Novel splice-affecting variants in CYP27A1 gene in two Chilean patients with Cerebrotendinous Xanthomatosis

Smalley, Susan V.; Preiss, Yudith; Suazo, José; Vega, Javier Andrés; Angellotti, Isidora; Lagos, Carlos F.; Rivera, Enzo; Kleinsteuber, Karin; Campión, Javier; Martínéz, J. Alfredo; Maíz, Alberto; Santos, José Luis

doi:10.1590/s1415-475738120140087

Cited by 11 publications

(9 citation statements)

References 24 publications

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“…At 42 y: severe spastic tetraparesis, flexum of the 4 limbs, severe dysphagia. 64 Involutive cerebellar and frontal regions, bulbar and CWML NA NA NA p.Val86Glufs30Ter / p.Arg395Cys [ 21 ] 26 M Japan 65 77 + + – + NA 13 (10.4 μg/mL) Normal Cervical dorsal column hyperintensities CDCA 750 mg NA p.Gln85Arg / p.Arg405Gln [ 22 ] 27 F NA 5 52 – NA + + NA Seizures, development delay, dystonia, ataxia, dysarthria, dysphagia, wheelchair at 30y., bedridden at 49 y. 19.6 Cerebral and CWML and atrophy, extensive, symmetric supra and infra-tentorial hyperintensities Central and posterior SCWM, C7 through thoracic vertebra NA NA Confirmed by genetic analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The p.Arg395Cys substitution affects a highly conserved sequence of the adrenodoxin binding site and was shown to strongly reduce CYP27A1 enzyme activity [ 51 ]. Tridimensional protein modelling showed that Arg395 is located within the ERR triad (the glutamine-arginine-arginine motif conserved in all cytochrome P450 sequence) and its substitution to cysteine was suggested to favour misfolding and possibly affects adrenodoxin binding [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

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Spinal cerebrotendinous xanthomatosis: A case report and literature review

Atallah¹,

Millán

Wicki

et al. 2021

Molecular Genetics and Metabolism Reports

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Background Classic cerebrotendinous xanthomatosis (CTX; OMIM # 213700 ) manifests with chronic diarrhea, juvenile cataracts, tendon xanthomas and neurological symptoms. It is due to biallelic inactivation of CYP27A1 wich leads to cholestanol accumulation in the central nervous system, eyes and tendons. Less commonly, the disease can present in young adults as spastic paraparesis in the absence of xanthomas. Case presentation We report a 38-year old woman who presented with chronic diarrhea and progressive spastic paraparesis in her twenties. Brain magnetic resonance imaging (MRI) showed cerebral atrophy with diffuse periventricular white matter hyperintensities. Spinal MRI was normal. CYP27A1 gene sequencing confirmed the diagnosis of CTX. Chenodeoxycholic acid (CDCA) treatment was introduced with remission of diarrhea. Unfortunately, the treatment had to be discontinued several times and the patient developed psychosis and an severe ataxospastic gait. Spinal MRI revealed new linear hyperintensities of the corticospinal and gracile tracts. Thirty-three spinal CTX patients were identified by searching in Pubmed, EMBASE™ and Web of Science databases. All patients presented pyramidal signs and 48% had dorsal column signs. Juvenile cataracts were described in 78% of patients, chronic diarrhea in 65%, and tendon xanthomas in 31%. Disease improvement or stabilization with chenodeoxycholic acid was observed in 69% of patients. A higher prevalence of the Arg395Cys allele was observed in patients with spinal CTX as compared to CTX in general (ᵡ 2 ; p < 0.00001). Conclusions The diagnosis of spinal CTX can be easily missed or delayed in absence of xanthomas. There is a higher prevalence of the Arg395Cys allele in spinal CTX as compared to classic childhood-onset CTX. CDCA treatment seems to stabilize or improve clinical symptoms in most patients. However, as seen in our patient and in two previously reported cases, sudden interruption of CDCA may lead to irreversible neurological complications.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Spinal cerebrotendinous xanthomatosis: A case report and literature review

Atallah¹,

Millán

Wicki

et al. 2021

Molecular Genetics and Metabolism Reports

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show abstract

“…Tridimensional protein modeling showed that Arg395 is located within the ERR triad (the glutamine-arginine-arginine motif conserved in all cytochrome P450 sequence) and its substitution to cysteine was suggested to favour misfolding and possibly affects adrenodoxin binding [23].…”

Section: Discussionmentioning

confidence: 99%

Spinal Cerebrotendinous Xanthomatosis: An Easily Overlooked Treatable Disorder

Atallah

Millán

Wicki

et al. 2020

Preprint

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Background: Classic cerebrotendinous xanthomatosis (CTX; OMIM #213700) manifests itself in childhood with chronic diarrhea, juvenile cataracts, tendon xanthomas and neurological symptoms. Biallelic inactivation of CYP27A1 is responsible for cholesterol 27-hydroxylation, leading to cholestanol accumulation in the central nervous system, eyes and tendons. Less commonly, the disease can present in young adults as spastic paraparesis in the absence of xanthomas. Methods: We report on a 28-year old woman diagnosed with CTX who worsened, under treatment, a spinal form of CTX. A review of spinal CTX in the literature is also described. Spinal CTX patients were identified by searching in Pubmed, EMBASE™ and Web of Science databases. Only patients with clinical features of spinal CTX and/or with a typical spinal MRI were included.Results: A woman presented with chronic diarrhea and progressive spastic paraparesis in her twenties. Brain magnetic resonance imaging (MRI) showed cerebral atrophy with diffuse periventricular white matter hyperintensities. Spinal MRI was normal. CYP27A1 gene sequencing confirmed the diagnosis of CTX. Chenodeoxycholic acid (CDCA) treatment was introduced with remission of diarrhea. Treatment was discontinued several times and patient developed psychosis and an ataxospastic gait. Spinal MRI revealed new linear hyperintensities of the corticospinal and gracile tracts, compatible with spinal CTX. Thirty-three patients with spinal CTX were identified in the literature. All patients presented pyramidal signs and 48% dorsal column signs. Juvenile cataracts were described in 78% of patients, chronic diarrhea in 65%, and tendon xanthomas in 31%. Disease improvement or stabilization with chenodeoxycholic acid was observed in 69% of patients. A higher prevalence of the Arg395Cys allele was observed in patients with spinal CTX as compared to CTX in general (ᵡ2; p<0.00001).Conclusions: The diagnosis of spinal CTX can be easily missed or delayed in absence of xanthomas. There is a higher prevalence of the Arg395Cys allele in spinal CTX as compared to classic childhood-onset CTX. CDCA treatment seems to stabilize or improve clinical symptoms in most patients. However, as seen in our patient and in two previously reported cases, sudden interruption of CDCA may lead to irreversible neurological complications.

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“…Es interesante destacar que esta variante tiene una alta prevalencia en España 16 . Otros reportes de CXT en Chile reflejan la variabilidad clínica de esta enfermedad: un caso con presentación típica asociado a xantomas tendíneos 18 , otro asociado a macrocefalia y dismorfias faciales, y otro sin xantomas tendíneos visibles 19 .…”

Section: Discussionunclassified

Xantomatosis cerebrotendinosa sin xantomas tendíneos. Caso clínico

Contreras

Guajardo²,

Martínez³

et al. 2019

Rev. méd. Chile

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Cerebrotendinous xanthomatosis. Report of one case Cerebrotendinous xanthomatosis (CTX) is an uncommon autosomal recessive disease caused by deficiency of 27-sterol-hydroxylase that results in an accumulation of cholestanol in the central nervous system, eyes, tendons, and blood vessels. We report a 22-year-old woman with a history of cataract surgery at the age of 14, cholecystectomy due to cholelithiasis at the age of 17 and chronic diarrhea, who presented with a six months period of gait instability and frequent falls. Physical examination revealed a bilateral pyramidal and cerebellar syndrome, with no visible tendon xanthomas. Cerebral magnetic resonance imaging showed an increase of the signal intensity on the T2-weighted images in periventricular cerebral white matter, dentate nuclei and spinal cord. With a high suspicion of CXT, a genetic study was conducted identifying a pathogenic variant in the CYP27A1 gene. There is considerable variation in clinical characteristics and age of onset of this disease, including absence of tendon xanthomas, delaying the diagnosis. Early recognition and chronic chenodeoxycholic acid therapy can improve outcome and quality of life.

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Novel splice-affecting variants in CYP27A1 gene in two Chilean patients with Cerebrotendinous Xanthomatosis

Cited by 11 publications

References 24 publications

Spinal cerebrotendinous xanthomatosis: A case report and literature review

Spinal cerebrotendinous xanthomatosis: A case report and literature review

Spinal Cerebrotendinous Xanthomatosis: An Easily Overlooked Treatable Disorder

Xantomatosis cerebrotendinosa sin xantomas tendíneos. Caso clínico

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