Walker–Warburg syndrome (WWS), also called Warburg syndrome, Chemke syndrome, HARD syndrome (Hydrocephalus, Agyria and Retinal Dysplasia), Pagon syndrome, cerebroocular dysgenesis (COD) or cerebroocular dysplasia-muscular dystrophy syndrome (COD-MD), is a rare form of

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...

muscular dystrophy Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affe ...

. It is associated with brain (

lissencephaly Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a ...

hydrocephalus Hydrocephalus is a condition in which cerebrospinal fluid (CSF) builds up within the brain, which can cause pressure to increase in the skull. Symptoms may vary according to age. Headaches and double vision are common. Elderly adults with n ...

cerebellar The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or e ...

malformations) and

eye An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the ey ...

abnormalities. This condition has a worldwide distribution. Walker-Warburg syndrome is estimated to affect 1 in 60,500 newborns worldwide.

Presentation

The clinical manifestations present at birth are generalized

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but it is a potential manifestation of many different dis ...

, muscle weakness, developmental delay with

intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

and occasional

seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

. The congenital muscular dystrophy is characterized by hypoglycosylation of α-dystroglycan. Those born with the disease also experience severe ocular and brain defects. Half of all children with WWS are born with encephalocele, which is a gap in the skull that will not seal. The meninges of the brain protrude through this gap due to the neural tube failing to close during development. A malformation of the a baby's cerebellum is often a sign of this disease. Common ocular issues associated with WWS are abnormally small eyes and retinal abnormalities cause by an underdeveloped light-sensitive area in the back of the eye.

Genetics

Several genes have been implicated in the etiology of Walker–Warburg syndrome, and others are as yet unknown. Several mutations were found in the protein

O-Mannosyltransferase In enzymology, a dolichyl-phosphate-mannose-protein mannosyltransferase () is an enzyme that catalyzes the chemical reaction :dolichyl phosphate D-mannose + protein \rightleftharpoons dolichyl phosphate + O-D-mannosylprotein Thus, the two subst ...

POMT1 Protein O-mannosyl-transferase 1 is an enzyme that in humans is encoded by the ''POMT1'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA ...

and POMT2 genes, and one mutation was found in each of the fukutin and fukutin-related protein genes. Another gene that has been linked to this condition is Beta-1,3-N-acetylgalactosaminyltransferase 2 ( B3GALNT2).

Diagnosis

Laboratory investigations usually show elevated

creatine kinase Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phos ...

, myopathic/dystrophic muscle pathology and altered α-dystroglycan. Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound may be helpful for diagnosis in families where the molecular defect is unknown.

Prognosis

No specific treatment is available. Management is only supportive and preventive. Those who are diagnosed with the disease often die within the first few months of life. Almost all children with the disease die by the age of three.

Eponym

WWS is named for

Arthur Earl Walker Arthur Earl Walker (March 12, 1907 – January 1, 1995) was a Canadian-born American neurosurgeon, neuroscientist and epileptologist remembered for the eponymous syndromes Dandy–Walker syndrome, Dandy–Walker-like syndrome and Walker–Warbur ...

and

Mette Warburg Mette Warburg (23 January, 1926 - 11 March, 2015) was a Danish eye specialist. Her specialist areas were pediatric ophthalmology and ophthalmic genetics. Biography Warburg was born in Copenhagen. Her father Erik was a notable cardiologist and her ...

. Its alternative names include Chemke’s syndrome and Pagon’s syndrome, named after

Juan M. Chemke ''Juan'' is a given name, the Spanish and Manx versions of ''John''. The name is of Hebrew origin and has the meaning "God has been gracious." It is very common in Spain and in other Spanish-speaking countries around the world and in the Philippi ...

and

Roberta A. Pagon Roberta is a feminine version of the given names Robert and Roberto. It is a Germanic name derived from the stems *hrod meaning "famous", "glorious", "godlike" and *berht meaning "bright", "shining", "light". People with the name * Roberta Achten ...

References

External links

{{DEFAULTSORT:Walker-Warburg syndrome Autosomal recessive disorders Muscular dystrophy Congenital disorders Syndromes affecting the nervous system Syndromes Enzyme defects Rare diseases Congenital disorders of glycosylation