Objective: Clinical manifestations, imaging findings, pathologic features, and genetic mutations of Chinese adult patients with cerebrotendinous xanthomatosis (CTX) were analyzed in order to achieve a greater understanding of CTX that can improve early detection, diagnosis, and treatment. Methods: Clinical data including medical history, neurologic and auxiliary examinations, imaging findings, and genetic profile were collected for an adult patient with CTX admitted to the Sixth Medical Center of Chinese People's Liberation Army General Hospital in August 2020. Additionally, a systematic review of genetically diagnosed Chinese adult CTX cases reported in major databases in China and other countries was performed and age of onset, first symptoms, common signs and symptoms, pathologic findings, imaging changes, and gene mutations were analyzed. Results: The proband was a 39-year-old female with extensive, early-onset nervous system manifestations including cognitive dysfunction and ataxia. Systemic lesions included juvenile cataract and a tendon mass. Cranial magnetic resonance imaging revealed cerebral atrophy, symmetric white matter changes predominantly in the pyramidal tract, and lesions in the cerebellar dentate nucleus. A novel homozygous mutation in the sterol-27-hydroxylase (CYP27A1) gene (c.1477-2A>C) was identified. There were no family members with similar clinical presentation although some were carriers of the c.1477-2A>C mutation. The patient showed a good response to deoxycholic acid treatment. Totally there were 56 cases of adult CTX patients in China, mostly in East China (31/56, 55.4%), at a male-to-female ratio of 1.8 to 1. Multiple organs and tissues including nervous system, tendon, lens, lung, and skeletal muscle were affected in these cases. The most common neurologic manifestations were cognitive dysfunction (44/52, 84.6%) and ataxia (44/51, 86.3%). The cases were characterized by early onset, chronic progressive damage of multiple systems, long disease course, and delayed diagnosis, making the disease difficult to manage clinically and resulting in poor prognosis. The 2 most common genetic mutations in Chinese adult CTX patients were c.1263+1G>A and c.379C>T. Exon 2 of the CYP27A1 gene was identified as a mutation hot spot. Conclusions: Chinese adult patients with CTX have complex clinical characteristics, a long diagnostic cycle, and various CYP27A1 gene mutations. Early diagnosis and intervention can improve the prognosis of these patients.
Humans ; Male ; Adult ; Female ; Xanthomatosis, Cerebrotendinous/pathology* ; Pedigree ; Cholestanetriol 26-Monooxygenase/genetics* ; Mutation ; Ataxia

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare and early-onset neurodegenerative disease caused by variants of the SACS gene which maps to chromosome 13q11 and encodes sacsin protein. Sacsin is highly expressed in large motor neurons, in particular cerebellar Purkinje cells. This article has provided a review for the structure and function of sacsin protein and the mechanisms underlying abnormalities of sacsin in ARSACS disease.
Humans ; Spinocerebellar Ataxias/pathology* ; Ataxia/genetics* ; Muscle Spasticity/genetics*

PURPOSE: To describe a technique for urodynamic diagnosis of detrusor sphincter dyssynergia (DSD) using urethral pressure measurements and examine potential associations between urethral pressure and bladder physiology among patients with DSD. METHODS: Multiple sclerosis (MS) and spinal cord injured (SCI) patients with known DSD diagnosed on videourodynamics (via electromyography or voiding cystourethrography) were retrospectively identified. Data from SCI and MS patients with detrusor overactivity (DO) without DSD were abstracted as control group. Urodynamics tracings were reviewed and urethral pressure DSD was defined based on comparison of DSD and control groups. RESULTS: Seventy-two patients with DSD were identified. Sixty-two (86%) had >20 cm H₂O urethral pressure amplitude during detrusor contraction. By comparison, 5 of 23 (22%) of control group had amplitude of >20 cm H₂O during episode of DO. Mean duration of urethral pressure DSD episode was 66 seconds (range, 10–500 seconds) and mean urethral pressure amplitude was 73 cm H₂O (range, 1–256 cm H₂O). Longer (>30 seconds) DSD episodes were significantly associated with male sex (81% vs. 50%, P=0.013) and higher bladder capacity (389 mL vs. 219 mL, P=0.0004). Urethral pressure amplitude measurements during DSD were not associated with significant urodynamic variables or neurologic pathology. CONCLUSIONS: Urethral pressure amplitude of >20 cm H2O during detrusor contraction occurred in 86% of patients with known DSD. Longer DSD episodes were associated with larger bladder capacity. Further studies exploring the relationship between urethral pressure measurements and bladder physiology could phenotype DSD as a measurable variable rather than a categorical observation.
Ataxia* ; Diagnosis* ; Electromyography ; Humans ; Male ; Multiple Sclerosis ; Pathology ; Phenotype ; Physiology ; Retrospective Studies ; Spinal Cord ; Spinal Cord Injuries ; Urinary Bladder ; Urodynamics*

The brain necrosis induced by radiation therapy (RT) is an uncommon pathology of brain. A case of spontaneous hemorrhage at necrotic brain is also rare. A 52-year-old man who had nasopharyngeal carcinoma and had been treated with RT, presented with gait disturbance, dizziness, ataxia, dysarthria, and dysphagia. Magnetic resonance imaging (MRI) demonstrated progressed radiation necrosis of pons, and spontaneous hemorrhage at the site of necrosis. The hematoma was diminished by conservative treatment. However, the patient’s neurologic symptoms did not recover. Two years later, spontaneous bleeding recurred at necrotic brain. His neurologic symptoms worsened. One year later, his neurologic symptoms were more progressed. He showed severe dysphagia, profound weakness and respiratory failure. This case provides the description of relapsed spontaneous hemorrhage and medullary dysfunction caused by pontine necrosis and progressed post-radiation injury, complicated with hemorrhage, and urges caution in that the necrotic brain tissue may be vulnerable to bleeding.
Ataxia ; Brain ; Deglutition Disorders ; Dizziness ; Dysarthria ; Gait ; Hematoma ; Hemorrhage* ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Necrosis* ; Neurologic Manifestations ; Pathology ; Pons ; Respiratory Insufficiency

OBJECTIVETo investigate miR-181a function and regulation mechanism by identifying miR-181a target genes in acute myeloid leukemia (AML).

METHODSThe HL-60 cells of human AML was transfected by small molecular analog miR-181a, the cell proliferation was detected by CCK-8 method after electroporation in HL-60 cell lines. Target genes of miR-181a were predicted and analyzed by the bioinformatics software and database. Target genes were confirmed by HL-60 cell line and the patient leukemia cells.

RESULTSOverexpressed miR-181a in HL-60 cell line significantly enhanced cell proliferation compared with that in control (P < 0.05). Dual luciferase reporter gene assay showed that miR-181a significantly suppressed the reporter gene activity containing ATM 3'-UTR by about 56.8% (P < 0.05), but it didn't suppress the reporter gene activity containing 3'-UTR ATM mutation. Western blot showed that miR-181a significantly downregulated the expression of ATM in human leukemia cells. It is also found that miR-181a was significantly increased in AML, which showed a negative correlation with ATM expression.

CONCLUSIONmiR-181a promotes cell proliferation in AML by regulating the tumor suppressor ATM, thus it plays the role as oncogene in pathogenesis of AML.

Ataxia Telangiectasia Mutated Proteins ; metabolism ; Cell Proliferation ; Down-Regulation ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute ; metabolism ; pathology ; MicroRNAs ; genetics ; metabolism ; Transfection

Ataxia ; Carbamazepine ; analogs & derivatives ; therapeutic use ; Carcinoma ; Central Nervous System ; pathology ; Diagnosis, Differential ; Female ; Gait ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Nasopharyngeal Neoplasms ; complications ; radiotherapy ; Nervous System Diseases ; complications ; diagnosis ; Radiotherapy ; adverse effects ; Seizures ; complications ; diagnosis ; Siderosis

OBJECTIVETo explore the clinical features and molecular mutation of HEXB gene in a case with juvenile Sandhoff disease.

METHODWe retrospectively reviewed the clinical, neuroimaging and biochemical findings in this Chinese child with juvenile Sandhoff disease. Hexosaminidase A and hexosaminidase A & B activities were measured in blood leukocytes by fluorometric assay. HEXB gene molecular analysis was performed by PCR and direct sequencing.

RESULTThe 9-year-old boy was admitted for psychomotor regression. He presented slowly progressive gait disorder and dysarthria during the last three years. Cranial MRI revealed a marked cerebellar atrophy with normal intensity in the thalamus and basal ganglia. Brain MRS showed normal in the thalamus and basal ganglia. Hexosaminidase A was 69.5 (mg·h) [normal controls 150-360 nmol/(mg·h)], hexosaminidase A & B activity was 119 nmol/(mg·h)[normal controls 600-3 500 nmol/(mg·h)], confirming the diagnosis of Sandhoff disease. The patient was a compound heterozygote for a novel deletion mutation c.1404delT (p. P468P fsX62) and a reported mutation c.1509-26G>A.

CONCLUSIONThe clinical features of juvenile Sandhoff disease include ataxia, dysarthria and cerebellar atrophy. The enzyme assay and molecular analysis of HEXB gene can confirm the diagnosis of Sandhoff disease. The novel mutation c.1404delT(p. P468P fsX62) is a disease-related mutation.

Brain ; diagnostic imaging ; pathology ; Cerebellar Ataxia ; diagnosis ; enzymology ; genetics ; Child ; DNA Mutational Analysis ; Heterozygote ; Hexosaminidase A ; blood ; metabolism ; Hexosaminidase B ; blood ; metabolism ; Humans ; Leukocytes ; enzymology ; Magnetic Resonance Imaging ; Male ; Mutation ; Radiography ; Retrospective Studies ; Sandhoff Disease ; diagnosis ; enzymology ; genetics ; beta-Hexosaminidase beta Chain ; genetics

Multiple system atrophy (MSA) is a rare, yet fatal neurodegenerative disease that presents clinically with autonomic failure in combination with parkinsonism or cerebellar ataxia. MSA impacts on the autonomic nervous system affecting blood pressure, heart rate and bladder function, and the motor system affecting balance and muscle movement. The cause of MSA is unknown, no definitive risk factors have been identified, and there is no cure or effective treatment. The definitive pathology of MSA is the presence of alpha-synuclein aggregates in the brain and therefore MSA is classified as an alpha-synucleinopathy, together with Parkinson's disease and dementia with Lewy bodies. Although the molecular mechanisms of misfolding, fibrillation and aggregation of alpha-synuclein partly overlap with other alpha-synucleinopathies, the pathological pathway of MSA is unique in that the principal site for alpha-synuclein deposition is in the oligodendrocytes rather than the neurons. The sequence of pathological events of MSA is now recognized as abnormal protein redistributions in oligodendrocytes first, followed by myelin dysfunction and then neurodegeneration. Oligodendrocytes are responsible for the production and maintenance of myelin, the specialized lipid membrane that encases the axons of all neurons in the brain. Myelin is composed of lipids and two prominent proteins, myelin basic protein and proteolipid protein. In vitro studies suggest that aberration in protein distribution and lipid transport may lead to myelin dysfunction in MSA. The purpose of this perspective is to bring together available evidence to explore the potential role of alpha-synuclein, myelin protein dysfunction, lipid dyshomeostasis and ABCA8 in MSA pathogenesis.
alpha-Synuclein ; Autonomic Nervous System ; Axons ; Blood Pressure ; Brain ; Cerebellar Ataxia ; Dementia ; Heart Rate ; Lewy Bodies ; Membranes ; Multiple System Atrophy* ; Myelin Proteins ; Myelin Sheath* ; Neurodegenerative Diseases ; Neurons ; Oligodendroglia ; Parkinson Disease ; Parkinsonian Disorders ; Pathology ; Risk Factors ; Urinary Bladder

Ataxia telangiectasia mutated (ATM) kinase plays an essential role in the maintenance of genomic stability. ATM-deficient (ATM(-/-)) mice exhibit hematopoietic stem cell (HSC) dysfunction and a high incidence of lymphoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM(-/-) HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM(-/-) mice. Instead, ATM and Gadd45a double knockout (ATM(-/-) Gadd45a(-/-)) HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM(-/-) HSCs in HSC transplantation experiments. Further experiments revealed that the aggravated defect of ATM(-/-) Gadd45a(-/-) HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signaling pathway. Additionally, ATM(-/-) Gadd45a(-/-) mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM(-/-) mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which subsequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM(-/-) HSCs.
Animals ; Ataxia Telangiectasia Mutated Proteins ; genetics ; B-Lymphocytes ; pathology ; Cell Cycle Proteins ; genetics ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; DNA Damage ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells ; metabolism ; pathology ; Leukemia ; genetics ; pathology ; Lymphoma ; genetics ; pathology ; Mice, Knockout ; Neoplasm Metastasis ; Nuclear Proteins ; genetics ; T-Lymphocytes ; pathology ; Tumor Suppressor Protein p53 ; metabolism

Ataxia Telangiectasia Mutated Proteins ; Breast ; metabolism ; pathology ; Breast Neoplasms ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; Carcinoma, Intraductal, Noninfiltrating ; metabolism ; pathology ; Cell Cycle Proteins ; metabolism ; Checkpoint Kinase 2 ; DNA-Binding Proteins ; metabolism ; Female ; Humans ; Lymphatic Metastasis ; Neoplasm Grading ; Protein-Serine-Threonine Kinases ; metabolism ; Tumor Burden ; Tumor Suppressor Protein p53 ; metabolism ; Tumor Suppressor Proteins ; metabolism