Cystinosis is a lysosomal cystine storage disorder in which cystine accumulates inside lysosomes. The certified gene list and the structured inheritance field in this packet are empty, so no gene or inheritance pattern is specified in the certified fields.

According to GeneReviews, some genotype-phenotype correlations have been reported. Variants that truncate the gene product, and a large 57-kb deletion, result in nephropathic cystinosis when present in homozygous form. Individuals with apparent residual activity and lower cystine accumulation in leukocytes often have missense variants. Later-onset (juvenile) or non-nephropathic (ocular) cystinosis is described as generally associated with one severe variant, typical of nephropathic cystinosis, together with one mild variant. GeneReviews also reports that the 57-kb deletion accounts for more than 50% of pathogenic variants in affected individuals of northern European ancestry and has not been reported in individuals from the Middle East, Asia and Africa, suggesting a northern European founder variant.

According to GeneReviews, nephropathic cystinosis is suspected in infants and young children with a combination of clinical, laboratory and imaging features. Clinical features include poor weight gain and growth deficiency by six to 12 months, vomiting and feeding difficulties, severe polyuria, polydipsia and dehydration, progressive rachitic skeletal changes, tetany, and corneal crystals seen on slit lamp examination in most individuals by age 12 months. Laboratory features include hypochloremic metabolic acidosis, renal Fanconi syndrome with increased urinary losses of electrolytes, minerals, glucose, amino acids and tubular protein, elevated serum alkaline phosphatase, hypocalcemia, hypophosphatemia, hypokalemia, and elevated cystine concentration in polymorphonuclear leukocytes, cultured fibroblasts or placenta. Imaging features include radiographic rickets and renal ultrasound findings of medullary nephrocalcinosis or increased echogenicity.

Later-onset (juvenile) cystinosis is described as suspected with proteinuria, mild renal tubular Fanconi syndrome and progressive glomerular insufficiency, and ocular cystinosis in adults with photophobia or corneal cystine crystals.

GeneReviews states that the diagnosis is established in a proband with biallelic pathogenic or likely pathogenic variants identified by molecular genetic testing, and that biallelic variants of uncertain significance neither establish nor rule out the diagnosis. It describes single-gene testing, multigene panels and comprehensive genomic testing, and notes that untreated nephropathic cystinosis is the most common identifiable cause of renal tubular Fanconi syndrome in childhood.

According to GeneReviews, there is no cure for cystinosis, and management involves a multidisciplinary team including nephrology, metabolic disease, ophthalmology, neurology, gastroenterology, nutrition and psychology, with a clinical care coordinator identified.

Supportive care. GeneReviews lists supplemental nutrition and feeding support for growth, including gastrostomy tube feeding in those with dysphagia or poor nutrition; replacement of tubular losses of electrolytes, bicarbonate and minerals in renal Fanconi syndrome; and growth hormone therapy as needed. It notes that early, diligent treatment of renal Fanconi syndrome with supplements and cystine-depleting agents can reduce the need for growth hormone. Kidney transplant is listed as a management option for chronic kidney disease.

Approved treatment. PROCYSBI (cysteamine bitartrate), a small molecule oral therapy approved by FDA's Center for Drug Evaluation and Research on 2013-04-30, is the one entry in the packet's approved treatments with active market status. GeneReviews describes cysteamine as a cystine-depleting therapy that does not cure the disease, and describes a cysteamine hydrochloride ophthalmic solution (Cystaran) for corneal cystine crystals; the orphan drug records list Cystaran with approved status for corneal cystine crystal accumulation.

Investigational. Orphan drug designation records exist for an autologous CD34+ cell gene therapy product, N-acetylcysteine amide and a third compound; designation is not approval. A phosphocysteamine record carries withdrawn status.

Surveillance. Long-term management includes regular surveillance for potential complications, described separately from treatment of active problems. GeneReviews lists periodic assessment of growth and nutrition (every 3-6 months through childhood), kidney function (every 3-6 months depending on severity), bone and metabolic status (annually or as needed), dental examination (every 6 months) and ophthalmologic evaluation.

Patient assistance programs may be available for this condition.

According to GeneReviews, untreated nephropathic cystinosis involves gradual deterioration of glomerular function, with kidney failure at approximately age ten years. GeneReviews states that treatment with cysteamine allows depletion of lysosomal cystine in most tissues and that, although it does not cure the disease, it dramatically improves the overall prognosis and life span. It also reports that renal tubular damage present at the usual time of diagnosis (about one year of age) is irreversible, while cystine-depleting therapy begun just after birth can attenuate renal tubular Fanconi syndrome, and that early and optimal cystine-depleting therapy allows a normal growth rate without catch-up growth. Specific survival figures and outlook for the later-onset and ocular forms are not certified in this packet, and individual courses vary.

Several certified active trial records are present for cystinosis. Many are registries and cohort studies, including a rare disease patient registry (NCT01793168), the European Cystinosis Cohort (NCT05901077), the European Cystinosis Cohort 2 (NCT07680751, not yet recruiting) and a national registry of rare kidney diseases (NCT06065852). Other records include DFT383 in pediatric participants with nephropathic cystinosis (NCT06910813, Phase 1, Novartis Pharmaceuticals, recruiting), a pilot study of TTI-0102 in cystinosis (NCT07837726, Phase 2, Thiogenesis Therapeutics, not yet recruiting), an early trial of allogeneic hematopoietic stem cell transplantation for patients who will receive a kidney transplant from the same donor (NCT05508009, Phase 1, recruiting) and further records on cysteamine use, mitochondrial metabolism and expanded newborn screening. Trial titles do not establish what any intervention does or whether it is effective. Active clinical trials for this condition are listed on ClinicalTrials.gov.