Neuropsychological and neuroanatomical phenotype in 17 patients with cystinosis

Abstract

Background: Cystinosis is a rare autosomal recessive disorder caused by intracellular cystine accumulation. Proximal tubulopathy (Fanconi syndrome) is one of the first signs, leading to end-stage renal disease between the age of 12 and 16. Other symptoms occur later and encompass endocrinopathies, distal myopathy and deterioration of the central nervous system. Treatment with cysteamine if started early can delay the progression of the disease. Little is known about the neurological impairment which occurs later. The goal of the present study was to find a possible neuroanatomical dysmorphic pattern that could help to explain the cognitive profile of cystinosis patients. We also performed a detailed review of the literature on neurocognitive complications associated with cystinosis. Methods: 17 patients (mean age = 17.6 years, [5.4-33.3]) with cystinosis were included in the study. Neuropsychological assessment was performed including intelligence (Intelligence Quotient (IQ) with Wechsler's scale), memory (Children Memory Scale and Wechsler Memory Scale), visuo-spatial (Rey's figure test) and visuoperceptual skills assessments. Structural brain MRI (3 T) was also performed in 16 out of 17 patients, with high resolution 3D T1-weighted, 3D FLAIR and spectroscopy sequences. Results: Intellectual efficiency was normal in patients with cystinosis (mean Total IQ = 93). However the Perceptual Reasoning Index (mean = 87, [63-109]) was significantly lower than the Verbal Comprehension Index (mean = 100, [59-138], p = 0.003). Memory assessment showed no difference between visual and verbal memory. But the working memory was significantly impaired in comparison with the general memory skills (p = 0.003). Visuospatial skills assessment revealed copy and reproduction scores below the 50th percentile rank in more than 70% of the patients. Brain MRI showed cortical and sub-cortical cerebral atrophy, especially in the parieto-occipital region and FLAIR hypersignals in parietal, occipital and brain stem/cerebellum. Patients with atrophic brain had lower Total IQ scores compared to non-atrophic cystinosis patients. Conclusions: Patients with cystinosis have a specific neuropsychological and neuroanatomical profile. We suggest performing a systematic neuropsychological assessment in such children aiming at considering adequate management.

Assessing the integrity of auditory processing and sensory memory in adults with cystinosis (CTNS gene mutations)

“…An active oddball paradigm, for instance, would allow one to measure deviant detection rate and test whether those with increased P2 amplitudes are more or less accurate in detecting the deviant tones. Behaviorally, in standardized tasks and during behavioral observations, children and adolescents with cystinosis appear to present some level of impairment in the domain of attention (52)(53)(54), but no study has yet focused on this process during adulthood. Thorough behavioral and electrophysiological investigations of voluntary and involuntary attention in this population are thus warranted.…”

Central Nervous System Complications in Cystinosis: The Role of Neuroimaging

“…Indeed, specific impairments in the processing of visual information, as well as relative weakness in visual motor, visual spatial, and visual memory skills have been described, which may be associated with learning difficulties, primarily in arithmetic. Significant difficulties are observed in executive-function-related abilities [ 12 , 31 , 32 , 33 , 34 , 35 ]. A fine-motor coordination deficit in children and adolescents with cystinosis has also been documented [ 11 ].…”

“…In addition, abnormalities seem to increase with age, which may reflect a progressive cognitive impairment, possibly as a result of cystine accumulation in the brain over time [ 30 ]. Impaired working memory has also been described, with visual memory being more impaired than auditory memory in one study [ 35 , 36 ].…”

“…Interestingly, there is a significant correlation between the total intelligence quotient (IQ) and the age at cysteamine treatment start: the sooner cysteamine is started, the less the IQ is impacted [ 35 ]. Of note, all cystinosis patients from the mentioned study who started cysteamine before 2 y of age had an IQ within the normal range, which is in accordance with another study showing that cystinosis patients treated before 2 y of age had a better outcome [ 12 ].…”

“…Importantly, such atrophy was specifically observed in cystinosis patients, and not in controls with nephropathy. In another study, also including younger patients, cystinosis patients presented significantly more atrophy than age- and sex-matched healthy controls in the frontal, parietal, temporal, and occipital regions, the corpus callosum, and the cerebellum [ 35 ]. It is worth noticing that atrophy was localized in parieto-occipital regions, which is consistent with the visuo-spatial-specific impairment described in these patients.…”