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Cerebrotendinous Xanthomatosis

CTX


Presentation

  • We present a case of a 25-year-old Asian Indian woman who presented with gait difficulty, fusiform swellings of bilateral tendo-Achilles and infrapatellar tendons, along with history of bilateral cataract surgery 1 year earlier.[ncbi.nlm.nih.gov]
  • , and a typical clinical presentation.[ncbi.nlm.nih.gov]
  • Cerebrotendinous xanthomatosis (CTX) is a rare inborn disorder of sterol storage with autosomal recessive inheritance and a variable clinical presentation.[ncbi.nlm.nih.gov]
  • Frequently bilateral juvenile cataracts present in early childhood which provides ophthalmologists an opportunity to aid in early diagnosis and initiate treatment.[ncbi.nlm.nih.gov]
  • CTX usually presents in the second or third decade with slowly progressive neurological dysfunction, cerebellar ataxia and premature atherosclerosis.[ncbi.nlm.nih.gov]
Juvenile Cataract
  • Frequently bilateral juvenile cataracts present in early childhood which provides ophthalmologists an opportunity to aid in early diagnosis and initiate treatment.[ncbi.nlm.nih.gov]
  • We describe two adolescent Indian siblings with cerebrotendinous xanthomatosis with cognitive impairment, progressive neurological deterioration, juvenile cataracts and chronic diarrhea. Both patients had bilateral Achilles tendon xanthomata.[ncbi.nlm.nih.gov]
  • The characteristic clinical symptoms are diarrhea, juvenile cataracts, tendon xanthomas and neuropsychiatric alterations. The aim of this study is to present a pair of identical adult twins with considerable differences in the severity of phenotype.[ncbi.nlm.nih.gov]
  • Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disease characterized by widespread tissue deposition of two neutral sterols, cholestanol and cholesterol, resulting in tendinous xanthomas, juvenile cataracts, progressive neurological[ncbi.nlm.nih.gov]
  • Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn error of bile acid metabolism characterized by diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas developing in the second to third decades of life, and progressive[ncbi.nlm.nih.gov]
Chronic Diarrhea
  • In Chinese CTX patients, xanthomatosis was the most common symptom while cataracts and chronic diarrhea were less frequent.[ncbi.nlm.nih.gov]
  • We describe two adolescent Indian siblings with cerebrotendinous xanthomatosis with cognitive impairment, progressive neurological deterioration, juvenile cataracts and chronic diarrhea. Both patients had bilateral Achilles tendon xanthomata.[ncbi.nlm.nih.gov]
  • We describe two Brazilian brothers with cognitive impairement and chronic diarrhea. One of them also presents bilateral cataracts. Neurological findings were progressive walking deficit, limb ataxia and pyramidal signs.[ncbi.nlm.nih.gov]
  • Pathogenic variants in CYP27A1 cause elevated cholestanol levels in the body, which leads to a variable clinical presentation that often includes cataracts, intellectual disability, neurological features, tendon xanthomas, and chronic diarrhea.[ncbi.nlm.nih.gov]
  • Pediatricians should be aware of this diagnostic possibility of cerebrotendinous xanthomatosis in children presenting with chronic diarrhea and juvenile cataracts.[ncbi.nlm.nih.gov]
Recurrent Diarrhea
  • Such juvenile lenticular findings should raise suspicion for this treatable metabolic disorder, especially when in the context of recurrent diarrhea during early childhood.[ncbi.nlm.nih.gov]
Learning Difficulties
  • Behavioral/personality disturbance in childhood or adolescence, especially when accompanied by learning difficulties, should therefore lead to further investigation to exclude CTX, as early diagnosis and treatment is critical for prognosis.[ncbi.nlm.nih.gov]
  • Both had epilepsy, learning difficulties, chronic diarrhoea and juvenile-onset cataracts. CTX was diagnosed by increased cholestanol levels and compound heterozygosity for CYP27A1 mutations.[ncbi.nlm.nih.gov]

Workup

  • Although seizures have been frequently noticed as part of CTX manifestations, there have not been reports of CTX being diagnosed in drug-resistant epilepsy diagnostic workup nor of seizure response to chenodeoxycholic acid treatment.[ncbi.nlm.nih.gov]
  • We present a two-week old girl who was diagnosed with cerebrotendinous xanthomatosis (CTX), an inborn error of bile acid synthesis, after a diagnostic workup for convulsions which were shown to be caused by a parechovirus encephalitis.[ncbi.nlm.nih.gov]
  • Results : Laboratory workup revealed cholestanol of 19.6 mmol/L (Reference: 2-12 mmol/L) increased cholestanol/cholesterol rate of 4.55 ( Reference : 0.16 /- 0.05 ) and increased cerebrospinal fluid albumin of 24.4 mg dL (Reference: up to 3.5).[mdsabstracts.org]
  • MRI studies of the brain are an important component of the diagnostic workup for CTX. It may show bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter.[eyewiki.aao.org]

Treatment

  • Five patients who started treatment after 25 years of age continued to deteriorate despite CDCA treatment. CONCLUSIONS: Beginning CDCA treatment as early as possible is crucial to preventing neurological damage and deterioration in CTX.[ncbi.nlm.nih.gov]
  • Oral chenodeoxycholic acid (CDCA) can lead to clinical stabilization, but in a subgroup of patients the disease progresses despite treatment.[ncbi.nlm.nih.gov]
  • Thereafter treatment with simvastatin was discontinued.[ncbi.nlm.nih.gov]
  • Treatment with chenodeoxycholic acid (CDCA) may slow the progression of the disease and reverse some symptoms in a proportion of patients.[ncbi.nlm.nih.gov]
  • Two young sisters started treatment at the preclinical stage before the appearance of major symptoms.[ncbi.nlm.nih.gov]

Prognosis

  • Spinal forms had a less severe prognosis. A delayed diagnosis could contribute to the lack of significant response to treatment.[ncbi.nlm.nih.gov]
  • These findings suggest the limited reversibility of the disease, and its poor prognosis, specially if treatment is not started early.[ncbi.nlm.nih.gov]
  • Behavioral/personality disturbance in childhood or adolescence, especially when accompanied by learning difficulties, should therefore lead to further investigation to exclude CTX, as early diagnosis and treatment is critical for prognosis.[ncbi.nlm.nih.gov]
  • Early diagnosis and treatment are essential to improve the prognosis of CTX.[ncbi.nlm.nih.gov]
  • On the other hand, the absence of dentate nuclei signal alteration should be considered an indicator of better prognosis. KEYWORDS: Cerebellar vacuolation; Cerebrotendinous xanthomatosis; Chenodeoxycholic acid; Dentate nuclei; MRI[ncbi.nlm.nih.gov]

Etiology

  • Etiology CTX is caused by mutations in the sterol 27-hydroxylase gene ( CYP27A1 ; 2q33-qter). Sterol 27-hydroxylase catalyzes the first step in the oxidation of the side-chain of sterol intermediates in the bile acid synthesis (BAS) pathway.[orpha.net]
  • ETIOLOGY – GENETICS CYP27A1 gene codes for the mitochondrial enzyme sterol 27-hydroxylase, which is involved in bile acid synthesis. The CYP27A1 gene is located on chromosome 2q33-qter and contains nine exons.[flipper.diff.org]

Epidemiology

  • Retrospective review of the clinical and epidemiological aspects and mutations of all the patients diagnosed since 1992 in the main reference centers for genetic testing of CTX in Spain. Twenty-five patients from 19 families were identified.[ncbi.nlm.nih.gov]
  • Abstract Cerebrotendinous xanthomatosis (CTX) is likely to be underdiagnosed and precise epidemiological characteristics of CTX are largely unknown as knowledge on the disorder is based mainly on case reports.[ncbi.nlm.nih.gov]
  • It is commonly held that CTX is exceedingly rare, but epidemiological studies are lacking.[ncbi.nlm.nih.gov]
  • The Sigma-Tau TMP team was given two main goals: 1) gain an in-depth understanding of the epidemiology of CTX; and, 2) generate a road map for the possible adoption and implementation of a test for CTX in the existing newborn screening panel.[kgi.edu]
  • Summary Epidemiology More than 300 patients have been reported worldwide. Prevalence is estimated to be approximately 1/50,000 among Caucasians.[orpha.net]
Sex distribution
Age distribution

Pathophysiology

  • In 1980, defects in mitochondrial sterol 27-hydroxylase were implicated in the biochemical pathophysiology of the disease by Oftebro et al. In 1991, mutations in the gene CYP27A1 were discovered as causative...[flipper.diff.org]
  • In 1980, defects in mitochondrial 27-hydroxylase were implicated in the biochemical pathophysiology of the disease by Oftebro et al [7]. In 1991, mutations in the gene CYP27A1 were discovered as causative [8-10].[faoj.org]
  • Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism. J Neurol Sci. 1993; 115 :67–70. [ PubMed : 8468594 ] Federico A, Dotti MT, Volpi N. Muscle mitochondrial changes in cerebrotendinous xanthomatosis.[ncbi.nlm.nih.gov]
  • PubMed CrossRef Google Scholar Federico A, Dotti MT, Lore F, Nuti R (1993) Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism. J Neurol Sci 115: 67–70.[link.springer.com]

Prevention

  • Prevention is particularly significant in light of the availability of early genetic diagnosis and the devastating effects of this illness if not treated.[ncbi.nlm.nih.gov]
  • Detection of CTX in the newborn period would be beneficial because an effective oral therapy for CTX is available to prevent disease progression. There is no suitable test to screen newborn dried bloodspots (DBS) for CTX.[ncbi.nlm.nih.gov]
  • If it is diagnosed at this point, treatment may prevent the onset of neurological problems. We present the case histories and developmental findings in two affected siblings treated from infancy.[ncbi.nlm.nih.gov]
  • Early identification of familial history with mental retardation, xanthomas and cognitive impairment might prevent the progression to this treatable type of dementia.[ncbi.nlm.nih.gov]
  • Diagnosis is usually delayed but early diagnosis and replacement therapy can prevent devastating neurological sequelae.[ncbi.nlm.nih.gov]

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