Cystinosis

The Swiss biochemist Emil Abderhalden (1877 - 1950) first described the "familial cystine accumulation disease", which he named, in 1903. At that time, he related his findings to an affected child named Eduard Kaufmann.

A detailed description of cystinosis was published in 1924 by the Dutch pathologist George Lignac (1891 - 1954). It was he who linked the most important clinical manifestations, such as kidney disease, rickets and growth retardation, to the disease. The disease was therefore initially named "Abderhalden- Kaufmann- Lignac syndrome".

Another name for the disease, the so-called "Lignac- Fanconi syndrome" was named after the Swiss pediatrician Guido Fanconi (1892 - 1979), who contributed significantly to the understanding of cystinosis (Elmonem 2016).

Cystinosis is one of the lysosomal transport defects (Hoffmann 2019). It is a hereditary disease in which the amino acid cystine accumulates in the lysosomes of almost all body cells (Herold 2021).

Cystinosis is differentiated into 3 different clinical manifestations:

• 1. infantile form (with renal involvement)
• 2. intermediate form (late- onset)
• 3. adult form (benign form)

(Risler 2008 / Scherberich 2003)

Cystinosis is one of the rare diseases whose incidence varies greatly depending on the population. In Germany, for example, the incidence is 1: 179,000, in Denmark 1: 115,000 live births, and in a Pakistani ethnic group living in the UK, the highest incidence worldwide is found at 1: 3,600 (Elmonem 2016).

Cystinosis is an autosomal recessive inherited disease. The disorder is found on chromosome 17, CTNS gene, which encodes 367 amino acids. In the OMIM (Online Mendelian Inheritance in Man database), the infantile form is registered under 219,800, the intermediate under 219,900, and the adult under 219,750 (Kuhlmann 2015).

In the lysosomes of the cells, cystine is physiologically produced during protein degradation. This free cystine is then transported into the cytosol of the cell, where it is converted into cysteine. It can then be used again for protein synthesis.

In cystinosis, a transport defect causes accumulation in the lysosomes. Since cystine is poorly soluble, it crystallizes, causing damage to organs such as the tubules of the kidney (Risler 2008).

Damage to the proximal tubule results in increased excretion:

• Water
• Minerals
• Electrolytes
• Amino acids
• Glucose
• Bicarbonate (Hohenfellner 2019)

The clinical symptoms of the disease result from the storage of cystine in the lysosomes (Kuhlmann 2015).

At birth, the children initially appear inconspicuous. At the age of 6 - 9 months, growth retardation is usually the first symptom to be noticed (Hohenfellner 2019).

Infantile form:

As the infantile form progresses, there is:

• renal Fanconi syndrome (results from impaired tubule function [Risler 2008]) with
  • Polyuria between 2 - 10 l / d
  • Polydipsia
  • Dehydration
  • Hypokalemia
  • Hypophosphatemia (leading to osteomalacia [Kuhlmann 2015]).
  • Hypochloremia
  • metabolic acidosis
• Renal failure (often seen before the age of 10 [Kuhlmann 2015])
• Rickets
• Hypotonia
• Photophobia
• Blindness (due to cystine deposits in the conjunctiva and cornea [Kuhlmann 2015])
• Hypothyroidism
• Osteoporosis
• Short stature

(Kasper 2015 / Hohenfellner 2019)

• depigmenting retinitis
• Hepatosplenomegaly
• diabetes mellitus (due to endocrine pancreatic insufficiency [Risler 2008])
• hypergonadotropic hypogonadism due to storage of cystine in the testis (vom Dahl 2014)
• cerebral symptoms may occur from the age of 20 onwards such as:
  • Gait disorders
  • Swallowing disorders
  • Speech difficulties (Kuhlmann 2015)

Intermediate form: In this case, the first of the above symptoms usually appear after the age of 8. Terminal renal failure usually occurs after the age of 15 (Kuhlmann 2015).

Adultform: Patients of the adult type are predominantly asymptomatic. Only ophthalmological examinations may reveal corneal cystine crystals (Kuhlmann 2015).

Since cystinosis is treatable, early detection of the disease plays a crucial role.

Prenatal diagnosis can be made as early as the first trimester by determining cystine incorporation after chorionic villus sampling or amniocentesis (Risler 2008).

In the case of a positive family history, an increased cystine content in cultured skin fibroblasts and in the placenta is shown at the time of birth.

In infants, the diagnosis is based primarily on evidence of increased cystine concentration in granulocytes.

In older children > 2 years of age, slit lamp examination can detect cystine crystals in the cornea (Hohenfellner 2019).

The heterozygous carrier type can be diagnosed by measuring cystine-binding protein in peripheral leukocytes (Kuhlmann 2015).

Typical in cystinosis is a normal concentration of cystine in body fluids in the analysis of amino acids (Hoffmann 2019)

Sonography

On ultrasound of the abdomen may be detectable, among other things:

• Hepatomegaly
• portal hypertension
• splenomegaly (Risler 2008)

Other metabolic diseases such as:

• Glycogen storage disease
• Galactosemia
• Tyrosinemia
• M. Dent
• Lowe's syndrome
• M. Wilson
• nephrogenic diabetes insipidus
• Bartter syndrome (Elmonem 2016)

Because cystine accumulates in almost all organs and tissues, treatment should be by a specialized, multidisciplinary team of pediatricians, endocrinologists, ophthalmologists, nephrologists, orthopedic surgeons, and geneticists.

Symptomatic therapy

• Adequate hydration: Children should have access to water and the ability to go to the toilet at all times. Strong sunlight and excessive heat should be avoided (Hohenfellner 2019).
• Substitution of the missing electrolytes / acid-base balance.

- Phosphate: initial dose of elemental phosphate: 30 mg - 40 mg / kg bw / day, divided into 4 - 5 doses. Phosphate administration may lead to nephrocalcinosis, but the dose should still be maintained. Reduction is necessary only when chronic renal failure occurs (Hohenfellner 2019).

- Bicarbonate: Bicarbonate or citrate should be administered 3 - 4 times a day until bicarbonate levels are ideally between 22 - 25 mmol / l. However, this value may not be achieved in all patients.

- Calcium: Calcium supplementation should be with native or active vitamin D. The initial dose ranges from 0.1 µg - 0.75 µg depending on the size of the patient and the degree of rickets with calcitriol or alfacalcidol (Hohenfellner 2019).

• Hormonal substitution with e.g.

- Growth hormones: Growth hormones should be given if height < the 3rd percentile. After kidney transplantation, treatment is usually interrupted and resumed after 12 months if necessary (Hohenfellner 2019).

- Thyroid hormones: The amount of dosage depends on the target value of age-appropriate free T4 and TSH (Hohenfellner 2019).

- Testosterone: Testosterone replacement therapy is indicated for multiple lowered plasma testosterone levels (Elmonem 2016).

• Ensure adequate nutrition: This requires the early use of a feeding tube in most cases (Elmonem 2016).

Cysteamine: Cysteamine reduces the cystine content in the lysosomes, reduces the occurrence of extrarenal organ damage and delays the deterioration of renal function (Levtchenko 2006).

Cysteamine should be used early and substituted throughout life (Herold 2021).

Dosage recommendation: The daily dose of initially 10 mg / kg bw p. o. is slowly increased up to 50 mg / kg bw (Kuhlmann 2015) and divided into 5 doses per day (Lentze 2007).

For the treatment of the eyes, 0.5% cysteamine eye drops are available for local treatment. These should be administered 4 x / d (Lentze 2007).

Sometimes there are - especially in adolescents - compliance problems when taking, because cysteamine has an unpleasant smell and taste and sometimes causes nausea or other digestive problems (Hohenfellner 2019).

Indometacin: Indometacin is used to treat polydipsia and polyuria. Dosage recommendation: 2 mg - 3 mg / kg bw / d (Scherberich 2003).

If kidney failure occurs, renal replacement therapy is required (see d. for more details).

Kidney transplantation is another option for treating kidney failure. The disease no longer occurs in the transplanted kidney, but cystinosis persists in all other organs (Elmonem 2016).

In the early 20th century, patients with cystinosis died at the end of the 1st or 2nd decade of life. Today, most patients reach adulthood (Elmonem 2016).

Extrarenal complications now ultimately determine prognosis (Herold 2021).

Provided the disease is diagnosed in the first year of life and consistently treated, glomerular function can usually be preserved until at least the second decade of life (Lentze 2007).

The long-term outcome of a kidney transplant after 5 years in patients with cystinosis is 92.9 %, which is significantly better than the average value of 73.4 % in Germany (Assmann 2014).

Male patients are - despite hormonal treatment - infertile. In women, pregnancies of healthy children without complications have been described (vom Dahl 2014).

• Control examinations

In children with cystinosis, regular checks should include:

• Sodium
• Phosphate
• Chlorine
• Potassium
• vitamin D
• BGA / Bicarbonate
• Kidney function parameters
• Pancreas function parameters
• Thyroid values
• Hormones of the parathyroid gland
• Sex hormones
• HbA1c level (Hohenfellner 2019)
• Control of possibly substituted hormones etc. (Elmonem 2016)
• Neuro-muscular status should be checked every 6 - 12 months after the age of 10 (vom Dahl 2014).

In adulthood, the following examinations are recommended:

• clinical examination every 3 - 6 months (especially looking at nutritional status, vision, muscle strength, psychosocial problems).
• control of leukocyte cystine every 3 - 6 months
• Laboratory parameters of bone metabolism every 6 months
• ophthalmological examination with slit lamp every 6 months
• Thyroid function every 12 months
• Check kidney function, possible graft function and immunosuppression at regular intervals
• Regular orthopaedic examination in the case of axial malposition and, if necessary, for surgical correction
• In case of neurological or psychiatric symptoms or recurrent headaches, a cranial MRI is indicated (vom Dahl 2014).

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