Zellweger, ... spectrum disorders (Zellweger spectrum disorder) - Genes PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, pEX26 and PEX11B
The spectrum of disorders Zellweger, also known as diseases peroxisome biogenesis, is a group of disorders in which the signs and symptoms overlap and affect many parts of the body. This group of disorders include Zellweger 's syndrome, neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease. It was thought that these diseases were different alterations, but are now considered part of the same spectrum of disease. Zellweger syndrome is the most severe form of the spectrum of alterations Zellweger, neonatal adrenoleukodystrophy (NALD) is the form of intermediate severity, and infantile Refsum disease is the mildest form. In some cases, it may be difficult to distinguish between the three alterations that make up the spectrum Zellweger.
People with Zellweger syndrome develop signs and symptoms of the disease during the neonatal period, including hypotonia, feeding problems, vision loss, hearing loss and seizures. These problems are due to degeneration of myelin. Demyelination results leukodystrophy. Children with Zellweger syndrome also develop problems in other organs and tissues such as the liver, heart and kidneys, life - threatening. In addition, they may have skeletal abnormalities, including bone fontanels and stains known as chondrodysplasia punctata that can be seen on a radiograph. Affected individuals have characteristic facial features, including a flattened face, broad nasal bridge and a high forehead. Children with Zellweger syndrome usually do not survive beyond the first year of life.
People with neonatal adrenoleukodystrophy (NALD) or infantile Refsum disease are more variables that people with Zellweger syndrome usually features and signs and symptoms of the disease do not develop until early childhood or late childhood. These individuals may have many of the features seen in people with more severe disease, but however, altering usually progresses more slowly. Often children with these disorders are less severe hypotonia, vision problems, hearing loss, liver dysfunction, developmental delays and some degree of intellectual disability. Most people with neonatal adrenoleukodystrophy survive infancy, and those with infantile Refsum disease may reach adulthood.
Mutations have been identified in at least 13 genes, which result in alterations of Zellweger spectrum: PEX1 (peroxisomal biogenesis factor 1, 7q21.2), PEX2 (peroxisomal biogenesis factor 2, 8q21.1), PEX3 (peroxisomal biogenesis factor 3 , 6q24.2), PEX5 (peroxisomal biogenesis factor 5, 12p13.31), PEX6 (peroxisomal biogenesis factor 6, 6p21.1), PEX10 (peroxisomal biogenesis factor 10 1p36.32), PEX12 (peroxisomal biogenesis factor 12, 17q12 ), PEX13 (peroxisomal biogenesis factor 13, 2p16.1), PEX14 (peroxisomal biogenesis factor 14 1p36.22), PEX16 (peroxisomal biogenesis factor 16, 11p11.2), PEX19 (peroxisomal biogenesis factor 19, 1q23.2), pEX26 (peroxisomal biogenesis factor 26 22q11.21) and PEX11B (peroxisomal biogenesis factor 11 beta, 1q21.1).
These genes encode a group of proteins known as peroxinas, essential for the formation and normal functioning of peroxisomes. Peroxisomes contain the enzymes necessary to decompose many different substances, including fatty acids and some toxic compounds. They are also important for the production of lipids that are used in digestion and in the nervous system. The encoded proteins from these genes help in peroxisome biogenesis constituting the membrane separating the peroxisome the rest of the cell and by importing peroxisome enzymes.
Mutations in the gene PEX1 (peroxisomal biogenesis factor 1), located on the long arm of chromosome 7 (7q21.2), are the most common cause Zellweger spectrum and are found in almost 70 percent of the individuals affected. They have identified at least 114 mutations in the gene PEX1 in people with Zellweger spectrum. Mutations in the gene PEX1 reduce or completely eliminate the activity of the protein Pex1p. Without sufficient operating Pex1p protein, enzymes are not successfully imported into the peroxisomes. As a result, cells containing peroxisomes gaps can not perform their usual functions. There are two mutations in the gene PEX1 frequent in people with Zellweger spectrum. A mutation replaces the amino acid glycine for aspartic acid amino acid at position 843 in the protein (or Gly843Asp G843D). This mutation leads to decreased levels of the protein Pex1p. People who have the G843D mutation tend to have signs and symptoms found in the less severe end of the spectrum Zellweger. The other common mutation (1700fs), results in the synthesis of an abnormally short, nonfunctional protein Pex1p. People who have the mutation 1700fs have signs and symptoms found in the most severe end of the spectrum Zellweger. Signs and symptoms of Zellweger syndrome are due to the absence of functional peroxisomes within the cells. In neonatal adrenoleukodystrophy or infantile Refsum disease mutations enable the formation of some peroxisomes.
Each of the other genes associated with Zellweger spectrum represents a smaller percentage of cases.
This disease is inherited in an autosomal recessive pattern, that is, 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 the spectrum of alterations Zellweger, by complete PCR amplification of the exons of PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, genes PEX14 , PEX16, PEX19, pEX26 and PEX111B, respectively, and subsequent sequencing. We recommend starting the study by the PEX1, responsible for most cases of the disease gene.
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).