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Open Access 01-12-2022 | Spastic Paraplegia | Case report

Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report

Authors: Shingo Koyama, Yuma Okabe, Yuya Suzuki, Ryosuke Igari, Hiroyasu Sato, Chifumi Iseki, Kazuyo Tanji, Kyoko Suzuki, Yasuyuki Ohta

Published in: BMC Neurology | Issue 1/2022

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Abstract

Background

Cerebrotendinous xanthomatosis (CTX) is an autosomal-recessive lipid storage disorder caused by mutations in the CYP27A1 gene encoding the key enzyme in the bile acid synthesis, sterol 27-hydroxylase. Here, we report two Japanese CTX siblings with a novel compound heterozygous CYP27A1 mutation, showing different clinical phenotypes and responses to chenodeoxycholic acid (CDCA) therapy.

Case presentation

The proband, a 32-year-old man, who had chronic diarrhea, bilateral cataracts, and xanthomas, demonstrated progressive neurological manifestations including ataxia, and spastic paraplegia during a 5-year follow-up period despite normalization of serum cholestanol after initiation of CDCA treatment. He also exhibited cognitive decline although improvement had been observed at the beginning of treatment. Follow-up brain magnetic resonance imaging (MRI) revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives on T2-weighted images. In contrast, the two-year-younger sister of the proband presented with chronic diarrhea, cataracts, xanthomas, and intellectual disability but no other neurological symptoms at the time of diagnosis. CDCA treatment lead to improvement of cognitive function and there were no characteristic CTX-related MRI features during the follow-up period. The siblings shared a paternally inherited c.1420C > T mutation (p.Arg474Trp) and a maternally inherited novel c.1176_1177delGA mutation, predicting p.(Glu392Asp*20).

Conclusions

Our cases suggest that early diagnosis and subsequent initiation of CDCA treatment are crucial before the appearance of characteristic MRI findings and severe neurological manifestations related to CTX. Further studies are required to elucidate mechanisms responsible for the clinical diversity of CTX and prognostic factors for long-term outcomes following initiation of CDCA treatment.
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Literature
1.
go back to reference Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem. 1991;266:7779–83.CrossRef Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem. 1991;266:7779–83.CrossRef
2.
go back to reference Verrips A, Hoefsloot LH, Steenbergen GC, Theelen JP, Wevers RA, Gabreëls FJ, et al. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain. 2000;123:908–19.CrossRef Verrips A, Hoefsloot LH, Steenbergen GC, Theelen JP, Wevers RA, Gabreëls FJ, et al. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain. 2000;123:908–19.CrossRef
3.
go back to reference Pilo-de-la-Fuente B, Jimenez-Escrig A, Lorenzo JR, Pardo J, Arias M, Ares-Luque A, et al. Cerebrotendinous xanthomatosis in Spain: clinical, prognostic, and genetic survey. Eur J Neurol. 2011;18:1203–11.CrossRef Pilo-de-la-Fuente B, Jimenez-Escrig A, Lorenzo JR, Pardo J, Arias M, Ares-Luque A, et al. Cerebrotendinous xanthomatosis in Spain: clinical, prognostic, and genetic survey. Eur J Neurol. 2011;18:1203–11.CrossRef
4.
go back to reference Mignarri A, Gallus GN, Dotti MT, Federico A. A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2014;37:421–9.CrossRef Mignarri A, Gallus GN, Dotti MT, Federico A. A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2014;37:421–9.CrossRef
5.
go back to reference Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2014;9:179.CrossRef Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2014;9:179.CrossRef
6.
go back to reference Salen G, Steiner RD. Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX). J Inherit Metab Dis. 2017;40:771–81.CrossRef Salen G, Steiner RD. Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX). J Inherit Metab Dis. 2017;40:771–81.CrossRef
7.
go back to reference Wong JC, Walsh K, Hayden D, Eichler FS. Natural history of neurological abnormalities in cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2018;41:647–56.CrossRef Wong JC, Walsh K, Hayden D, Eichler FS. Natural history of neurological abnormalities in cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2018;41:647–56.CrossRef
8.
go back to reference Duell PB, Salen G, Eichler FS, DeBarber AE, Connor SL, Casaday L, et al. Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis. J Clin Lipidol. 2018;12:1169–78.CrossRef Duell PB, Salen G, Eichler FS, DeBarber AE, Connor SL, Casaday L, et al. Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis. J Clin Lipidol. 2018;12:1169–78.CrossRef
9.
go back to reference Sekijima Y, Koyama S, Yoshinaga T, Koinuma M, Inaba Y. Nationwide survey on cerebrotendinous xanthomatosis in Japan. J Hum Genet. 2018;63:271–80.CrossRef Sekijima Y, Koyama S, Yoshinaga T, Koinuma M, Inaba Y. Nationwide survey on cerebrotendinous xanthomatosis in Japan. J Hum Genet. 2018;63:271–80.CrossRef
10.
go back to reference Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med. 1984;311:1649–52.CrossRef Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med. 1984;311:1649–52.CrossRef
11.
go back to reference van Heijst AF, Verrips A, Wevers RA, Cruysberg JR, Renier WO, Tolboom JJ. Treatment and follow-up of children with cerebrotendinous xanthomatosis. Eur J Pediatr. 1998;157:313–6.CrossRef van Heijst AF, Verrips A, Wevers RA, Cruysberg JR, Renier WO, Tolboom JJ. Treatment and follow-up of children with cerebrotendinous xanthomatosis. Eur J Pediatr. 1998;157:313–6.CrossRef
12.
go back to reference Yahalom G, Tsabari R, Molshatzki N, Ephraty L, Cohen H, Hassin-Baer S. Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis. Clin Neuropharmacol. 2013;36:78–83.CrossRef Yahalom G, Tsabari R, Molshatzki N, Ephraty L, Cohen H, Hassin-Baer S. Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis. Clin Neuropharmacol. 2013;36:78–83.CrossRef
13.
go back to reference Stelten BML, Huidekoper HH, van de Warrenburg BPC, Brilstra EH, Hollak CEM, Haak HR, et al. Long-term treatment effect in cerebrotendinous xanthomatosis depends on age at treatment start. Neurology. 2019;92:e83–95.CrossRef Stelten BML, Huidekoper HH, van de Warrenburg BPC, Brilstra EH, Hollak CEM, Haak HR, et al. Long-term treatment effect in cerebrotendinous xanthomatosis depends on age at treatment start. Neurology. 2019;92:e83–95.CrossRef
14.
go back to reference Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci. 2006;27:143–9.CrossRef Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci. 2006;27:143–9.CrossRef
15.
go back to reference Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17:405–14.CrossRef Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17:405–14.CrossRef
16.
go back to reference Nagai Y, Hirano M, Mori T, Takakura Y, Tamai S, Ueno S. Japanese triplets with cerebrotendinous xanthomatosis are homozygous for a mutant gene coding for the sterol 27-hydroxylase (Arg441Trp). Neurology. 1996;46:571–4.CrossRef Nagai Y, Hirano M, Mori T, Takakura Y, Tamai S, Ueno S. Japanese triplets with cerebrotendinous xanthomatosis are homozygous for a mutant gene coding for the sterol 27-hydroxylase (Arg441Trp). Neurology. 1996;46:571–4.CrossRef
17.
go back to reference Suh S, Kim HK, Park HD, Ki CS, Kim MY, Jin SM, et al. Three siblings with cerebrotendinous xanthomatosis: a novel mutation in the CYP27A1 gene. Eur J Med Genet. 2012;55:71–4.CrossRef Suh S, Kim HK, Park HD, Ki CS, Kim MY, Jin SM, et al. Three siblings with cerebrotendinous xanthomatosis: a novel mutation in the CYP27A1 gene. Eur J Med Genet. 2012;55:71–4.CrossRef
18.
go back to reference Zádori D, Szpisjak L, Madar L, Varga VE, Csányi B, Bencsik K, et al. Different phenotypes in identical twins with cerebrotendinous xanthomatosis: case series. Neurol Sci. 2017;38:481–3.CrossRef Zádori D, Szpisjak L, Madar L, Varga VE, Csányi B, Bencsik K, et al. Different phenotypes in identical twins with cerebrotendinous xanthomatosis: case series. Neurol Sci. 2017;38:481–3.CrossRef
19.
go back to reference Mandia D, Besson G, Lamari F, Castelnovo G, Curot J, Duval F, et al. Cholic acid as a treatment for cerebrotendinous xanthomatosis in adults. J Neurol. 2019;266:2043–50.CrossRef Mandia D, Besson G, Lamari F, Castelnovo G, Curot J, Duval F, et al. Cholic acid as a treatment for cerebrotendinous xanthomatosis in adults. J Neurol. 2019;266:2043–50.CrossRef
20.
go back to reference Mignarri A, Dotti MT, Federico A, De Stefano N, Battaglini M, Grazzini I, et al. The spectrum of magnetic resonance findings in cerebrotendinous xanthomatosis: redefinition and evidence of new markers of disease progression. J Neurol. 2017;264:862–74.CrossRef Mignarri A, Dotti MT, Federico A, De Stefano N, Battaglini M, Grazzini I, et al. The spectrum of magnetic resonance findings in cerebrotendinous xanthomatosis: redefinition and evidence of new markers of disease progression. J Neurol. 2017;264:862–74.CrossRef
Metadata
Title
Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report
Authors
Shingo Koyama
Yuma Okabe
Yuya Suzuki
Ryosuke Igari
Hiroyasu Sato
Chifumi Iseki
Kazuyo Tanji
Kyoko Suzuki
Yasuyuki Ohta
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2022
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-022-02711-4

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