Objective:

To present a man with cystinosis-related cerebral lesions including a literature review focused on longitudinal clinical, imaging and pathology data.

Background:

Cystinosis is caused by CTNS mutations leading to autophagy-lysosomal pathway impairment and cystine crystals accumulation. Neurologic involvement is variable and includes both neurodevelopmental and neurodegenerative disturbances, as well as focal neurologic deficits. Compliance to depleting therapy with cysteamine still represents the main treatment option.

Design/Methods:

We selected studies describing clinical, imaging, and pathological features of patients with cystinosis-related cerebral lesions between 1979 and 2023. Inclusion criteria were one morphological (neuroimaging/neuropathology data) and one clinical criterion (slowly progressive vs acute/subacute neurologic symptoms). Other variables encompassed age, sex, onset of neurologic symptoms, age at cystinosis diagnosis, disease duration since kidney transplantation, age at kidney transplantation, years of cysteamine therapy, lesion topography, presence of epilepsy and lesion load.

Results:

Eleven cystinosis patients (mean age 24.1 years, male 78.8%) were included. Seven out of 11 patients presented with acute/subacute focal neurological deficits, whereas 4/11 showed a slowly progressive neurological deterioration. Five out of 10 patients had epilepsy. Brain lesions variably showed crystals, inflammation, necrosis and calcification. Furthermore, our patient showed new evidence of 4-repeat-tauopathy and increased serum neurofilament light chains (NfL). Lesion load positively correlated with age of neurological symptoms onset. Two patients showed improvement after steroid therapy. Two patients remained stable at follow-up under cysteamine treatment. The other patients (7/10) encountered neurologic deterioration and death.

Conclusions:

Cystinosis-related cerebral lesions occur in advanced disease phases and variably show accumulation of crystals, vasculitis-like features, necrosis, and calcification. Epilepsy is a frequent comorbidity. Steroids might play a role in the symptomatic treatment of edematous-inflammatory lesions. New evidence of 4R-tauopathy might suggest concurrent neurodegeneration shedding light on the crosstalk between proteinopathies and autophagy-lysosomal system defects. Biomarkers (e.g. NfL) might influence in future the management of (sub)clinical neurologic involvement in cystinosis.