Autism spectrum disorder: an early and frequent feature in cerebrotendinous xanthomatosis

Abstract

We conclude that ASD is an early and probably underestimated frequent feature in CTX. Metabolic screening for CTX should be performed in patients with ASD when accompanied by diarrhea, intellectual disability, juvenile cataract, and/or neurological involvement. Early recognition allows for earlier initiation of specific treatment and will improve clinical outcome. Our results add CTX to the list of treatable IEMs associated with ASD.

Familial variability of cerebrotendinous xanthomatosis lacking typical biochemical findings

“…Her clinical workup consisted of biochemical testing for CTX which revealed an elevation of the cholestanol precursor 7α,12α‐dihydrocholest‐4‐en3‐one (Table 1) and molecular analysis of the CYP27A1 gene that revealed two pathogenic variants: c.410G > A (p.Arg137Gln) and c.1183C > T (p.Arg395Cys). Both of these variants have been reported previously (Table 2), including some cases with corresponding biochemical data 12‐19 . This patient's imaging has been described previously 20 and is consistent with rare previous reports of spinal xanthomatosis occurring both with 4 and without brain lesions 21 .…”

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

“…Neurologic symptoms are an important clinical hallmark of CTX, are present in many cases at diagnosis, and distinguish CTX from other lipid disorders (e.g., familial hypercholesterolemia; sitosterolemia) (Moghadasian 2004). A broad range of neurologic findings have been reported in patients with CTX, with low intelligence, pyramidal signs (e.g., spasticity, hyperreflexia, extensor plantar responses), cerebellar signs (e.g., ataxia, dysarthria, (Berginer et al 1993); d (Berginer and Abeliovich 1981); e (Verrips et al 1999a); f (Waterreus et al 1987); g (Verrips et al 2000a); h (Berginer et al 1994) (Appadurai et al 2015) nystagmus), and peripheral neuropathy among the most common (Verrips et al 2000c;Pilo-de-la-Fuente et al 2011;Ly et al 2014); others include dementia, psychiatric symptoms, autism, epileptic seizures, and parkinsonism (e.g., spasticity, resting tremors) (Kuriyama et al 1991b;Verrips et al 2000c;Degos et al 2016;Berginer et al 2015;Stelten et al 2017). Symptoms reflecting neurologic dysfunction, such as intellectual disability and gait disturbances, are common presenting symptoms (Pilo-de-la-Fuente et al 2011).…”

“…As the disease progresses, intellectual function continues to deteriorate and frank dementia may be present (Lorincz et al 2005;Berginer et al 2015). Psychiatric manifestations may appear during childhood or adolescence in the form of behavioral/personality disorders, sometimes presenting as autism, and may be associated with learning difficulties (Fraidakis 2013;Ly et al 2014;Stelten et al 2017). Attentional deficits, including attention deficit hyperactivity disorder (ADHD), may be presenting symptoms in young children (Fraidakis 2013;Ly et al 2014).…”

“…Hallmark clinical manifestations of CTX include chronic diarrhea, bilateral cataracts, tendon xanthomas, and neurologic dysfunction (Verrips et al 2000c;Mignarri et al 2014). The progressive disease course is potentially debilitating or fatal, particularly with respect to neurologic presentations that can include intellectual disability, autism, behavioral and psychiatric problems, and dementia, among others (Berginer et al 2015;Stelten et al 2017). We review key aspects of CTX, including its etiology, epidemiology, presentation, diagnosis, treatment, and prognosis, as well as future research directions.…”

Treatment with chenodeoxycholic acid in cerebrotendinous xanthomatosis: clinical, neurophysiological, and quantitative brain structural outcomes

“…We have recently highlighted that diarrhea almost always develops within the first year of life, cataract and school difficulties between 5 and 15 years of age, usually preceding by about a decade of motor or psychiatric symptoms (Degos et al 2016). Although some patients may have autistic features early in the disease course (Stelten et al 2017), there is a critical therapeutic window in most patients with CTX before the onset of disabling neuropsychiatric symptoms (Yahalom et al 2013, Degos et al 2016.…”