Abstract
Development of noninvasive methodology to reproducibly measure tissue cystine crystal load to assess disease status and guide clinical care in cystinosis, an inherited lysosomal storage disorder characterized by widespread cystine crystal accumulation. To develop an unbiased and semi-automated imaging methodology to quantify dermal cystine crystal accumulation in patients to correlate with disease status. 101 participants, 70 patients and 31 healthy controls, were enrolled at the University of California, San Diego, Cystinosis Clinics, Rady Children's Hospital, San Diego and at the annual Cystinosis Research Foundation family conference for an ongoing prospective longitudinal cohort study of cystinosis patients with potential yearly follow-up. Intradermal reflectance confocal microscopy (RCM) imaging, blood collection via standard venipuncture, medical record collection, and occasional skin punch biopsies. The primary outcome was to establish an automated measure of normalized confocal crystal volume (nCCV) for each subject. Secondary analysis examined the association of nCCV with various clinical indicators to assess nCCV's possible predictive potential. Over 2 years, 57 patients diagnosed with cystinosis (median [range] age: 15.1 yrs [0.8, 54]; 41.4% female) were intradermally assessed by RCM to produce 84 image stacks. 27 healthy individuals (38.7 yrs [10, 85]; 53.1% female) were also imaged providing 37 control image stacks. Automated 2D crystal area quantification revealed that patients had significantly elevated crystal accumulation within the superficial dermis. 3D volumetric analysis of this region was significantly higher in patients compared to healthy controls (mean [SD]: 1934.0 μm3 [1169.1] for patients vs. 363.1 μm3 [194.3] for controls, P<0.001). Medical outcome data was collected from 43 patients with infantile cystinosis (media [range] age: 11 yrs [0.8, 54]; 51% female). nCCV was positively associated with hypothyroidism (OR = 19.68, 95% CI: [1.60, 242.46], P = 0.02) and stage of chronic kidney disease (slope estimate = 0.53, 95%CI: [0.05, 1.00], P = 0.03). This study used non-invasive RCM imaging to develop an intradermal cystine crystal quantification method. Results showed that cystinosis patients had increased nCCV compared to healthy controls. Level of patient nCCV correlated with several clinical outcomes suggesting nCCV may be used as a potential new biomarker for cystinosis to monitor long-term disease control and medication compliance.
Highlights
Cystinosis is an autosomal recessive lysosomal storage disorder (LSD) with a prevalence of 1:100,000 live births [1]
Medical outcome data was collected from 43 patients with infantile cystinosis. normalized confocal crystal volume (nCCV) was positively associated with hypothyroidism (OR = 19.68, 95% CI: [1.60, 242.46], P = 0.02) and stage of chronic kidney disease
Results showed that cystinosis patients had increased nCCV compared to healthy controls
Summary
Cystinosis is an autosomal recessive lysosomal storage disorder (LSD) with a prevalence of 1:100,000 live births [1]. It is characterized by the accumulation of cystine within lysosomes leading to the build-up of crystallized cystine, which is pathognomonic of cystinosis [2, 3]. The most frequent and severe clinical manifestation of cystinosis is the infantile form that initially presents with renal Fanconi syndrome within the first year of life [6, 7]. Accumulation of soluble cystine and cystine crystals throughout the body progressively causes multiorgan dysfunction such as hypothyroidism, photophobia, neuromuscular disease, and diabetes, leading to lethality [2, 9]. Long-term compliance is difficult due to frequent daily dosing, as well as significant side effects including gastrointestinal discomfort, halitosis and body odor [10, 11]
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