Clinical Note: Bipolar disorder in Cerebrotendinous Xanthomatosis: a case report.

Cerebrotendinous X anthomatosis (CTX) is a rare autosomal recessive disorder presenting with possible psychiatric manifestations that, once established, are difficult to control. We present the case of a 29-year-old woman diagnosed with CTX who developed bipolar disorder. Owing to difficulties in pharmacological management, the patient underwent electroconvulsive therapy (ECT), which lead to a favorable outcome. Little is known about the treatment of psychiatric symptoms of CTX, un uncommon disorder, though ECT may be an effective and safe approach.

Nota Clínica: Trastorno bipolar en xantomatosis cerebrotendinosa: a propósito de un caso / Clinical Note: Bipolar disorder in Cerebrotendinous Xanthomatosis: a case report

La xantomatosis cerebrotendinosa (XCT) es una rara enfermedad autosómica recesiva que puede cursar con manifestaciones psiquiátricas cuyo tratamiento puede resultarcomplejo. Presentamos el caso de una mujer de 29 años, diagnosticada de XCT, que desarrolló un trastorno bipolar queno respondió a tratamiento farmacológico, precisando terapia electroconvulsiva (TEC), cuyo resultado fue positivo. Alser la XCT una enfermedad rara, existe poca evidencia sobreel abordaje farmacológico de la sintomatología psiquiátricaque puede aparecer en el curso de la enfermedad. En estesentido, planteamos que la TEC pueda ser una opción de tratamiento segura y eficaz. (AU)

Cerebrotendinous X anthomatosis (CTX) is a rare autosomal recessive disorder presenting with possible psychiatricmanifestations that, once established, are difficult to control. We present the case of a 29-year-old woman diagnosedwith CTX who developed bipolar disorder. Owing to difficulties in pharmacological management, the patient underwentelectroconvulsive therapy (ECT), which lead to a favorableoutcome. Little is known about the treatment of psychiatricsymptoms of CTX, un uncommon disorder, though ECT maybe an effective and safe approach. (AU)

Clinical and molecular genetic features of cerebrotendinous xanthomatosis patients in Chinese families.

Cerebrotendinous xanthomatosis (CTX) is a lipid-storage disease caused by mutations in CYP27A1. Current publications of Chinese CTX were mainly based on case reports. Here we investigated the clinical manifestations, genetic features in Chinese CTX patients. The clinical materials of 4 Chinese CTX pedigrees were collected. The genetic testing was done by polymerase chain reaction plus Sanger sequencing. The features of Chinese CTX patients reported previously were also reviewed. Three novel mutations of p.Arg513Cys, c.1477-2A > C in family 1 and p.Arg188Stop in family 4 (NM 000784.3) in CYP27A1 were found. The probands in our study manifested cerebellar ataxia, tendon xanthoma and spastic paresis in family 1 and 4, tendon xanthoma plus spastic paraparesis in family 2, asymptomatic tendon xanthoma in family 3. Three known mutations of p.Arg137Gln, p.Arg127Trp and p.Arg405Gln were found respectively in Family 2, 3 and 4. For the Chinese patients reviewed, the most common findings were xanthomatosis (100%), pyramidal signs (100%), cerebellar ataxia (66.7%), cognitive impairment (66.7%), cataracts (50.0%), and peripheral neuropathy (33.3%). Chronic diarrhea was infrequently seen (5.6%). No mutation was found associated with any given clinical features. We identified 3 novel mutations in CYP27A1. In Chinese CTX patients, xanthomatosis was the most common symptom while cataracts and chronic diarrhea were less frequent. The special features in Chinese CTX patients might caused by the lack of serum cholestanol test and should be confirmed in larger number of patients in the future.

A novel frameshift mutation in the sterol 27-hydroxylase gene in an Egyptian family with cerebrotendinous xanthomatosis without cataract.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by deficiency of the mitochondrial cytochrome P450 sterol 27-hydroxylase enzyme encoded by CYP27A1 gene. CTX is characterized by tendon xanthomas, juvenile cataracts and multiple progressive neurological symptoms. Here we report on the clinical and molecular findings of a 35-years old Egyptian patient with CTX without cataract. Parents were first cousins with family history of two deceased sibs with mild impaired cognitive functions and epilepsy without appearance of tendon xanthomas. Our proband had learning disabilities and developed seizures at 9 years old. Tendon xanthomata appeared at the age of 16 and his neurological symptoms remained stationary till 28 years followed by progressive cerebello-pyramidal signs, dementia and psychiatric disturbance. Cataract was not evident in our patient. Brain MRI showed the characteristic focal lesions appeared as xanthomas in cerebellum and occipital horns of lateral ventricles. Molecular study identified a novel homozygous frameshift mutation in CYP27A1 gene, c.1169delT (p.K391Rfs*17). Our study emphasizes the important role of early genetic testing in prevention of morbidity and mortality of the disease and proper counseling. Moreover, it shows that the absence of cataract should not rule out the diagnosis of CTX.

Novel cerebrotendinous xanthomatosis mutation causes familial early dementia in Colombia.

INTRODUCTION: Cerebrotendinous xanthomatosis is an infrequent cause of dementia. It is an autosomal recessive disorder with clinical and molecular heterogeneity. OBJECTIVE: To identify the presence of a possible mutation in a Colombian family with several affected siblings and clinical characteristics compatible with cerebrotendinous xanthomatosis associated to early dementia. MATERIALS AND METHODS: We studied a series of cases with longitudinal follow-up and genetic analysis. RESULTS: These individuals had xanthomas, mental retardation, psychiatric disorders, behavioral changes, and multiple domains cognitive impairment with dysexecutive dominance that progressed to early dementia. CYP27A1 gene coding region sequencing revealed a novel mutation (c.1183_1184insT). CONCLUSION: The mutation found in this family is responsible for the described dementia features. Early identification of familial history with mental retardation, xanthomas and cognitive impairment might prevent the progression to this treatable type of dementia. Even though this mutation lies in the most frequently mutated codon of CYP27A1 gene, it has not been reported previously.

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.

Fluoxetine-responsive depression in a Chinese cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive, lipid storage disorder which is extremely rare in the Chinese population. It is characterized by progressive neurologic dysfunction and enlargement of tendon xanthomas, and is often accompanied with neuropsychiatric symptoms. Few reports are available regarding depression and antidepressant medication in CTX patients. Here, we report a Chinese case of CTX associated with fluoxetine-responsive major depression.

Unusual cerebrotendinous xanthomatosis with fronto-temporal dementia phenotype.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP27). We report a 53-year-old man, with an unusual phenotype of CTX. He had xanthomas since adolescence. He had no mental retardation and developed at 44 years a progressive neuropsychiatric phenotype, suggestive of fronto-temporal dementia according to clinical Neary criteria. Cataract and ataxia were absent. Cerebral MRI revealed diffuse hyperintense T2 abnormalities in the supratentorial white matter without cerebellar atrophy or lesions, while Technetium-99m-ECD brain SPECT revealed a severe cerebellar hypoperfusion. Serum cholestanol level was elevated with excessive urinary bile alcohols excretion. Mutation analysis revealed that he was compound heterozygous for two mutations in the CYP27A1 gene: 1016 C > T (exon 5) on one allele and a novel mutation, 1435C > G (exon 8) on the other allele. A follow-up study was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) and simvastatin treatment during 3 years. In spite of this treatment, cognitive functions declined but no other signs of neurological deterioration appeared.

Cerebrotendinous xanthomatosis: 11-year treatment with chenodeoxycholic acid in five patients. An electrophysiological study.

We report the electrophysiological follow-up of five cerebrotendinous xanthomatosis patients treated for 11 years with chenodeoxycholic acid (CDCA). Nerve conduction velocity (NCV) was reduced in three cases. P100 latency of visual evoked potentials was delayed in four cases, interpeaks I-III and I-V of brainstem auditory evoked potentials (BAEPs) was increased in two and interpeak N13-20 of upper limb somatosensory evoked potentials (SEPs) was slowed in one. After 4 months of therapy with CDCA, NCV was normal and did not show any significant change during the 11 years of observation. Central motor conduction time of motor evoked potentials (MEPs) and N24-P40 interpeak latency of lower limb SEPs were increased in five and four cases, respectively, in spite of 2/3-year treatment with CDCA. Improvement of evoked potentials, especially of MEPs and SEPs, was slower and continued over the whole 11-year period. The size of xanthomas slightly decreased in some patients during treatment and the clinical manifestations stabilized, avoiding progressive worsening, but there was no significant improvement in neurological deficit. Two sisters of patients who never took CDCA showed progressive worsening of clinical manifestations, upper limb SEPs and BAEPs.