Neurocognitive Complications of Cystinosis.

Until effective treatments for the renal complications of nephropathic cystinosis became available, cystinosis was not thought to affect the brain. Any neurologic problems reported in patients with cystinosis were attributed to the chronic renal disease and associated metabolic derangements, or to treatments such as steroids and other immunosuppressant agents. Since the successful advent of renal transplantation, individuals with cystinosis have been living well into adult life. Over the past 20 years, treatment with cysteamine has been widely available and has been shown to effectively clear cystine from cells and allow for maintenance of renal function for many years before renal transplantation is needed. As children have been living longer and healthier lives, other organ involvement (including brain and muscle) have been identified. There are several potential neurologic complications found in patients with cystinosis (Table). These include cognitive dysfunction, particularly in visual spatial and visual memory domains; structural brain differences, particularly changes in white matter volume and integrity; motor incoordination; difficulties with academic function; neuromuscular problems; seizures; idiopathic intracranial hypertension (pseudotumor cerebri with increased intracranial pressure); Chiari I malformation; memory impairment; and progressive myopathy. One of the earliest and most common areas of neurologic dysfunction in cystinosis is that of neurocognitive differences A specific cognitive profile has been described in individuals with nephropathic cystinosis. This consists of a background of normal intelligence, language, and visual perceptual functions but difficulty with visual spatial skills, visual memory, visual motor coordination, and attention (Figures 1-3). In addition, many children with cystinosis experience academic difficulties especially in math and spelling, which have been attributed to the deficits in visual spatial/visual memory skills. Visual spatial and memory deficits can be demonstrated with a number of cognitive tasks, but results are remarkably consistent across tasks, across ages, and across treatments. Differences in brain structural development have also been found in children with cystinosis, and many of these changes correlate with performance on visual spatial tasks. Children with cystinosis have evidence of volume loss in the brain, with enlarged ventricles, and reduced volume of both cerebral cortex and cerebral white matter (Figure 4). More specifically, there are delays in the maturation of white matter fiber tracts in areas of the brain associated with visual spatial and visual memory functions. We have found reduced thickness of parietal lobe structures and delayed myelination in the parietal lobes of children with cystinosis compared with age-matched controls. Furthermore, these structural changes correlate with performance on visual spatial tasks (Figure 5), indicating a relationship between brain structure and function in this condition. These findings are present in young children with cystinosis who have been treated early with cysteamine, suggesting that the cognitive and structural differences are not merely due to cystine accumulation in the brain but perhaps to an early effect of the genetic mutation on brain development. The most compelling evidence for a direct effect of the cystinosin gene on brain function is based on studies of carriers of the gene, who do not exhibit any symptoms of cystinosis. Heterozygous carriers have normal renal function and never develop renal or other systemic manifestations of the disease. However, otherwise asymptomatic carriers of the gene demonstrate the same cognitive deficits as do homozygous individuals with cystinosis. Asymptomatic parents of children with cystinosis are obligate heterozygotes. These parents demonstrate similar difficulties with visual spatial, visual memory, and visual motor tasks as do their homozygous children (Figures 6 and 7). Thus, it is unlikely that the neurocognitive deficits are secondary to the renal disease or treatments. Further, there is evidence that brain structure is altered in cystinosis, even in young children, supporting the idea that the brain develops differently in the face of the genetic mutation. Treatment with cysteamine has been shown to have a striking effect on renal function. When children are treated from a young age, renal function can be preserved into the third decade of life. Some other manifestations of cystinosis, such as thyroid dysfunction, may also be delayed or prevented with cysteamine therapy. In the case of the brain, however, there are indications that the neurocognitive changes are present from early life and may not be affected to any notable extent by early treatment. For example, visual motor coordination is no better in children treated before 2 years of age from that of children treated later in childhood. Also, unlike other organs, it appears that the brain of the child with cystinosis develops differently from that of children without cystinosis. Specific structural and functional differences suggest an early influence of the gene on brain development. These cannot be explained merely by renal dysfunction, cystine accumulation, or medical treatments because similar changes are present in asymptomatic carriers of the cystinosis gene. Even very early treatment From the Departments of Neurosciences and Pediatrics, University of California, San Diego School of Medicine, La Jolla CA