Information Theory Analysis of CTX Shows Consistent Clinical Presentation.

Cerebrotendinous xanthomatosis (CTX) is a rare, metabolic disorder caused by pathogenic variants in CYP27A1. The classic clinical presentation includes infantile-onset chronic diarrhea, juvenile-onset bilateral cataracts, with development of tendon xanthomas and progressive neurological dysfunction. These multisystem clinical features typically appear in different decades of life often confounding diagnosis of CTX. Further complicating diagnosis is the generally held belief that the clinical presentation of CTX varies highly between individuals and even within families. We applied information theory analyses to CTX patient data to quantitatively assess clinical variability in CTX. We conducted a systematic review of the literature to identify all CTX families reported with CYP27A1 genotype (N = 218). Information theory analyses of subject data across 12 clinical features of CTX showed a remarkably consistent clinical presentation within families, with just four out of 83 families demonstrating notable phenotypic variability. Further analysis of subjects with two pathogenic missense variants versus two loss of function variants showed higher clinical burden in loss-of-function group (p = 0.0001). We surmise that the multi-system, progressive nature of CTX developing across decades leads to variable characterizations of the disease and that standardization of terms and comparison of clinical features within age decade reveals a more consistent clinical presentation. The identification of the common, consistent features of CTX may be useful for screening and diagnosis of this treatable disorder. This study illustrates that information theory analyses can be leveraged to detect clinically relevant information even in the absence of large-scale datasets, such as is often the case for rare disease.