Cystinosis

Cystinosis is an autosomal recessive lysosomal storage disease. The disease is a rare genetic disorder characterized by impaired transport of the amino acid cystine from lysosomes, creating an accumulation of cystine within cells. The excess cystine impairs cells and can cause crystals to form throughout the body. If left untreated, cystinosis can lead to health issues such as vision loss, renal disease, thyroid failure, and multi-organ dysfunction. Three forms of cystinosis exist: nephropathic, intermediate, and non-nephropathic or ocular. Age of onset and symptoms vary by type. Cystinosis is the leading cause of Fanconi syndrome in children, which occurs when cells within the kidney become damaged and cause malabsorption of nutrients in the renal tubes. Following diagnosis, treatment for cystinosis almost always involves kidney transplantation.

Background

Cystinosis first entered the medical language in 1903, when Swiss chemist Emil Abderhalden described it as a hereditary cystine accumulation disease. Abderhalden used the term in reference to a medical case in Switzerland involving a child who died at twenty-one months. Upon postmortem examination, doctors reported that the child had a large amount of cystine accumulation in multiple organs. Dutch pathologist George Lignac expanded on Abderhalden's description in 1924 and became the first to discover the association between cystinosis and impairments such as rickets, renal disease, and growth delays. Swiss pediatrician Guido Fanconi further supplemented the medical community's understanding of the disease by detailing his findings, which showed loss of important metabolic substances through urination. During these early days of discovery, cystinosis was varyingly referred to as Abderhalden-Kaufmann-Lignac syndrome and Lignac-Fanconi syndrome. The modern term is derived from the German term cystindiathese, or "hereditary cystine disease," which was Anglicized in medical literature as cystine disease before becoming cystinosis.

Cystinosis is classified as a lysosomal storage disorder. Lysosomes—membrane-bound organelles found in the cytoplasm of eukaryotic cells—are responsible for breaking down nutrients such as fats, proteins, and carbohydrates. Lysosomes contain enzymes, substances that cause biochemical reactions within organisms. Some enzymes inside lysosomes break down, or metabolize, nutrients while others transport leftover substances out of lysosomes. If lysosomes lack the enzymes that remove excess substances, substances can build up within them. In the case of cystinosis, cystine accumulation forms crystals within cells. As the cystine accumulates and crystallization proliferates throughout the body, organs and tissues gradually become damaged.

Cystinosis effects between 1 in 100,000 and 1 in 200,000 people worldwide and has been found in all ethnic groups. Prevalence is especially high in children. The disease's three manifestations include nephropathic or classic infantile cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. About 95 percent of cystinosis patients have nephropathic cystinosis. Nephropathic cystinosis is the most severe form of the disease and commonly results in kidney failure in children before age ten. It is also the main cause of Fanconi syndrome in children. Intermediate cystinosis is as severe as the nephropathic form but does not manifest until adolescence. The non-nephropathic or ocular form is the least severe of the three types, resulting only in crystal formation in the cornea and sensitivity to light.

Overview

Cystinosis is a genetic disorder, which means that a person inherits it through his or her genes. The disease is caused by a mutation in the CTNS gene, which encodes the cystinosin protein in humans. Cystinosin is responsible for transporting cystine out of the lysosome. If cystinosin malfunctions, cystine can build up in the lysosome and crystalize, damaging tissues and organs. Symptoms of cystinosis vary from person to person. The disease's severity usually depends on age of onset and timeliness of diagnosis. Symptoms may also present themselves at varying ages. An early diagnosis significantly improves a person's chance of recovery.

With nephropathic cystinosis, symptoms usually first appear in children between six and twelve months old. These symptoms can range in severity. Growth impairment and Fanconi syndrome are the most common indicators. Infants who are born healthy often fail to grow or gain an ample amount of weight by age one. Other symptoms include vomiting, lack of appetite, and feeding issues. These difficulties lead to nutritional deficiency, which in turn leads to further growth problems. Apart from growth issues, infants with nephropathic cystinosis commonly suffer from renal Fanconi syndrome, a rare disorder involving kidney dysfunction. The kidneys' functions include filtering waste products from the blood and removing them from the body. The kidney also releases hormones that help balance important chemicals found in the body. When a person has nephropathic cystinosis, the tiny tubes within the kidneys that help absorb these vital substances fail to function properly, thereby depriving a person of these crucial chemicals. Fanconi syndrome can cause extreme thirst, excessive urination, and dehydration. Kidney dysfunction can also lead to rickets, which manifests when the body's inability to reabsorb phosphorus leads to softening and weakening of the bones.

Apart from kidney issues, nephropathic cystinosis can also lead to the formation of cystine crystals throughout the body, often in the cornea of the eye. Cystine buildup in the eye can cause pain and sensitivity to light and can lead to blindness if left untreated long enough. Further signs and symptoms that manifest in untreated people include muscle deterioration, swallowing issues, diabetes, thyroid and nervous system issues, and infertility in men.

The signs and symptoms of intermediate cystinosis are largely the same as those seen in nephropathic cystinosis, except intermediate cystinosis occurs at a later age. This type of cystinosis usually manifests during adolescence. Kidney malfunction and crystal formation in the eyes are usually the first symptoms to present. Without treatment, complete kidney failure will normally occur between the late teens and mid-twenties.

Those diagnosed with non-nephropathic or ocular cystinosis usually experience only corneal crystal formation, which increases their sensitivity to light. Kidney issues and most other symptoms associated with nephropathic/intermediate patients normally do not display in patients with this type of cystinosis. The age at which patients are diagnosed with non-nephropathic or ocular cystinosis varies widely due to the lack of acute symptoms.

Once a medical professional has observed symptoms and diagnosed a patient, treatment is tailored to individual need. Most treatments involve cystine reduction therapies along with kidney transplantation. Doctors commonly prescribe cysteamine bitartrate, a cystine-depleting agent administered orally. This treatment can delay the need for a kidney transplant, though most patients will eventually require a new kidney. Oral treatments usually do not affect corneal crystallization, however, and doctors will prescribe a separate eye drop treatment to eliminate eye crystals. Doctors also prescribe individualized treatments for the varying symptoms caused by cystinosis, such as dehydration, nausea, and nutrient deficiency.

Bibliography

"Cystinosis." Genetics Home Reference, www.ghr.nlm.nih.gov/condition/cystinosis. Accessed 2 Nov. 2016.

"Cystinosis." Medscape, 30 Aug. 2015, www.emedicine.medscape.com/article/981650-overview. Accessed 2 Nov. 2016.

"Cystinosis." National Organization for Rare Disorders, www.rarediseases.org/rare-diseases/cystinosis/. Accessed 2 Nov. 2016.

"Cystinosis." WebMD, LLC, www.webmd.com/children/cystinosis-10731. Accessed 2 Nov. 2016.

Elmonem, Mohamed A., et al. "Cystinosis: A Review." Orhpanet Journal of Rare Diseases, vol. 11, no. 47, 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4841061/. Accessed 2 Nov. 2016.

"FDA Approves Procysbi for Rare Genetic Condition." U.S. Food and Drug Administration, 30 Apr. 2013, www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm350091.htm. Accessed 2 Nov. 2016.

Nesterova, Galina, and William A. Gahl. "Cystinosis: The Evolution of a Treatable Disease." Pediatric Neurology, vol. 28, no. 1, 2016, 51–59.

"Symptoms & Treatment." Cystinosis Research Network, www.cystinosis.org/what-is-cystinosis/symptoms-treatment. Accessed 2 Nov. 2016.