Cystinosis

Also known as: Infantile nephropathic cystinosis (CTNS gene)

OMIM#219800  https://omim.org/entry/219800

1. The Disease:

Cystinosis is a lysosomal storage disorder resulting in the accumulation of cystine in kidneys, eyes, liver, muscles, pancreas, brain, and leukocytes. Excess of cystine damages cells and often forms crystals that can build up and cause problems in many organs and tissues. The kidneys and eyes are especially vulnerable to damage; the muscles, thyroid, pancreas, and testes may also be affected. The three types of cystinosis, i.e., nephropathic (classic renal and systemic disease), intermediate (a late-onset variant of nephropathic cystinosis), and non-nephropathic (ocular), are allelic disorders caused by pathogenic variants in CTNS. Cystinosis is inherited in an autosomal recessive pattern – a mutation must be present in the copies inherited from both the mother and the father – for the disease to manifest itself.

2. The Symptoms:

Newborns with cystinosis are asymptomatic at birth, although a clinical diagnosis is typically made by two years of age.  The lack of early signs or symptoms does not exclude the diagnosis.  

• Nephropathic cystinosis – characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment.
  • The typical untreated child has short stature, rickets, and photophobia.
  • Failure to thrive is generally noticed after approximately age six months.
  • Signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months.
  • Corneal crystals can be present before age one year and are always present after age sixteen months.
• Intermediate Cystinosis – characterized by all the typical manifestations of nephropathic cystinosis, but with a later age of onset. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years.
• Non-nephropathic (Ocular) Form – characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.  In certain cases, bone marrow can also be involved.

3. Actions to take in case of early diagnosis

Patients with a positive genetic result should have confirmatory testing through demonstration of elevated cystine levels in polymorphonuclear leukocytes. Individuals with nephropathic cystinosis generally have values of 3.0-23.0 nmol half-cystine/mg protein. Individuals with non-nephropathic cystinosis have values of 1.0-3.0 nmol half-cystine/mg protein. Normal values are < 0.2 nmol half-cystine/mg protein.

• Cystine depletion with cysteamine bitartrate (CystagonÒ):
  • The worldwide treatment of choice for cystinosis, with the ability to deplete cystinotic cells of more than 90% of their cystine component.
  • It has significantly improved the prognosis for individuals with nephropathic cystinosis. With early diagnosis and treatment, many patients survive into the third or fourth decade of life (some even survive into the fifth decade of life), and are able to pursue fulfilling lifestyles.
  • Oral therapy should be initiated as soon as the diagnosis is made.

• Surgery:
  • Kidney transplantation corrects kidney failure and prolongs survival in patients with infantile cystinosis, but does not prevent progression of the disease in non-renal organs.  Therefore, oral cysteamine therapy is indicated in patients after kidney transplantation.
  • Thyroid replacement is indicated in patients diagnosed with hypothyroidism.
  • Some patients with severe gastroesophageal reflux and cystinosis may require gastric/jejunal tube placement or Nissen fundoplication to achieve optimal nutrition.
• Treatment with recombinant human growth hormone improves growth velocity in young children with nephropathic cystinosis prior to renal replacement therapy.
• Supportive care in the management of nephropathic cystinosis includes the following:
  • Replacement of urinary losses (eg, hydration, potassium and bicarbonate supplementation, vitamin D and phosphate supplementation; carnitine).
  • Management of volume depletion/dehydration states.
• Genetic counseling is of benefit for patients and their families.

4. For more information:

• Orphanet:https://www.orpha.net/consor/cgibin/Disease_Search.php?lng=EN&data_id=23023&Disease_Disease_Search_diseaseGroup=cystinosis&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Infantile-nephropathic-cystinosis&title=Infantile%20nephropathic%20cystinosis&search=Disease_Search_Simple
• Biblio:

-https://www.ncbi.nlm.nih.gov/books/NBK1400/

-Elmonem MA, Veys KR, Soliman NA, van Dyck M, van den Heuvel LP, Levtchenko E. Cystinosis: a review. Orphanet J Rare Dis. 2016;11:47. Published 2016 Apr 22. PMID: 27102039.