Nephropathic cystinosis specifically is a rare, inherited autosomal recessive disease developed due to the cystine accumulation in lysosomes. A dysfunctional or missing cystine transport protein, cystinosin, causes accumulation of cystine, which is destroying to tissues as well as organs, mainly initially renal and eyes, and later thyroid, testes, pancreas, brain, muscles, bone marrow, liver, and spleen. Nephropathic cystinosis is an ultra-orphan disease with an incidence of approximately 0.5 to 1.0 per 100,000 live births.
There are an approximated 500 cases of nephropathic cystinosis in the US and 2000 worldwide. There are three main types of cystinosis based on the signs/symptoms, severity and age of onset.
1. Infantile nephropathic cystinosis: Infantile nephropathic cystinosis affects approximately 95% of patients and is usually diagnosed during the initial two years of life. The most frequent and severe phenotype (95% of cases) is the infantile nephropathic form. In this type, kidneys are affected and patients develop Fanconi syndrome: a condition when minerals and nutrients are not absorbed into the blood and excreted into urine.
If left untreated, nephropathic cystinosis can lead to poor growth, failure to thrive, renal tubular Fanconi syndrome, renal failure and other non-renal complications. Although untreated nephropathic cystinosis is the most common identifiable cause of renal Fanconi syndrome in young children, diseases such as Wilson’s disease, Lowe syndrome, Dent’s disease, and other metabolic diseases including glycogen storage diseases, classic galactosaemia, tyrosinemia should be considered in the differential diagnosis of renal Fanconi syndrome.
2. Juvenile nephropathic cystinosis: Juvenile nephropathic cystinosis is typically diagnosed in the later phase of childhood or during adolescence. It is less common and it has milder symptoms than those with the infantile type.
3. Ocular or adult cystinosis: The ocular form of the disease is basically diagnosed around always during adulthood, with signs/symptoms isolated to corneal cystine crystal deposits. The ocular non-nephropathic form is extremely rare.
All the forms of nephropathic cystinosis are developed because of the mutations in the gene of CTNS (17p13.2), which are involved in encoding the lysosomal cystine transporter cystinosin. The CTNS gene is expressed in all cells. The defective cystinosin transport process causes intralysosomal accumulation of cystine that crystallizes in a maximum number of cells. There are over 100 reported mutations in the gene of CTNS. The most commonly reported mutation is a large 57kb base pair deletion involving exons 1 through 10. This founder mutation has been noted in more than 60% of patients with cystinosis, based in northern Europe. Patients suffering with infantile nephropathic cystinosis have a couple of mutations that lead to whole loss of functional protein. The milder mutations, linked with certain residual protein function, established in patients with the juvenile and ocular forms of the disease.
Aforementioned, the most commonly noted initial clinical manifestation of infantile nephropathic cystinosis is Fanconi syndrome (dehydration, growth retardation, rickets, polyuria, electrolyte imbalance, polydipsia), which generally occurs at aged 6 to 12 months, because of the inability of the renal tubules to reabsorb small molecules. In case left untreated, glomerular function progressively deteriorates, and renal failure, which may lead to end-stage renal disease by age 10 years, can develop. The rate of the end-stage renal disease development does, although, vary among patients.
Juvenile nephropathic cystinosis manifests identical renal symptoms, but development is generally much unhurried, with renal function sustained until patients are in their 4’th decade. As the complication does not recur in renal grafts, the choice of therapy in patients with cystinosis is renal transplantation.
Photophobia is one of the most recurring ocular symptoms in patients with cystinosis. Patients present with crystal accumulation affecting the cornea and conjunctiva, but crystals may also be deposited in the iris, ciliary body, choroid and retinal pigment epithelium (RPE), and lens capsule. Deposition of Corneal crystal begins in infancy in the anterior periphery of the cornea, and headway centrally and posteriorly. The crystals, that have a thin, steady needle-shaped design, are diffusely dispensed within the corneal tissues. Retinal pigment epithelium hypopigmented mottling has also been noted in cystinosis patients; this may occur as early as 5 weeks of age, but more typically appears during the 2’nd decade of life. A pigmentary retinopathy may result from accumulated destruction to the retina and also retinal pigment epithelium. The differential diagnosis of photophobia and corneal crystals includes multiple myeloma (MM) and Bietti crystalline corneal dystrophy.
The diagnosis of Cystinosis is performed by measuring the levels of free non-protein cystine within the polymorphonuclear leukocytes. This diagnosis is favoured by slit-lamp examination showing corneal crystals, which usually exist in all affected patients by 16 months of age. Because of the rarity of disease, diagnosis is often delayed and only occurs in some patients who present with end-stage renal disease; this has a remarkable impact on the overall prognosis of the disease. Early diagnosis of cystinosis is therefore imperative in order to ensure successful treatment and improve QoL, as most of its clinical manifestations can be prevented or delayed.
Early Detection Approaches for Ophthalmic Complications of Cystinosis: Because of the enhanced treatment and renal transplantation, patients with cystinosis are now living longer and comparatively are more prone to non-renal complications, such as those affecting the eyes. Aforementioned, early detection and optimised management of these complications helps ensure that patients not only live longer with a better QoL. A variety of early detection approaches are discussed below.
Diagnostic Testing: The early diagnosis is usually performed by a paediatric nephrologist when patients exist with the growth retardation and signs/symptoms of Fanconi syndrome. Advance referral to the ophthalmologist is suggested, as patients will inevitably establish cystine crystals, and their clinical image often offers a strong indication of diagnosis. The ophthalmic evaluation involves recording symptoms, such as photophobia, visual disturbances, ocular surface discomfort and epiphora (watering eyes). Assessment should include visual acuity measurements, careful slit-lamp examination to detect anterior portion crystals, particularly in cornea and conjunctiva, and tonometry.
The Best-corrected visual acuity (BCVA) is evaluated for both distance (6 m) and near (33 cm) through a consistent scale, such as Snellen or LogMAR.
The Slit-lamp examination may often reveal the existence of crystals in young patients with subtle crystal deposition in the cornea, and tonometry is done in order to compute the intraocular pressure using either Goldman tonometry in older co-operative children, or rebound tonometry (e.g. iCare tonometer).
Images of the corneal crystals may be compared against a scale of library images presented by Gahl et al., which shows corneas with CCCS (corneal cystine crystal scores) of 0-3.00, in increments of 0.25.
Self- and Clinician-Assessed Photophobia: Photophobia can be graded with the help of a grading system published by Liang et al. (and previously published for vernal keratoconjunctivitis or other inflammatory ocular surface diseases); the system typically includes both self-assessed and clinician-assessed grading for photophobia. These grades are productive in standardising the approach for detecting cystinosis and monitoring patients.
Anterior Portion of the Eye: Imaging the Cornea
Anterior Segment Optical Coherence Tomography (AS-OCT): AS-OCT is a non-invasive imaging method that provides detailed cross-sectional images in biological systems, using low-coherence interferometry. This approach is now widely available and is commonly considered for imaging the cornea and anterior portion. Corneal pachymetry mapping software can be used to compute the thickness of the corneal. The crystal deposition can also appear in the ciliary body, but this cannot be imaged as precisely with AS-OCT. Anterior Segment Optical Coherence Tomography is well tolerated, as it uses an infrared light source, which is not uncomfortable for patients with cystinosis; although, the machine is expensive, and tissue penetration may be limited because of its inability to visualise through the iris and sclera.
Ultrasound Biomicroscopy (UBM): Ultrasound Biomicroscopy is a non-invasive approach which uses high-frequency ultrasound, usually 35 to 50 MHz, to visualise the anterior portion of the eye in detail. The ultrasound waves have the potential to progress through the iris and ciliary body pigment epithelia, enabling the capture of high-resolution images of the anterior portion, specifically the ciliary body and ciliary processes, which are not otherwise visualised using AS-OCT. Ultrasound Biomicroscopy allows visualisation of both morphological and topographical changes in the anterior chamber angle, but the tolerance can be an issue, as it needs an immersion technique.
In Vivo Confocal Microscopy (IVCM): IVCM uses the concept of a light source that is confocal with the microscope objective lens and is focused onto a plane of the tissue being imaged. It gives absolutely high-resolution images at a defined depth within the cornea, blurring out parts that are distinct from the specific plane being imaged. In Vivo Confocal Microscopy can be used for scanning a tissue part and enabling creation of an image field in a specific tissue plane or depth. IVCM can give deets on the crystal density, corneal nerve damage and inflammatory cell infiltration, and has proved productive for evaluating the efficacy of treatment of topical ocular cystinosis. The tissue components such as cells, nerves, blood vessels and connective tissue may be easily visualised with IVCM; although, the machine is expensive.
Posterior Portion of the Eye: Imaging the Retina
Widefield Retinal Imaging Using Optos Optomap: Widefield retinal imaging provides a 200° view of the retina and combines scanning laser ophthalmoscopy with an ellipsoidal mirror in order to get images of the retinal periphery. This is attained with one capture and does not require bright illumination lighting or a contact lens. Widefield retinal imaging is well tolerated, mainy in children, as it uses scanning laser instead of incandescent light; thus, photosensitivity is not a challenge. Although, one disadvantage of this approach is the obvious distortion and reduced resolution of the far temporal and nasal peripheral retina.
Optical Coherence Tomography (OCT): Optical coherence tomography can be considered to assess the retinal layers integrity, specifically the posterior retina, and also to compute retinal thickness. The crystal deposition within the retinal layers can be evaluated using optical coherence tomography. This technique is also very beneficial in monitoring the disc volume and retinal nerve fibre layer to provide affirmation of progressive optic neuropathy or enlarged intracranial pressure over time.
Spectral-domain or swept-source optical coherence tomography scans (10,000 images/s) allow highly detailed anatomical review of the retinal layers; although, optical coherence tomography is unable to accurately quantify the aggregate of deposits within the retina.
Other Diagnostic Methodologies: There are zillions of other useful methods, including the visual field testing and electroretinography. With advanced age, cystinosis patients show affirmation of increasing loss of visual field, and most have moderate to severe constriction of the visual field towards their later years. Electroretinography (ERG) can be considered to compute attenuated rod- and cone-mediated signals, which denote widespread retinopathy and correlate with the signs/symptoms of nyctalopia and/or visual field loss.
The medications involved in cystinosis therapy are referred to as “orphan medicines”, which means they are approved for rare diseases. They may only be accessed with a valid prescription, and treatment must be initiated under the precise supervision of a health specialist experienced in treating cystinosis. The ophthalmologic complications are treated with the help of cystine-depleting agents and symptomatically. Cysteamine eye drops dissolving cornea crystals relieve ocular patients’ complaints, mainy photophobia unless a band keratopathy, pannus, or scars have developed.
The cysteamine can deplete the cells over 90% of their cystine content. Advance initiation of, and strict adherence to, cysteamine treatment has a long-term prognosis, as it has been demonstrated to retard or prevent the renal deterioration, enhance growth, delay non-renal complications and enhanced patient life expectancy. Cysteamine treatment comes as oral, ophthalmic solution and lubricant gel formulations.
Oral Cysteamine: Oral cysteamine (Cystagon), which was approved by the EMA in the year of 1997, is used on behalf of body surface area; for children aged ≤ 12 years, the recommended dose is 1.30 g/m2 per day of the free base divided 4-times daily. For patients aged > 12 years and > 50 kg weight, the standard dose is 2 g per day, divided 4-times daily. Although oral cysteamine is useful in order to prevent pigmentary retinopathy, it has no effect on the corneal cystine crystals. Topical cysteamine hydrochloride (CH) is therefore used in order to dissolve the cystine crystals. The most commonly reported adverse events for oral cysteamine include diarrhoea, vomiting, nausea, fever, loss of appetite and somnolence.
Topical Cysteamine Eye Drops / Ophthalmic Solution: Cysteamine ophthalmic solution (Cystaran) was approved by the US FDA in the year of 2012. The formulation basically contains 6.5 mg/ml of CH, which is corresponding to 4.4 mg/ml of cysteamine, as the active ingredient. The major drawback of topical cysteamine eye drops is the necessity to use either every waking hour, or 6 to 12 times daily. In addition, the cysteamine oxidises to its disulphide form, cystamine, at room temperature; thus, the formulation needs cold storage in order to ensure stability. The most commonly reported adverse events for topical cysteamine eye drops include redness, sensitivity to light, eye pain and irritation, headache and visual field defects.
Topical Cysteamine Eye Drops: Lubricant (Gel) Formulation: In a strive to lessen the frequency of use, a novel cysteamine-containing gels have been originated. The suitability of these formulations for delivery of cysteamine to the cornea has been evaluated through rheology, bioadhesion, dissolution stability and optical clarity evaluations.
One such CH formulation (Cystadrops) was approved by the EMA in the year of 2017. This formulation contains 5.5 mg/ml of CH, identical to 3.8 mg/ml of cysteamine, as the active pharmaceutical ingredient, with a standard dose of 1- drop to be inserted into each eye 4-times daily. The gel formulation basically contains viscous agent named carboxymethylcellulose sodium, which prolongs the contact of the active pharmaceutical ingredient with the eye, thereby enabling a reduction in frequency of dosing regimen. Prior to opening, the formulation must be refrigerated (2 °C to 8 °C), but following opening, it may be stored at room temperature for up to 1 week.