eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Cystinosis

Author: Ewa Elenberg, MD, Assistant Professor, Department of Pediatrics, Renal Section, Texas Children's Hospital, Baylor College of Medicine
Contributor Information and Disclosures

Updated: Nov 29, 2007

Introduction

Background

Nephropathic cystinosis is an inherited (autosomal recessive) lysosomal storage disorder caused by defective transport of the amino acid cystine out of lysosomes. The stored cystine is poorly soluble and crystallizes within the lysosomes of many cell types, leading to widespread tissue and organ damage.

Three types of cystinosis have been described based on the age at diagnosis and magnitude of cellular cystine deposition: infantile onset, adolescent onset, and adult onset. Patients with the infantile nephropathic form of cystinosis (the most common and the most severe) develop symptoms early in life and develop end-stage kidney failure by late childhood, if untreated. 

Specific therapy with a drug that allows for removal of cystine from its lysosomal accumulation has been associated with marked improvement in the outlook for kidney function and quality of life in patients with nephropathic cystinosis.

Pathophysiology

Ingested protein enters the lysosome, where acid hydrolases degrade it to its component amino acids, including cysteine. Within the lysosome, cysteine is readily oxidized to cystine (a disulfide of the amino acid cysteine). In healthy individuals, both cystine and cysteine can normally enter the cytoplasm, where cystine is rapidly converted to cysteine by the reducing agent glutathione. Cytoplasmic cysteine is incorporated into protein or degraded to inorganic sulfate for excretion.

Cystinosis is caused by one of several mutations in the gene that encodes cystinosin, the cystine-lysomal exporter. Because of the defect in cystinosin, cystine cannot leave the lysosomes and is accumulated there as birefringent, hexagonal, or rectangular crystals within cells of various organ systems.

In the infantile nephropathic form of cystinosis, the kidney is affected early in life by cystine crystals deposited in proximal tubule cells. This leads eventually to a Fanconi syndrome, characterized by wasting of substances reabsorbed in this nephron segment, including sodium, potassium, phosphate, calcium, magnesium, bicarbonate, and others. Metabolic acidosis and electrolyte disturbances ensue and contribute to the stunting of growth in children with cystinosis. Cystinosis is the most common inherited cause of Fanconi syndrome.

Frequency

United States

In North America, the incidence of infantile nephropathic cystinosis is 1 case per 100,000-200,000 live births; an estimated 300-400 children in the United States have cystinosis.

International

The incidence of cystinosis is higher in certain subpopulations. France's Brittany province has an estimated incidence of 1 case per 26,000 population; the incidence in the rest of France is 1 case per 326,440 population. The incidence rate of infantile and adolescent cystinosis in the former Federal Republic of Germany was reported to be approximately 1 case per 179,000 live births.

Mortality/Morbidity

Medical perceptions regarding the complications and outcome of cystinosis have changed over the years. Prior to the availability of renal transplantation, infantile cystinosis was considered a fatal disease. By the early 1970s, the salutary effects of renal transplants had been recognized.
 
Cysteamine, introduced in the early 1980s, was shown to blunt the decline in renal function and improve linear growth in these children, despite the fact that it does not ameliorate the defect in renal tubule transport. However, the increased life expectancy afforded by the progress in medical and surgical treatment was accompanied by the development of serious complications due to the continuous accumulation of cystine in nonrenal organs, including the eye, thyroid, brain, liver, pancreas, and muscle. However, many patients survive into the third or fourth decade of life and are able to pursue fulfilling lifestyles.

Race

Cystinosis is often considered a disease of fair-skinned individuals of European descent; however, it is known to occur in blacks, Hispanics, and people of Middle Eastern descent. It has also been described in at least one Chinese patient and in several Japanese patients.

Sex

The male-to-female ratio among cystinotic children has been reported to be 1.4:1.

Age

Patients with infantile nephropathic cystinosis develop initial symptoms in infancy, frequently when younger than 1 year. In the adolescent form, symptoms are evident by age 8-12 years, and the progression is slow. The adult form of cystinosis does not include renal involvement and is limited to the eye (ocular cystinosis).

Clinical

History

Cystinosis is classified into 2 general phenotypes: nephropathic and nonnephropathic cystinosis (benign variant).

• Nephropathic cystinosis is further subdivided into infantile and late-onset (intermediate cystinosis), based on the age at presentation.
  • Nephropathic infantile cystinosis is the most common and most severe variant.
    • Symptoms of multiorgan involvement may be mild to severe, depending on the patient's age at diagnosis, the age when treatment was instituted, and genetic factors.
    • Early in the natural history of infantile nephropathic cystinosis, clinical involvement follows a fairly predictable chronology. Patients usually present during the first year of life with polyuria, polydipsia, dehydration, metabolic acidosis (normal anion gap hyperchloremic acidosis), hypophosphatemic rickets, failure to thrive, and laboratory findings consistent with Fanconi syndrome. If untreated, renal failure develops by age 7-10 years.
    • Oral cysteamine therapy postpones the need for renal transplantation.
    • Renal transplantation has prolonged the lives of children with cystinosis. Renal transplantation is highly successful, disease does not recur in the graft, but cystine continues to accumulate in other tissues, resulting in such complications as eye disease (eg, severe photophobia, corneal ulcerations, retinal blindness), delayed puberty, hypothyroidism, pancreatic disease (eg, exocrine insufficiency, insulin-dependent diabetes mellitus), liver disease (eg, hepatosplenomegaly, nodular degenerative hyperplasia), distal vacuolar myopathy, swallowing difficulties, and CNS involvement (eg, calcifications, atrophy, pseudotumor cerebri).
  • Late-onset (intermediate) nephropathic cystinosis is a more indolent form of the disease. The first symptoms most commonly appear at age 8-12 years. The features of Fanconi syndrome are less severe, and end-stage renal disease occurs after age 15 years.
• Nonnephropathic cystinosis is considered a benign variant and is usually diagnosed by an ophthalmologist treating patients for photophobia. Photophobia may not begin until middle age and is not usually as debilitating as in the nephropathic form of the disease. Slit-lamp examination reveals corneal crystal deposits. In addition to the eye, cystine crystals are present in the bone marrow and leukocytes but are absent in the kidney and the retina.

Physical

A typical cystinotic patient has pale blond hair and blue eyes, although the disease also occurs among dark-haired individuals.

• Initial presentation of infantile nephropathic cystinosis
  • The initial symptoms include polydipsia, polyuria, vomiting, loss of appetite, constipation, and failure to thrive.
  • The first signs may go unrecognized for several months until the patient develops severe dehydration, electrolyte imbalance, and metabolic acidosis during a mild illness. Some children may have recurrent bouts of fever and manifestations of heat intolerance (becoming red like beets) caused by a defect in sweat production.
  • Patients typically have short stature and renal Fanconi syndrome.
  • They have poor appetite, crave salty and hot and spicy foods, and prefer specific food textures. Each patient has specific preferences that may already be evident by age 2 years.
• Initial presentation of late-onset nephropathic (intermediate) cystinosis
  • Most cases are diagnosed by age 12 years.
  • Complete Fanconi syndrome often does not develop in late-onset cystinosis, but renal function deteriorates as in infantile nephropathic cystinosis, and patients often experience end-stage renal failure within a few years of diagnosis.
• Nephropathic cystinosis (progressive disease)
  • Children younger than 1 year usually show growth retardation, rickets, metabolic acidosis, and other chemical evidence of renal tubular abnormalities, such as increased renal excretion of glucose, amino acids, phosphate, and potassium. They may require frequent hospital admissions because of dehydration.
  • As children age, failure to thrive is prominent. Without specific therapy, children remain below the third percentile in both height and weight throughout life.
  • Corneal crystals are apparent by age 1-2 years. The untreated cornea is packed with crystals by age 3-4 years, leading to photophobia in early childhood.
  • By age 7-10 years, previously noted symptoms become more severe, and patients develop renal failure, increased photophobia, and thyroid insufficiency.
  • Sexual maturation is almost always late.
  • Retinal damage does not occur until the second or third decade of life.
  • Cerebral calcifications and muscular and swallowing difficulties cluster around the third decade of life.
  • The major complication of cystinosis in patients older than 20 years is legal blindness, distal myopathy, cerebral calcifications or atrophy, swallowing dysfunction, diabetes mellitus, and liver disease (eg, hepatomegaly, nodular degenerative hyperplasia).

Causes

All forms of cystinosis have autosomal recessive patterns of inheritance. Cystinosis is caused by a defect in transport of cystine across the lysosomal membrane due to defective function of the lysosomal membrane protein cystinosin, resulting from mutations of the cystinosis gene (CTNS). CTNS has been mapped to chromosome arm 17p13. The CTNS gene has 12 exons, the last 10 of which code for cystinosin.

Cystinosin (an integral lysosomal membrane protein) has 367 amino acids and 7 transmembrane domains. In nephropathic cystinosis patients, CTNS mutations can cause either an absence of cystinosin or a disruption of transmembrane domains and loss of protein function, leading to inhibition of cystine transport through the lysosomal membrane (which is carrier-dependent). More than 80 different CTNS mutations (missense, nonsense, splice-site, deletion, and promoter mutations) are described in patients with nephropathic cystinosis; the most common are 57 kilobases (kb) (approximately 60% of the mutations in US patients).¹

Patients with a mild form of cystinosis that is diagnosed when patients are younger than 7 years or patients with late-onset (intermediate) cystinosis have mutations of CTNS that affect functionally unimportant regions of cystinosin, accounting for a milder clinical course. The various CTNS mutations can explain why patients have a wide spectrum of clinical symptomatology.

The parents of patients with cystinosis are obligate heterozygotes for cystinosis; they each carry a single gene for the disease. Individuals heterozygous for cystinosis have never been reported to have cystine crystals in any tissue or cell. Despite the clinically normal appearance of individuals who are heterozygous for cystinosis, their polymorphonuclear cells contain an increased amount of cystine.

Late-onset (intermediate) cystinosis appears to be due to the inheritance of a mutation known to cause infantile disease in one allele and a relatively less clinically severe mutation in the other or due to the inheritance of a relatively less severe mutation in both alleles.

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