OBJECTIVETo study the clinical and genetic characteristics of twins and siblings affected with Wilson's disease (WD).

METHODSClinical data and blood samples were collected from the subjects after informed consent was obtained. Genomic DNA was extracted and potential mutations in the exons in ATP7B gene were detected with PCR-DNA sequencing. Short tandem repeat (STR) genotyping was performed to determine the zygosity of the twins.

RESULTSThe 5 pairs of twins have all met the diagnostic criteria for WD. STR genotyping has confirmed that 4 pairs were monozygotic twins. 3 pairs of twins had an onset with liver symptoms, the other 2 had an onset with brain symptoms. ATP7B gene mutations were detected in 4 pairs of twins, which have all located in exons 8 and 13. A heterozygous p.R778W mutation in exon 8 and homozygous p.P992L mutation in exon 13 were detected in all patients from one family, whose parents have carried a heterozygous p.R778W mutation and p.P992L heterozygous mutation, respectively, which suggested loss of heterozygosity (LOH). In one family, no mutation was detected in all exons of the ATP7B gene in the patients and their parents. For a triplet, one female was with definite WD and brain symptoms at the onset, one male had subclinical type with WD, whilst another female was completely normal. The triplets and their mother have all carried a p.P992L heterozygous mutation .

CONCLUSIONAbove results have confirmed an important role for genetic factors in the pathogenesis of WD. In addition to point mutations, LOH is also involved in the pathogenesis for WD.

Adenosine Triphosphatases ; genetics ; Adolescent ; Base Sequence ; Cation Transport Proteins ; genetics ; Child ; Child, Preschool ; Copper-transporting ATPases ; Exons ; Female ; Genotype ; Hepatolenticular Degeneration ; diagnosis ; genetics ; Humans ; Loss of Heterozygosity ; Male ; Mutation ; Siblings ; Twins ; Young Adult

Objective: To report a case of peripheral neuropathy secondary to copper deficiency (CD) by long-term decoppering chelation in Wilson′s disease (WD) to enhance understanding of the disease, and to pay more attention to individualized treatment of WD. Methods: A case of WD diagnosed 12 years ago confirmed by gene detection and since then treated with anti-copper agent was diagnosed as CD based peripheral neuropathy and significant neutropenia and followed up for six months, and the clinical manifestations, laboratory examination, electrophysiology, imaging features were summarized. The related literatures were reviewed. Results: A total of 16 cases of WD complicated with CD were reviewed and analyzed, including seven males and nine females aged 13-56 years. All of them were treated with zinc for 1-38 years, and nine cases with peripheral neuropathy. Hematological indicators can be significantly improved and neurological symptoms can be partially alleviated after stopping copper removal treatment. Conclusions Peripheral neuropathy in a WD with treatment-related CD may occur in blind treatment, irregular treatment monitoring and without individualized treatment adjustment. It is necessary to monitor blood routine, copper and zinc metabolism regularly and advocate individualized treatment of WD.

Objective To detect the molecular regulatory mechanism of co-treatment with LA and PCA on P38 MAPK signaling Pathway in the Neurons of Wilson's Disease Model-TX mice.Methods The neurons of TX suckling mice were isolated and cultured by primary method,and were divided into control group,model group,ALA group,PCA group and combined group.Flow cytometry was used to analyze the expression of ROS and JC-1.Western blot was used to detect the expression of P38 MAPK,Cyt C,Caspase 9 and Caspase 3.Results Flow cytometry results showed that MFI of ROS was 59.29±1.22,53.19±1.34 and 52.46±1.23 in ALA,PCA and co-treatment.ALA,PCA and co-treatment could significantly reduce the release of ROS and enhance the fluorescence intensity of JC-1 (P＜0.01).Compared with ALA group and PCA group,combined group could reduce the release of ROS and significantly enhance the fluorescence intensity of JC-1.Western blot indicated that the expression levels of P38 MAPK,Cyt C,Caspase 9,Caspase 3 in the neurons of model group had a remarkable increase compared with control group.Compared with the model group,the three treatment groups could decrease the expression levels of P38 MAPK,Cyt C,Caspase 9 and Caspase 3 in the neurons of TX suckling mice (P＜0.01).Meanwhile,the protein levels of P38 MAPK,Cyt C,Caspase 9 and Caspase 3 had a significant decrease compared with ALA group and PCA group.Conclusion he present findings suggest that co-treatment with LA and PCA can increase the copper excretion,reduce copper-induced mitochondria damage and attenuate the neurotoxicity,which in turn decrease neuronal apoptosis and improve neurological impairment of WD.

OBJECTIVETo analyze a case of cerebrotendinous xanthomatosis (CTX) with mental retardation as the initial neurological symptom.

METHODSMedical imaging, histopathological assay and genetic testing were carried out to analyze the patient.

RESULTSNeurological manifestations of the 27-year-old male patient were initiated by mental retardation and subsequently memory lapses, ataxia, spastic paraplegia and fuzzy language. Other symptoms included cataract, xanthomatosis in Achilles tendon, kidney stones and high arches. The total bile acid in serum has risen to 14.7 umol/L. There were symmetrical abnormal signals in bilateral cerebellar dentate nuclei, hypointensities on T1WI and DWI and mixed signals on T2WI. Cholesterol crystallization and cholesterol granulomatous inflammation were found upon pathological examination of the Achilles tendon. The patient was found to have carried a compound heterozygous mutation of the CTX gene, which consisted of two novel mutations including c.379C>T (p.Arg127Trp) in exon 2 and c.1174G>A (p.Glu392Lys) in exon 6 of the CYP27A1 gene.

CONCLUSIONClinicians should be alert to cerebrotendinous xanthomatosis when the patient has mental retardation caused by genetic and metabolic factors beginning at a young age, particularly accompanied with tendinous xanthomatosis and cataracts. CTX can be readily diagnosed by histopathological assay and sequencing of the CYP27A1 gene.

Adult ; Cholestanetriol 26-Monooxygenase ; genetics ; Humans ; Intellectual Disability ; etiology ; Male ; Xanthomatosis, Cerebrotendinous ; complications ; genetics