Wolfram syndrome ... (Wolfram syndrome) - Genes CISD2 and WFS1

Wolfram syndrome is a disorder that affects many body systems. The distinctive features of the syndrome are high concentrations of blood sugar due to diabetes mellitus and progressive loss of vision due to optic atrophy. Often, people with Wolfram syndrome are also of a dysfunction of the pituitary gland that causes diabetes insipidus, sensorineural hearing loss, urinary tract problems, hypogonadism, or neurological or psychiatric disorders.

Normally, diabetes mellitus is the first symptom of the syndrome, which is usually diagnosed around age 6. Almost all people with Wolfram syndrome who develop diabetes require insulin replacement therapy. Often the next symptom to appear is optic atrophy, usually around 11 years. The first signs of atrophy include optical loss of peripheral vision and color. Eventually, vision problems worsen, and people with optic atrophy become blind at age 8 to start the first signs. In diabetes insipidus, pituitary gland does not function normally. This anomaly disrupts the release of the hormone vasopressin, which helps control water balance and urine production in the body. Approximately 70% of people with Wolfram syndrome has diabetes insipidus. Dysfunction of the pituitary gland may also cause hypogonadism in men. Lack of testosterone produced with hypogonadism affects growth and sexual development. About 65% of people with Wolfram syndrome has sensorineural hearing loss, which can vary in severity from deafness at birth to mild hearing loss from adolescence, worsening over time. Furthermore, 60 to 90% of people with Wolfram syndrome has the problem of the urinary tract including the ureter obstruction, high capacity atonal bladder sphincter dyssynergia and bladder incontinence is included.

About 60% of people with Wolfram syndrome develop a neurological or psychiatric disorder, most commonly including balance and coordination problems usually start in early adulthood. Other neurological problems manifesting people with Wolfram syndrome include irregular breathing due to central apnea, loss of sense of smell, loss of gag reflex, myoclonus, seizures, peripheral neuropathy and intellectual impairment. Psychiatric disorders associated with the syndrome often include psychosis, major depressive episodes, and an impulsive and aggressive behavior.

There are two types of Wolfram syndrome, which differ in their genetic cause. In addition to the usual features of Wolfram syndrome, individuals with type 2 Wolfram syndrome develop gastric or intestinal ulcers and bleeding after an injury. The bleeding tendency, combined with ulcers, usually leads to abnormal bleeding in the gastrointestinal system. People with type 2 Wolfram syndrome do not develop diabetes insipidus.

This process is due, in 90% of cases, to mutations in the gene WFS1 (wolframin ER transmembrane glycoprotein), located on the short arm of chromosome 4 (4p16.1), which encodes the protein responsible for regulating wolframina the amount of calcium in the cells. The wolframina protein is found in many different tissues, including the pancreas, brain, heart, bones, muscles, lungs, liver and kidneys. Inside the cells, wolframina is in the endoplasmic reticulum, involved in the production, processing and transport of proteins. Wolframina function is important in the pancreas, where it is believed that helps process a protein called proinsulin mature insulin hormone. This hormone helps control the levels of blood sugar. In the inner ear, wolframina can help maintain appropriate calcium ions or other charged particles that are essential for hearing concentrations.

They have identified at least 200 mutations in the gene WFS1 in people with type 1 Wolfram syndrome These mutations result in the synthesis of a protein with reduced or wolframina nonfunctional function. As a result, the concentrations of calcium inside cells are unregulated and the endoplasmic reticulum is not working properly. When the endoplasmic reticulum does not have enough functional wolframina, the cell triggers your own cell death. The death of cells in the pancreas, specifically the cells that produce insulin (beta cells), causing diabetes mellitus. Gradual loss of cells along the optic nerve eventually leads to blindness in people affected. The death of cells in other body systems probably cause various signs and symptoms of Wolfram syndrome type 1. Mutations in the gene cause WFS1 a lack of insulin resulting in diabetes mellitus, optic atrophy, and other features involving urinary tract, brain and ear.

In addition to mutations in the WFS1 gene, it has been identified at least one mutation in the gene CISD2 (CDGSH iron sulfur domain 2) responsible for the development of type 2 Wolfram This gene, located on the long arm of chromosome 4 syndrome (4q24 ) encodes a protein found in the outer membrane of mitochondria. The exact function of the protein is unknown but is believed to help maintain normal functioning of mitochondria. The identified in this gene, mutation replaces glutamic acid amino acid with the amino acid glutamine at position 37 in the protein CISD2 (Glu37Gln or E37Q). This mutation results in the synthesis of an abnormally small and non - functional protein. As a consequence, mitochondria are not maintained properly, decomposing with time and thus decreasing the energy provided to the cells. Without sufficient power to operate, the cells eventually die. Cells with high energy demands, such as nerve cells in the brain, eye , or gastrointestinal tract are more susceptible to cell death due to energy reduction.

This 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 performed in IVAMI: in IVAMI perform detection of mutations associated with Wolfram syndrome, by complete PCR amplification of the exons of CISD2 and WFS1 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).