OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: CTNS

CTNS
Nephropathic cystinosis
Lysosomal cystine transport deficiency
Cystinosin defect
Infantile nephropathic cystinosis

Cystinosis
Hypothyroidism
Corneal deposits
Retinopathy
Photophobia
Failure to thrive
Dehydration
Hypokalemia
Glucosuria
Acidosis
Hypophosphatemia

Cystinosis

Clinical Characteristics

General description (for patients):

Cystinosis is a disease of metabolism that causes primarily eye and kidney problems.  It has its onset in early childhood when children fail to grow normally with serious episodes of nausea, vomiting, excessive thirst, and become dehydrated.  This results from kidney damage and dysfunction so that electrolytes become unbalanced.  Permanent mental slowness may result.  Medical treatment can be effective if started early but, later, kidney transplantation becomes necessary.  Damage to the thyroid also occurs and crystals in the corneas and retinas can cause sensitivity to light.

Medical description:  

Nephropathic cystinosis is considered a lysosomal disorder because of the intra-lysosomal cystine storage, although it is not due to a dysfunction of lysosomes per se.  It presents in early childhood usually as an acute metabolic problem with acidosis as a result of glomerular and tubular damage in the kidneys with characteristic dysfunction.  Hypokalemia, hypophosphatemia, and glucosuria may be seen in association with vomiting, polydipsia, polyuria, and dehydration.  Slit lamp examination reveals refractile crystals in the cornea and conjunctiva due to intracellular accumulation of cystine.  Photophobia and pigmentary retinal changes are common.  The chronic condition results in failure to thrive and mental slowness.  Skin and hair pigmentation is generally lighter than in other family members.  Thyroid damage often leads to hypothyroidism requiring replacement therapy.  Myopathy is also a feature and late damage to other organs such as the pancreas, gonads and CNS are common.

Genetics:  

This disorder is caused by a mutation in the CTNS gene which encodes cystinosin, important to the transmembrane transport of cystine.  The CTNS gene is located on chromosome 17 (17P13).  Heterozygotes can be identified by large increases in concentration of cystine in leukocytes.  The most common mutation (in nearly half of American patients) is that of a large deletion in this gene but recently a homozygous single molecule substitution (1354G>A) has been found in several Amish patients.

Treatment: 

Oral cysteamine therapy is beneficial especially if given early before renal damage occurs.  While evidence suggests that the time to renal failure is extended with rigorous treatment it does not obviate the eventual need.  Topical ocular application of cysteamine reduces the density of corneal crystals and decreases the photophobia.  Orthotopic renal transplantation is required for those with end stage disease and, curiously, cystine crystals do not accumulate in glomeruli or tubules of transplanted kidneys indicating that this disease is a local cellular defect.  Thus, renal transplantation corrects the systemic metabolic problems but has no impact on the thyroid or ocular problems.

Prognosis:

Good prognosis to adulthood with cysteamine treatment.

Ancillary treatments and support:

Special education, general monitoring

Specialists and speciality centers:

Nephrologist, nutritionist, pediatrician, ophthalmologist.

References:

Rupar, C.A., Matsell, D., Surry, S., and Siu, V.:  A G339R mutation in the CTNS gene is a common cause of nephropathic cystinosis in the south western Ontario Amish Mennonite population.  J. Mol. Genet. 38: 615-616, 2001. PubMed ID: 11565547

Gahl, W.A., Kuehl, E.M., Iwata, F., Lindblad, A., Kaiser-Kupfer, M.I.:  Corneal crystals in nephropathic cystinosis, natural history and treatment with cysteamine eyedrops.  Molec. Genet. Metab. 71: 100-120, 2000.  PubMed ID: 11001803

Gahl, W.A., Thoene, J.G., and Schneider, J.A.:  Cystinosis.  New Eng. J. Med. 347: 111-121, 2002.  PubMed ID: 12110740

Resources:

The Cystinosis Foundation
National Kidney Foundation

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