Dandy-Walker Malformation ... (Dandy-Walker malformation) - Genes FOXC1, ZIC1 and ZIC4  

The Dandy-Walker malformation is a disorder that affects brain development, mainly the cerebellum. In people affected various parts of the cerebellum develop abnormally, causing malformations. The vermis is absent or is very small. Cysts appear in the fourth ventricle, causing an enlargement of it. The posterior fossa is abnormally large. These alterations usually lead to problems with movement, coordination, intellect and other neurological functions.

In 80 to 90 percent of those affected, the signs and symptoms caused by abnormal brain development are present at birth or manifest themselves throughout the first year of life. Some children have hydrocephalus can cause macrocephaly. Although some affected people have normal intelligence, up to half of affected individuals have mild to profound intellectual disability. Often, children with Dandy-Walker malformation have developmental delays, particularly delays in motor skills such as crawling, walking and coordination of movement. Affected individuals often manifest muscle stiffness and spastic paraplegia, seizures, hearing and visual. Less commonly, there have been other brain malformations including holoprosencephaly, agenesis of corpus callosum, occipital encephalocele, Schizencephaly or neural tube defects. These additional brain malformations are associated with signs and severe symptoms. Other signs and symptoms may include heart defects, urogenital tract malformations, polydactyly or syndactyly, or abnormal facial features.

In the 10 to 20 percent of people with Dandy-Walker malformation, signs and symptoms do not appear until late childhood or adulthood. These people often have a different range of signs and symptoms, such as headaches, unsteady gait, facial paralysis, increased muscle tone, muscle spasms, and intellectual or behavioral changes. Problems related to hydrocephalus or treatment complications are the most frequent causes of death in people affected. Rarely, people with Dandy-Walker malformation have no health problems related to the disease.

A small number of cases are due to mutations in FOXC1 (forkhead box C1), ZIC1 (Zic family member 1) and ZIC4 genes (Zic family member 4). Other cases have been associated with chromosomal abnormalities in most chromosomes. Malformation Dandy-Walker may be a feature of some processes in which there is an extra copy of a chromosome in each cell. Malformation Dandy-Walker occurs most often in people with Trisomy 18, but can also occur in individuals with trisomy 13, trisomy 21 or trisomy 9. This disease may also be associated with deletions or duplications of certain chromosomes units. They have identified other cases of the disease in newborns with triploidía, a fatal condition in which individuals have an extra complete set of chromosomes in each cell. It is believed that Malformation Dandy-Walker also could be due to environmental factors affecting development before birth, as rubella infections or toxoplasmosis. Fetal exposure to teratogens may also be involved in the development of this disease.

The FOXC1 (forkhead box C1) gene, located on the short arm of chromosome 6 (6p25), encodes a protein that acts as a transcription factor. The protein plays a critical role in early development, particularly in the formation of structures in front of the eye such as the iris, the lens and cornea. It is believed that the protein may also have roles in the adult eye, helping cells respond to oxidative stress. The protein is also involved in the normal development of other parts of the body, including the heart, kidneys and brain. Mutations in the gene responsible FOXC1 Malformation Dandy-Walker change the amino acids in the protein. Other changes cause deletions of genetic material from a region of chromosome 6.

The ZIC1 gene (Zic family member 1), located on the long arm of chromosome 3 (3q24), encodes a member of the protein family ZIC C2H2 type zinc. Members of this family are important in early organogenesis CNS as well as during the development of the dorsal spinal cord and cerebellum maturation. Aberrant expression of this gene is in medulloblastoma, childhood brain tumor. This gene is closely linked to the protein cerebellar 4, a related family member on chromosome 3. This gene encodes a transcription factor that can bind and transactivate the apolipoprotein E.

The ZIC4 gene (Zic family member 4), located on the long arm of chromosome 3 (3q24), encodes a member of the protein family ZIC C2H2 type. Members of this family are important during development, and have been associated with visceral heterotaxia X - linked and holoprosencephaly type 5. This gene is closely linked to the protein of the cerebellum 1, a family member related in chromosome 3.

Most cases of the disease are sporadic, meaning that occur in people with no history of disease in your family. It reported a small percentage of cases in families, although no clear pattern of inheritance. Multiple genetic and environmental factors may play a role in determining the risk of developing the disorder. First - degree relatives of individuals with Dandy-Walker malformation have a higher risk of developing the disease compared to the general population.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with Dandy-Walker, by complete PCR amplification of the exons of FOXC1, ZIC1 and ZIC4, respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).