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Progressive Myoclonic Epilepsy'-like presentation of Cerebrotendinous Xanthomatosis in an Indian Family with A Novel C.646+1G>A Splice Site Mutation.

ABSTRACT: Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal-recessive inborn disorder of bile acid metabolism due to mutations in the CYP27A1 gene. It presents with a diverse range of neurological and non-neurological symptoms. We present a case of CTX with a progressive myoclonic epilepsy (PME) like phenotype and a family history of CTX. The proband had a generalized epilepsy with prominent myoclonus. He also had intellectual decline, ataxia, bipyramidal dysfunction and peripheral neuropathy. The younger sibling had a milder generalized epilepsy without myoclonus along with behavioral issues, ataxia, neuropathy, and prominent tendon xanthomas. Both the siblings had developmental cataracts. MRI Brain of both had dentate hyperintensities with cerebellar atrophy. The proband's EEG showed severe background slowing with multifocal interictal discharges. Targeted gene of analysis proband revealed a novel homozygous 5' splice site variation in intron 3 of the CYP27A1 gene. We present a novel phenotype and genotype of CTX presenting with a syndrome of myoclonic epilepsy. This is the first PME-like presentation of CTX to the best of our knowledge. CTX may present with a PME-like clinical phenotype and should be considered as a treatable cause within the differential diagnostic evluation of syndromic epilepsies involving an atypical familial myoclonic epilepsy.

SUBMITTER: Desai KM

PROVIDER: S-EPMC7797504 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Progressive Myoclonic Epilepsy'-like presentation of Cerebrotendinous Xanthomatosis in an Indian Family with A Novel C.646+1G>A Splice Site Mutation.

Desai Karan M KM Kumar Piyush P Ravat Parthvi S PS Ravat Sangeeta H SH Jain Neeraj N Agrawal Shruti S Ansari Rahil R

Epilepsy & behavior reports 20201116

Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal-recessive inborn disorder of bile acid metabolism due to mutations in the <i>CYP27A1</i> gene. It presents with a diverse range of neurological and non-neurological symptoms. We present a case of CTX with a progressive myoclonic epilepsy (PME) like phenotype and a family history of CTX. The proband had a generalized epilepsy with prominent myoclonus. He also had intellectual decline, ataxia, bipyramidal dysfunction and peripheral neuropath ...[more]

PMID: 33458645

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Project description:BackgroundCerebrotendinous xanthomatosis (CTX) is a rare recessive genetic disease characterized by disruption of bile acid synthesis due to inactivation of the CYP27A1 gene. Treatment is available in the form of bile acid replacement. CTX is likely underdiagnosed, and prevalence estimates based on case diagnosis are probably inaccurate. Large population-based genomic databases are a valuable resource to estimate prevalence of rare recessive diseases as an orthogonal unbiased approach building upon traditional epidemiological studies.MethodsWe leveraged the Hardy-Weinberg principle and allele frequencies from gnomAD to calculate CTX prevalence. ClinVar and HGMD were used to identify high-confidence pathogenic missense variants and to calculate a disease-specific cutoff. Variant pathogenicity was also assessed by the VarSome implementation of the ACMG/AMP algorithm and the REVEL in silico predictor.ResultsCTX prevalence estimates were highest in Asians (1:44,407-93,084) and lowest in the Finnish population (1:3,388,767). Intermediate estimates were found in Europeans, Americans, and Africans/African Americans (1:70,795-233,597). The REVEL-predicted pathogenic variants accounted for a greater increase in prevalence estimates for Europeans, Americans, and Africans/African Americans compared with Asians. We identified the most frequent alleles designated pathogenic in ClinVar (p.Gly472Ala, p.Arg395Cys), labeled pathogenic based on sequence consequence (p.Met1?), and predicted to be pathogenic by REVEL (p.Met383Lys, p.Arg448His) across populations. Also, we provide a prospective geographic map of estimated disease distribution based on CYP27A1 variation queries performed by healthcare providers from selected specialties.ConclusionsPrevalence estimates calculated herein support and expand upon existing evidence indicating underdiagnosis of CTX, suggesting that improved detection strategies are needed. Increased awareness of CTX is important for early diagnosis, which is essential for patients as early treatment significantly slows or prevents disease progression.

Project description:BackgroundClassic 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 presentationWe 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 (ᵡ2; p < 0.00001).ConclusionsThe 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.

Dataset Information

Progressive Myoclonic Epilepsy'-like presentation of Cerebrotendinous Xanthomatosis in an Indian Family with A Novel C.646+1G>A Splice Site Mutation.

Publications

Progressive Myoclonic Epilepsy'-like presentation of Cerebrotendinous Xanthomatosis in an Indian Family with A Novel C.646+1G>A Splice Site Mutation.

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