Cystinosis

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Cystinosis
Other namesCystine storage disease, [1] Abderhalden–Lignac–Kaufmann disease, [2] Abderhalden–Kaufmann–Lignac syndrome
Cystine-skeletal.png
Chemical structure of cystine formed from L-cysteine (under biological conditions)
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. [3] It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosomal recessive disorder resulting from accumulation of free cystine in lysosomes, eventually leading to intracellular crystal formation throughout the body. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules is impaired, leading to abnormal amounts of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.

Contents

Cystinosis was the first documented genetic disease belonging to the group of lysosomal storage disease disorders. [4] Cystinosis is caused by mutations in the CTNS gene that codes for cystinosin, the lysosomal membrane-specific transporter for cystine. Intracellular metabolism of cystine, as it happens with all amino acids, requires its transport across the cell membrane. After degradation of endocytosed protein to cystine within lysosomes, it is normally transported to the cytosol. But if there is a defect in the carrier protein, cystine is accumulated in lysosomes. As cystine is highly insoluble, when its concentration in tissue lysosomes increases, its solubility is immediately exceeded and crystalline precipitates are formed in almost all organs and tissues. [5]

However, the progression of the disease is not related to the presence of crystals in target tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are not fully understood. Increased intracellular cystine profoundly disturbs cellular oxidative metabolism and glutathione status, [6] leading to altered mitochondrial energy metabolism, autophagy, and apoptosis. [7]

Cystinosis is usually treated with cysteamine, which is prescribed to decrease intralysosomal cystine accumulation. [8] However, the discovery of new pathogenic mechanisms and the development of an animal model of the disease may open possibilities for the development of new treatment modalities to improve long-term prognosis. [4]

Symptoms

There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems (sometimes called renal Fanconi syndrome). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis).

Slit-lamp photographs of three-year-old patient with nephropathic cystinosis before (left) and after (right) cysteamine eyedrop therapy. The drops dissolve the crystals in the cornea. Nephropathic cystenosis NHGRI-79209.jpg
Slit-lamp photographs of three-year-old patient with nephropathic cystinosis before (left) and after (right) cysteamine eyedrop therapy. The drops dissolve the crystals in the cornea.

By about age two, cystine crystals may also be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia). Without treatment, children with cystinosis are likely to experience complete kidney failure by about age ten. With treatment this may be delayed into the patients' teens or 20s. Other signs and symptoms that may occur in patients include muscle deterioration, blindness, inability to swallow, impaired sweating, decreased hair and skin pigmentation, diabetes, and thyroid and nervous system problems.

The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.

People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.

Crystal morphology and identification

Cystine crystals are hexagonal in shape and are colorless. They are not found often in alkaline urine due to their high solubility. The colorless crystals can be difficult to distinguish from uric acid crystals which are also hexagonal. Under polarized examination, the crystals are birefringent with a polarization color interference. [9]

Genetics

Cystinosis has an autosomal recessive pattern of inheritance. Autorecessive.svg
Cystinosis has an autosomal recessive pattern of inheritance.

Cystinosis occurs due to a mutation in the gene CTNS, located on chromosome 17, which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria (excessive urination), followed by poor growth, photophobia, and ultimately kidney failure by age 6 years in the nephropathic form.

All forms of cystinosis (nephropathic, juvenile and ocular) are autosomal recessive, which means that the trait is located on an autosomal chromosome, and only an individual who inherits two copies of the gene – one from both parents – will have the disorder. There is a 25% risk of having a child with the disorder, when both parents are carriers of an autosomal recessive trait.

Cystinosis affects approximately 1 in 100,000 to 200,000 newborns. [1] and there are only around 2,000 known individuals with cystinosis in the world [ citation needed ]. The incidence is higher in the province of Brittany, France, where the disorder affects 1 in 26,000 individuals. [10]

Diagnosis

Cystinosis is a rare genetic disorder [11] that causes an accumulation of the amino acid cystine within cells, forming crystals that can build up and damage the cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes. [3]

The accumulation is caused by abnormal transport of cystine from lysosomes, resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alter apoptosis in such a way that cells die inappropriately, leading to loss of renal epithelial cells. This results in renal Fanconi syndrome, [12] and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.

Definitive diagnosis and treatment monitoring are most often performed through measurement of white blood cell cystine level using tandem mass spectrometry.

Types

Treatment

Cystinosis is normally treated with cysteamine, which is available in capsules and in eye drops. [13] Cysteamine acts to solubilize the cystine by (1) forming a mixed disulfide cysteine-cysteamine and (2) reducing cystine to cysteine. People with cystinosis are also often given sodium citrate to treat the blood acidosis, as well as potassium and phosphorus supplements as well as others. If the kidneys become significantly impaired or fail, then treatment must be begun to ensure continued survival, up to and including renal transplantation. [14]

History

A historical case of cystinosis was originally termed Abderhalden–Kaufmann–Lignac syndrome (AKL syndrome), also called nephropathic cystinosis, which was observed to be an autosomal recessive renal disorder of childhood comprising cystinosis and renal rickets. It was named for Emil Abderhalden, Eduard Kaufmann and George Lignac. [15] [16] Affected children are developmentally delayed with dwarfism, rickets and osteoporosis. Renal tubular disease is usually present causing aminoaciduria, glycosuria and hypokalemia. Cysteine deposition is most evident in the conjunctiva and cornea.


See also

Related Research Articles

<span class="mw-page-title-main">Cystine</span> Chemical compound

Cystine is the oxidized derivative of the amino acid cysteine and has the formula (SCH2CH(NH2)CO2H)2. It is a white solid that is poorly soluble in water. As a residue in proteins, cystine serves two functions: a site of redox reactions and a mechanical linkage that allows proteins to retain their three-dimensional structure.

<span class="mw-page-title-main">Lysosomal storage disease</span> Medical condition

Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.

<span class="mw-page-title-main">Cystinuria</span> Amino acid metabolic disorder involving cystine stones forming in the kidneys, ureter, and bladder

Cystinuria is an inherited autosomal recessive disease characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureters, and bladder. It is a type of aminoaciduria. "Cystine", not "cysteine," is implicated in this disease; the former is a dimer of the latter.

George Otto Emil Lignac was a Dutch pathologist-anatomist.

<span class="mw-page-title-main">Hartnup disease</span> Metabolic disorder

Hartnup disease is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids. Niacin is a precursor to nicotinamide, a necessary component of NAD+.

<span class="mw-page-title-main">Salla disease</span> Medical condition

Salla disease (SD) is an autosomal recessive lysosomal storage disease characterized by early physical impairment and intellectual disability. It was first described in 1979, after Salla, a municipality in Finnish Lapland and is one of 40 Finnish heritage diseases.

<span class="mw-page-title-main">Renal tubular acidosis</span> Medical condition

Renal tubular acidosis (RTA) is a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine. In renal physiology, when blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for exchange of salts, acid equivalents, and other solutes before it drains into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by insufficient secretion of hydrogen ions into the latter portions of the nephron or by failure to reabsorb sufficient bicarbonate ions from the filtrate in the early portion of the nephron. Although a metabolic acidosis also occurs in those with chronic kidney disease, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have different syndromes and different causes. RTA is usually an incidental finding based on routine blood draws that show abnormal results. Clinically, patients may present with vague symptoms such as dehydration, mental status changes, or delayed growth in adolescents.

<span class="mw-page-title-main">Mannosidosis</span> Medical condition

Mannosidosis is a deficiency in mannosidase, an enzyme. There are two types: alpha-mannosidosis and beta-mannosidosis. Both disorders are related to the lysosome and have similar presentation; the former is caused by defective lysosomal α-mannosidase and the latter by defective lysosomal β-mannosidase. In both cases, the defect causes accumulation of oligosaccharides rich in mannose in the neural tissue and organ tissue. Both alpha- and beta-mannosidosis are known to result from autosomal recessive genetic mutations.

<span class="mw-page-title-main">Hermansky–Pudlak syndrome</span> Medical condition

Heřmanský–Pudlák syndrome is an extremely rare autosomal recessive disorder which results in oculocutaneous albinism, bleeding problems due to a platelet abnormality, and storage of an abnormal fat-protein compound. It is thought to affect around 1 in 500,000 people worldwide, with a significantly higher occurrence in Puerto Ricans, with a prevalence of 1 in 1800. Many of the clinical research studies on the disease have been conducted in Puerto Rico.

<span class="mw-page-title-main">Cysteamine</span> Chemical compound

Cysteamine is an organosulfur compound with the formula HSCH2CH2NH2. A white, water-soluble solid, it contains both an amine and a thiol functional groups. It is often used as salts of the ammonium derivative [HSCH2CH2NH3]+ including the hydrochloride, phosphocysteamine, and the bitartrate.The intermediate pantetheine is broken down into cysteamine and pantothenic acid.

<span class="mw-page-title-main">Oculocerebrorenal syndrome</span> Medical condition

Oculocerebrorenal syndrome is a rare X-linked recessive disorder characterized by congenital cataracts, hypotonia, intellectual disability, proximal tubular acidosis, aminoaciduria and low-molecular-weight proteinuria. Lowe syndrome can be considered a cause of Fanconi syndrome.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

Vici syndrome, also called immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum, is a rare autosomal recessive congenital disorder characterized by albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, severe psychomotor retardation, seizures, immunodeficiency and recurrent severe infections. To date, about 50 cases have been reported.

<span class="mw-page-title-main">CTNS (gene)</span> Protein-coding gene in the species Homo sapiens

CTNS may also refer to the Center for Theology and the Natural Sciences.

<span class="mw-page-title-main">William A. Gahl</span> American geneticist

William A. Gahl currently serves as the Clinical Director of the National Human Genome Research Institute at the NIH main campus in Bethesda, MD.

Joseph Daniel Schulman is a physician, medical researcher, and biomedical entrepreneur in the fields of genetic diseases and human reproduction.

<span class="mw-page-title-main">GRACILE syndrome</span> Medical condition

GRACILE syndrome is a very rare lethal autosomal recessive genetic disorder, one of the Finnish heritage diseases. GRACILE syndrome has also been found in the UK and Sweden, but not nearly as much as in Finland. It is caused by a mutation in the BCS1L gene and it occurs in approximately 1 out of 50,000 live births in Finnish people. To date, there have only been 32 cases of GRACILE syndrome reported.

Fanconi syndrome or Fanconi's syndrome is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity, or by adverse drug reactions. It results in various small molecules of metabolism being passed into the urine instead of being reabsorbed from the tubular fluid. Fanconi syndrome affects the proximal tubules, namely, the proximal convoluted tubule (PCT), which is the first part of the tubule to process fluid after it is filtered through the glomerulus, and the proximal straight tubule, which leads to the descending limb of loop of Henle.

Proximal renal tubular acidosis (pRTA) or type 2 renal tubular acidosis (RTA) is a type of RTA caused by a failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia. The distal intercalated cells function normally, so the acidemia is less severe than dRTA and the urine can acidify to a pH of less than 5.3. pRTA also has several causes, and may occasionally be present as a solitary defect, but is usually associated with a more generalised dysfunction of the proximal tubular cells called Fanconi syndrome where there is also phosphaturia, glycosuria, aminoaciduria, uricosuria and tubular proteinuria.

The lysosomal cystine transporter (LCT) family is part of the TOG Superfamily and includes secondary transport proteins that are derived from animals, plants, fungi and other eukaryotes. They exhibit 7 putative transmembrane α-helical spanners (TMSs) and vary in size between about 200 and 500 amino acyl residues, although most have between 300 and 400 residues.

References

  1. 1 2 "Cystinosis on Genetic home reference".
  2. ↑ "Abderhalden Kaufmann Lignac syndrome". rarediseases.info.nih.gov. Archived from the original on 15 May 2018. Retrieved 15 May 2018.
  3. 1 2 A. Gahl, William; Jess G. Thoene; Jerry A. Schneider (2002). "Cystinosis". N Engl J Med. 347 (2): 111–121. doi:10.1056/NEJMra020552. PMID   12110740.
  4. 1 2 Nesterova G, Gahl WA. Cystinosis: the evolution of a treatable disease. Pediatr Nephrol 2012;28:51–9.
  5. ↑ Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med 2002;347:111-121.
  6. ↑ Kumar A, Bachhawat AK. A futile cycle, formed between two ATP-dependent γ-glutamyl cycle enzymes, γ-glutamyl cysteine synthetase and 5-oxoprolinase: the cause of cellular ATP depletion in nephrotic cystinosis?; J Biosci 2010;35:21–25.
  7. ↑ Park MA, Thoene JG. Potential role of apoptosis in development of the cystinotic phenotype. Pediatr Nephrol 2005;20:441–446.
  8. ↑ Besouw M, Masereeuw R, Van den Heuvel L et al. Cysteamine: an old drug with new potential. Drug Discov Today 2013.
  9. ↑ Spencer, Daniel. "Cystine". CRYSTALS. Urinalysis (Texas Collaborative for Teaching Excellence). Retrieved 4 March 2012.
  10. ↑ Kalatzis, V; Cherqui S; Jean G; Cordier B; Cochat P; Broyer M; Antignac C (October 2001). "Characterization of a putative founder mutation that accounts for the high incidence of cystinosis in Brittany". J Am Soc Nephrol. 12 (10): 2170–2174. doi: 10.1681/ASN.V12102170 . PMID   11562417 . Retrieved 31 March 2011.
  11. ↑ "Cystinosis". Archived from the original on 2011-07-18. Retrieved 2008-07-20.
  12. ↑ Howard G. WORTHEN; Robert A. GOOD (1958). "The de Toni-Fanconi Syndrome with Cystinosis". Am J Dis Child. 95 (6): 653–688. doi:10.1001/archpedi.1958.02060050657011. PMID   13532161.
  13. ↑ Besouw, Martine; Masereeuw, Rosalinde; Van Den Heuvel, Lambert; Levtchenko, Elena (2013). "Cysteamine: An old drug with new potential". Drug Discovery Today. 18 (15–16): 785–792. doi:10.1016/j.drudis.2013.02.003. PMID   23416144.
  14. ↑ Nesterova, Galina; Gahl, William A. (October 6, 2016). "Cystinosis". GeneReviews. University of Washington, Seattle. PMID   20301574.
  15. ↑ B.G. Firkin & J.A.Whitworth (1987). Dictionary of Medical Eponyms. Parthenon Publishing. ISBN   1-85070-333-7
  16. ↑ Who Named It?
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