Walker-Warburg syndrome ... (Walker-Warburg syndrome) - Genes POMT1, POMT2, FKRP, FKTN, ISPD and LARGE
The Walker-Warburg syndrome (WWS: Walker-Warburg Syndrome), also known as COD-MD (eye-brain-Muscular Dystrophy--Dystrophy), or syndrome HARD +/- E (Hydrocephalus, Retinal Dysplasia Agyria and with or without syndrome encephalocele [+/- E]) was initially described by Walker (1942), when describing a case in which there lissencephaly, hydrocephalus, microphthalmia and retinal dysplasia. The description was completed by Warburg (1971-1978). These diseases usually present lissencephaly, cerebellar abnormalities and retinal defects. Furthermore, they may have other characteristics, variables of each other patients, such as: macrocephaly or microcephaly, hypoplasia midbrain structures, ventricular dilatation, microphthalmia, lip and / or palate, among others. The most severe form corresponds to Walker-Warburg syndrome of, and those affected usually die in the first year of life and live up to 3 years, while those with the mild form (muscle-eye-brain disease -MEB- ) can get to walk and say a few words.
Clinical manifestations of syndrome Walker-Warburg include cerebral effects, as lissencephaly, hydrocephalus or abnormalities of certain parts of the brain, including the cerebellum and brain stem. These changes in brain structure lead to a significant developmental delay and intellectual disability. In addition, some people with Walker-Warburg syndrome of suffering from seizures. Ocular abnormalities are also features Walker-Warburg syndrome of. These abnormalities include microphthalmia, buphthalmos, cataracts and problems with the optic nerve.
This may be due to mutations in at least a dozen genes. It is likely that other genes, some of which have not been identified, involved in the development of the syndrome.
- POMT1 (O-mannosyltransferase protein 1).
- POMT2 (O-mannosyltransferase protein 2),
- FKRP (fukutin related protein)
- FKTN (fukutin),
- ISPD (isoprenoid synthase domain containing),
- LARGE (LARGE xylosyl- and glucuronyltransferase 1),
- B3GALNT2 (beta-1,3-N-acetylgalactosaminyltransferase 2),
- B4GAT1 (beta-1,4-glucuronyltransferase 1),
- DAG1 (dystroglycan 1),
- POMGNT1 (protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2)),
- POMGNT2 (protein O-linked mannose N-acetylglucosaminyltransferase 2 (beta 1,4)),
- POMK (protein kinase-O-mannose),
- TMEM5 (transmembrane protein 5)
In about half of cases, Walker-Warburg syndrome is due to mutations in genes POMT1, POMT2, FKRP, FKTN, ISPD and LARGE. The proteins encoded by these genes from another protein called modified ?-destroglicano; this modification called glycosylation, are required for the operation of ?-destroglicano. The protein ?-destroglicano helps to fix the cytoskeletal network of proteins and other molecules on the outside of the extracellular matrix. In skeletal muscle, the function ?-anchor destroglicano helps stabilize and protect the muscle fibers. In the brain, helping to direct the migration of neurons in early development.
Have identified at least 24 mutations in the POMT1 gene, 8 mutations POMT2 gene, five mutations in the FKRP gene, 18 mutations in the FKTN gene, 17 mutations in the ISPD gene and 7 mutations in the LARGE gene, people with Walker-Warburg syndrome of. Mutations in these genes inhibit glycosylation of ?-destroglicano, interrupting its normal function. No functional to stabilize muscle cells ?-destroglicano, muscle fibers are damaged due to repeated contraction and muscle relaxation. Damaged fibers weaken and eventually die, resulting in progressive weakness of the skeletal muscles. In addition, the defective ?-destroglicano affects the migration of neurons in early brain development. Instead of stopping when they reach their intended destinations, some neurons migrate beyond the surface of the brain into the cerebrospinal fluid space. It is likely that this problem with neuronal migration cause lissencephaly in children with Walker-Warburg syndrome of. Less is known about the effects of genetic mutations in other parts of the body, including the eyes.
The Walker-Warburg syndrome is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform the detection of mutations associated with Walker-Warburg syndrome, by complete PCR amplification of the exons of POMT1, POMT2, FKRP, FKTN, ISPD and LARGE genes, respectively, and subsequent sequencing. For more frequency of mutations in the gene POMT1, and then the POMT2 gene have been described, it is recommended to start with the first (POMT1), and if not find mutations, the study of the second. However, as mentioned, we have published case series Walker-Warburg syndrome of, where they have not found mutations in these 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).