To the best of our knowledge, this is the first report to describe the clinical and genetic characteristics of nephropathic cystinosis patients in a Latin American country with their long-term follow-up. We registered 9 patients diagnosed in the last 27 years, which was less than expected based on the birth rate in Chile during this period. Misdiagnosis or underdiagnosis cannot be ruled out since the predominant infantile clinical presentation is characterized by a silent period during gestation and even during the first semester of life. Additionally, physicians often lack the experience to perform diagnosis and clinical management.
Our data shows a nephropathic cystinosis prevalence of 0.36 per million people in Chile. The reported worldwide incidence rate is 1 in 100,000-200,000 live births, and its prevalence is approximately 1.6 per million people. This lower prevalence could be due to underdiagnosis or fewer carriers of CTNS defective alleles in the Chilean population [4, 13, 14].
The median age at diagnosis of our NIC cases was 16.5 months, ranging from 6 months to 2.3 years, similar to the results in other developing or developed countries . The single NJC case was a 21-year-old woman diagnosed by an ophthalmologist, and a subsequent evaluation showed she had CKD stage 4, suggesting cystinosis might have started during adolescence without evident symptoms.
Our patients received a late diagnosis, which is partly explained by the late appearance of symptoms that usually appear after six months of age despite prior cystine accumulation during gestation. Early detection and treatment are critical in slowing the development and progression of symptoms associated with cystinosis. If treatment is started immediately after birth, progression might be reduced or even prevented [14, 15]. Therefore, the most cost-efficient approach to prevent the multi-organ damage secondary to cystinosis might be to diagnose it as part of a newborn screening program, similar to that recently reported by German research groups [16, 17]. Limited financial resources in developing countries still restrict next-generation sequencing approaches even though they represent an excellent chance to improve outcomes in patients with medically-actionable genetic conditions .
Regarding the clinical phenotype in NIC patients, we first observed laboratory and clinical findings associated with Fanconi's tubulopathy and variable initial eGFR that fell to values below 50 ml/min/1.73m2 within the first four years after diagnosis and then remained between 25 and 50 ml/min/1.73m2. Due to the drop in eGFR, proteinuria and tubular losses decrease, and therefore the requirements for oral supplements to replace losses of Fanconi's tubulopathy also decrease.
Two of the patients diagnosed before 2000 had significant difficulties establishing their diagnosis and receiving cysteamine, resulting in a worse evolution, requiring KT in the first decade after diagnosis, possibly related to a lack of medication or intermittent administration. In contrast, the last two NIC patients to be diagnosed had an early genetic diagnosis. In their short-term follow-up, they both had a stable eGFR, and p7 showed a slight improvement from CKD stage 4 to 3 after 5 years of cysteamine treatment. The drop in eGFR in the remaining patients within the first years of follow-up drew our attention; even patient P5, who had prompt access to cysteamine since she was the younger sister of patient P6, diagnosed one year before. This could be a consequence of non-adherence since drug tolerance was suboptimal for these siblings whose mother reported a high frequency of vomiting. Gastrostomy was recommended, but the family rejected the procedure.
All patients had bone mineral abnormalities at diagnoses, such as increased PTH levels and hypophosphatemia; however, all improved at least partially after CKD management. Extrarenal manifestations such as hypothyroidism, hypogonadism, central nervous system involvement, myopathies, swallowing difficulties, and diabetes mellitus were infrequent in our cohort or were observed only in patients at more advanced ages and disease stages.
We observed ocular involvement in all patients with corneal deposits of cystine crystals or photophobia; consequently, cysteamine eye drops were recommended. However, we did not observe a substantial improvement, possibly due to a lack of commercially available eye drops in Chile. Therefore, parents request their preparation with prescription formulas in pharmacies without any regulation to assure their quality and effectiveness.
Growth impairment is frequently observed in cystinosis because of tubulopathy losses. Our patients' Z-scores were severely impacted as CKD progressed, including those cases provided with rhGH. Patient 4 presented hypogonadism that could have interfered with growth and muscle mass gain, among other metabolic alterations, despite using rhGH. Patient P6 has not been able to initiate rhGH 6 months after its medical recommendation due to a lack of financial support.
Previous reviews from Ariceta in 2015 and Topaloglu in 2021 describe a similar clinical course of cystinosis to the cases reported here [8, 19].
Graft survival of kidney transplantation was good, and recurrence was not observed. One of our patients is a 26-years old male who underwent KT when he was 10 and to date still has normal creatinine clearance.
Digestive losses represent a high risk of morbidity and mortality in cystinosis patients who are highly dependent on the oral intake of supplements and medications to maintain their fluid homeostasis, electrolyte and acid-base balance. Severe gastrointestinal episodes lead to the risk of shock and death, as observed in patient P1 diagnosed in 1997. Patient P2 underwent peritoneal dialysis and KT in her early childhood but suffered a decline in allograft function not related to cystinosis disease. She had insufficient cysteamine therapy during her life, which might have contributed to the development of multi-organic complications associated with cystinosis.
Cysteamine therapy is not commercially available in Chile and the health system does not finance it. As occurs with other orphan drugs, cysteamine is imported as an individualized request, increasing therapy costs. Furthermore, cysteamine has a financial cost of approximately 1.5 times the Chilean minimum wage, resulting in restrictive access to treatment for most of the patient's families. Access to therapy is achieved after requesting it through legal channels in courts of justice; in the meantime, other families supply the treatments while waiting for the Chilean state or private insurance health system to finance it.
Over the last 23 years, most patients started oral cysteamine less than 12–13 months after initiating legal actions. However, donations and solidarity from other families partially supply the drug requirements in the meantime. The period without therapy might increase cystine lysosomal accumulation and damage to their kidneys and eyes, as these are the first organs to manifest functional decline during the second year of life. Moreover, most patients in our cohort belong to the public health system, but even the two patients from the private system had difficulties obtaining drug therapy at the appropriate dosages.
Adherence to cysteamine therapy is a major problem associated with less favorable outcomes. Intra-leukocyte cystine quantification to monitor compliance and control dosage is not routinely performed in Chile; it requires fresh blood samples that must arrive in less than 24 hours at external laboratories overseas.
The genetic analysis yielded a 100% mutation detection rate, resulting 5 out of the 7 cases homozygous del57kb carriers according to LDM/D17S829 PCR results, which emerges as a cost-effective diagnostic method in comparison to measuring intra-leukocyte cystine. Case P7 was the first Chilean case genetically tested in 2017 and harbored the del57kb mutation in homozygosis . The del57kb mutation involves a major portion of the CTNS gene that originated in Germany and is frequently detected in Europe. The Chilean population is recognized as an admixed population secondary to the migration of Europeans since the XV century .
Additionally, rare recessive diseases are associated with endogamy, and all our patients were homozygous carriers. A study involving genetic and demographic patterns was performed in Chile, showing that most consanguineous marriages occurred among first cousins, but none of the parents of our patients recognized consanguinity before second-degree relatives .
We identified a novel allele in exon 12 that cannot be ruled out as a variant of European origin. However, it might also have arisen in Native Amerindians or even Asians before settlement in America. In terms of the certainty of the diagnosis in this patient, NIC was confirmed by quantifying intra-leukocyte cystine. The single NJC patient carried a variant in exon 7 described as a variant of Spanish origin, compatible with the European ancestry in the Chilean population .
We confirmed a heterozygous carrier status in all the families that requested parent testing, which will facilitate access to genetic counseling for forthcoming gestations. They may also be considered for living donor studies in the future.
Analyses of CTNS variants in other Latin American countries, particularly Mexico and Brazil, have shown that one-third of all cystinosis diagnosed patients carry the del57kb variant [24–25]. Although our dataset is limited and patient recruitment might be biased, based on our results, we propose to assay the presence of del57kb firstly and, if negative, sequence all CTNS exons in suspected patients with recognized European ancestry.
The impact of different genetic variants as determinants of clinical evolution has not shown a difference between types of CTNS mutations and kidney survival [8, 26, 27]. In our cohort, the truncating del57kb variant was exclusively found in the infantile form of cystinosis, suggesting it might be associated with the early development of the disease symptoms. Carriers of CTNS truncating mutations with late CKD stage 5 have been reported worldwide, highlighting opportune diagnosis and precocious cysteamine therapy as key factors for improving kidney survival [26, 27].
A promising therapeutic approach has been developed in cystinosis mouse models and culminated with the approval of a Phase 1/2 clinical trial in cystinosis patients. Briefly, the authors will perform autologous transplantation of CD34 hematopoietic stem and progenitor cells modified ex vivo using a GMP lentiviral vector to introduce the cystinosin protein (product name: CTNS-RD-04). The impact on clinical outcomes and cystine levels will be evaluated over two years .