Refsum disease ... (Refsum disease) - Genes PHYH and PEX7

Refsum disease, also known as phytanic acid storage disease is an inherited process leading to vision loss and anosmia, among other signs and symptoms.

The vision loss associated with Refsum disease is due to retinitis pigmentosa. The first sign of retinitis pigmentosa is usually a loss of night vision, which is usually evident in infancy. With Over the years, the disease alters peripheral vision and can lead to blindness. Loss of vision and anosmia are seen in almost all patients with Refsum disease. About one - third of affected individuals are born with skeletal abnormalities of the hands and feet. Other clinical manifestations that develop later may include progressive muscle weakness, ataxia, hearing loss and ichthyosis. In addition, some people with Refsum disease develop cardiac arrhythmia and other related problems that can endanger life.

This process is due, in over 90 percent of all cases, alterations in the gene PHYH (phytanoyl-CoA hydroxylase 2-). The remaining cases are due to mutations in the gene PEX7 (peroxisomal biogenesis factor 7).

The PHYH gene (phytanoyl-CoA hydroxylase 2-), located on the short arm of chromosome 10 (10p13), encoding the hydroxylase enzyme fitanoil-CoA. This enzyme is critical for the normal function of peroxisomes. These compartments saclike contain processing enzymes many different substances, such as fatty acids and certain toxic compounds. A substance which decomposes into peroxisomes is phytanic acid, a type of fatty acid obtained from the diet (particularly meat and dairy products). Fitanoil-CoA hydroxylase is responsible for one of the first steps in the decomposition of phytanic acid as part of a process known as alpha-oxidation. In later stages, certain additional enzymes in peroxisomes and other parts of the cell process this compound into smaller molecules that the body can use for energy. In addition, it is believed that fitanoil-CoA hydroxylase may have other functions besides its role in the degradation of phytanic acid. For example, this enzyme appears to help determine the number of peroxisomes inside cells and is involved in the regulation of its activity.

About 30 have been identified mutations in the gene PHYH in individuals with Refsum disease. These mutations alter the structure or synthesis fitanoil-CoA hydroxylase, which reduces the enzyme activity. A deficiency of this enzyme alters the degradation of phytanic acid in peroxisomes. Consequently, phytanic acid and related compounds accumulate in body tissues. The accumulation of phytanic acid is toxic to cells, although it is unclear how an excess of this substance affects vision and smell and causes other specific characteristics of Refsum disease.

Meanwhile, the PEX7 gene (peroxisomal biogenesis factor 7), located on the long arm of chromosome 6 (6q23.3), encoding factor synthesis peroxisomal biogenesis 7, which is part of a group peroxisomal assembly protein (PEX). Inside the cells, PEX proteins are responsible for the incorporation of certain enzymes in peroxisomes. In these compartments, enzymes break down many different substances, including fatty acids and some toxic compounds. They are also important for the synthesis of lipids, which are used in the nervous system. Factor biogenesis peroxisomal 7 carries several enzymes essential for assembly and normal function of peroxisomes. The most important of these enzymes is alkylglycerol phosphate synthase enzyme (encoded gene from AGPS). Factor biogenesis peroxisomal 7 also carries fitanoil-CoA hydroxylase enzyme encoded by the gene PHYH.

Mutations in the gene PEX7 are responsible for a small percentage of all cases Refsum disease. The three mutations that are known to be responsible for this process reduce the activity of peroxisomal biogenesis factor 7 of, interrupting the import of several critical enzymes (including fitanoil-CoA hydroxylase) in peroxisomes. Without sufficient concentration of these enzymes, peroxisomes can not break down fatty acids and other substances effectively. In people with Refsum disease, deficiency fitanoil-CoA hydroxylase prevents peroxisomes phytanic acid decompose. Instead, this substance gradually accumulates in body tissues. But over time, the accumulation of phytanic acid becomes toxic to cells, it is not clear how an excess of this substance affects vision and smell and leads to the other specific characteristics of Refsum disease.

This disease 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 detection of mutations associated with Refsum disease by the complete PCR amplification of the exons of PHYH and PEX7 genes, respectively, and subsequent sequencing.

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).