Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Cystinosis

Cystinosis is an autosomal recessive lysosomal storage disorder that presents with a proximal renal tubular damage also called Fanconi syndrome.

Classification

Occording to the age of onset, infantile, adolescent and adult forms can be distinguished. The predominant manifestation can be described as nephropathic or non-nephropathic (ocular).

Epidemiology

The estimated incidence of cystinosis is one in 100,000–200,000 live births. The incidence peaks 6 per 100,000 in Newfoundland, Canada.[Error: Macro 'ref' doesn't exist]

Clinical Findings

Kidney

The kidney manifestation of cystinosis can be summarized as Fanconi syndrome which includes proteinuria (predominantly low- molecular-weight), glucosuria, metabolic acidosis, hyperphospaturia. Furthermore wastage of water and salts including sodium, potassium, and calcium is observed. Finally the disorder develops into progressive renal failure.

Eye

The dominating ocular symptom is photophobia beause of cystein crystals accumulating in the cornea.

Other organs

Cystein deposits can damage other organs too. Endocrine glands, liver, pancreas, and pancreas can become dysfunctional.

Natural history

Most common is the infantile type which becomes apperent at 6-month of age after normal pregnancy and birth. The first symptoms are rather unspecific lack of appetite and a failure to thrive. Next water wastage and thurst is observed. Later photophobia is the first pathognomonic symptom. If not treated properly rickets and end-stage renal failure develop.

Pathogenesis

When proteins are catabolized in lyzosomes, cystin is normally carrieed by a transporter to the cytosol where it transformed to cysteine and reutilized for protein synthesis. If the transporter protein is deficient, cystin accumulates and because of its poor solubility crystalizes. Large cystin crystals impair cellular function in many organs.

Management

Cysteamine effectively can be applied to treat the disorder systemically and locally. Cysteamine binds cystin in Lysosomes allowing it to leave the organelle with the help of the lysin transporter. Corneal cystinosis can be treated with cysteamine eye drops.

Registry

CEMARA Cystinosis database

Symptoms

Proximal tubular damage syndrome
Cystinosis is the most common cause of hereditary proximal tubular damage, also called Fanconi syndrome.
Renal insufficiency
95% of patient with cystinosis develop renal failure. It starts with 8-12 years of age.
Ocular abnormalities
Cystinosis is accompanied by photophobia that results from corneal cystin deposits. Later in life, retinal blindeness may occur in some cases.
Nephrocalcinosis
Nephrocalcinosis is relatively common in cystinosis though calculi are rare probably because of alkalization and dilution of the urine.
Hypothyroidism
Hypothyroidism is common and presents early in the course of the disease.

Systematic

Metabolic disturbances of proximal tubular function
Cystinosis
CTNS
Dent disease
Fanconi renotubular syndrome
Fanconi-Bickel syndrome
Fructose intolerance
Galactosemia
Glycogen storage disease 1
Hepatorenal tyrosinemia
Lowe disease
MELAS syndrome
Wilson disease

References:

1.

Bois E et al. (1976) Infantile cystinosis in France: genetics, incidence, geographic distribution.

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2.

Forestier L et al. (1999) Molecular characterization of CTNS deletions in nephropathic cystinosis: development of a PCR-based detection assay.

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3.

McGowan-Jordan J et al. (1999) Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation.

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4.

Attard M et al. (1999) Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin.

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5.

Touchman JW et al. (2000) The genomic region encompassing the nephropathic cystinosis gene (CTNS): complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion.

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6.

Gahl WA et al. (2002) Cystinosis.

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7.

Kalatzis V et al. (2002) Identification of 14 novel CTNS mutations and characterization of seven splice site mutations associated with cystinosis.

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8.

Mason S et al. (2003) Mutational spectrum of the CTNS gene in Italy.

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9.

Town M et al. (1998) A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis.

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10.

Shotelersuk V et al. (1998) CTNS mutations in an American-based population of cystinosis patients.

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11.

Gahl WA et al. () Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops.

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12.

None (1958) Cystine storage disease; report of a case.

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13.

Pisoni RL et al. (1992) Description of a selection method highly cytotoxic for cystinotic fibroblasts but not normal human fibroblasts.

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14.

Schnaper HW et al. (1992) Early occurrence of end-stage renal disease in a patient with infantile nephropathic cystinosis.

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15.

Tsilou ET et al. (2006) Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy.

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16.

Trauner DA et al. (2007) Specific cognitive deficits in young children with cystinosis: evidence for an early effect of the cystinosin gene on neural function.

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17.

None (1991) Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada).

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18.

Sonies BC et al. (1990) Swallowing dysfunction in nephropathic cystinosis.

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19.

Gahl WA et al. (1988) NIH conference. Cystinosis: progress in a prototypic disease.

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20.

Gahl WA et al. (1988) Myopathy and cystine storage in muscles in a patient with nephropathic cystinosis.

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21.

Reiss RE et al. (1988) Successful pregnancy despite placental cystine crystals in a woman with nephropathic cystinosis.

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22.

Fivush B et al. (1987) Pancreatic endocrine insufficiency in posttransplant cystinosis.

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23.

Fivush B et al. (1988) Pancreatic exocrine insufficiency in a patient with nephropathic cystinosis.

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24.

Malekzadeh MH et al. (1977) Cadaver renal transplantation in children with cystinosis.

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25.

Gahl WA et al. (1987) Cysteamine therapy for children with nephropathic cystinosis.

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26.

Patrick AD et al. (1987) First trimester diagnosis of cystinosis using intact chorionic villi.

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27.

Smolin LA et al. (1987) An improved method for heterozygote detection of cystinosis, using polymorphonuclear leukocytes.

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28.

Jonas AJ et al. (1987) Nephropathic cystinosis with central nervous system involvement.

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29.

Kaiser-Kupfer MI et al. (1987) Removal of corneal crystals by topical cysteamine in nephropathic cystinosis.

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30.

Smith ML et al. (1987) Prenatal diagnosis of cystinosis utilizing chorionic villus sampling.

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31.

da Silva VA et al. (1985) Long-term treatment of infantile nephropathic cystinosis with cysteamine.

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32.

None (1985) Therapy of cystinosis.

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33.

Lucky AW et al. (1977) Endocrine studies in cystinosis: compensated primary hypothyroidism.

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34.

Schneider JA et al. (1974) Prenatal diagnosis of cystinosis.

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35.

Mahoney CP et al. (1970) Renal transplantation for childhood cystinosis.

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36.

Teree TM et al. (1970) Cystinosis and proximal tubular nephropathy in siblings. Progressive development of the physiological and anatomical lesion.

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37.

Schulman JD et al. (1970) Identification of heterozygous genotype for cystinosis in utero by a new pulse-labeling technique: preliminary report.

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38.

Schulman JD et al. (1971) Cystinosis: therapeutic implications of in vitro studies of cultured fibroblasts.

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39.

Schneider JA et al. (1967) Increased cystine in leukocytes from individuals homozygous and heterozygous for cystinosis.

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40.

Jonas AJ et al. (1982) ATP-dependent lysosomal cystine efflux is defective in cystinosis.

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41.

Gahl WA et al. (1984) Lysosomal cystine counter-transport in heterozygotes for cystinosis.

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42.

Gahl WA et al. (1984) Decreased sweat production in cystinosis.

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43.

Steinherz R et al. (1982) Patterns of amino acid efflux from isolated normal and cystinotic human leucocyte lysosomes.

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44.

Steinherz R et al. (1982) Heterozygote detection in cystinosis, using leukocytes exposed to cystine dimethyl ester.

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45.

Gahl WA et al. (1982) Cystine transport is defective in isolated leukocyte lysosomes from patients with cystinosis.

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46.

Steinherz R et al. (1981) Association of certain human leukocyte antigens with nephropathic cystinosis in the absence of linkage between these loci.

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47.

Yudkoff M et al. (1981) Effects of cysteamine therapy in nephropathic cystinosis.

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48.

Burke JR et al. (1978) Hypothyroidism in children with cystinosis.

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49.

Kimonis VE et al. (1995) Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis.

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50.

Williams BL et al. (1994) Global intellectual deficits in cystinosis.

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51.

Markello TC et al. (1993) Improved renal function in children with cystinosis treated with cysteamine.

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52.

Jean G et al. (1996) High-resolution mapping of the gene for cystinosis, using combined biochemical and linkage analysis.

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53.

Hurley JK et al. (1977) Myxedema coma in cystinosis.

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54.

OMIM.ORG article

Omim 219800 [^]
55.

Orphanet article

Orphanet ID 213 [^]
56.

Wikipedia article

Wikipedia EN (Cystinosis) [^]
Update: May 9, 2019