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| {{Infobox medical condition (new)
| | Cystinosis |
| | name = Cystinosis
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| | synonyms = Cystine storage disease<ref name=gen/>
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| | image = Cystine-skeletal.png
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| | caption = Chemical structure of [[cystine]] formed from L-cysteine (under biological conditions)
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| | Cystinosis is a rare, inherited metabolic disorder characterized by the accumulation of the amino acid cystine within lysosomes, leading to cellular damage. This condition primarily affects the kidneys and eyes, but can also impact other organs and tissues. |
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| '''Cystinosis''' is a [[lysosomal storage disease]] characterized by the abnormal accumulation of the [[amino acid]] [[cystine]]. It is a [[genetic disorder]] that follows an [[dominance relationship|autosomal recessive]] [[inheritance]] pattern. It is a rare autosomal recessive disorder resulting from accumulation of free cystine in [[lysosome]]s, 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 tubule]]s is impaired, leading to abnormal amounts of [[carbohydrate]]s and amino acids in the [[urine]], excessive urination, and low blood levels of [[potassium]] and [[phosphate]]s.
| | ==Pathophysiology== |
| | Cystinosis is caused by mutations in the [[CTNS gene]], which encodes the protein cystinosin. Cystinosin is responsible for transporting cystine out of lysosomes. When this transport is impaired, cystine accumulates, forming crystals that can cause cellular dysfunction and damage. |
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| Cystinosis was the first documented genetic disease belonging to the group of lysosomal storage disease disorders. Cystinosis is caused by mutations in the ''[[CTNS (gene)|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 [[endocytosis|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. | | ==Types of Cystinosis== |
| | Cystinosis is classified into three main types based on the age of onset and severity of symptoms: |
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| | ===Nephropathic Cystinosis=== |
| | This is the most common and severe form, typically presenting in infancy. It is characterized by renal tubular Fanconi syndrome, leading to excessive loss of water, sodium, potassium, and other substances in the urine. |
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| 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,
| | ===Intermediate Cystinosis=== |
| | Also known as juvenile or adolescent cystinosis, this form presents later in childhood or adolescence. It is less severe than nephropathic cystinosis but can still lead to significant kidney damage over time. |
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| Cystinosis is usually treated with [[cysteamine]], which is prescribed to decrease intralysosomal cystine accumulation.<ref>Besouw M, Masereeuw R, Van den Heuvel L et al. Cysteamine: an old drug with new potential. Drug Discov Today 2013. | | ===Ocular Cystinosis=== |
| | This form primarily affects the eyes, causing photophobia and corneal crystal deposits. It usually presents in adulthood and does not typically involve kidney dysfunction. |
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| ==Symptoms== | | ==Clinical Manifestations== |
| 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]]).
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| 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]]).
| | ===Renal Symptoms=== |
| | - '''Fanconi Syndrome''': Characterized by polyuria, polydipsia, and growth retardation due to renal tubular dysfunction. |
| | - '''Chronic Kidney Disease''': Progressive renal impairment leading to end-stage renal disease if untreated. |
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| [[File:Nephropathic cystenosis NHGRI-79209.jpg|right|thumb|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.]]
| | ===Ocular Symptoms=== |
| | - '''Photophobia''': Sensitivity to light due to corneal cystine crystal deposits. |
| | - '''Corneal Crystals''': Visible deposits in the cornea that can be detected by slit-lamp examination. |
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| 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.
| | ===Other Symptoms=== |
| | | - '''Hypothyroidism''': Due to cystine accumulation in the thyroid gland. |
| 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.
| | - '''Diabetes Mellitus''': Resulting from pancreatic involvement. |
| | | - '''Muscle Weakness''': Due to cystine accumulation in muscle tissue. |
| 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.
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| ===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.
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| ==Genetics==
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| [[Image:autorecessive.svg|thumb|right|Cystinosis has an autosomal recessive pattern of inheritance.]]
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| Cystinosis occurs due to a mutation in the gene [[CTNS (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 [[renal failure|kidney failure]] by age 6 years in the nephropathic form.
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| All forms of cystinosis (nephropathic, juvenile and ocular) are [[autosomal recessive]], which means that the trait is located on an autosomal gene, and 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.
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| Cystinosis affects approximately 1 in 100,000 to 200,000 newborns.
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| ==Diagnosis== | | ==Diagnosis== |
| Cystinosis is a rare genetic disorder 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.
| | Diagnosis of cystinosis is based on clinical presentation, family history, and laboratory tests. Measurement of cystine levels in leukocytes is a key diagnostic test. Genetic testing can confirm mutations in the CTNS gene. |
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| The accumulation is caused by abnormal transport of cystine from [[lysosome]]s, 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]], and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.
| | ==Treatment== |
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| Definitive diagnosis and treatment monitoring are most often performed through measurement of white blood cell [[cystine]] level using [[tandem mass spectrometry]].
| | ===Cysteamine Therapy=== |
| | Cysteamine is the primary treatment for cystinosis. It reduces cystine accumulation by converting cystine into cysteine and cysteine-cysteamine mixed disulfide, which can exit the lysosome. |
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| ===Types=== | | ===Supportive Care=== |
| * {{OMIM|219800}} – Infantile nephropathic
| | - '''Renal Replacement Therapy''': Dialysis or kidney transplantation for end-stage renal disease. |
| * {{OMIM|219900}} – Adolescent nephropathic
| | - '''Electrolyte Replacement''': To manage Fanconi syndrome. |
| * {{OMIM|219750}} – Adult nonnephropathic
| | - '''Ocular Drops''': Cysteamine eye drops to reduce corneal crystal deposits. |
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| ==Treatment== | | ==Prognosis== |
| Cystinosis is normally treated with [[cysteamine]], which is available in capsules and in eye drops. 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]].
| | With early diagnosis and treatment, individuals with cystinosis can have improved outcomes. However, untreated cystinosis can lead to significant morbidity and mortality due to renal failure and other complications. |
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| ==Cystinotic== | | ==See Also== |
| The related adjective "cystinotic" indicates "relating to, or afflicted with, cystinosis".
| | - [[Lysosomal storage disease]] |
| * {{NLM|cystinosis}}
| | - [[Fanconi syndrome]] |
| *[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ctns GeneReviews/NCBI/NIH/UW entry on Cystinosis]
| | - [[End-stage renal disease]] |
| {{Amino acid metabolic pathology}}
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| [[Category:Autosomal recessive disorders]] | | {{Medical condition (new)}} |
| [[Category:Amino acid metabolism disorders]] | | [[Category:Genetic disorders]] |
| [[Category:Lysosomal storage diseases]]
| | [[Category:Metabolic disorders]] |
| [[Category:Rare diseases]] | | [[Category:Rare diseases]] |
| {{rarediseases}}
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Cystinosis
Cystinosis is a rare, inherited metabolic disorder characterized by the accumulation of the amino acid cystine within lysosomes, leading to cellular damage. This condition primarily affects the kidneys and eyes, but can also impact other organs and tissues.
Pathophysiology
Cystinosis is caused by mutations in the CTNS gene, which encodes the protein cystinosin. Cystinosin is responsible for transporting cystine out of lysosomes. When this transport is impaired, cystine accumulates, forming crystals that can cause cellular dysfunction and damage.
Types of Cystinosis
Cystinosis is classified into three main types based on the age of onset and severity of symptoms:
Nephropathic Cystinosis
This is the most common and severe form, typically presenting in infancy. It is characterized by renal tubular Fanconi syndrome, leading to excessive loss of water, sodium, potassium, and other substances in the urine.
Intermediate Cystinosis
Also known as juvenile or adolescent cystinosis, this form presents later in childhood or adolescence. It is less severe than nephropathic cystinosis but can still lead to significant kidney damage over time.
Ocular Cystinosis
This form primarily affects the eyes, causing photophobia and corneal crystal deposits. It usually presents in adulthood and does not typically involve kidney dysfunction.
Clinical Manifestations
Renal Symptoms
- Fanconi Syndrome: Characterized by polyuria, polydipsia, and growth retardation due to renal tubular dysfunction.
- Chronic Kidney Disease: Progressive renal impairment leading to end-stage renal disease if untreated.
Ocular Symptoms
- Photophobia: Sensitivity to light due to corneal cystine crystal deposits.
- Corneal Crystals: Visible deposits in the cornea that can be detected by slit-lamp examination.
Other Symptoms
- Hypothyroidism: Due to cystine accumulation in the thyroid gland.
- Diabetes Mellitus: Resulting from pancreatic involvement.
- Muscle Weakness: Due to cystine accumulation in muscle tissue.
Diagnosis
Diagnosis of cystinosis is based on clinical presentation, family history, and laboratory tests. Measurement of cystine levels in leukocytes is a key diagnostic test. Genetic testing can confirm mutations in the CTNS gene.
Treatment
Cysteamine Therapy
Cysteamine is the primary treatment for cystinosis. It reduces cystine accumulation by converting cystine into cysteine and cysteine-cysteamine mixed disulfide, which can exit the lysosome.
Supportive Care
- Renal Replacement Therapy: Dialysis or kidney transplantation for end-stage renal disease.
- Electrolyte Replacement: To manage Fanconi syndrome.
- Ocular Drops: Cysteamine eye drops to reduce corneal crystal deposits.
Prognosis
With early diagnosis and treatment, individuals with cystinosis can have improved outcomes. However, untreated cystinosis can lead to significant morbidity and mortality due to renal failure and other complications.
See Also
- Lysosomal storage disease
- Fanconi syndrome
- End-stage renal disease
Template:Medical condition (new)
