Nephropathic Cystinosis and Feeding Problems
Nephropathic cystinosis is a genetic disorder in which the amino acid cystine accumulates in lysosomes, resulting in multiorgan dysfunction. Progressive neuromuscular dysfunction, with bulbar and upper extremity weakness, has been described in adults with this disorder. There was evidence of early bulbar involvement, suggested by feeding difficulties or oral motor dysfunction in these patients, and whether the feeding and oral motor problems were associated with other evidence of neurologic dysfunction. The majority of children had a history of feeding difficulties.
Some children required a gastrostomy tube. Abnormalities on oral motor examination included hypotonia, abnormal gag reflex, and throaty or congested voice. Abnormalities on neurologic examination included hypotonia, muscle weakness, gross and fine motor dysfunction, and ataxia. Feeding difficulties and oral motor dysfunction are common in children with cystinosis and appear to correlate with the general degree of neurologic dysfunction. Long-term follow-up is necessary to determine whether the early oral motor problems predict the later development of the progressive myopathy observed in adults with cystinosis.
Cystinosis is an inherited condition in which the body accumulates the amino acid cystine (a building block of proteins) within the cells. Excess cystine forms crystals that can build up and damage cells. These crystals can negatively affect many systems in the body, especially the kidneys and eyes. There are three distinct types of cystinosis: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. All three types of cystinosis are caused by mutations in the CTNS gene and inherited in an autosomal recessive pattern.
Cystinosis is an autosomal recessive disorder characterised by lysosomal cystine accumulation due to mutations in the CTNS gene encoding the lysosomal cystine transporter cystinosin. Cystinosis is the most frequent cause of inherited Fanconi syndrome in children, which usually manifests during the first year of life and progresses towards end-stage renal failure before 10 years of age. The development of renal replacement therapy allowed cystinotic patients to survive into adulthood, consequently changing the mainly renal disorder into a multisystemic disease.
Treatment with the cystine-depleting agent cysteamine (Cystagon™) postpones the deterioration of renal function and reduces extra-renal organ damage, and therefore should be continued even after renal transplantation. The diagnosis of cystinosis is based on the detection of elevated intracellular cystine content in white blood cells and is confirmed by molecular analysis of the CTNS gene.
Cystinosis is an autosomal recessive disorder caused by genetic defects in the lysosomal cystine carrier cystinosin leading to cystine accumulation in the lysosomes. Cystinosis is the most common cause of inherited generalised proximal tubulopathy, known as de Toni-Debré-Fanconi syndrome (renal Fanconi syndrome). Three clinical forms of cystinosis with varying severity and age at onset are distinguished: the most frequent and most severe infantile form (MIM 219800), the intermediate late-onset or juvenile form (MIM219900) and benign ocular cystinosis (MIM219750). The estimated incidence of cystinosis is one in 100,000–200,000 live births.
Lysosomal cystine accumulation due to the impairment of cystine transport across the lysosomal membrane is the hallmark of cystinosis. After the identification of CTNS as the mutated gene in cystinosis, it was confirmed that cystinosin is localised in the lysosomal membrane, functioning as cystine efflux transporter.Several mutations have been reported throughout the 12 exons of the CTNS gene, of which a 57kb deletion is the most common mutation found in the Northern European population.This deletion includes the flanking CARKL gene, which is involved in the phosphorylation of sedoheptulose, an intermediate of the pentose phosphate pathway.
Treatment with the cystine-depleting agent cysteamine and the availability of renal transplantation improved the prognosis of cystinotic patients, allowing them to survive into adulthood. However, administration of the amino thiol cysteamine does not reverse renal Fanconi syndrome, but rather retards the progression of renal disease. The complications of cystine accumulation in extra-renal organs became more evident in adolescent and adult patients, emphasising the need for cysteamine treatment posttransplantation.Nephropathic cystinosis cannot be cured: although the possibility of gene therapy is promising, it is still far from being used in clinical practice.
The pathogenesis of cystinosis remains obscure. Several hypotheses based on in vitro studies have been postulated. First, alterations in adenosine triphosphate (ATP) metabolism that may cause renal Fanconi syndrome have been described. Second, enhanced apoptosis has been suggested to account for the multisystemic nature of cystinosis.15 Finally, increased oxidative stress and altered glutathione metabolism have repeatedly been suggested to be involved in the pathogenesis of cystinosis. How these processes are linked to cystine accumulation in the lysosomes remains to be elucidated.
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