Excerpt from Cystinosis

Please click here to view the full topic text: Cystinosis

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).

Please click here to view the full topic text: Cystinosis