The spectrum of magnetic resonance findings in cerebrotendinous xanthomatosis: redefinition and evidence of new markers of disease progression

Abstract

Cerebrotendinous xanthomatosis (CTX) is a metabolic disease characterized by systemic signs and neurological impairment, which can be prevented if chenodeoxycholic acid (CDCA) treatment is started early. Despite brain MRI represents an essential diagnostic tool, the spectrum of findings is worth to be reappraised, and follow-up data are needed. We performed clinical evaluation and brain MRI in 38 CTX patients. Sixteen of them who were untreated at baseline examination underwent clinical and MRI follow-up after long-term treatment with CDCA. Brain MRI abnormalities included cortical and cerebellar atrophy, and T2W/FLAIR hyperintensity involving subcortical, periventricular, and cerebellar white matter, the brainstem and the dentate nuclei. Regarding the dentate nuclei, we also observed T1W/FLAIR hypointensity consistent with cerebellar vacuolation and T1W/FLAIR/SW hypointense alterations compatibly with calcification in a subgroup of patients. Long-term follow-up showed that clinical and neuroradiological stability or progression were almost invariably associated. In patients with cerebellar vacuolation at baseline, a worsening over time was observed, while subjects lacking vacuoles were clinically and neuroradiologically stable at follow-up. The brains of CTX patients very often show both supratentorial and infratentorial abnormalities at MRI, the latter being related to clinical disability and including a wide spectrum of dentate nuclei alterations. The presence of cerebellar vacuolation may be regarded as a useful biomarker of disease progression and unsatisfactory response to therapy. On the other hand, the absence of dentate nuclei signal alteration should be considered an indicator of better prognosis.

Patients with Lately Diagnosed Cerebrotendinous Xanthomatosis

“…The study showed that the development of vacuoles was neither related to age nor to the extent of dentate nucleus hyperintensity. Cerebellar vacuolation was correlated to disability expressed by Rankin (RS) and Expanded Disability Status Scale (EDSS) and strongly to ataxia [15]. Accordingly, in our cohort, cases 1, 2, 6, and 7, who clinically had severe disability, showed marked vacuolation in cerebellar white matter.…”

“…Mignarri et al [15] suggested that cerebellar vacuolation with hypointensity in T2 and FLAIR images may be regarded as a biomarker of disease progression and unsatisfactory response to therapy. Besides, the absence of dentate nucleus signal alterations should be considered as an indicator of a better prognosis [15]. The study showed that the development of vacuoles was neither related to age nor to the extent of dentate nucleus hyperintensity.…”

“…Molecular genetic analysis provides definitive confirmation of CTX [2,13]. Neuroimaging of the brain reveals cerebellar atrophy and hyperintense lesions of the dentate nucleus and cerebellar white matter [9,14,15]. Since the diagnosis is often delayed due to heterogeneous manifestations and early-stage replacement therapy, chenodeoxycholic acid (CDCA) might suppress clinical deterioration, including neurological manifestations, and a diagnostic tool called "Mignarri suspicion index" has been developed [7,[16][17][18], which facilitates early diagnosis and helps with long-term treatment.…”

Movement Disorders in Treatable Inborn Errors of Metabolism

“…The average diagnostic delay for CTX is estimated to 15 to 20 years, highlighting the need to improve clinical recognition . Brain MRI shows cortical and cerebellar atrophy, white matter signal alterations, and symmetric hyperintensities in the dentate nuclei . Plasma cholestanol levels are elevated and, together with low levels of bile alcohols in plasma or urine, are usually diagnostic.…”

“…108 Brain MRI shows cortical and cerebellar atrophy, white matter signal alterations, and symmetric hyperintensities in the dentate nuclei. 109 Plasma cholestanol levels are elevated and, together with low levels of bile alcohols in plasma or urine, are usually diagnostic. Confirmation is obtained by sequencing of CYP27A1.…”