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Objective: To evaluate different injury factors and pathological characteristics of the brain at different disease stages in toxic milk (TX) mice, an animal model of Wilson's disease (WD)., Methods: Thirty TX mice (10 each at 3, 6 and 12 months old) and 30 age-matched C57 mice were used in this study. Corrected phase (CP) values were determined from susceptibility-weighted images. Myelin content was determined by measuring inhibition optical density values of Luxol fast blue-stained sections. Neurofilament protein 68 kDa (NF68), β-amyloid precursor protein (β-APP), and myelin basic protein (MBP) levels, as well as copper and iron content, in brain nuclei of the TX mouse were evaluated. Gene amplification ratios for catalase (CAT), GSH peroxidase (GSH-PX), nitric oxide synthase (NOS), and superoxide dismutase (SOD) in mouse brain were also determined., Results: Compared with C57 mice, neuronal cell counts were decreased in 12-months-old TX mice (p = .011). Myelin content was decreased in the lenticular nucleus (p = .029), thalamus (p = .030), and brainstem (p = .034) of 6-months-old TX mice; decreases in the corresponding nuclei (p = .044, .037, and .032, respectively) were also found in 12-months-old TX mice. MBP values were lower in the lenticular nucleus and thalamus (p = .027 and .016, respectively) of 6-months-old TX mice and in the corresponding nuclei (p = .24 and .040) of 12-months-old TX mice. NF-68 values were lower in the lenticular nucleus and thalamus (p = .034 and .037, respectively) of 6-months-old TX mice and in the corresponding nuclei (p = .006 and .012) of 12-months-old TX mice. β-APP values were higher in the thalamus of 6-months-old (p = .037) and 12-months-old (p = .012) TX mice. Iron content was higher in the lenticular nucleus, thalamus, and cerebellum (p = .044, .038, and .029, respectively) of 6-months-old TX mice and in the corresponding nuclei (p = .017, .024, and .029) of 12-months-old TX mice. The NOS gene amplification multiple was higher (p = .039), whereas the SOD1 gene amplification multiple was lower (p = .041) in 12-months-old TX mice. There was no correlation between metal content or oxidation index and pathological index., Conclusions: The pathological characteristics of the brains of TX mice may differ at different ages. Different pathogenic factors, including copper and iron deposition and abnormal oxidative stress, are present at different stages., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Objective: To investigate the cause of the motor asymmetry in Wilson's disease (WD) patients using functional MRI., Methods: Fifty patients with WD and 20 age-matched healthy controls were enrolled. Neurological symptoms were scored using the modified Young Scale. All study subjects underwent diffusion tensor imaging (DTI), susceptibility-weighted imaging (SWI), and resting-state functional MRI (rs-fMRI) of the brain. Six regions of interest (ROI) were chosen. Fiber volumes between ROIs on DTI, corrected phase (CP) values on SWI, amplitude of low-frequency fluctuation (ALFF), and regional homogeneity (REHO) values on rs-fMRI were determined. Asymmetry index (right or left value/left or right value) was evaluated., Results: Asymmetry of rigidity, tremor, choreic movement, and gait abnormality (asymmetry index = 1.33, 1.39, 1.36, 1.40), fiber tracts between the GP and substantia nigra (SN), GP and PU, SN and thalamus (TH), SN and cerebellum, head of the caudate nucleus (CA) and SN, PU and CA, CA and TH, TH and cerebellum (asymmetry index = 1.233, 1.260, 1.269, 1.437, 1.503, 1.138, 1.145, 1.279), CP values in the TH, SN (asymmetry index = 1.327, 1.166), ALFF values, and REHO values of the TH (asymmetry index = 1.192, 1.233) were found. Positive correlation between asymmetry index of rigidity and fiber volumes between the GP and SN, SN and TH ( r  = .221, .133, p  = .043, .036), and tremor and fiber volumes between the CA and TH ( r  = .045, p  = .040) was found., Conclusions: The neurological symptoms of patients with WD were asymmetry. The asymmetry of fiber projections may be the main cause of motor asymmetry in patients with WD.

Objective: To evaluate damage to the extracorticospinal tract in Wilson disease (WD) patients using diffusion tensor imaging (DTI)., Methods: 70 patients with WD, including 50 with cerebral type and 20 with hepatic type, and 20 age-matched healthy controls were enrolled. Neurological symptoms were scored using the modified Young Scale. Patients with cerebral type WD were divided into four subgroups: those with (1) hypokinesia, (2) parkinsonism, (3) mouth and throat dystonia, and (4) psychiatric symptoms. All study subjects underwent DTI of the brain. Five regions of interest (ROIs) were chosen. Fractional anisotropy (FA) and fiber volumes between ROIs were determined, and the relationships between DTI metrics and clinical status were evaluated., Results: FA values and fiber volumes between subcortical nuclei were lower in WD patients. Fiber volumes between the putamen (PU) and the globus pallidus (GP), substantia nigra (SN), and thalamus (TH); between the head of the caudate nucleus (CA) and the GP and TH; and between the TH and cerebellum were lower in group 1 than in the other groups of WD patients. Fiber volumes between the GP and the SN and TH were lower in group 2, and fiber volumes between the SN and TH were lower in group 3. DTI metrics differed between patients with the cerebral and hepatic types of WD., Conclusions: DTI can reconstruct the network of the extracorticospinal tract. Fiber projection between subcortical nuclei was abnormal in WD patients. Damage to fiber connections may correlate with neurological symptoms in WD patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Wilson disease is an inherited disorder of excessive copper accumulation. The commonly used drug d-penicillamine (PA) or trientine both cause a high incidence (10-50%) of neurological worsening, which rarely occurs with tetrathiomolybdate (TM) treatment. To investigate the mechanisms of neurologic deterioration after the initiation of chelation therapy, brain hydroxyl radical and free copper were assessed in vivo in this study. On days 3, 7, 14, and 21 after PA or TM administration, striatal hydroxyl radical levels of both TX mice and controls were assessed by terephthalic acid (TA) combined with microdialysis and high-performance liquid chromatography (HPLC). Within the same microdialysis samples, free copper was measured by inductively coupled plasma mass spectrometry (ICP-MS). The results showed that both hydroxyl radical and free copper markedly increased in the striatum of TX mice during PA administration but were not elevated when administering TM. These results suggested that the further increased free copper in the brain and oxidative stress caused by some chelators might contribute to the neurological deterioration., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to evaluate the feasibility of characterizing the brain-mineral deposition in patients with Wilson disease (WD) using susceptibility-weighted imaging (SWI)., Materials and Methods: The study enrolled 30 WD patients and 20 age-matched healthy controls. Neurological symptoms were scored using the modified Young Scale. The hepatic function indices, serum and urinary copper content, and serum iron content were determined. All study objects received the magnetic resonance imaging (MRI) and SWI test of the brain. The values of corrected phase (CP) were calculated on SWI. The relationship between CP values and the clinical status were evaluated., Results: The serum iron content of WD patients was higher than the normal. The CP values of substantia nigra, caudate nucleus, and globus pallidus of WD were lower than the normal values, while the CP value of substantia nigra was the lowest. No correlations were determined between the CP values and the iron and copper parameters. There was negative correlation between the scores of dysarthria and the CP values of the globus pallidus. There was negative correlation between the scores of tremor and the CP values of caudate nucleus. Some regions, which had high signals on T2-weighted image, had low signals on SWI., Conclusions: There might be abnormal iron metabolism in patients with WD. The decreased CP values might reflect a deposition of both copper and iron. SWI may be more sensitive than the ordinary MRI. The mineral deposition may contribute to the neural symptoms.

Wilson disease (WD) is characterized by the accumulation of copper arising from a mutation in the ATP7B gene. Penicillamine (PA) makes 10-50% of the patients with neurologic symptoms neurologically worse at the early stage of administration. The aim of this study was to determine how the copper metabolism changes and whether the change impairs the brain of toxic milk (tx) mice, an animal model of WD, during the PA administration. The free copper and protein-bound copper concentrations in the serum, cortex and basal ganglia of tx mice with PA administration for 3 days, 10 days and 14 days, respectively, were investigated. The expression of copper transporters, ATP7A and CTR1,was analyzed by real-time quantitative PCR, immunofluorescence and Western blot. Then SOD, MDA and GSH/GSSG were detected to determine whether the oxidative stress changed correspondingly. The results revealed the elevated free copper concentrations in the serum and brain, and declined protein-bound copper concentrations in the brain of tx mice during PA administration. Meanwhile, transiently increased expression of ATP7A and CTR1 was observed generally in the brain parenchyma by immunofluorescence, real-time quantitative PCR and Western blot. Additionally, ATP7A and CTR1 were observed to locate mainly at Golgi apparatus and cellular membrane respectively. Intense staining of ATP7A in the choroid plexus was found in tx mice on the 3rd and 10th day of PA treatment, but rare staining of ATP7A and CTR1 in the blood-brain barrier (BBB). Decreased GSH/GSSG and increased MDA concentrations were also viewed in the cortex and basal ganglia. Our results suggested the elevated free copper concentrations in the brain might lead to the enhanced oxidative stress during PA administration. The increased free copper in the brain might come from the copper mobilized from brain parenchyma cells but not from the serum according to the ATP7A and CTR1 expression analysis.

Objective To report a case of peroxisomal acyl-CoA oxidase (ACOX1) deficiency, which was caused by an unreported mutation of ACOX1 gene, and review its clinical characteristics. Methods and Results The male child patient suffered from neonatal hypotonia, developmental retardation and epilepsy seizure once since neonatal period. Neurodegeneration appeared at the age of 3 and developed rapidly to difficulty of sitting, standing and walking independently and retrogressive language expression ability. Physical examination showed special face, pyramidal tract sign and cerebellar signs. Cranial MRI revealed symmetric demyelinating lesions in bilateral brain stem and cerebellum along with increased serum very-long-chain fatty acids (VLCFAs). Whole exome sequencing revealed c. 1589A > G (p. His530Arg) homozygous mutation in ACOX1 gene. His parents carried the same heterozygous mutation without symptoms and this phenomenon was in accord with co-segregation. According to the guidelines of American College of Medical Genetics and Genomics (ACMG), we considered this new variation to be possibly pathogenic variation. Finally, the patient was diagnosed as ACOX1 deficiency. Conclusions As for patients who suffer from hypotonia, epilepsy seizure and growth retardation since neonatal period, they should be altered to ACOX1 deficiency if cranial MRI shows symmetrical abnormal foci in cerebellum and brain stem. Positive family history, increased VLCFAs level, and gene detection would be beneficial to definite diagnosis. [ABSTRACT FROM AUTHOR]