Hepatotoxicity due to chenodeoxycholic acid supplementation in an infant with cerebrotendinous xanthomatosis: implications for treatment.

UNLABELLED: 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. The diagnosis of CTX was confirmed with CYP27A1 mutation analysis. She was started on chenodeoxycholic acid (CDCA) supplementation, which inhibits cholestanol production through a feedback mechanism, at the advised dosage of 15 mg/kg/day. Within 6 weeks, she developed jaundice with hepatomegaly. CDCA supplementation was stopped after which liver size and function rapidly normalised. CDCA supplementation was then restarted and maintained at 5 mg/kg/day. Cholestanol, liver enzymes and total bilirubin were frequently monitored in the patient, who is now 2.8 years of age, and have remained within normal range. Her psychomotor development has been normal. CONCLUSION: adequate metabolic control was achieved in an infant with CTX with CDCA supplementation at a dosage of 5 mg/kg/day and was well tolerated. CDCA supplementation at 15 mg/kg/day seems hepatotoxic in infants and should not be used. This is relevant in view of the possible inclusion of CTX in newborn screening programs in the near future. WHAT IS KNOWN: Cerebrotendinous xanthomatosis (CTX), an inborn error of bile acid synthesis, is a progressive neurological disorder. Symptoms of CTX can be halted, and likely prevented, with chenodeoxycholic acid (CDCA) supplementation, making CTX a good candidate for newborn screening. What is New: CDCA supplementation at the advised dosage of 15 mg/kg/day in children seems hepatoxic in infants with CTX. Adequate metabolic control in an infant with CTX was achieved with CDCA supplementation at 5 mg/kg/day and well tolerated.

Myoclonus and dystonia in cerebrotendinous xanthomatosis.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an inherited neurometabolic disorder. The main neurological manifestations of the disease are pyramidal syndrome, ataxia, peripheral neuropathy, cognitive impairment, epilepsy, and psychiatric disturbances. Myoclonic dystonia has been reported on in the setting of various neurometabolic diseases. Anecdotal reports describe movement disorders associated with CTX, but no dystonia with myoclonic events. METHODS: We collected clinical, biochemical, electrophysiological, neuroradiological, and genetic data of 6 patients with myoclonus and mild dystonia associated with CTX. From a systematic literature review, we analyzed 31 patients with movement disorders secondary to CTX. RESULTS: Our 6 patients presented distal myoclonus with mild dystonia of the upper limbs. Myoclonus was of subcortical origin, based on neurophysiological recordings, and differed from oromandibular myoclonus previously described in CTX patients. CONCLUSIONS: These results expand the phenotype of CTX and suggest that myoclonus and/or dystonia are underdiagnosed. In keeping with our findings, tremors previously observed in CTX patients might actually correspond to myoclonic events. We hypothesize that a dysfunction of the dentate nuclei-basal ganglia pathway may be involved.

Differential diagnosis of tendon tumors: xanthomas caused by hyperlipidemia in children.

Tumors of tendons and tendon sheaths causing pain and mechanical problems are often because of overstraining, and in most cases the resulting common ganglia can be easily removed. We describe an 8-year-old child in whom the tumor's origin had remained undetected and was related to a homozygous familial hypercholesterolemia, which can be associated with multiple xanthomas of the skin and tendons. After a thorough investigation and therapy, a program to prevent arteriosclerosis and myocardial infarct in this patient was initiated.

Leukoencephalopathies associated with inborn errors of metabolism in adults.

The discovery of a leukoencephalopathy is a frequent situation in neurological practice and the diagnostic approach is often difficult given the numerous possible aetiologies, which include multiple acquired causes and genetic diseases including inborn errors of metabolism (IEMs). It is now clear that IEMs can have their clinical onset from early infancy until late adulthood. These diseases are particularly important to recognize because specific treatments often exist. In this review, illustrated by personal observations, we give an overview of late-onset leukoencephalopathies caused by IEMs.

Sterol 27-hydroxylase deficiency: a rare cause of xanthomas in normocholesterolemic humans.

Cerebrotendinous xanthomatosis is characterized by the accumulation of cholestanol and cholesterol in xanthomas and brain causing a number of severe symptoms. More than 20 different mutations have been identified in the gene encoding sterol 27-hydroxylase. Defects in the gene lead to reduced bile acid biosynthesis, with accumulation of 7 alpha-hydroxylated intermediates, one of which is a precursor to cholestanol. The disease can be treated successfully with chenodeoxycholic acid, which reduces the upregulation of cholesterol 7 alpha-hydroxylase and, therefore, the formation of cholestanol. Disruption of the gene encoding sterol 27-hydroxylase in mice does not have the same metabolic consequences as in humans.

Exon skipping in the sterol 27-hydroxylase gene leads to cerebrotendinous xanthomatosis.

We report a new mutation in the sterol 27-hydroxylase (CYP 27) gene in a Dutch family with cerebrotendinous xanthomatosis: a G-->A transition in the splice donor site in intron 4. This mutation leads to skipping of exon 4, resulting in a loss of 66 amino acids in the CYP 27 enzyme molecule.