Cerebrotendinous xanthomatosis without tendon xanthomas mimicking Marinesco-Sjoegren syndrome: a case report.

A 39 year old patient with cerebellar signs, juvenile cataracts, and dull normal intelligence had cerebrotendinous xanthomatosis without tendon xanthomas, diagnosed previously as Marinesco-Sjoegren syndrome. Cerebrotendinous xanthomatosis was proved by a greatly increased excretion of bile alcohols in the patient's urine. Cerebrotendinous xanthomatosis is a sterol storage disorder due to an autosomal recessive inherited defect of sterol 27-hydroxylase characterised by high cholestanol concentration in multiple tissues. If tendon xanthomas are not present, a diagnosis of cerebrotendinous xanthomatosis will often not be made, unless biochemical tests are performed. The clinical features of cerebrotendinous xanthomas strongly resembles Marinesco-Sjoegren syndrome. Marinesco-Sjoegren syndrome is a autosomal recessive disorder characterised by the triad cerebellar ataxia, congenital cataract, and mental retardation. Although a late onset after the first decade of life favours cerebrotendinous xanthomatosis as the underlying disease, a definite distinction between cerebrotendinous xanthomatosis without tendon xanthomas and Marinesco-Sjoegren syndrome based on clinical presentation may be difficult. It is considered that some patients with Marinesco-Sjoegren syndrome reported in the medical literature had cerebrotendinous xanthomatosis without tendon xanthomas. This is of crucial clinical relevance, because, by contrast with Marinesco-Sjoegren syndrome, treatment for cerebrotendinous xanthomatosis is already available.     

Cerebrotendinous xanthomatosis: a rare disease with diverse manifestations

This mini-review deals with a new appraisal of cerebrotendinous xanthomatosis. In addition to neurologic symptoms, patients with cerebrotendinous xanthomatosis develop cataracts, diarrhea, Achilles tendon xanthoma, atherosclerotic vascular disease, and many other abnormalities. Although the pathophysiology of the disease is not completely understood, excess production and consequent accumulation of cholestanol in tissues may play a crucial role. Chenodeoxycholic acid is the most effective therapy. The causative role and detrimental effects (at a low plasma level) of cholestanol merit further investigation.     

Cerebrotendinous xanthomatosis as a multisystem disease mimicking premature ageing.

The authors report the clinical findings in 10 Italian cases of cerebrotendinous xanthomatosis (CTX). In addition to the classical neurological manifestations, the presence of psychiatric symptoms and osteopenia is stressed. Chronic treatment with chenodeoxycholic acid resulted in decreased plasma cholestanol levels and improvement of some central and peripheral neurophysiological parameters including EEG, VEP, SEP and conduction velocities. Due to the presence of cataracts, ischemic heart disease, premature atherosclerosis, mental deterioration and osteoporosis, usually found in old age, CTX can be considered a useful model of premature ageing.     

Cerebrotendinous xanthomatosis: clinical manifestations, diagnostic criteria, pathogenesis, and therapy

In this report, we review the clinical, biochemical, pathophysiologic, and therapeutic aspects of cerebrotendinous xanthomatosis. We stress the importance of early diagnosis and treatment. In addition, we describe our experience in treating patients with chenodeoxycholic acid, an essential drug for this disorder that is no longer available.     

Psychiatric signs and symptoms in treatable inborn errors of metabolism

Possible underlying organic causes of psychiatric symptoms can be overlooked in the clinical setting. It is important to increase awareness amongst psychiatric and neurological professionals with regard to certain inborn errors of metabolism as, in some cases, disease-specific therapies are available that can, for instance, treat underlying metabolic causes. The following article describes the basic pathophysiology, clinical and neurological features, and available diagnostic procedures of six treatable metabolic diseases that are associated with neuropsychiatric symptoms: Wilson’s disease, cerebrotendinous xanthomatosis, porphyrias, homocysteinemia, urea cycle disorders, and Niemann-Pick disease type C (NP-C). NP-C is taken as a particularly relevant example because, while it is traditionally considered to be a condition that presents with severe neurological and systemic manifestations in children, an increasing number of patients are being detected who have the adolescent- or adult-onset form, which is frequently associated with neuropsychiatric signs. A notable proportion of adult-onset cases have been reported where NP-C has mistakenly been diagnosed and treated as a psychiatric condition, usually based on patients’ initial presentation with psychotic or schizophrenia-like symptoms. Underlying organic causes of psychiatric disorders such as psychosis should be considered among patients with atypical symptoms and/or resistance to standard therapy. Alongside improved frameworks for additional multidisciplinary diagnostic work in patients with suspected organic disease, the development of convenient and affordable biochemical screening and/or diagnostic methods has enabled new ways to narrow down differential diagnoses.     

Cerebrotendinous xanthomatosis: a rare cause of spinocerebellar syndrome

A 34-year-old patient demonstrating pyramidal and cerebellar signs, accompanied by epilepsy, peripheral neuropathy, mental retardation and bilateral cataract was diagnosed with cerebrotendinous xanthomatosis based on the clinical picture, magnetic resonance imaging of the brain and serum sterol analysis. Tendon xanthomas were not observed in this case. After establishing the diagnosis, treatment with chenodeoxycholic acid and statin was introduced. During the next two years of the follow-up, serum cholestanol and 7α-hydroxycholesterol levels decreased in response to the therapy, but this was not reflected in the patient's neurological condition, which was slowly progressing. Treatment effectiveness in cerebrotendinous xanthomatosis is variable, notably better in patients who had started therapy before the injury to the nervous system took place. The present case report points to cerebrotendinous xanthomatosis as a rare cause of spinocerebellar syndrome, which might be treatable if diagnosed in early life.     

Cerebrotendinous xanthomatosis: treatments with simvastatin, lovastatin, and chenodeoxycholic acid in 3 siblings

We report 3 sisters treated for cerebrotendinous xanthomatosis. We treated one, with a severe neurologic form of the illness, with chenodeoxycholic acid, then lovastatin and simvastatin. These drugs had different efficacy and tolerance, but induced no clinical improvement. Her sisters, without neurologic symptoms, received chenodeoxycholic acid, which normalized the cholestanol level. Optimal treatment of this illness must begin before there is significant clinical symptomatology.     

Peripheral neuropathy in a sporadic case of cerebrotendinous xanthomatosis]

The authors report the case of a 22-year old man presenting with cerebrotendinous xanthomatosis who developed peripheral neuropathy. Nerve biopsy showed evidence of demyelination and remyelination, suggesting axonal degeneration. The neurological symptoms improved after treatment with chenodesoxycholic acid.     

Treatable hereditary neuro-metabolic diseases

Hereditary metabolic diseases may appear during adolescence or young adulthood, revealed by an apparently unexplained neurological or psychiatric disorder. Certain metabolic diseases respond to specific treatments and should be identified early, particularly in emergency situations where rapid introduction of a treatment can avoid fatal outcome or irreversible neurological damage. The main diseases leading to an acute neurological syndrome in the adult are urea cycle disorders, homocysteine metabolisms disorders and porphyria. More rarely, Wilson's disease, aminoacid diseases, organic aciduria, or pyruvate dehydrogenase deficiency, beta-oxidation disordes or biotin metabolism may be involved. Most emergency situations can be screen correctly with simple tests (serum ammonia, homocysteine, lactate, urinary prophyrines, acylcarnitine pattern, amino acid and organic acid chromatography). For chronic situations, the main treatable diseases are Wilson's disease, homocysteine, cerebrotendinous xanthomatosis, Refsum's disease, vitamin E deficiency, Gaucher's disease, Fabry's disease, and neurotransmitter metabolism disorders. We present treatable metabolic disorders as a function of the different clinical situations observed in adults.     

Étude rétrospective multicentrique de 15 cas adultes de xanthomatose cérébrotendineuse : aspects cliniques et paracliniques typiques et atypiques

IntroductionCerebrotendinous xanthomatosis, a metabolic leukodystrophy with an autosomal recessive inheritance, is secondary to deficiency of sterol 27-hydroxylase, an enzyme involved in cholesterol catabolism. Classical symptoms include clinical or infraclinical xanthomas affecting the skin and tendons, early cataracts, neurological signs and diarrhea. Brain imaging reveals involvement of the dentate nuclei and periventricular white matter hyperintensities. The diagnosis is based on an increased cholestanol level in serum, confirmed by the presence of a mutation in the CYP27A1 gene. Treatment is based on chenodeoxycholic acid.MethodWe report a retrospective multicentric study of 15 cases of cerebrotendinous xanthomatosis diagnosed in French adults. Clinical, molecular and MRI findings were recorded in all patients.ResultsThe average age at diagnosis was 39 years (range 27–65). Disease onset occurred in childhood in 73% of patients and in adulthood in 27%. All patients with a pediatric onset were diagnosed during adulthood (age range 28–65 years). Clinical symptoms variably associated cerebellar syndrome, pyramidal syndrome, cognitive decline, epilepsy, neuropathy (sought in 10 of our patients, present in forms in 8), psychiatric disorders, cataract and xanthomas. One patient had an atypical presentation: monoparesis associated with xanthomas. Brain MRI was abnormal in all: findings consisted in T2-weighted hyperintensity of the dentate nuclei (47%), periventricular leuoencephalopathy (73%) which preferentially involved the posterior cerebral part (60%), leucoencephalopathy with a vascular pattern (7%), hyperintensity of the cortico-spinal tracts (53%), globi pallidi, corpus callosum and cerebral atrophy (33%). Serum cholestanol was elevated in 93% of patients. The most frequent mutation was 1183C>T (n = 5/15). Under treatment with chenodeoxycholic acid, eight patients improved initially, followed by stabilization in five of them, and worsening in the others. Four patients died.ConclusionPatients with the xanthoma-neurological disorder association should be tested for cerebrotendinous xanthomatosis. The disease often begins in childhood with a diagnostic delay but also in adulthood. Involvement of the dentate nuclei is specific but not sensitive and the supratentorial leucoencephalopathy is not specific but with an antero-posterior gradient. A vascular distribution and involvement of the corpus callosum are possible. Serum cholestanol assay is very reliable: an elevated level provides the diagnosis, which must nevertheless be confirmed by molecular biology.     

Chronic demyelinating peripheral neuropathy in cerebrotendinous xanthomatosis

Three siblings with chemically proved cerebrotendinous xanthomatosis presented with typical neurological manifestations of dementia and spinocerebellar disorder. Electrodiagnostic tests revealed demyelinating neuropathy in all three. Sural nerve biopsies showed loss of myelinated large fibers, marked Schwann cell proliferation, and onion bulb formation. Teased-fiber preparations confirmed the occurrence of segmental demyelination and remyelination. We suggest that demyelinating neuropathy is part of the neurological spectrum of cerebrotendinous xanthomatosis and should be considered in the differential diagnosis of a recessively inherited motor and sensory neuropathy.     

Treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid

We describe a patient with cerebrotendinous xanthomatosis who was treated for one year with chenodeoxycholic acid. Modest clinical improvement was accompanied by marked improvement in visual and brainstem auditory evoked potentials. Improved central nervous system function coincided with return of plasma and cerebrospinal fluid cholestanol levels to normal.     

Somatosensory and motor evoked potentials in the assessment of cerebrotendinous xanthomatosis before and after treatment with chenodeoxycholic acid: a preliminary study.

We studied two unrelated patients with cerebrotendinous xanthomatosis, in whom clinical examination revealed central nervous system long tract involvement. Brain and spinal cord magnetic resonance imaging showed no signs supporting the involvement of the long pathways. Somatosensory and motor evoked potentials demonstrated central sensory and motor conduction abnormalities, which suggested distal degeneration of longer fibers, rather than scattered focal lesions in the CNS. In one of the patients the neurophysiological study was repeated 6 and 12 months after the beginning of treatment with chenodeoxycholic acid, showing a progressive improvement. Therefore, our data suggest that central motor and sensory conduction studies may be useful in the assessment of the disease and in monitoring treatment.     

Combined treatment with LDL-apheresis, chenodeoxycholic acid and HMG-CoA reductase inhibitor for cerebrotendinous xanthomatosis

The effects of combined treatment with low-density lipoprotein (LDL)-apheresis, chenodeoxycholic acid (CDCA) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor were studied in 2 patients with cerebrotendinous xanthomatosis. Patient 1 was initially treated with LDL-apheresis alone: serum cholestanol levels decreased by 50% after each apheresis, but returned to their initial levels within 2 weeks. After an addition of CDCA administration, the serum cholestanol levels steadily decreased, resulting in slight improvement of neurological symptoms. Patient 2 received a combined treatment with LDL-apheresis, CDCA and HMG-CoA reductase inhibitor. This combination showed less LDL-apheresis-dependent fluctuation and more rapid decrease of serum cholestanol levels than those in Patient 1, resulting in improvement and stabilization of the symptoms. Our results suggest that LDL-apheresis in combination with CDCA and HMG-CoA reductase inhibitor may have beneficial effects and can be one of the treatment options.     

Psychiatric manifestations in cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare and severe, but treatable, inborn disorder of bile acid biosynthesis and sterol storage with autosomal recessive inheritance and variable clinical presentation. CTX treatment consists of chenodeoxycholic acid and must be started as early as possible to prevent permanent disability. Psychiatric manifestations are rare and non-specific, and often lead to significant diagnostic and treatment delay. Therefore, better recognition of the gamut of psychiatric manifestations in CTX can diminish the risk of misdiagnosis and irreversible neurological deterioration. We hereby describe the psychiatric features in CTX. A complete review of all published cases of CTX in the medical literature was undertaken and the case reports with psychiatric presentation were collected and analyzed. We also describe the psychiatric features in relation to the neurological semeiology in six patients with CTX diagnosed at the La Salpêtrière Hospital. We conclude that psychiatric manifestations in CTX follow a bimodal/bitemporal pattern, appearing early in the disease course in the form of a behavioral/personality disorder associated with learning difficulties or mental retardation, or manifesting in advanced disease in the setting of dementia as rich neuropsychiatric syndromes, such as frontal, orbitofrontal or frontotemporal syndromes of cortico-subcortical dementia encompassing behavioral/personality disturbance, affective/mood disorders or psychotic disorders. 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.     

Cerebrotendinous xanthomatosis: evidence of lipomatous hypertrophy of the atrial septum

Premature atherosclerosis and cardiac complications have been reported among the systemic manifestations of cerebrotendinous xanthomatosis (CTX), a rare bile acid disorder with predominantly neurological features. In some cases, myocardial infarction has been the cause of sudden death. We examined nine CTX patients to determine whether they also had clinical or subclinical signs of cardiovascular disorders. In four of them, transthoracic echocardiography showed thickening of the interatrial septum compatible with lipomatous hypertrophy. The unexpected association of the two abnormalities is unlikely to be coincidental and suggests that careful cardiac examination should be considered, even in the absence of clinical manifestations. Received: 2 February 1998 Received in revised form: 23 March 1998 Accepted: 20 April 1998     

Cerebrotendinous xanthomatosis. Controversies about nerve and muscle: observations in ten patients

Neuromuscular characteristics were documented in ten patients with biochemically and genetically confirmed cerebrotendinous xanthomatosis. An array of genotypes was found in these patients. Only one patient complained of muscle weakness, while clinical signs of peripheral neuropathy were present in six patients. Electromyogram showed predominantly axonal neuropathy in seven patients. Neurogenic changes were seen in muscle biopsies of nine patients. Sural nerve biopsies of three patients showed features of axonal neuropathy. In addition, in one patient, extensive onion bulb formation was seen, which is indicative of a primarily demyelinating process. Five patients had normal mitochondrial respiratory chain enzyme activity. It is concluded that myopathy is not a feature of cerebrotendinous xanthomatosis and that the most prominent neuromuscular abnormality is sensorimotor axonal polyneuropathy.     

Cerebrotendinous cholestanolosis in relation to other cerebral xanthomatoses.

A synopsis is given of 37 reported patients with cerebrotendinous xanthomatosis; divided in 11 possible, but not proven cases of C.T.Ch (cerebrotendinous cholestanolosis), and 26 proven cases. An increased content of cholestanol in serum or tissue, was used as the main criterion. The ophthalmological and neurological signs are tabulated. Attention is drawn to the fact that cholestanol is not mentioned in the extensive literature on related diseases with possible cerebrospinal xanthomas, such as eosinophilic granulomatosis and hyperlipoproteinemia. The importance of a possible role of cholestanol in these diseases is stressed. A hypothetical form of cerebrotendinous cholesterolosis is discussed. A family with a sibship of parents and twelve children, three of which showed C.T.Ch is described. The development of the clinical picture confirmed the variable expression of the autosomal recessive disease. Two patients showed disturbances of steroid metabolism. A first contribution to the search for linkage with the H.L.A. system is presented. Cholestanol over cholesterol ratio, appeared to be independent of the type of lipoprotein. In search for therapy we found in patients with hyperlipoproteinemia type II A, that cholestyramine alone gave dangerously high blood levels of cholestanol; in combined treatment of cholestyramine with clofibrate cholestanol, levels were comparable to those of the controls. The possibilities of therapy are discussed.     

Psychiatric symptoms related to interferon therapy for chronic hepatitis C: clinical features and prognosis

Psychiatric symptoms during interferon (IFN) therapy for viral hepatitis have been a crucial problem in consultation-liaison psychiatry. However, there have been few studies on psychiatric management for these symptoms and their prognosis. Among 943 patients who were treated with IFN for chronic hepatitis C between 1991 and 1995, 43 patients (4.6%) developed psychiatric symptoms during IFN treatment. Three patients (0.3%), with pre-existing psychiatric disorders showed aggravated symptoms and were excluded from the study. All three patients were able to finish the IFN therapy with psychiatric management. Forty patients (4.2%) manifested psychiatric symptoms induced by IFN. Thirteen patients (1.4%) were diagnosed as anxiety disorder and 21 patients (2.2%) revealed mood disorder with depressive features. There were other psychiatric disorders in six patients (0.6%), including psychotic disorder with delusions/hallucinations in four patients (0.4%), mood disorder with manic features in one patient (0.1%) and delirium in one patient (0.1%). Women developed psychiatric symptoms significantly more than men. Ten of 40 patients (25%) stopped IFN treatment because of manifesting psychiatric symptoms induced by IFN. Twelve patients (30%) required psychiatric treatment for more than 24weeks after ceasing IFN, and seven patients still had anxiety, insomnia and mild hypothymia at the end of the present study. Statistical analysis revealed that IFN-beta therapy and psychiatric manifestations including psychotic symptoms, delirium and manic symptoms were significantly related to long-term psychiatric problems. There are considerable numbers of patients who have required long-term psychiatric management even after cessation of IFN treatment.