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Objective: To evaluate the changes of extrapyramidal network in Wilson disease (WD) patients after 5 years of copper excluding treatment using diffusion tensor imaging (DTI). Methods: 50 patients with WD, including 41 with cerebral type and 9 with hepatic type, and 10 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. After 5 years of copper excluding treatment, DTI review was performed.Results: After 5 years of copper excluding treatment, the volumes of fibers between the globus pallidus (GP) and the putamen (PU), the GP and the caudate nucleus (CA), the substantia nigra (SN)and the PU, the SN and the thalamus (TH), the PU and the TH, the TH and the CA, the TH and the cerebellum were also significantly higher in WD patients (P=0.013,0.040,0.037, 0.021,0.042, 0.038, 0.019). The volumes of fibers between the SN and the PU were higher in WD patients of group 3 after therapy (P=0.027). FA values of the fibers between the GP and the PU, the GP and the CA were significantly higher in WD patients of group 4 after therapy (P=0.026, 0.047). FA values of the fibers between the GP and the CA in WD patients with hepatic type were higher in WD patients after therapy (P=0.019).Conclusions: After the treatment with metal chelating agent, the damage of extrapyramidal neural network connection fibers in WD patients were repaired to a certain extent. Different types of WD patients have different responses to copper excluding treatment.

BACKGROUND Mitochondrial diseases are a heterogenous group of multisystemic disorders caused by genetic mutations affecting mitochondrial oxidation function. Brain involvement is commonly found in most cases but rarely as the unique clinical manifestation. Since the knowledge of its clinical manifestation combined with genetic testing is important for preventing misdiagnosis and delay in treatment, we report here how we diagnosed and managed a very unusual case of mitochondrial encephalopathy. CASE SUMMARY We report a 52-year-old woman with recurrent stroke-like episodes carrying the m.10158T>C mutation in the MT-ND3 gene, which is also responsible for fatal infant-onset Leigh syndrome. Despite the common mutation, the present case featured a distinct clinical and neuroimaging manifestation from Leigh syndrome. This patient presented with sudden onset of right-sided hemiparesis and hemilateral sensory disturbance accompanied by a left temporal cluster-like headache and later developed epilepsy during hospitalization, with no other signs suggestive of myopathy, lactate acidosis, or other systemic symptoms. Brain magnetic resonance imaging revealed variable lesions involving multiple cortical and subcortical regions. Furthermore, a negative genetic test obtained from peripheral blood delayed the diagnosis of mitochondrial disease, which was eventually established through second-generation DNA sequencing using biopsied muscle. CONCLUSION Based on this report, we suggest that clinicians pursue proper genetic testing for patients when the clinical phenotype is suggestive of mitochondrial diseases.

The objective of the present study was to characterize the muscle magnetic resonance imaging (MRI) features of a 1-year-old girl with merosin-deficient congenital muscular dystrophy type 1A (MDC1A). Beginning as an infant, this patient exhibited severe hypotonia and proximal weakness, as well as delays in developmental milestones. Her serum creatine kinase levels at 3 months, 8 months and 1 year were 2,959, 1,621 and 1,659 U/l, respectively. Brain MRI indicated symmetric, mild T1WI low, mild T2WI and FLAIR high radial patterns in the white matter of the Cornu posterius of the ventricular lateral. Gene sequencing demonstrated a heterozygous frame-shift mutation in the LAMA2 gene, consisting of an AG deletion at nucleotides 2049–2050 (LAMA2 c.2049_2050delAG). Lower limb muscle MRI presented obvious fatty infiltration of the muscles and muscle atrophy during the early stage of the disease. The gluteus maximus, erector spinae, vastus intermedius, vastus lateralis, adductor magnus, soleus and gastrocnemius muscles were involved, whereas the piriformis, obturator internus, pectineus, adductor longus, adductor brevis and sartorius muscles presented mild or no involvement. Fatty infiltration of the erector spinae was observed during the early stage of the disease. As an additional tool in the differential diagnosis of muscle disorders, muscle MRI can delay the need for muscle biopsy.

AIMS: To detect specific oculomotor deficits in preclinical stage of spinocerebellar ataxia type 3 (SCA3) and evaluate whether these abnormalities prove useful as potential biomarkers of disease progression. METHODS: A Chinese cohort of 56 patients with SCA3, including 12 preclinical carriers of SCA3 (pre‐SCA3) and 44 manifest SCA3, and 26 healthy control individuals were recruited. We performed a detailed investigation on central oculomotor performance including fixation, gaze, smooth pursuit, prosaccade, and antisaccade using video‐oculography. RESULTS: Common oculomotor features of pre‐SCA3 included square‐wave jerk during central fixation and gaze holding, impaired vertical smooth pursuit, slow upward saccade, and increased antisaccade error rate. In our SCA3 cohort, all oculomotor parameters were correlated with the score of the Scale for the Assessment and Rating of Ataxia, whilst some of them were correlated with disease duration. CONCLUSION: This study showed that a series of neuropathological changes reflected by oculomotor abnormalities appeared preferentially in preclinical stage of SCA3. Accordingly, objective oculomotor preclinical signs may be useful to detect the optimum time‐point for therapeutic interventions in future clinical trials of SCA3. Larger and longitudinal data are warranted to confirm our results.

Objectives: There are limited pharmacological treatments for patients with neurological Wilson’s disease (WD) and a history of copper-chelating treatment failure. Methods: We retrospectively evaluated the clinical records of 38 patients with WD who were treated with sodium dimercaptopropanesulfonate (DMPS) and zinc (group 1) or zinc alone (group 2). All patients had a history of neurological deterioration during their previous treatment with D-penicillamine (DPA). Results: Twenty-one patients were treated with intravenous DMPS for 4 weeks, followed by zinc gluconate for 6 months, and the treatment protocol was repeated twice. Relative to the baseline, repeated DMPS therapy and zinc maintenance therapy decreased neurological scores continuously ( p < 0.01). Sixteen patients (76.2%) demonstrated neurological improvements after 1 year of therapy and four patients (19.0%) exhibited neurological deterioration at the follow-up session. In addition, 17 patients were treated with zinc monotherapy for 12 months. Two patients (11.8%) demonstrated neurological improvements and five patients (29.4%) exhibited neurological deterioration. Compared with the patients in group 2, a greater improvement ratio ( p < 0.01) and lower deterioration ratio ( p < 0.01) were observed in the patients in group 1 after 1 year of therapy. Conclusions: Our findings indicate that the safety and efficacy of combined treatment of DMPS and zinc is superior to those of zinc monotherapy in patients with neurological WD with a history of DPA treatment failure.

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.

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.

To explore the effects of gene transfer of insulin like growth factor-1 (IGF-1) on the penis of senile rats and the altered levels of mRNA and protein of endothelial nitric oxide synthase (eNOS).Ten young (4 months) and 20 senile (24 months) Sprague-Dawley male rats were selected. The senile rats were divided into 2 groups: phosphate buffer solution (PBS)-only (n = 10) and 100 µg IGF-1 plasmid treatment group (n = 10). After a 4-week injection of IGF-1, the responses of intracavernous pressure (ICP) with electrical stimulation to the cavernous nerve and systemic mean arterial pressure (MAP) were evaluated. In the control and transfected senile rats, the levels of eNOS mRNA and protein were examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot respectively.The ICP/MAP and total ICP were significantly higher in the young control group versus the PBS-only group at Week 4 (P0.05). The ICP/MAP and total ICP were significantly higher in the young control group and the 100 µg IGF-1 treatment group versus the PBS-only group at Week 4 (P0.05). The levels of mRNA and protein of eNOS were higher in the 100 µg IGF-1 treatment group versus the PBS-only group at Week 4 (0.62 ± 0.16 vs 0.25 ± 0.08, 0.71 ± 0.19 vs 0.27 ± 0.09, both P0.05, respectively).The gene therapy of IGF-1 can ameliorate erectile functions and improve the levels of mRNA and protein of eNOS in senile rats.

To explore the values of serum copper and serum free copper in the diagnosis of Wilson's disease (WD), its carrier and viral hepatitis and explore the guiding significance of monitoring serum copper in the treatment of WD.A total of 80 WD patients (hepatic type, n = 60; encephalic type, n = 20), 30 carriers, 20 patients with viral hepatitis were enrolled and their levels of serum copper were determined. The neural symptoms were scored by modified Young grade. Hemogram, hepatic functions, blood clotting functions, serum copper and urinary copper were tested throughout all 8 courses of treatment with sodium dimercaptopropane sulfonate (DMPS). The patients were treated with zinc after discharging. All data were analyzed.The free serum copper increased in the patients with WD (0.17 mg/L ± 0.04 mg/L), carriers (0.13 mg/L ± 0.03 mg/L) and severe viral hepatitis (0.12 mg/L). A slight increase was also observed in the WD carriers. The level of serum copper was correlated with hepatic functions but not with the severity of neural symptoms. The serum copper increased in the patients with no improvement of neural symptoms. However, the serum copper decreased in the WD patients with the improvement of neural symptoms. The serum copper was stabilized at approximately 0.2 mg/L during the long-term treatment period.There is auxiliary diagnosis significance of serum copper in the determination of WD. Hepatic functions in hepatic type WD affect the level of serum copper. The serum copper of encephalic type WD can not indicate the severity of neural symptoms. The elevated level of serum copper indicates a poor prognosis. The serum copper is an effective marker in monitoring the development and therapeutic efficacy of the disease.