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Nephropathic Cystinosis

Diathesis Cystine

Nephropathic cystinosis (NC) is a lysosomal storage disease inherited in an autosomal recessive manner. It is caused by mutations in the CTNS gene that eventually lead to the intralysosomal accumulation of cystine crystals in all organs and tissues. NC patients typically present with renal Fanconi syndrome during their first year of life and subsequently develop ophthalmological, skeletal, and endocrine disorders. Intracellular cystine accumulation may be reduced by cysteamine therapy, which is generally complemented by symptomatic therapy. This way, end-stage renal failure can be postponed and possibly even avoided.


Presentation

Renal Fanconi syndrome is the cardinal symptom in >90% of NC patients suffering from the infantile form of the disease, whereas sole proteinuria in the absence of Fanconi syndrome is rare [1]. Juvenile NC is associated with mild renal Fanconi syndrome or isolated proteinuria and manifests in childhood or adolescence [2].

Renal Fanconi syndrome causes polyuria, polydipsia, dehydration, vomiting, and failure to thrive [3]. It results from a generalized proximal tubular dysfunction and is characterized by an abnormal urinary loss of proteins, amino acids, glucose, and other solutes [4]. This condition can be confirmed by urine sample analysis. In case of infantile NC, aminoaciduria may be detected as early as the neonatal period and is soon followed by proteinuria, glucosuria as well as excess loss of bicarbonate and phosphate. Podocytes and proximal tubular cells are also lost into urine and can be seen during the microscopic examination of urine samples [1].

The accumulation of cystine crystals is not restricted to the kidneys and eventually causes extrarenal complications. In infants suffering from NC, corneal cystine crystal deposits may be detected during the second year of life, while skeletal deformities and gait disorders due to hypophosphatemic rickets become apparent in childhood or adolescence. Corneal crystals typically appear as needle-shaped and highly reflective crystals; skeletal deformities are commonly associated with bone pain [2]. Hypothyroidism has been described in some patients [4]. Adolescent males present hypergonadotropic hypogonadism and are generally infertile, while delayed puberty is observed in females, who usually preserve fertility [2]. The function of other organs, namely pancreas and intestines, muscles and lungs may be increasingly compromised as the disease progresses [2].

Isolated symptoms of corneal disease are to be expected in those suffering from non-nephropathic ocular cystinosis. This variant of the disease is not usually diagnosed before adulthood [2]. Photophobia may be described by patients suffering from NC-associated corneal disease [3]. Blepharospasm, superficial punctate keratopathy and recurrent corneal erosions may also be observed in these individuals [2] [1].

Splenomegaly
  • Routine examination revealed normal liver function without hepatomegaly but asymptomatic splenomegaly. An abdominal ultrasound suggested mild oesophageal varices, confirmed later on endoscopy.[ncbi.nlm.nih.gov]
  • RESULTS: Gastrointestinal signs and symptoms were as follows: vomiting in 16 patients (69.6%), hepatomegaly in 8 (34.8%), diarrhea in 6 (26.1%), splenomegaly in 5 (21.7%), constipation in 4 (17.4%), anorexia in 4 (17.4%), abdominal pain in 3 (13.0%),[ncbi.nlm.nih.gov]
Splenomegaly
  • Routine examination revealed normal liver function without hepatomegaly but asymptomatic splenomegaly. An abdominal ultrasound suggested mild oesophageal varices, confirmed later on endoscopy.[ncbi.nlm.nih.gov]
  • RESULTS: Gastrointestinal signs and symptoms were as follows: vomiting in 16 patients (69.6%), hepatomegaly in 8 (34.8%), diarrhea in 6 (26.1%), splenomegaly in 5 (21.7%), constipation in 4 (17.4%), anorexia in 4 (17.4%), abdominal pain in 3 (13.0%),[ncbi.nlm.nih.gov]
Respiratory Insufficiency
  • Two patients died of respiratory insufficiency. All the patients had lived at least 17 years, while lacking compliant cystine-depleting therapy with oral cysteamine.[ncbi.nlm.nih.gov]
Cognitive Deficit
  • Individuals with cystinosis exhibit specific cognitive deficits in visual spatial function.[ncbi.nlm.nih.gov]

Workup

The identification of CTNS mutations is the gold standard of NC diagnosis, but genetic studies aren't usually carried out if there is no concrete suspicion. In most cases, blood and urine sample analyses, renal biopsy and measurements of cystine levels in leukocytes precede genetic tests:

As has been indicated above, the tentative diagnosis of NC should be confirmed by genetic studies. Rapid tests are available for common mutations, e.g., the 57-kb deletion accounting for about 75% of northern European cases. Sequencing of the total coding region, the exon-intron boundaries, and promoter region of the CTNS gene is more cumbersome, but possible. If genetic analyses cannot be carried out, the association of renal Fanconi syndrome with corneal crystal deposits observed during slit-lamp examination may be considered confirmatory of NC [6].

Delayed Bone Age
  • All patients were growth retarded with delayed bone ages. Puberty occurred late, but was generally complete by 17 years of age. Hepatic function appeared normal.[ncbi.nlm.nih.gov]
Glycosuria
  • Diagnostic methods The diagnosis is based on blood and urine analysis showing features of Fanconi syndrome (metabolic acidosis, hypokalemia, hyponatremia, hypophosphatemia, hyperaminoaciduria, glycosuria), detection of cystine crystals in the cornea by[orpha.net]
  • Renal tubular disease is usually present causing aminoaciduria, glycosuria and hypokalemia. Cysteine deposition is most evident in the conjunctiva and cornea. It is named for Emil Abderhalden, Eduard Kaufmann and George Lignac. Cystinosin[en.wikipedia.org]
  • Renal tubular disease, aminoaciduria, glycosuria, and hypokalemia are usually present. Cystinosis occurs primarily in children; only two cases are believed to have been observed in adults.[whonamedit.com]
  • It is associated with slight increase of the plasma cystine, cystinuria, aminoaciduria, glycosuria, polyuria, hypophosphatemia, rickets, and renal tubular dysfunction Constellation of clinical and laboratory manifestations produced by generalized proximal[icd9data.com]
Liver Biopsy
  • Severe accumulation of cystine was demonstrated on liver biopsy, predominantly localized in Kupffer cells, together with morphological signs of sclerosing cholangitis on liver biopsy.[ncbi.nlm.nih.gov]
  • A liver biopsy revealed an abundance of cystine crystals within the hepatic Kupffer cells, with preserved hepatic architecture.[ncbi.nlm.nih.gov]

Treatment

The oral application of cysteamine, a cystine-lowering drug, is the mainstay of treatment. The drug is given throughout life and current formulations require administration every six hours [7]. In order to prevent ocular complications, cysteamine-containing eye drops may be applied additionally.

In general, cysteamine therapy has to be complemented by symptomatic treatment:

  • Indomethacin is frequently used to reduce diuresis and urinary electrolyte losses [8], but this measure remains an issue of ongoing debate. Some authors argue chronic indomethacin toxicity on the renal interstitium to be of particular concern in NC patients [2].
  • Even if indomethacin is administered, bicarbonate, phosphate and potassium supplementation may be required to maintain electrolyte homeostasis.
  • Nutritional support, possibly in form of gastric tube placement, should also be provided to prevent electrolyte imbalances and to reduce the negative impact of NC on growth.
  • If necessary, vitamin D and recombinant human growth hormone may be administered to that same end.

Despite all efforts, NC may progress to end-stage renal failure and patients may eventually require renal replacement therapy. Of note, cysteamine therapy has to be continued even after renal transplantation [9]. Hematopoietic stem cell transplantation may be an option to cure NC, but results gained from practical experience have not been as promising as those obtained in animal models [7].

Prognosis

Patients who are diagnosed early and adhere to cysteamine treatment have a more favorable prognosis and frequently survive into adulthood. By means of cysteamine therapy, extrarenal complications can be prevented and end-stage renal disease may be postponed to the second or third decade of life or even avoided [7]. By contrast, treatment accessibility is a major concern of NC patients in developing countries and affected individuals often develop end-stage renal disease before reaching the age of 10 years [6].

Etiology

According to current knowledge, NC is a monogenic, autosomal recessive disease with complete penetrance. It is caused by mutations in the CTNS gene. This gene is located on the short arm of chromosome 17 and encodes for a seven-transmembrane domain lysosomal cystine transporter. This transporter is sometimes referred to as cystinosin and functions as an ATP-dependent symporter that couples cystine and proton transport across the lysosomal membrane [2].

CTNS mutations related to NC interfere with cystinosin function. There are clear genotype-phenotype correlations: Patients with biallelic severe truncating mutations will develop severe infantile NC. By contrast, mutations allowing for residual activity of the cystine transporter result in late-onset forms of the disease. More than 100 mutations have been reported to date. They comprise deletions, insertions, duplications, missense and nonsense point mutations, and splice-site mutations, mutations in the promoter sequence and genomic rearrangements [2]. Novel mutations are still being reported [3] [5].

Epidemiology

In developed nations, the overall incidence of NC has been estimated to <1 in 100,000 life births [6], but higher incidence rates have been reported for determined regions such as Brittany, France [8]. Boys and girls are affected equally. In its infantile form, the disease manifests by the age of six months and, if left untreated, progresses to end-stage renal disease towards the end of the first decade of life [1].

Sex distribution
Age distribution

Pathophysiology

As has been indicated above, NC patients suffer from the deficiency of lysosomal cystine transporter cystinosin. Under physiological conditions, cystinosin exports cystine from lysosomes, which is why CTNS mutations causing NC are associated with the intralysosomal accumulation of cystine crystals. These crystals inflict mechanical cell damage, primarily in the kidney and the cornea, but they have also been shown to increase oxidative stress and trigger inflammatory processes, provoke mitochondrial dysfunction and apoptosis [1].

Cysteamine, the mainstay of NC treatment, is able to convert intralysosomal cystine into cysteine and cysteine-cysteamine mixed disulfide that can then be released from the lysosome through cysteine and PQLC2 transporters, respectively [4]. Somewhat surprisingly though, cysteamine therapy does not suffice to prevent all pathological features of the disease: It offers no cure from Fanconi syndrome and doesn't prevent NC-associated endocrine disorders [7]. In this context, the results of recent studies suggest a role of cystinosin in vesicle trafficking, lysosomal biogenesis, mTOR signaling, and autophagy [1]. Possibly, this role cannot be assumed or replaced by cysteamine, and may explain why this drug is unable to provide cure.

On the other hand, it is known that severe truncating CTNS mutations also affect genes SHPK and TRPV1 [2]. These encode for the enzyme sedoheptulokinase and transient receptor potential cation channel subfamily V member 1, respectively. Although increased sedoheptulose levels have been described in tissues, serum, and urine of NC patients, SHPK and TRPV1 mutations have not been related to clinical symptoms. It cannot be ruled out, though, that they are involved in disease progression despite cysteamine treatment.

Prevention

The detection of the underlying mutation in the CTNS gene does not only resolve any doubts regarding the causes of renal disease, but also facilitates the identification of family members that carry this mutation. Knowledge regarding this mutation is thus the basis for genetic counseling and prenatal diagnosis: Affected families may definitely benefit from genetic counseling. The prenatal diagnosis of NC is feasible and can be achieved achieved by analyzing chorionic villus or amniotic fluid samples; it allows for an early initiation of treatment [2].

Summary

NC is a rare metabolic disorder leading to progressive renal failure. The disease is provoked by the deficiency of the lysosomal cystine transporter cystinosin, which causes the accumulation of cystine crystals in all organs and tissues [4]. Proximal tubular epithelial cells and glomerular podocytes are affected first and thus, NC patients typically suffer from proteinuria and the progressive deterioration of kidney function [1].

Infantile NC is the most severe form of NC and is related to a complete loss of function of cystinosin [4]. The vast majority of NC patients develops this form of the disease. Less than 5% of NC patients suffer from the juvenile variant of the disease, and a non-nephropathic ocular form of cystinosis has also been described [1]. All types of cystinosis are ideally diagnosed by identifying the causal mutation in the gene encoding for cystinosin, but clinical features may allow for a strong suspicion.

Renal Fanconi syndrome is the clinical hallmark of infantile NC, manifests within six months of life and is soon followed by NC-associated corneal disease. If left untreated, the disease progresses to end-stage renal failure within the first decade of life. Treatment with cystine-lowering cysteamine, however, significantly improves the patients' prognosis: It may postpone renal failure by several decades or even prevent it, and helps to avoid extrarenal complications [7]. Nevertheless, NC patients are likely to develop additional disorders of skeletal and endocrine nature. These are treated symptomatically.

Patient Information

Nephropathic cystinosis (NC) is a rare metabolic disorder. It is inherited in an autosomal recessive manner, i.e., a child affected by NC has inherited defective alleles from both of their parents. The disease typically manifests during the first year of life. Parents of affected infants may note excessive passage of urine, great thirst but dehydration, vomiting, and growth retardation. These symptoms are caused by the progressive impairment of renal function: The gene mutation causing NC leads to the intracellular accumulation of cystine crystals that inflict mechanic damage and provoke cell death. Certain cells located in the kidneys are most susceptible to cystine accumulation and lose their function. During the second year of life, NC patients are likely to develop ophthalmological complications and show symptoms of increased susceptibility to light. In childhood and adolescence, additional complications may arise, e.g., skeletal deformities and gait disorders, endocrine disorders such as hypothyroidism, hypogonadism, and infertility.

In order to delay progression to end-stage renal disease and to prevent the onset of extrarenal complications, patients should receive cysteamine therapy as early as possible. This drug is able to enter the cell and to dissolve cystine crystals. It has to be administered throughout life. If progression to end-stage renal disease cannot be avoided, a renal transplant will be required. In most cases, NC patients require additional symptomatic treatment to alleviate electrolyte imbalances and to reduce the negative impact of NC on growth.

Of note, there are rare forms of cystinosis that manifest later in life. On the one hand, there is juvenile NC, a milder form of the disease with first symptoms appearing in childhood or adolescence. On the other hand, there is a non-nephropathic ocular form of cystinosis that doesn't affect the kidneys and is rarely diagnosed before adulthood.

References

Article

  1. Veys KR, Elmonem MA, Arcolino FO, van den Heuvel L, Levtchenko E. Nephropathic cystinosis: an update. Curr Opin Pediatr. 2017; 29(2):168-178.
  2. Emma F, Nesterova G, Langman C, et al. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014; 29 Suppl 4:iv87-94.
  3. Doneray H, Aldahmesh M, Yilmaz G, Cinici E, Orbak Z. Infantile Nephropathic Cystinosis: A Novel CTNS Mutation. Eurasian J Med. 2017; 49(2):148-151.
  4. Ivanova EA, De Leo MG, Van Den Heuvel L, et al. Endo-lysosomal dysfunction in human proximal tubular epithelial cells deficient for lysosomal cystine transporter cystinosin. PLoS One. 2015; 10(3):e0120998.
  5. Sadeghipour F, Basiratnia M, Derakhshan A, Fardaei M. Mutation analysis of the CTNS gene in Iranian patients with infantile nephropathic cystinosis: identification of two novel mutations. Hum Genome Var. 2017; 4:17038.
  6. Bertholet-Thomas A, Berthiller J, Tasic V, et al. Worldwide view of nephropathic cystinosis: results from a survey from 30 countries. BMC Nephrol. 2017; 18(1):210.
  7. Besouw MT, Levtchenko EN. Improving the prognosis of nephropathic cystinosis. Int J Nephrol Renovasc Dis. 2014; 7:297-302.
  8. Levtchenko E, van den Heuvel L, Emma F, Antignac C. Clinical utility gene card for: cystinosis. Eur J Hum Genet. 2014; 22(5).
  9. Berryhill A, Bhamre S, Chaudhuri A, Concepcion W, Grimm PC. Cysteamine in renal transplantation: A report of two patients with nephropathic cystinosis and the successful re-initiation of cysteamine therapy during the immediate post-transplant period. Pediatr Transplant. 2016; 20(1):141-145.

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Last updated: 2019-07-11 20:45