Megalencefálica leukoencephalopathy with subcortical cysts; Leukoencephalopathy with subcortical cysts vacuolizante megalencefálica; Van der Knapp disease (Megalencephalic leukoencephalopathy With subcortical cysts; vacuolating megalencephalic leukoencephalopathy With subcortical cysts; Van der Knapp disease) - Genes MLC1 and HEPACAM.
The megalencefálica leukoencephalopathy with subcortical cysts is a progressive disease that affects brain development and function. Affected individuals have megalencephaly, which is evident at birth or during the first year of life, which induces a macrocefalia and altered cerebral white matter (leukoencephalopathy). The white substance is swollen and vacuolated, and eventually decreases swelling and myelin atrophies, developing subcortical cysts. Clinically, they have affected muscle spasticity and ataxia, with a variable motor incapacitation of some affected others. Some affected individuals lose the ability to walk, while others can do so for years. Other signs and symptoms of the disease include athetosis, dysphagia and dysarthria. Despite widespread brain abnormalities, intellectual ability is unaffected. More than half of those affected develop seizures that can occur spontaneously or after some cranial involvement.
They described three types of megalencefálica leukoencephalopathy with subcortical cysts, which differ in their signs and symptoms as well as its genetic cause. Types 1 and 2A have different genetic causes, but are almost identical in terms of signs and symptoms. 2A and 2B types have the same genetic cause, but the signs and symptoms of type 2B often begin to improve after one year. Overall, after improvement, people with type 2B show macrocefalia and can manifest intellectual disabilities.
This disease is due to mutations in the MLC1 (Megalencephalic Leukoencephalopathy With subcortical Cyst 1) gene, or the gene HEPACAM (Hepatic and Glial Cell Adhesion Molecule). About 5% of people with megalencefálica leukoencephalopathy with subcortical cysts have identified mutations in the gene MLC1 or HEPACAM. In these individuals, the cause of the disease is unknown.
The MLC1 gene, located on the long arm of chromosome 22 (22q13.33), encodes a protein found in the brain, spleen and leukocytes. Within the brain, the protein is found in astroglial cells, which protect and maintain neurons. Also involved in the joints between astroglial cells, and probably in the transport of molecules across the blood brain barrier and between the brain and cerebrospinal fluid. The precise function of the protein in astroglial cells in the spleen and leukocytes is unknown. They have identified more than 80 mutations in the gene cause megalencefálica MLC1 leukoencephalopathy with subcortical cysts. Mutations in the gene MLC1 are responsible for type 1 disease and represent approximately 75% of all cases. Most of these mutations change amino acids used in the synthesis of protein MLC1, which prevents encoding a functional protein MLC1. Most probably mutations alter the structure of the protein or prevent its synthesis. It is unclear how the lack of protein functional MLC1 affects the development and functioning of the brain, leading to the signs and symptoms of the disease.
The HEPACAM gene, located on the long arm of chromosome 11 (11q24.2), encoding the protein GlialCAM. This protein is found in liver cells and glial cells. In liver cells, the GlialCAM protein plays a role in cell adhesion and movement. In glial cells, it binds to other proteins or GlialCAM MLC1 and ClC-2 proteins. GlialCAM ensures that these proteins are transported to the joints that connect the neighboring glial cells. However, the function of the cell binding GlialCAM is unclear. They have identified at least 20 mutations in the gene HEPACAM in people with megalencefálica leukoencephalopathy with subcortical cysts. Mutations in the gene are responsible for HEPACAM 2A and 2B disease types. Together, these types account for 20% of all cases. All mutations result in a nonfunctional protein. It is unclear how functional protein deficiency GlialCAM alters the development and functioning of the brain, causing signs and symptoms of the disease.
In all cases of megalencefálica leukoencephalopathy with subcortical cysts due to mutations in the MLC1 gene and some cases due to mutations in the HEPACAM gene is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations so that the 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. However, megalencefálica leukoencephalopathy with subcortical cysts 2B type is inherited in an autosomal dominant pattern, meaning that an altered copy of the gene in every cell HEPACAM is sufficient for alteration is expressed. Most cases of the disease type 2B, are due to new mutations in the gene HEPACAM during the formation of reproductive cells or early embryonic development. These cases occur in people with no history of disease in your family.
Tests in IVAMI: in IVAMI perform detection of mutations associated with megalencefálica leukoencephalopathy with subcortical cysts, by complete PCR amplification of the exons of MLC1 and HEPACAM, 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).