CYSTINOSIS

Cystinosis — where cysteamine therapy started in infancy preserves kidney function for decades, but without it, children progress to end-stage renal failure by age 10.

Whole genome sequencing identifies all CTNS pathogenic variants — including the common 57-kb deletion that accounts for 50% of Northern European alleles — providing the molecular diagnosis that initiates life-preserving cysteamine therapy.

CTNS

About this condition

Cystinosis

Cystinosis is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in CTNS (cystinosin, chromosome 17p13.2), which encodes the lysosomal cystine transporter. CTNS deficiency causes cystine accumulation within lysosomes of all cell types, leading to progressive cellular damage. Three clinical forms exist: infantile nephropathic cystinosis (most common, ~95%, presenting at 6-12 months with renal Fanconi syndrome), juvenile/adolescent nephropathic cystinosis (milder, later onset), and ocular non-nephropathic cystinosis (adult-onset, corneal crystals only). Incidence is approximately 1 in 100,000-200,000 births.

Infantile nephropathic cystinosis presents with renal Fanconi syndrome — proximal renal tubular dysfunction producing polyuria, polydipsia, aminoaciduria, phosphaturia (causing rickets), glucosuria, and failure to thrive. Without treatment, chronic kidney disease progresses to end-stage renal disease (ESRD) by approximately age 10. Beyond the kidneys, cystine accumulates in corneas (characteristic refractile crystals on slit-lamp examination), thyroid (hypothyroidism), pancreas (diabetes), muscles (myopathy), and CNS (progressive encephalopathy). Renal transplantation corrects the renal failure but does not prevent cystine accumulation in other organs.

Cysteamine (Cystagon, Procysbi) is the specific therapy — a cystine-depleting agent that enters lysosomes and reacts with cystine to form a compound that exits via a different transporter, bypassing the defective cystinosin. Cysteamine therapy started early in life (ideally before significant renal damage at 6-12 months) preserves kidney function for decades — median age of ESRD has shifted from ~10 years (untreated) to ~20+ years (treated), and many treated patients maintain native kidney function into their 30s and beyond. Cysteamine must be taken lifelong and requires strict adherence — interruptions allow cystine re-accumulation.

A common 57-kb CTNS deletion accounts for ~50% of cystinosis alleles in Northern European populations. This deletion removes the entire CTNS gene and extends into the adjacent CARKL gene — standard sequencing-only approaches may not detect it without copy number analysis.

Gene locus: CTNS (17p13.2)

The 57-kb CTNS deletion — the most common cystinosis mutation — is a structural variant that requires deletion detection. WGS identifies both sequence variants and the common deletion from a single test.

Cysteamine started in infancy delays ESRD by decades — every month of delayed diagnosis is measurable kidney function lost

The natural history of untreated cystinosis is relentless: ESRD by approximately age 10. Cysteamine started before age 2 shifts ESRD to age 20+, and increasingly into the 30s and beyond with optimal adherence. Each month of delayed diagnosis allows continued cystine accumulation in renal tubular cells that cannot be fully reversed. Newborn screening for cystinosis is not yet universal — most patients are diagnosed after presenting with Fanconi syndrome symptoms at 6-12 months. WGS performed for any indication in infancy can identify CTNS variants presymptomatically, enabling cysteamine initiation before clinical presentation.

Renal transplant does NOT cure cystinosis — lifelong cysteamine must continue to prevent extrarenal cystine accumulation

Following kidney transplantation, the transplanted kidney is not affected by cystinosis (donor cells have functional CTNS). However, cystine continues to accumulate in all non-renal tissues — corneas, thyroid, pancreas, muscles, and brain. Without continued cysteamine therapy after transplantation, progressive extrarenal complications develop. Some families mistakenly believe transplantation is curative and discontinue cysteamine — with devastating consequences for long-term non-renal organ function. Molecular CTNS diagnosis ensures that the family and all treating physicians understand the systemic nature of the disease.

Cystinosis — where cysteamine therapy started in infancy preserves kidney function for decades, but without it, children progress to end-stage renal failure by age 10.

Cystinosis

The 57-kb CTNS deletion — the most common cystinosis mutation — is a structural variant that requires deletion detection. WGS identifies both sequence variants and the common deletion from a single test.

Cysteamine started in infancy delays ESRD by decades — every month of delayed diagnosis is measurable kidney function lost

Renal transplant does NOT cure cystinosis — lifelong cysteamine must continue to prevent extrarenal cystine accumulation

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