Primary neurolymphomatosis with MAG antibody: a case report.

Neurolymphomatosis (NL) is a rare neurologic manifestation of non-Hodgkin lymphoma (NHL) with poor prognosis. Investigations including MRI, PET/CT, nerve biopsy and cerebrospinal fluid (CSF) analysis can aid the diagnosis of NL. In this study, we presented a case of NL with co-existing myelin-associated glycoprotein (MAG) antibody. The patient first presented with symptoms of peripheral neuropathy involving multiple cranial nerves and cauda equina, and later developed obstructive hydrocephalus and deep matter lesions. He also had persistently positive MAG antibody, but did not develop electrophysiologically proven neuropathy and monoclonal immunoglobulin. The final brain biopsy confirmed diffuse large B cell lymphoma.

Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/ß-Catenin signaling.

Inflammatory bowel disease (IBD) is characterized by persistent damage to the intestinal barrier and excessive inflammation, leading to increased intestinal permeability. Current treatments of IBD primarily address inflammation, neglecting epithelial repair. Our previous study has reported the therapeutic potential of notoginsenoside R1 (NGR1), a characteristic saponin from the root of Panax notoginseng, in alleviating acute colitis by reducing mucosal inflammation. In this study we investigated the reparative effects of NGR1 on mucosal barrier damage after the acute injury stage of DSS exposure. DSS-induced colitis mice were orally treated with NGR1 (25, 50, 125 mg·kg-1·d-1) for 10 days. Body weight and rectal bleeding were daily monitored throughout the experiment, then mice were euthanized, and the colon was collected for analysis. We showed that NGR1 administration dose-dependently ameliorated mucosal inflammation and enhanced epithelial repair evidenced by increased tight junction proteins, mucus production and reduced permeability in colitis mice. We then performed transcriptomic analysis on rectal tissue using RNA-sequencing, and found NGR1 administration stimulated the proliferation of intestinal crypt cells and facilitated the repair of epithelial injury; NGR1 upregulated ISC marker Lgr5, the genes for differentiation of intestinal stem cells (ISCs), as well as BrdU incorporation in crypts of colitis mice. In NCM460 human intestinal epithelial cells in vitro, treatment with NGR1 (100 µM) promoted wound healing and reduced cell apoptosis. NGR1 (100 µM) also increased Lgr5+ cells and budding rates in a 3D intestinal organoid model. We demonstrated that NGR1 promoted ISC proliferation and differentiation through activation of the Wnt signaling pathway. Co-treatment with Wnt inhibitor ICG-001 partially counteracted the effects of NGR1 on crypt Lgr5+ ISCs, organoid budding rates, and overall mice colitis improvement. These results suggest that NGR1 alleviates DSS-induced colitis in mice by promoting the regeneration of Lgr5+ stem cells and intestinal reconstruction, at least partially via activation of the Wnt/ß-Catenin signaling pathway. Schematic diagram of the mechanism of NGR1 in alleviating colitis. DSS caused widespread mucosal inflammation epithelial injury. This was manifested by the decreased expression of tight junction proteins, reduced mucus production in goblet cells, and increased intestinal permeability in colitis mice. Additionally, Lgr5+ ISCs were in obviously deficiency in colitis mice, with aberrant down-regulation of the Wnt/ß-Catenin signaling. However, NGR1 amplified the expression of the ISC marker Lgr5, elevated the expression of genes associated with ISC differentiation, enhanced the incorporation of BrdU in the crypt and promoted epithelial restoration to alleviate DSS-induced colitis in mice, at least partially, by activating the Wnt/ß-Catenin signaling pathway.

Common and Key Differential Pathogenic Pathways in Desminopathy and Titinopathy.

Myofibrillar myopathy (MFM) is a group of hereditary myopathies that mainly involves striated muscles. This study aimed to use tandem mass tag (TMT)-based proteomics to investigate the underlying pathomechanisms of two of the most common MFM subtypes, desminopathy and titinopathy. Muscles from 7 patients with desminopathy, 5 with titinopathy and 5 control individuals were included. Samples were labelled with TMT and then underwent high-resolution liquid chromatography-mass spectrometry analysis. Compared with control samples, there were 436 differentially abundant proteins (DAPs) in the desminopathy group and 269 in the titinopathy group. When comparing the desminopathy with the titinopathy group, there were 113 DAPs. In desminopathy, mitochondrial ATP production, muscle contraction, and cytoskeleton organization were significantly suppressed. Activated cellular components and pathways were mostly related to extracellular matrix (ECM). In titinopathy, mitochondrial-related pathways and the cellular component ECM were downregulated, while gluconeogenesis was activated. Direct comparison between desminopathy and titinopathy revealed hub genes that were all involved in glycolytic process. The disparity in glycolysis in the two MFM subtypes is likely due to fiber type switching. This study has revealed disorganization of cytoskeleton and mitochondrial dysfunction as the common pathophysiological processes in MFM, and glycolysis and ECM as the differential pathomechanism between desminopathy and titinopathy. This offers a future direction for targeted therapy for MFM.

Clinicopathological-genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre.

Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. The aim of this study was to characterize the clinical, physiological, pathohistological and genetic features of nine unrelated Chinese patients with CMS from a single neuromuscular centre. A total of nine patients aged from neonates to 34 years were enrolled who exhibited initial symptoms. Physical examinations revealed that all patients exhibited muscle weakness. Muscle biopsies demonstrated multiple myopathological changes, including increased fibre size variation, myofibrillar network disarray, necrosis, myofiber grouping, regeneration, fibre atrophy and angular fibres. Genetic testing revealed six different mutated genes, including AGRN (2/9), CHRNE (1/9), GFPT1 (1/9), GMPPB (1/9), PLEC (3/9) and SCN4A (1/9). In addition, patients exhibited differential responses to pharmacological treatment. Prompt utilization of genetic testing will identify novel variants and expand our understanding of the phenotype of this rare syndrome. Our findings contribute to the clinical, pathohistological and genetic spectrum of congenital myasthenic syndrome in China.

Findings of limb-girdle muscular dystrophy R7 telethonin-related patients from a Chinese neuromuscular center.

Limb-girdle muscular dystrophy (LGMD) is a group of clinically and genetically heterogeneous neuromuscular disorders. LGMD-R7, which is caused by telethonin gene (TCAP) mutations, is one of the rarest forms of LGMD, and only a small number of LGMD-R7 cases have been described and mostly include patients from Brazil. A total of two LGMD-R7 patients were enrolled at a Chinese neuromuscular center. Demographic and clinical data were collected. Laboratory investigations and electromyography were performed. Routine and immunohistochemistry staining of muscle specimens was performed, and a next-generation sequencing panel array for genes associated with hereditary neuromuscular disorders was used for analysis. The patients exhibited predominant muscle weakness. Electromyography revealed myopathic changes. The muscle biopsy showed myopathic features, such as increased fiber size variation, muscle fiber atrophy and regeneration, slight hyperplasia of the connective tissue, and disarray of the myofibrillar network. Two patients were confirmed to have mutations in the open reading frame of TCAP by next-generation sequencing. One patient had compound heterozygous mutations, and the other patient harbored a novel homozygous mutation. Western blotting analysis of the skeletal muscle lysate confirmed the absence of telethonin in the patients. We described two LGMD-R7 patients presenting a classical LGMD phenotype and a novel homozygous TCAP mutation. Our research expands the spectrum of LGMD-R7 due to TCAP mutations based on patients from a Chinese neuromuscular center.

Integrating 16S RRNA gene sequencing and metabolomics to evaluate the association between gut microbiota and serum metabolites in patients with myositis.

AIMS: Gut microbiota and metabolites have a profound impact on the maintenance of body health. In this study, we assessed the association between gut microbiota and serum metabolite changes in myositis using 16S rRNA gene sequencing and metabolomics to provide new ideas for screening and treating myositis. METHODS AND RESULTS: Blood and faecal samples were collected from 20 myositis patients and 20 healthy control subjects. Then, 16S rRNA gene sequencing, enzyme-linked immunosorbent assays and untargeted metabolomics study were performed to evaluate the relationship between gut microbiota and serum metabolites in patients with myositis. Compared to healthy control subjects, the blood samples from the patients with myositis had elevated levels of interleukin-4 (IL-4), tumour necrosis factor-α (TNF-α), and malondialdehyde (MDA) and decreased superoxide dismutase (SOD) levels. The increase in Bacteroidota (including Bacteroides and Parabacteroides, but not Prevotella) and the decrease in Firmicutes in the patients were accompanied by functional changes in amino acid and lipid metabolism. The gut microbiota (Bacteroides and Parabacteroides) were negatively correlated with the differential serum metabolites (glutamate and taurine). The differential serum metabolites (glutamate, pyrrolidonecarboxylic acid, and taurine) were also correlated with inflammatory factors (IL-4 and TNF-α) and oxidative stress indexes (MDA and SOD). CONCLUSION: Dysbiosis of gut microbiota in patients with myositis was accompanied by changes in inflammatory factors, oxidative stress indexes, and small molecule metabolites in serum. SIGNIFICANCE AND IMPACT OF STUDY: Blood and faecal biomarkers could be used for screening myositis.

Expanding the clinicopathological-genetic spectrum of GNE myopathy by a Chinese neuromuscular centre.

GNE myopathy is a heterogeneous group of ultrarare neuromuscular disorders caused by mutations in the GNE gene. An estimated prevalence of 1~21/1,000,000 leads to a deficiency of data and a lack of availability of samples to conduct clinical research on this neuromuscular disorder. Although GNE, which is the mutated gene responsible for the disease, is well known as the key enzyme in the biosynthesis pathway of sialic acid, the clinicopathological-genetic spectrum of GNE mutant patients is still unclear and expanding. This study presents ten unrelated patients with GNE myopathy, discovering five novel missense mutations. Clinical, electrophysiological, imaging, pathological and genetic data are presented in a retrospective manner. Interestingly, several patients in the cohort were found to have peripheral neuropathy and inflammatory cell infiltration in muscle biopsies, which have seldom been reported. This study, conducted by a neuromuscular centre in China, is the first attempt to highlight these abnormal clinicopathological features and associate them with genetic mutations in GNE myopathy.

Alantolactone exhibits antiproliferative and apoptosis-promoting properties in colon cancer model via activation of the MAPK-JNK/c-Jun signaling pathway.

Colorectal cancer (CRC) is one of the most common human malignancies in the digestive tract with high mortality. Alantolactone (ATL), as a plant-derived sesquiterpene lactone, has shown a variety of pharmacological activities, such as antibacterial, anti-inflammatory, anti-virus and so on. However, the exact molecular mechanism of ATL in colorectal cancer remains largely unknown. Here, we performed a study to explore the effect and mechanism of ATL on colorectal cancer. The CCK-8 assay, colony formation assay, Wound-healing and Transwell assays were performed to evaluate the cytotoxic effect, antiproliferative effect, anti-migratory and anti-invasive properties of ATL respectively. The xenograft tumor model was established in Balb/c mice to evaluate the anti-tumor effect. The expression levels of proteins involved the MAPK-JNK/c-Jun signaling pathway were measured by Western blot and RT-qPCR both in cells and tumor tissues. The results showed that ATL could inhibit the cells activities of various colon cancer cell lines. Moreover, ATL could induce HCT-116 cells nuclear pyknosis, mitochondrial membrane potential loss, G0/G1 phase arrest, as well as enhance the proportion of apoptosis cells and inhibit colony formation. The migration distance and invasion rate of cells were significantly reduced after treated with ATL. Additionally, in the xenograft model, ATL (50 mg/kg) significantly decreased the tumor tumor volume and weight (p < 0.001). For the anti-colon cancer mechanism, the ATL showed the anti-proliferative and pro-apoptosis effect by activating MAPK-JNK/c-Jun signaling pathway. In conclusion, ATL exhibits anti-proliferation and apoptosis-promoting potential in colon cancer via the activation of MAPK-JNK/c-Jun signaling pathway.

Clinicopathological features of titinopathy from a Chinese neuromuscular center.

Titin, one of the largest proteins in humans, is a major component of muscle sarcomeres. Pathogenic variants in the titin gene (TTN) have been reported to cause a range of skeletal muscle diseases, collectively known as titinopathy. Titinopathy is a heterogeneous group of disabling diseases characterized by muscle weakness. In our study, we aimed to establish the clinicopathological-genetic spectrum of titinopathy from a single neuromuscular center. Three patients were diagnosed as having definite titinopathy, and additional three patients were diagnosed as having possible titinopathy according to the diagnostic criteria. All the patients showed initial symptoms from age one to 40 years. Physical examination revealed that five patients had muscle weakness, and that one patient experienced behavioral changes. Muscle biopsy specimens obtained from all six patients demonstrated multiple myopathological changes, including increased fiber size variation, muscle fiber hypertrophy or atrophy, formation of centralized cell nuclei, necklace cytoplasmic bodies, and formation of rimmed vacuoles and cores. Genetic testing revealed 11 different TTN alterations, including missense (6/11), nonsense (2/11), frameshift (2/11), and splicing (1/11) mutations. Our study provides further evidence that TTN mutations are more likely to be responsible for an increasing proportion of various myopathies, such as hereditary myopathy with early respiratory failure (HMERF), core myopathy, and distal myopathy with rimmed vacuoles, than currently recognized mutations. Our findings expand the clinical, pathohistological and genetic spectrum of titinopathy.

Investigation of adult-onset multiple acyl-CoA dehydrogenase deficiency associated with peripheral neuropathy.

Multiple Acyl-CoA dehydrogenase deficiency (MADD), one of the most common lipid storage myopathies (LSMs), is a heterogeneous inherited muscular disorder that is pathologically characterized by numerous lipid droplets in muscle fibers due to lipid metabolism disturbance. MADD exhibits a wide range of clinical features, including skeletal muscle weakness and multisystem dysfunctions. However, MADD, as well as other types of LSM, associated with peripheral neuropathy has rarely been reported during the past four decades. Here, we present four Chinese patients affected by MADD with peripheral neuropathy in our neuromuscular center. Clinically, these four patients showed skeletal muscle weakness and prominent paresthesia. Muscle biopsy detected characteristic myopathological patterns of LSM, such as obvious lipid droplets in muscle fibers. Sural nerve biopsy revealed a severe reduction in number of myelinated nerve fibers, which is a typical neuropathological pattern of peripheral neuropathy. Causative ETFDH mutations were found in all four cases. The skeletal muscle weakness was rapidly improved after some treatments while paresthesia showed unsatisfactory improvement. The features of previously reported patients of this specific type are also summarized in this paper. We propose that MADD with peripheral neuropathy may be a new phenotypic subtype because the pathology and reaction to riboflavin treatment are different from those of traditional MADD, although further research on the precise pathogenesis and mechanisms is needed.

Obacunone reduces inflammatory signalling and tumour occurrence in mice with chronic inflammation-induced colorectal cancer.

CONTEXT: Obacunone, a limonoid abundantly found in Citrus fruits, exhibits a variety of bioactivities. OBJECTIVE: To investigate the effects of obacunone on a colorectal cancer (CRC) mouse model, and clarify its potential molecular mechanisms. MATERIALS AND METHODS: The male Balb/c mice were induced with azoxymethane and dextran sulfate sodium for 12 weeks. Obacunone (50 mg/kg) was administered via oral gavage three times every week until the end of the experiment. Disease indexes including body weight, spleen weight, bloody diarrhea, colon length, histopathological score, and tumor size were measured. The anti-proliferation activities of obacunone were analyzed by MTT or flow cytometry. The expression of protein and mRNA related to cell proliferation or inflammatory cytokines was determined by Western blot, q-PCR and IHC. RESULTS: Obacunone significantly alleviated bloody diarrhea, colon shortening (7.35 ± 0.2128 vs. 8.275 ± 0.2169 cm), splenomegaly, histological score (9 ± 0.5774 vs. 6 ± 0.5774) and reduced tumor size (4.25 ± 0.6196 vs. 2 ± 0.5669). Meanwhile, the expression of protein and mRNA related to cell proliferation or inflammatory cytokines was remarkably decreased in tumor tissue. Obacunone inhibited the proliferation activities of colorectal cancer cells. Moreover, obacunone induced colorectal cancer cells G1 and G2 phases arrest, and suppressed the expression of cell cycle genes. CONCLUSIONS: Obacunone could alleviate CRC via inhibiting inflammatory response and tumor cells proliferation. The results may contribute to the effective utilization of obacunone or its derivatives in the treatment of human CRC.

Short Synthesis of the Monoterpene Indole Alkaloid (±)-Arbornamine.

The first total synthesis of the monoterpene indole alkaloid (±)-arbornamine (1) has been completed, which proceeds in only 6 steps and 31% overall yield from three readily available, known compounds. The synthesis features a cascade involving a Pictet-Spengler cyclization/intramolecular ammonolysis to create the tetracyclic core of arbornamine (1) in a single chemical operation. The subsequent elaboration of 5 into 1 was effected by a key reductive Heck reaction and global reduction.

Anti-Inflammatory Effects of Fargesin on Chemically Induced Inflammatory Bowel Disease in Mice.

Fargesin is a bioactive lignan from Flos Magnoliae, an herb widely used in the treatment of allergic rhinitis, sinusitis, and headache in Asia. We sought to investigate whether fargesin ameliorates experimental inflammatory bowel disease (IBD) in mice. Oral administration of fargesin significantly attenuated the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice by decreasing the inflammatory infiltration and myeloperoxidase (MPO) activity, reducing tumor necrosis factor (TNF)-α secretion, and inhibiting nitric oxide (NO) production in colitis mice. The degradation of inhibitory κBα (IκBα), phosphorylation of p65, and mRNA expression of nuclear factor κB (NF-κB) target genes were inhibited by fargesin treatment in the colon of the colitis mice. In vitro, fargesin blocked the nuclear translocation of p-p65, downregulated the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and dose-dependently inhibited the activity of NF-κB-luciferase in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Taken together, for the first time, the current study demonstrated the anti-inflammatory effects of fargesin on chemically induced IBD might be associated with NF-κB signaling suppression. The findings may contribute to the development of therapies for human IBD by using fargesin or its derivatives.

[Clinical, pathological and genetic studies of two cases of childhood-onset nemaline myopathy].

This article reports two cases of childhood-onset nemaline myopathy diagnosed by muscle pathology and genetic diagnosis. The two patients had onset in early childhood, with muscle weakness as the first manifestation, as well as long disease duration and slow progression. Gomori staining and hematoxylin-eosin staining showed red-stained rods in the sarcoplasmic cytoplasm and sarcolemma under a light microscope. Electron microscopy showed that the dense nemaline rods were located under the muscle fiber sarcolemma and parallel to the long axis of the muscle fibers, and some muscle fiber myofilaments were dissolved and necrotic. Gene testing found that one of the two patients had heterozygous mutation (c.1013A>C) in the ACTA1 gene, and the other had compound heterozygous mutation (c.18676C>T and c.9812C>A) in the NEB gene. The two mutations were more common in nemaline myopathy. Nemaline myopathy is a recessive or dominant inheritance myopathy, in which the nemaline rod in the cytoplasm of myocytes is a characteristic muscle pathological change. Pathological and genetic diagnosis is the gold standard for diagnosis of nemaline myopathy.

IFNA-AS1 regulates CD4+ T cell activation in myasthenia gravis though HLA-DRB1.

Abnormal CD4+T cell activation is known to play roles in the pathogenesis of myasthenia gravis (MG). However, little is known about the mechanisms underlying the roles of lncRNAs in regulating CD4+ T cell. In this study, we discovered that the lncRNA IFNG-AS1 is abnormally expressed in MG patients associated with quantitative myasthenia gravis (QMG) and the positive anti-AchR Ab levels patients. IFNG-AS1 influenced Th1/Treg cell proliferation and regulated the expression levels of their transcription factors in an experimental autoimmune myasthenia gravis (EAMG)model. IFNG-AS1 could reduce the expression of HLA-DRB and HLA-DOB and they had a negative correlation in MG. Furthermore IFNG-AS1 influenced the expression levels of CD40L and CD4+ T cells activation in MG patient partly depend on effecting the HLA-DRB1 expression. It suggests that IFNG-AS1 may be involved in CD4+T cell-mediated immune responses in MG.

Dermatomyositis, polymyositis and immune-mediated necrotising myopathies.

Dermatomyositis, polymyositis and immune-mediated necrotising myopathy are major forms of idiopathic inflammatory myopathy. We review here recent developments in understanding the pathology and pathogenesis of these diseases, and characterisation of autoantibody biomarkers. Dermatomyositis is traditionally considered to be due to a complement-mediated microangiopathy but the factors responsible for complement activation remain uncertain. Recent studies have emphasised the importance of the type I interferon pathway in the pathogenesis of the disease and have identified autoantibodies with specificities for different clinical subgroups of patients. Polymyositis is characterised by a cytotoxic T cell response targeting as yet unidentified muscle antigens presented by MHC Class I molecules, and can occur in isolation but is more often part of a multi-systemic overlap syndrome. The immune-mediated necrotising myopathies are heterogeneous and are distinguished from polymyositis by the sparseness of inflammatory infiltrates and recognition of an association with specific autoantibodies such as anti-SRP and anti-HMGCR in many cases. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

MiR-15a contributes abnormal immune response in myasthenia gravis by targeting CXCL10.

MiR-15a is likely to be associated with autoimmunity. Here, we aimed to examine the expression of miR-15 cluster in PBMCs from myasthenia gravis (MG) patients and investigate the potential roles of miR-15a in MG. We found that the expression of all miR-15 cluster was decreased in MG, furthermore, miR-15a levels in ocular MG (oMG) were much lower, while CXCL10 production was increased in MG. We display that CXCL10 was a functional target gene of miR-15a in MG. Increasing miR-15a expression could reduce CXCL10 expression and alleviate the abnormal T cells activation in immune response, while decreasing miR-15a expression could activate immune response abnormally. Moreover, miR-15a expression was significantly decreased after stimulation, and prednisone treatment could upregulate miR-15a expression in steroid-responsive MG patients. Take together, our data suggest that decreased miR-15a expression facilitates proinflammatory cytokines production and contributes to immune response at least in part via regulating CXCL10 expression in MG.

Normal and aberrant splicing of LMNA.

The LMNA gene gives rise to at least three isoforms (lamin A, C, lamin AΔ10) as a result of normal alternative splicing, regulated by cis- and trans-acting regulatory factors, as well as the 5' and 3' untranslated regions of the gene. The two main isoforms, lamin A and C, are constitutive components of the fibrous nuclear lamina and have diverse physiological roles, ranging from mechanical nuclear membrane maintenance to gene regulation. The clinical spectrum of diseases (called 'laminopathies') caused by LMNA mutations is broad, including at least eight well-characterised phenotypes, some of which are confined to the skeletal muscles or skin, while others are multisystemic. This review discusses the different alternatively spliced isoforms of LMNA and the regulation of LMNA splicing, as well as the subgroup of mutations that affect splicing of LMNA pre-mRNA, and also seeks to bridge the mis-splicing of LMNA at transcript level and the resulting clinical phenotypes. Finally, we discuss the manipulation of LMNA splicing by splice-switching antisense oligonucleotides and its therapeutic potential for the treatment of some laminopathies.

Biomarker studies in multiple sclerosis: from proteins to noncoding RNAs.

Multiple sclerosis (MS) is a neuroimmunological disorder characterized by central nervous system demyelination, axonal injury and loss. Considering the complexity of its aetiopathogenesis, early diagnosis of MS and individualized management are challenging in clinical practice. As the pathophysiologic and pharmacological indicators, studies on biomarkers in MS are useful for early prediction and diagnosis, monitoring of disease activity and predicting treatment response. In this review, we will summarize recent development of biomarker studies in MS from protein molecules to noncoding RNAs.

Twinkle mutations in two Chinese families with autosomal dominant progressive external ophthalmoplegia.

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a common adult onset mitochondrial disease caused by mutations in nuclear DNA (nDNA). Twinkle is one of the nuclear genes associated with adPEO. Clinical, histochemical, and molecular genetics findings of 6 patients from two Chinese families with adPEO were reported. Two point mutations (c.1423G>C, p.A475P and c.1061G>C, p.R354P) of Twinkle gene have been found. Multiple mtDNA deletions were also detected in patient's muscle and fibroblasts. This study confirms two mutations in Chinese adPEO families, which were first reported in the Chinese population.