PracticeUpdate Neurology February 2019

EDITOR’S PICKS 16

Treatment Effect in Cerebrotendinous Xanthomatosis Depends on Age at Start of Treatment Neurology

Take-home message • The authors describe a large cohort of patients with cerebrotendinous xanthoma- tosis (CTX) and assess the different responses to therapy by age and timing of therapy. The mean age at diagnosis was 25.6 years, and the authors estimate that correctly applying the suspicion index would have allowed an earlier diagnosis by approximately 8 years. All patients were treated with chenodeoxycholic acid after diagnosis, with doses ranging from 5 to 15 mg/kg/d in children <16 years of age and up to 750 mg/d in adults. There was a significant difference in response to therapy in patients who initiated treatment before age 24 compared with those who did so after age 24. With good treatment adherence, neurologic symptoms disappeared in all patients treated before age 24 years, and no new symptoms developed. However, deterioration was seen in 61% of patients diagnosed and treated after age 24 years. • The results serve as an important reminder of the need for early diagnosis and therapy in CTX. Treatment appears to be effective when started early. Codrin Lungu MD

Abstract OBJECTIVE To evaluate the effect of chenodeoxy- cholic acid treatment on disease progression in cerebrotendinous xanthomatosis (CTX). METHODS In this retrospective cohort study, we report the clinical long-term follow-up charac- teristics of 56 Dutch patients with CTX. Age at diagnosis was correlated with clinical charac- teristics and with the course of modified Rankin Scale (mRS) and Expanded Disability Status Scale (EDSS) scores at follow-up. RESULTS Median follow-up time was 8 years (6 months-31.5 years). Patients diagnosed and treated before the age of 24 years had a sig- nificantly better outcome at follow-up. When considering only patients with a good treat- ment adherence (n = 43), neurologic symptoms, if present, disappeared in all patients who were diagnosed before the age of 24 and treated since. Furthermore, treatment prevented the development of new neurologic symptoms dur- ing follow-up. In contrast, 61% of the patients diagnosed and treated after the age of 24 showed deterioration of the neurologic symp- toms, with parkinsonism as a treatment-resistant feature. There was an improvement or stabiliza- tion in favor of patients diagnosed and treated before the age of 24 compared to those treated after the age of 24: 100% vs 58% for mRS scores and 100% vs 50% for EDSS scores, respectively. " …a tremendous effort such as newborn screening program should be considered to achieve early diagnosis and treatment

COMMENT By Shuke Nie MD, PhD W e read with great interest the recent article report by Stelten et al on the long-term treatment effect of chenodeoxycholic acid (CDCA) in cerebrotendinous xanthomatosis (CTX). CTX is a rare, autosomal-recessive, lipid storage disease caused by muta- tions in the CYP27A1 gene, and, currently, CDCA is the only effective therapy that can treat the neurological and non-neu- rological symptoms of CTX. 1 Patients with CTX have an average age of 35 years at diagnosis and a diagnostic delay of 16 years; therefore, an early diagnosis could contribute to a better prognosis. The mean age at diagnosis in Stelten and colleagues’ study is 17.3 years, and the substantial mean diagnostic delay is 8 years. It is noteworthy that they found that the deterioration with this disease was seen only in patients diagnosed and treated after the age of 24. The authors’ results further confirmed that patients diagnosed and treated earlier would have a significantly better out- come. Based on the above findings, a tremendous effort such as newborn screening program should be considered to achieve early diagnosis and treatment for the populations with familial history

and suspicious clinical symptom and signs (for example, diarrhea and cataract most commonly appear during infancy and early childhood). Overall, 50% of mutations in CYP27A1 have been found in exons 6–8; how- ever, no genotype correlations have been identified. In this study, c.1016C>T (p.Thr339Met) in exon 5 and c.1183C>T (p.Arg395Cys) in exon 6 accounted for almost half of the alleles in CTX, which indicated that these two mutations might be involved in the pathogenesis of CTX and need to be identified in animal models and basic research. Lastly, we commend the authors for their thought- ful and comprehensive approach to addressing the importance of early diag- nosis and treatment in patients with CTX. Reference 1. Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of patho- genesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:179. Dr. Nie is a Postdoc Fellow in the Department of Pathology at Johns Hopkins University School of Medicine in Baltimore, Maryland, and Attending Doctor in the Department of Neurology at Renmin Hospital of Wuhan University in Hubei, China.

for the populations with familial history and suspicious clinical symptom and signs… "

CONCLUSIONS Treatment start at an early age can reverse and even prevent the development of neurologic symptoms in CTX. This study empha- sizes the importance of early diagnosis in CTX and provides a rationale to include CTX in new- born screening programs. Long-Term Treatment Effect in Cerebrotendi- nous Xanthomatosis Depends on Age at Treatment Start. Neurology 2019 Jan 08;92(2) e83-e95, BML Stelten, HH Huidekoper, BPC van de Warrenburg, et al. www.practiceupdate.com/c/78392

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