CYSTINOSIS
Cystinosis is
a multisystemic, autosomal recessive disorder of lysosomal transport that
results in intracellular accumulation of the amino acid cystine, which leads to
cellular dysfunction and death. The incidence of this disease is estimated at 1
per 100,000 to 200,000 live births, and it occurs in all ethnic groups.
There are three forms of cystinosis. The most severe
is nephropathic (infantile) cystinosis (NC), which accounts for 95% of cases.
Intermediate (juvenile) cystinosis has a later onset of renal complications,
whereas ocular (non-nephropathic) cystinosis generally causes only corneal
crystals.
NC first presents in early infancy with generalized
renal proximal tubular dysfunction. Untreated, it progresses to chronic kidney
disease in the first decade of life. In the past, an affected child’s lifespan
was limited to 10 years; however, with the emergence of kidney transplantation
and effective medical treatment (including cystine-depleting agents), patients
can now expect a reasonably normal quality of life for several decades.
PATHOPHYSIOLOGY
Patients with cystinosis have mutations in the CTNS
gene, located on chromosome 17p13. This gene encodes cystinosin, a lysosomal
membrane transport protein that contains 367 amino acids and 7 transmembrane
domains. CTNS mutations account for all types of cystinosis, and more
severe mutations are associated with the NC form. Approximately 100 different CTNS
mutations have been identified; the most common is a 57,257 base pair
deletion, which is present in the homozygous or heterozygous state in about 76%
of NC patients of northern European origin.
Functional cystinosin deficiency causes impaired efflux
of cystine from lysosomes to the cytoplasm, where it is normally further
processed and then reused. As a result, cystine accumulates in lysosomes,
forming crystals that are poorly soluble and hexagonal, rectangular, or
needle-shaped. Cystine crystals are thought to induce cellular apoptosis, which
leads to dysfunction in multiple organ systems.
The most prominent defect occurs in the kidneys, where
proximal tubular dysfunction leads to impaired reabsorption of electrolytes,
water, amino acids, glucose, bicarbonate, and other molecules, a phenomenon
known as the renal Fanconi syndrome (FS). The cellular mechanism of renal FS in
this instance, however, is not well understood. Tubular and interstitial
cystine accumulation may impede the normal transport and cotransport of small
molecules in tubular cells; however, recent studies indicate that lysosomal
cystine accumulation disrupts the interaction of lysosomes and mitochondria
needed for normal apoptotic and autophagic processes. The result is adenosine
triphosphate (ATP) deficiency, which leads to intracellular energy depletion,
oxidative stress, and inexorable deterioration of renal cell function.
PRESENTATION AND DIGANOSIS
The typical child with cystinosis appears normal at
birth and then presents between 6 and 12 months of age as a small, listless
infant. Early diagnosis is critical so that life-saving treatment may be
rapidly instituted. The most striking features are usually referable to the presence of renal FS, which causes polyuria, proximal renal tubular acidosis (see Plate 3-25), and wasting
of electrolytes, glucose, amino acids, carnitine, and tubular proteins. The
profound homeostatic abnormalities that result can cause failure to thrive,
cardiac dysfunction, muscle hypotonia, and hypophosphatemic rickets. In some
patients who present later in infancy, one of these sequelae may be the
presenting complaint.
Any patient found to have renal FS should undergo slit
lamp examination because corneal cystine crystal accumulation occurs in all
patients by 16 months of age. The presence of both renal FS and corneal
crystals is diagnostic of NC. The clinical diagnosis can be confirmed by
measuring cystine concentrations in polymorphonuclear leukocytes using mass
spectroscopy or the cystine
binding protein assay. Targeted testing for a panel of CTNS mutations,
including the most common 57-kb deletion, is also available.
If corneal crystals are not seen, other inherited or
acquired causes of renal FS should be investigated, such as heavy metal
poisoning, adverse medication effect, multiple myeloma, hereditary fructose
intolerance, galactosemia, Dent disease, and Lowe disease.
Prenatal diagnosis can be performed if there is a
family history of cystinosis. Elevated cystine concentrations may be noted in
the placenta, cultured skin fibroblasts, amniocytes, and chorionic villus cells.
Because of dramatic improvements in the average
lifespan of an affected patient, several additional sequelae of this disorder are becoming better appreciated. Some of the
many manifestations, grouped by organ system, include:
Renal Disease. In addition to
renal FS, patients develop medullary nephrocalcinosis (secondary to
phosphaturia and calciuria) and renal insufficiency that eventually leads to
end-stage renal failure. In untreated patients, renal insufficiency becomes
apparent by 5 years of age.
Ocular Disease. As corneal
crystal accumulation becomes severe, it may cause photophobia and
blepharospasm. Visual loss may occur if the retina is involved.
Endocrine
Disease. Patients often develop hypothyroidism late in the first decade
of life. Males develop primary testicular hypogonadism that leads to delayed
puberty and infertility, while females have spared ovarian and reproductive
functions. A subset of patients may develop pancreatic insufficiency, with
resulting failure of endocrine function (leading to type 1 diabetes mellitus)
and/or exocrine function (leading to intestinal malabsorption).
Muscle Disease. Patients
develop myopathies later in life that begin as distal muscle weakness and
atrophy, then progress to involve the oropharyngeal muscles, causing dysphagia,
malnutrition, and risk of aspiration. Thoracic muscle weakness can cause
restrictive pulmonary disease.
Cardiovascular Disease. Vascular calcification may occur, including in the coronary arteries.
Gastrointestinal Disease. Patients may develop hepatic nodular regenerative hyperplasia, leading
to hepatomegaly and portal hypertension. Inflammatory bowel disease and bowel
perforation have been noted in some patients.
Central Nervous System Disease. Cerebral atrophy, calcifications of the basal ganglia, and benign
intracranial hypertension (causing headaches and papilledema) may be seen.
Cognitive abilities are in the low-normal range in most patients, but specific
neurologic and neurobehavioral issues are characteristic, including visual
memory defects.
Hematologic Disease. Although cystine accumulates in bone marrow, hematopoietic function
generally remains stable. Anemia may nonetheless occur, however, as chronic
kidney disease becomes more advanced.
TREATMENT
The treatment of cystinosis can be divided into
symptomatic and pathophysiologic management.
Symptomatic management addresses the numerous complications of cystine accumulation in
different organ systems. The major early complication is renal FS, as described
previously, which must be treated with replacement of wasted fluids,
electrolytes (including potassium, phosphate, and bicarbonate), vitamin D, and
carnitine.
To address the many additional complications listed
previously, follow-up care should include measurement of serum creatinine
concentration, thyroid panels, insulin levels, lipid panels, testosterone, and
sex hormone levels; glucose tolerance tests; electromyography; barium swallow
studies; computed tomography of the brain and chest (for detecting calcification
of cerebral and other major vessels); renal ultrasonography (to assess for
nephrocalcinosis); and pulmonary function tests.
As renal disease progresses, renal replacement therapy
is commonly required. Transplantation of both living donor and cadaveric
kidneys has led to excellent out-comes, with no recurrence of renal FS in the
donor kidney. Pathophysiologic management, meanwhile, involves
the use of cystine-depleting agents to actually slow disease progression.
Cysteamine, an aminothiol, reacts with cystine to form cystine-cysteamine mixed
disulfide and cysteine, which exit the lysosome via lysine and cysteine
transporters, respectively. As a result, cysteamine depletes intracellular
cystine levels by 90%. Oral cysteamine is indicated for all patients,
independent of age and transplantation status. Meanwhile, topical cysteamine
eye drops can also dissolve corneal crystals and ameliorate the photophobia of
cystinosis within a few weeks. Regular measurement of the leukocyte cystine level documents the
efficacy of treatment.
PROGNOSIS
The use of cystine-depleting therapy has
revolutionized the prognosis of NC. With prompt and compliant cysteamine
treatment, many children do not develop renal failure until their second or
third decade of life. The severity of the various complications depends largely
on genetic heterogeneity and compliance with medical therapy. Most
complications are preventable and possibly even reversible with optimal
treatment. Newborn screening for early diagnosis will further advance the treatment of cystinosis.
