process described above. Listed alphabetically below are the genes identified thus far and the proteins they produce.

•B3GALNT2: Beta-1,3-N-acetylgalactosaminyltransferase 2 protein •B4GAT1 or B3GNT1: Beta-1,4-glucuronyltransferase 1 protein •DAG1: Dystrophin-associated glycoprotein 1 •FKRP: Fukutin-related protein •FKTN: Fukutin protein* •GMPPB: GDP-mannose pyrophosphorylase B protein •ISPD: Isoprenoid synthase domain-containing protein •LARGE: Acetylglucosaminyltransferase-like protein •POMT1: O-mannosyltransferase 1 protein •POMT2: O-mannosyltransferase 2 protein •POMGNT1: O-mannose beta-1,2-N-acetylglucosaminyltransferase protein •POMGNT2 or GTDC2: O-mannose beta-1,4-N-acetylglucosaminyltransferase 2 protein •POMK or SGK196: Protein-O-mannose kinase •TMEM5: Transmembrane protein 5

*FKTN mutations are associated with several other conditions.

Recent advances in genetic research and testing, such as whole genome and whole exome sequencing, have determined that these genes are associated with WWS. The discovery of these genes and the characterization of symptoms they cause when not functioning properly has demonstrated variability in the clinical presentation of WWS in affected individuals. Although the 14 above-mentioned genes have been identified as causes of WWS, they explain only half of known WWS cases, and changes in all these genes can also cause less severe forms of muscular dystrophy. Because of this, genetic testing may not be able to identify a genetic cause of WWS in every individual or family. It is also likely that more genes associated with WWS, and related conditions will be discovered in the future, which could introduce additional variability to the spectrum of WWS.

What are the treatments for walker warburg syndrome?

There is no cure for WWS at this time and treatment is individualized based on specific symptoms. Medical management can require the coordinated efforts of a team of specialists including pediatricians, geneticists/genetic counselors, orthopedic surgeons, neurologists, ophthalmologists, and other health care professionals to systematically and comprehensively plan an affected child’s treatment.

Treatments might include anti-seizure medication, surgery for hydrocephalus, such as the placement of shunts to drain excess cerebrospinal fluid and reduce pressure in the brain, and physical therapy to improve muscle strength and prevent contractures. Some children might need a gastric tube to assist with feeding. Other symptomatic and supportive treatments could also be necessary. Due to the severe brain and muscle abnormalities, life expectancy is reduced with almost all affected children not surviving past age three.

What are the risk factors for walker warburg syndrome?

A genetic condition called Walker-Warburg syndrome (WWS) affects how the muscles, brain, and eyes grow. It is the most severe instance of a class of genetic disorders called congenital muscular dystrophies, which result in early-life muscle weakening and atrophy.

Walker-Warburg syndrome's warning signs and symptoms appear at birth or in the first few months of life. The majority of those affected by Walker-Warburg syndrome do not live past the age of three due to the severity of the problems it causes.

Skeletal muscles, which the body utilizes to move, are impacted by Walker-Warburg syndrome. Babies who have affected exhibit hypotonia, or weak muscular tone, and are commonly referred to as "floppy." Over time, the muscle weakness gets worse.

Risk factors of Walker-Warburg syndrome (WWS)

1. The cause of WWS is abnormally functioning or non-functional genes that are crucial for the growth of the eye, brain, and muscle. It is inherited autosomally recessive and affects people who have two faulty copies of the same gene, one from each parent.

2. A person who is a carrier for WWS but does not often exhibit any symptoms has one copy of the gene that is normally functioning and one copy of the gene that is not functioning. With each pregnancy, there is a 25% chance, or one in four, that two carriers who have children together may pass on the defective or non-working gene to their offspring.

3. With each pregnancy, these parents run a 50%, or 1 in 2, chance of having a kid who is just a carrier (unaffected). With each pregnancy, they have a 25%, or 1 in 4, chance of giving birth to a kid who carries two copies of the gene that are healthy (unaffected and not a carrier). Both male and female kids run the same dangers.

Congenital muscular dystrophy, or a weakening and loss of muscle at birth
Malformations in the back of the brain,Intellectually slow, and display signs of seizures
Anti-seizure medication,Surgery

Is there a cure/medications for walker warburg syndrome?

An uncommon genetic condition called Walker-Warburg syndrome (WWS) affects how the muscles, brain, and eyes grow. WWS is distinguished by:

Cure or Medication for Walker-Warburg syndrome (WWS)

1. Currently, there is no known treatment for Walker-Warburg syndrome (WWS); instead, care is tailored to each patient's unique set of symptoms.
2. To carefully and thoroughly arrange a child's treatment, medical management may call for the coordinated efforts of a team of specialists, including pediatricians, geneticists/genetic counselors, orthopedic surgeons, neurologists, ophthalmologists, and other health care providers.
3. Anti-seizure medication, hydrocephalus surgery, such as the implantation of shunts to drain extra cerebrospinal fluid and lower pressure in the brain, and physical therapy to strengthen muscles and prevent contractures are possible treatments. Some kids might require a gastric tube to help them eat.
4. There may also be a need for further symptomatic and supportive therapies. Life expectancy is shortened as a result of severe brain and muscular abnormalities, with nearly no affected children living past the age of three.

Diagnosis for Walker-Warburg syndrome

Walker-Warburg syndrome is diagnosed based on the detection of defining symptoms, a comprehensive clinical assessment, and a range of specialized diagnostics. Genetic testing at the molecular level can support a diagnosis.

During the final stages of pregnancy, regular ultrasound and/or fetal MRI can be used to raise a diagnosis that can then be verified at the time of delivery or very soon after. When there is type II lissencephaly (smooth brain), cerebellar abnormalities, and other early alterations in the brain and eye during pregnancy, imaging can imply WWS.

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