PEDIATRICS Vol. 123 No. 1 January 2009, pp. 143-147 (doi:10.1542/peds.2008-0192)
EXPERIENCE & REASON |
Chronic Diarrhea and Juvenile Cataracts: Think Cerebrotendinous Xanthomatosis and Treat
a Department of Neurology, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel
b Department of Neurology
d Institute of Human Genetics, Western Galilee Hospital-Nahariya, Nahariya, Israel
c Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
e Sherutei Briut Klalit, Western Galilee District, Israel
ABSTRACT
Cerebrotendinous xanthomatosis is an autosomal recessive disease of bile acid synthesis caused by 27-hydroxylase deficiency. Treatment with chenodeoxycholic acid normalizes cholestanol concentrations and abrogates progression of the disease. We present 4 patients with cerebrotendinous xanthomatosis within 1 family who were treated with chenodeoxycholic acid for 14 years. Two young sisters started treatment at the preclinical stage before the appearance of major symptoms. Their 2 older uncles, who had already developed the complete phenotypic form of cerebrotendinous xanthomatosis when diagnosed, commenced treatment at the same time as the sisters, thus establishing a natural control group. After 14 years of chenodeoxycholic acid therapy, the cholestanol levels of all 4 patients decreased to normal levels (<6 µg/mL). Both sisters remained asymptomatic. Only moderate improvement in symptoms was observed in their uncles. In this long-term study, prompt preclinical administration of chenodeoxycholic acid in early childhood completely prevented the cerebrotendinous xanthomatosis phenotype in 2 sisters. Pediatricians should be aware of this diagnostic possibility of cerebrotendinous xanthomatosis in children presenting with chronic diarrhea and juvenile cataracts. Prevention is particularly significant in light of the availability of early genetic diagnosis and the devastating effects of this illness if not treated.
Key Words: cerebrotendinous xanthomatosis • CTX • chronic diarrhea in infancy and childhood • juvenile cataracts • cholestanol • chenodeoxycholic acid • CDCA • CYP27A1 gene
Abbreviations: CTX, cerebrotendinous xanthomatosis • CDCA, chenodeoxycholic acid • EEG, electroencephalogram • CT, computed tomography • PCR, polymerase chain reaction • EMG, electromyogram
Cerebrotendinous xanthomatosis (CTX [Online Mendelian Inheritance in Man No. 213700]) is a rare autosomal recessive inborn error of bile acid metabolism. The CTX phenotype was first described in 1937.1 Subsequently, it was demonstrated that the accumulation of cholestanol in multiple organs2 and the absence of chenodeoxycholic acid (CDCA) in the bile of patients with CTX results in shunting of the bile acid metabolism to the cholestanol pathway.3 We have documented the major clinical manifestations and natural progression of untreated patients with CTX.4–6 Early symptoms may include neonatal/infantile diarrhea and juvenile cataracts. Therefore, the pediatrician has a key role in diagnosing this disease. Seizures, developmental delay, and learning disorders typically appear during school years. A recent publication by Clayton et al7 indicated that neonatal cholestatic jaundice (hepatitis of infancy) might be an additional early feature of CTX. Tendon xanthomas usually appear in the second or third decades of life, commonly in the Achilles tendon and other extensor tendons. MRI features may include bilateral hyperintensity of the dentate nuclei, diffuse cerebral and cerebellar atrophy, and white matter signal abnormalities.8 When untreated, CTX progresses to severe mental, physical, and neurologic deterioration (see Table 1).
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Oral supplementation with CDCA inhibits excessive cholesterol and cholestanol syntheses,9 thus preventing their accumulation in different organs. Regressions of clinical presentations were documented with long-term treatment with CDCA.4,5
Cali et al10 localized the molecular defect of CTX to the 27-hydroxylase gene (CYP27A1). Since 1991, >50 different mutations of this gene have been reported. Nevertheless, no specific genotype-phenotype correlation has been established.8,11 Molecular analysis enables presymptomatic and prenatal diagnosis.12
For 20 years Berginer5 and his colleagues have hypothesized that early diagnosis and therapy commenced at the preclinical and incomplete stages of CTX may result in a functional cure of the disease, preventing appearance of clinical manifestations. This long-term study affords examination of this hypothesis.
Here we present 2 young sisters with CTX who began CDCA treatment at the presymptomatic stage and have remained symptom-free after 14 years of follow-up. Treatment during the same period of time of 2 severely afflicted older family members, their uncles, afforded a natural control group.
CASE REPORTS
We present 4 patients with CTX within 1 family who received long-term therapy with CDCA. Two young sisters started treatment early, at the presymptomatic and incomplete stages, whereas their 2 older uncles began treatment late, after presentation of the complete form of CTX.
All patients belong to a consanguineous Druze family (Fig 1A). Members of this family were investigated clinically, biochemically, radiologically, electrophysiologically, and genetically, as has been described.13,14
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Patient 1.
A 2-year-old girl (Fig 1A, III4) was diagnosed with CTX molecularly (Fig 1B) and biochemically after screening of family members.14 She had no clinical manifestations, and her serum cholestanol concentration was 26.9 µg/mL (normal range: <6 µg/mL). Treatment with CDCA was initiated promptly.
Patient 2.
Patient 2 (Fig 1A, III5), now 21 years old, was diagnosed molecularly and biochemically with CTX at age 7. Her diagnosis followed presentation with chronic diarrhea and operated bilateral juvenile cataracts. An electroencephalogram (EEG) showed irregular diffuse slow activity with periodic sharp wave discharges. Mild brain atrophy was seen with computed tomography (CT). Her neurologic status and psychomotor development were normal. Her serum cholestanol concentration was 36.2 µg/mL. Treatment with CDCA was initiated promptly.
Patient 3.
A 41-year-old man (Fig 1A, II11) (uncle of patients 1 and 2), married and a father of 7 children, was diagnosed with CTX at age 27. He then presented with bilateral cataracts, pes cavus, Achilles tendon xanthomas, dementia, epileptic seizures, and pyramidal and cerebellar signs. An EEG showed irregular diffuse slow activity and periodic sharp wave discharges. Brain CT showed cortical atrophy and bilateral hypodense areas in the white matter. His serum cholestanol level was 36.8 µg/mL. Molecular analysis confirmed CTX14 (Fig 1B), and CDCA treatment was initiated.
Patient 4.
Patient 3's brother (Fig 1A, II12) was diagnosed with CTX at the age of 16, presenting with a positive family history, episodes of prolonged diarrhea, seizures, pes cavus, bilateral cataracts, pyramidal and cerebellar signs, brain atrophy on CT, and abnormal EEG results. His serum cholestanol level was then 32.1 µg/mL. Molecular analysis confirmed the diagnosis of CTX14 (Fig 1B), and CDCA treatment was initiated.
Mutational Analysis
Polymerase chain reaction (PCR) amplification was performed. The sense primer (5'-GCTTGGCCCAGTTATTCAGTTTTG-3') and the antisense primer (5'-GCCCTGTTCCAGTCCCTTCAG-3') were used along with the following PCR conditions: denaturation at 94°C for 5 minutes; 35 subsequent amplification cycles performed at 94°C for 15 seconds, at 55°C for 30 seconds, and at 72°C for 10 seconds; and a final step at 72°C for 5 minutes. The PCR products were subsequently digested with Fnu4HI (New England Biolabs, Ipswich, MA) and analyzed on 8% acrylamide gels (Biological Industries, Bet Haemek, Israel).
Presentation of Patients
Patient 1.
At age 16, after 14 years of treatment with 750 mg of CDCA daily, patient 1 has remained symptom-free with a serum cholestanol level of 4.3 µg/mL. Complete physical and neurologic examinations have remained normal. Results of an EEG, an electromyogram (EMG), and brain MRI have been normal. Her kidney- and liver-function tests and lipid profile have also been within normal ranges. Academic achievement for this high school student has been normal, and there has been no evidence of learning disabilities, xanthomas, or cataracts.
Patient 2.
At age 21, patient 2 is married and the mother of 2 healthy children. She has been treated with 750 mg of CDCA daily with suboptimal compliance. Her physical and neurologic examinations have been normal. Results of an EEG, an EMG, and brain MRI have been normal. Her recent cholestanol level was 7.7 µg/mL. She has been symptom-free after 14 years of treatment, without tendon xanthomas or motor abnormalities and without any limitations in her daily activities.
Patient 3.
Patient 3 has been treated with 750 mg of CDCA daily for 14 years with suboptimal compliance. As of this writing, he has had no complaints, but he has been unable to work and shows cognitive decline. Physical examination shows muscle atrophy in his hands, mild weakness in his lower extremities, and decreased vibration and pinprick sensations in a stocking-glove distribution. Pyramidal and cerebellar signs have disappeared, and he has been seizure-free without antiepileptic drugs. Pes cavus and xanthomas of Achilles tendon were present bilaterally. An EMG showed demyelinating and axonal motor and sensory neuropathy. An EEG returned normal results. His recent cholestanol level was 4.5 µg/mL, and his serum lipid levels have been normal.
Patient 4.
Now 29 years old, patient 4 has been treated with 1000 mg of CDCA daily since being diagnosed with CTX. Epileptic seizures and pyramidal and cerebellar signs have disappeared. Results of EEGs and MRI of the brain have been normal. At the time of this writing, he does not work and his wife reports aggressive behavior. He takes minor tranquillizers. Physical examination shows muscle atrophy in his hands and mild weakness in his lower extremities, decreased reflexes, bilateral pes cavus, and Achilles tendon xanthomas. An EMG showed demyelinating and axonal polyneuropathy. His recent serum cholestanol level was 4.9 µg/mL, and his serum lipid levels have been normal
Mutational Analysis
The causative mutation was detected during PCR amplification of a 262-base pair (bp) fragment containing the mutation from genomic DNA. Normal allele digests to 2 fragments: 138 and 124 bp. The mutant allele was not digested.
All patients (II11, II12, III4, and III5 [Fig 1A]) presented here were homozygous for the same 355delC mutation. The parents (II8 and II9 [Fig 1B]) of the affected sisters were found to be heterozygous for this mutation. These results are compatible with previously published data.12
Molecular testing of patient 2's husband found him not to be a carrier for CTX. Thus, this couple is not at risk of having affected children.
DISCUSSION
CTX is more common than previously recognized, with prevalence estimated at 1 per 50 000.15 The disease has been reported in many countries worldwide.4,8,15–18
The homozygotic CTX genotype results in an error in bile acid biosynthesis pushing newly synthesized cholesterol into the cholestanol pathway. CDCA is markedly reduced. Plasma cholesterol levels remain normal while significantly increased cholestanol and bile alcohols accumulate and then excrete with bile alcohols in bile, urine, and feces.19 Cholestanol easily crosses biological membranes and the blood-brain barrier20,21 and deposits in different organs, especially in the brain, peripheral nerves, lenses, and tendons. Pretreatment cholestanol levels were elevated 4 to 6 times in these patients with CTX.
Despite its effect on multiple organs, CTX in many patients remains misdiagnosed for years and even decades, leaving the patients deprived of effective treatment. CDCA administration inhibits abnormal bile acid synthesis and reduces the formation and concentration of cholestanol and bile alcohols.4,5,9
In the differential diagnosis of CTX, the cholestanol level is not a distinguishing diagnostic tool, because elevated cholestanol levels also present with primary biliary cirrhosis and cholestasis. Other diagnostic indications of CTX are increased urinary excretion of bile alcohol glucuronides and homozygosity or compound heterozygosity for CYP271A mutant allele(s). Identification of the causative mutation is the most precise verification of the diagnosis. After diagnosis is confirmed, cholestanol levels provide a guide for dosage regulation and compliance.
The 4 patients presented here are members of 1 family residing in a Druze village in northern Israel, where the prevalence of CTX is unusually high because of the incidence of traditional consanguineous marriages.13,14
Two of these patients were misdiagnosed until the ages of 27 and 16 despite characteristic manifestations of CTX. By the time their diagnoses were confirmed biochemically and genetically, they were severely affected by CTX, presenting with mental retardation, psychiatric abnormalities, pyramidal and cerebellar dysfunction, seizures, and tendon xanthomas. After treatment with CTX, their cholestanol levels decreased to normal levels, but their clinical symptoms improved only slightly. These brothers have served as controls to their nieces, 2 sisters diagnosed with CTX before neurologic presentations.
At diagnosis the younger sister (patient 1) was asymptomatic, and the older sister (patient 2) was diagnosed with the condition after an operation for juvenile cataracts. Fourteen years later, both were without CTX symptoms. No adverse effects or complications have been observed during the 14 years of CDCA treatment in any of the 4 patients described.
These 4 CTX cases support our earlier suggestion5 that for years CTX can remain a diffuse, mostly demyelinating, potentially reversible metabolic encephalopathy. Long-term treatment with CDCA for CTX normalizes the biochemical abnormalities, stops the progression of the disease, and may result in psychoneurologic improvement.4–6,22,23
We have demonstrated that the timing of CDCA initiation is of particular significance. Our previous studies, and those of other authors, support our findings that early administration of CDCA therapy is mandatory even for asymptomatic or minimally affected patients.5,10,22 This is particularly critical in light of the great phenotypic variability of CTX, even within families.11,14,18 A long-term (11-year) electrophysiological study conducted in Italy23 detected only limited efficacy of CDCA when administered late, after manifestations of CTX. EEG and EMG results and nerve conduction velocity improved with CDCA treatment. In contrast, the neurologic and psychiatric condition of the untreated subjects worsened progressively. Our study is important in that we present comparisons to family members who commenced treatment with CDCA already in the presymptomatic stage.
Other drugs, particularly 3-hydroxy-3-methylglutaryl coenzyme A inhibitors, have been used in combination with CDCA in the treatment of CTX, but no additional benefits have been observed when compared with CDCA alone.24–26 Gene therapy and liver transplant may also offer cures for CTX. However, the remarkable efficacy of CDCA therapy, its lack of adverse effects, and its low cost are advantages that are hard to surpass.
CONCLUSIONS
In this long-term (14-year) study, prompt preclinical administration of CDCA completely prevented the CTX phenotype in 2 sisters. Prevention is particularly significant in light of the availability of early genetic diagnosis of CTX and the devastating effects of this illness when not treated. Three essential steps can prevent irreversible multiorgan damage in patients with CTX: (1) recognition by pediatricians of early symptoms, especially chronic diarrhea and juvenile cataracts; (2) definitive diagnosis of CTX biochemically and by mutation analysis; and (3) prompt treatment with CDCA to prevent the CTX phenotype.
ACKNOWLEDGMENTS
This research was self-funded by resources from the Institute of Human Genetics at Western Galilee Hospital-Nahariya.
FOOTNOTES
Accepted Mar 26, 2008.
Address correspondence to Vladimir M. Berginer, MD, PhD, PO Box 941, Omer 84965, Israel. E-mail: tzipora.falik{at}naharia.health.gov.il
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2009 by the American Academy of Pediatrics
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