Clinical and pathological characteristics of OPDM4 patients in advanced disease.

INTRODUCTION/AIMS: Oculopharyngodistal myopathy type 4 (OPDM4) arises from a CGG repeat expansion in the 5' UTR of the RILPL1 gene. Reported cases of OPDM4 have been limited. The aim of this study was to investigate the clinical and myopathological characteristics of OPDM4 patients with advanced disease. METHODS: We assessed a total of 8 affected and 12 unaffected individuals in an OPDM4 family with autosomal dominant inheritance. Muscle biopsy tissue from the proband underwent histological, enzyme histochemical, and immunohistochemical stains, and electron microscopy analysis. Whole exome sequencing and repeat primer PCR (RP-PCR) were conducted to investigate underlying variants. RESULTS: OPDM4 patients displayed a progressive disease course. Most experienced lower limb weakness and diminished walking ability in their 20s and 30s, followed by ptosis, ophthalmoplegia, swallowing difficulties, and dysarthria in their 30s to 50s, By their 50s to 70s, they became non-ambulatory. Muscle magnetic resonance imaging (MRI) of the proband in advanced disease revealed severe fatty infiltration of pelvic girdle and lower limb muscles. Biopsied muscle tissue exhibited advanced changes typified by adipose connective tissue replacement and the presence of multiple eosinophilic and p62-positive intranuclear inclusions. Immunopositivity for the intranuclear inclusions was observed with anti-glycine antibody and laboratory-made polyA-R1 antibody. RP-PCR unveiled an abnormal CGG repeat expansion in the 5' UTR of the RILPL1 gene. DISCUSSION: The clinical and radiological features in this family broaden the phenotypic spectrum of OPDM4. The presence of intranuclear inclusions in the proliferative adipose connective tissues of muscle biopsy specimens holds diagnostic significance for OPDM4 in advanced disease.

Encephalitis-like episodes with cortical edema and enhancement in patients with neuronal intranuclear inclusion disease.

OBJECTIVES: Neuronal intranuclear inclusion disease (NIID) exhibited significant clinical heterogeneities. However, the clinical features, radiographic changes, and prognosis of patients with encephalitis-like NIID have yet to be systematically elucidated. METHODS: Clinical data including medical history, physical examination, and laboratory examinations were collected and analyzed. Skin and sural nerve biopsies were conducted on the patient. Repeat-primed PCR (RP-PCR) and fluorescence amplicon length PCR (AL-PCR) were used to detect the expansion of CGG repeat. We also reviewed the clinical and genetic data of NIID patients with cortical enhancement. RESULTS: A 54-year-old woman presented with encephalitis-like NIID, characterized by severe headache and agitative psychiatric symptoms. The brain MRI showed cortical swelling in the temporo-occipital lobes and significant enhancement of the cortical surface and dura, but without hyperintensities along the corticomedullary junction on diffusion-weighted image (DWI). A biopsy of the sural nerve revealed a demyelinating pathological change. The intranuclear inclusions were detected in nerve and skin tissues using the p62 antibody and electron microscopy. RP-PCR and AL-PCR unveiled the pathogenic expansion of CGG repeats in the NOTCH2NLC gene. A review of the literature indicated that nine out of the 16 patients with cortical lesions and linear enhancement exhibited encephalitis-like NIID. CONCLUSION: This study indicated that patients with encephalitis-like NIID typically exhibited headache and excitatory psychiatric symptoms, often accompanied by cortical edema and enhancement of posterior lobes, and responded well to glucocorticoid treatment. Furthermore, some patients may not exhibit hyperintensities along the corticomedullary junction on DWI, potentially leading to misdiagnosis.

Novel mutations in FLVCR1 cause tremors, sensory neuropathy with retinitis pigmentosa.

The mutations of the feline leukemia virus subgroup C receptor-related protein 1 (FLVCR1) cause ataxia with retinitis pigmentosa. Recent studies indicated a large variation in the phenotype of FLVCR1-associated diseases. In this report, we describe an adult male who manifested first with tremors in his third decade, followed by retinitis pigmentosa, sensory ataxia, and sensory neuropathy in his fourth decade. While retinitis pigmentosa and sensory ataxia are well-recognized features of FLVCR1-associated disease, tremor is rarely described. Whole-exome sequencing revealed novel compound heterozygous pathogenic FLVCR1 variants: c.498 G > A; p.(Trp166*) and c.369 T > G; p.(Phe123Leu). In addition, we have highlighted the ultrastructural abnormalities of the sural biopsy in this patient.

Aquaporin 4 Mediates the Effect of Iron Overload on Hydrocephalus After Intraventricular Hemorrhage.

BACKGROUND: Iron overload plays an important role in hydrocephalus development following intraventricular hemorrhage (IVH). Aquaporin 4 (AQP4) participates in the balance of cerebrospinal fluid secretion and absorption. The current study investigated the role of AQP4 in the formation of hydrocephalus caused by iron overload after IVH. METHODS: There were three parts to this study. First, Sprague-Dawley rats received an intraventricular injection of 100 µl autologous blood or saline control. Second, rats had IVH and were treated with deferoxamine (DFX), an iron chelator, or vehicle. Third, rats had IVH and were treated with 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a specific AQP4 inhibitor, or vehicle. Rats underwent T2-weighted and T2* gradient-echo magnetic resonance imaging to assess lateral ventricular volume and intraventricular iron deposition at 7, 14, and 28 days after intraventricular injection and were then euthanized. Real-time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence analyses were conducted on the rat brains to evaluate the expression of AQP4 at different time points. Hematoxylin and eosin-stained brain sections were obtained to assess the ventricular wall damage on day 28. RESULTS: Intraventricular injection of autologous blood caused a significant ventricular dilatation, iron deposition, and ventricular wall damage. There was increased AQP4 mRNA and protein expression in the periventricular tissue in IVH rats through day 7 to day 28. The DFX treatment group had a lower lateral ventricular volume and less intraventricular iron deposition and ventricular wall damage than the vehicle-treated group after IVH. The expression of AQP4 protein in periventricular tissue was also inhibited by DFX on days 14 and 28 after IVH. The use of TGN-020 attenuated hydrocephalus development after IVH and inhibited the expression of AQP4 protein in the periventricular tissue between day 14 and day 28 without a significant effect on intraventricular iron deposition or ventricular wall damage. CONCLUSIONS: AQP4 located in the periventricular area mediated the effect of iron overload on hydrocephalus after IVH.

Pathologic changes in neuronal intranuclear inclusion disease are linked to aberrant FUS interaction under hyperosmotic stress.

CGG repeat expansion in NOTCH2NLC is the genetic cause of neuronal intranuclear inclusion disease (NIID). Previous studies indicated that the CGG repeats can be translated into polyglycine protein (N2CpolyG) which was toxic to neurons by forming intranuclear inclusions (IIs). However, little is known about the factors governing polyG IIs formation as well as its molecular pathogenesis. Considering that neurogenetic disorders usually involve interactions between genetic and environmental stresses, we investigated the effect of stress on the formation of IIs. Our results revealed that under hyperosmotic stress, N2CpolyG translocated from the cytoplasm to the nucleus and formed IIs in SH-SY5Y cells, recapitulating the pathological hallmark of NIID patients. Furthermore, N2CpolyG interacted/ co-localized with an RNA-binding protein FUS in the IIs of cellular model and NIID patient tissues, thereby disrupting stress granule formation in cytoplasm under hyperosmotic stress. Consequently, dysregulated expression of microRNAs was found both in NIID patients and cellular model, which could be restored by FUS overexpression in cultured cells. Overall, our findings indicate a mechanism of stress-induced pathological changes as well as neuronal damage, and a potential strategy for the treatment of NIID.

A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data.

BACKGROUND: We aimed to analyse genome-wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. METHODS: One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle-derived genome-wide RNA-sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single-sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA-Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real-time PCR (qRT-PCR) analysis, western blot analysis, and single-nucleus RNA-sequencing (snRNA-seq) were performed in the remaining patients to validate the most correlated gene signature. RESULTS: Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA-Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs  = 0.744, P < 0.001; MRI rs  = 0.718, P < 0.001). Muscle qRT-PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs  = 0.883, P < 0.001) and histological fibrofatty replacement (rs  = 0.804, P < 0.001) and disease duration (rs  = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs  = -0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA-seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro-adipogenic progenitors, satellite cells, and myoblasts. CONCLUSIONS: We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.

Skin biopsy and neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with variable clinical phenotypes. There is a considerable delay in the definite diagnosis, which primarily depends on postmortem brain pathological examination. Although CGG repeat expansion in the 5'-untranslated region of NOTCH2NLC has been identified as a disease-associated variant, the pathological diagnosis is still required in certain NIID cases. Intranuclear inclusions found in the skin tissue of patients with NIID dramatically increased its early detection rate. Skin biopsy, as a minimally invasive method, has become widely accepted as a routine examination to confirm the pathogenicity of the repeat expansion in patients with suspected NIID. In addition, the shared developmental origin of the skin and nerve system provided a new insight into the pathological changes observed in patients with NIID. In this review, we systematically discuss the role of skin biopsy for NIID diagnosis, the procedure of skin biopsy, and the pathophysiological mechanism of intranuclear inclusion in the skin.

Complex I deficiency in m.3243A>G fibroblasts is alleviated by reducing NADH accumulation.

Introduction: Mitochondrial disease is a spectrum of debilitating disorders caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA that compromises the respiratory chain. Mitochondrial 3243A>G (m.3243 A>G) is the most common mutation showing great heterogeneity in phenotype. Previous studies have indicated that NADH: ubiquinone oxidoreductase (complex I) deficiency accompanied by a decreased nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) ratio may play a pivotal role in the pathogenesis of m.3243A>G mutation. Methods: To evaluate the potential effects of strategies targeting the imbalanced NAD+/NADH ratio in m.3243A>G mutation, we treated fibroblasts derived from patients with the m.3243 A>G mutation using nicotinamide riboside (NR) or mitochondria-targeted H2O-forming NADH oxidase (mitoLbNOX). Results: M.3243 A>G fibroblasts showed a significant reduction in complex I core subunit 6, complex I enzymatic activity, complex I-dependent oxygen consumption rate (OCR), and adenosine triphosphate (ATP) production compared to the controls. The NAD+/NADH ratio was also significantly reduced in m.3243 A>G fibroblasts, and, using fluorescence lifetime imaging microscopy, we also found that the NADH level was elevated in m.3243 A>G fibroblasts. After NR treatment, the NAD+/NADH ratio, complex I-dependent OCR, and ATP levels increased, whereas NADH levels remained unchanged. More excitingly, after treatment with mitoLbNOX, the NAD+/NADH ratio, complex I-independent OCR, and ATP levels increased more pronouncedly compared with the NR treatment group, accompanied by significantly reduced NADH levels. Discussion: The present study suggests that compared with repletion of NAD+ alone, the combination of this therapeutic modality with alleviation of NADH overload may amplify the treatment effect of restoring NAD+/NADH balance in m.3243A>G fibroblasts.

The role of AFAP1-AS1 in mitotic catastrophe and metastasis of triple-negative breast cancer cells by activating the PLK1 signaling pathway.

Triple-negative breast cancer (TNBC) is characterized by fast growth, high metastasis, high invasion, and a lack of therapeutic targets. Mitosis and metastasis of TNBC cells are two important biological behaviors in TNBC malignant progression. It is well known that the long noncoding RNA AFAP1-AS1 plays a crucial role in various tumors, but whether AFAP1-AS1 is involved in the mitosis of TNBC cells remains unknown. In this study, we investigated the functional mechanism of AFAP1-AS1 in targeting Polo-like Kinase 1 (PLK1) activation and participating in mitosis of TNBC cells. We detected the expression of AFAP1-AS1 in the TNBC patient cohort and primary cells by in situ hybridization (ISH), northern blot, fluorescent in situ hybridization (FISH) and cell nucleus/cytoplasm RNA fraction isolation. High AFAP1-AS1 expression was negatively correlated with overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS) and recurrence-free survival (RFS) in TNBC patients. We explored the function of AFAP1-AS1 by transwell, apoptosis, immunofluorescence (IF) and patient-derived xenograft (PDX) models in vitro and in vivo. We found that AFAP1-AS1 promoted TNBC primary cell survival by inhibiting mitotic catastrophe and increased TNBC primary cell growth, migration and invasion. Mechanistically, AFAP1-AS1 activated phosphorylation of the mitosis-associated kinase PLK1 protein. Elevated levels of AFAP1-AS1 in TNBC primary cells increased PLK1 pathway downstream gene expression, such as CDC25C, CDK1, BUB1 and TTK. More importantly, AFAP1-AS1 increased lung metastases in a mouse metastasis model. Taken together, AFAP1-AS1 functions as an oncogene that activates the PLK1 signaling pathway. AFAP1-AS1 could be used as a potential prognostic marker and therapeutic target for TNBC.

Novel variants, muscle imaging, and myopathological changes in Chinese patients with VCP-related multisystem proteinopathy.

OBJECTIVE: The objective of this research was to study the clinical features, genetic characteristics, muscle imaging, and muscle pathological changes of a cohort of Chinese patients with mutations in the valosin-containing protein (VCP) gene. METHODS: Nine patients from seven Chinese pedigrees were recruited. Variants were detected by next-generation sequencing and confirmed by Sanger sequencing. Thigh muscle MRIs were performed in five patients. All the patients received muscle biopsies. RESULTS: Seven variants in VCP were identified, and two were novel. All the patients presented with adult-onset muscle weakness. The appearance of "isolated island sign" or "contra-isolated island sign" was observed in four of the five the patients on muscle MRIs. Muscle biopsies demonstrated the combination of neuropathic and myopathic changes in seven patients and muscle dystrophic changes in two patients. Notably, rimmed vacuoles and cytoplasmic VCP and p62-positive protein aggregates were observed in all the patients. CONCLUSION: Our finding of novel variants expanded the mutational spectrum of the VCP gene. This cohort of Chinese patients with VCP mutations mainly present with inclusion body myopathy with predominant limb-girdle distribution. The characteristic pattern of fatty infiltration, especially the "isolated island" and "contra-isolated island" on muscle MRI, along with rimmed vacuoles in muscle biopsy, provides valuable clues for guiding genetic diagnostic workup.

A Myb enhancer-guided analysis of basophil and mast cell differentiation.

The transcription factor MYB is a crucial regulator of hematopoietic stem and progenitor cells. However, the nature of lineage-specific enhancer usage of the Myb gene is largely unknown. We identify the Myb -68 enhancer, a regulatory element which marks basophils and mast cells. Using the Myb -68 enhancer activity, we show a population of granulocyte-macrophage progenitors with higher potential to differentiate into basophils and mast cells. Single cell RNA-seq demonstrates the differentiation trajectory is continuous from progenitors to mature basophils in vivo, characterizes bone marrow cells with a gene signature of mast cells, and identifies LILRB4 as a surface marker of basophil maturation. Together, our study leads to a better understanding of how MYB expression is regulated in a lineage-associated manner, and also shows how a combination of lineage-related reporter mice and single-cell transcriptomics can overcome the rarity of target cells and enhance our understanding of gene expression programs that control cell differentiation in vivo.

Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation.

Objects: This study was intended to find out more about the clinical characterizations of patients carrying transthyretin (TTR) E61K (p.Glu81Lys) gene mutation and the biochemical characterization of this mutant protein. Materials and methods: Five patients who had been diagnosed with hereditary transthyretin amyloidosis and two asymptomatic carriers carrying TTR E61K gene mutation were reported. Biochemical and biophysical tests were conducted to observe the thermodynamic and kinetic stability. Fibril formation tests measured by turbidity assay were performed to explore the pathogenicity of this mutation. Kinetic stabilizer responsiveness was measured to determine the inhibitory effect on protein aggregation. Results: The average age of onset for the five patients was 62 years, and the course of the disease ranged from 2 to 10 years. Cardiac disease was prominent in this group of patients. Nerve pathology revealed a mildly to moderately reduced myelinated fiber density and muscle pathology showed predominant neurogenic impairment accompanied by possible myogenic impairment. E61K-TTR was characterized as a kinetically destabilized protein compared to WT-TTR but its thermodynamic stability was not compromised. In addition, the subunit exchange of E61K with WT-TTR further destabilized the heterozygous tetramer. Meanwhile, the E61K:WT heterozygous tetramer exhibited a poor response to kinetic stabilizers in the fibril formation assay. Finally, the serum TTR tetramer concentration was low in E61K-TTR symptomatic patients and in one asymptomatic gene carrier. Vyndamax (Tafamidis) could increase the TTR tetramer concentration. Conclusions: Patients with E61K mutation tended to be late-onset. The concentration of TTR tetramer in the serum might serve as a biomarker to monitor disease progress, therapeutic window time, and therapeutic response to TTR kinetic stabilizer drugs.

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease.

Objective: The diagnosis of neuronal intranuclear inclusion disease (NIID) is currently based on CGG repeat expansion in the 5'UTR of the NOTCH2NLC gene, or p62-positive intranuclear inclusions in skin biopsy. The purpose of this study is to explore the value of non-invasive pathological findings in urine sediment cells from NIID patients. Materials and methods: Ten patients with clinically suspected NIID were enrolled for skin biopsy and gene screening. Morning urine (500 ml) was collected from each patient, and cell sediment was obtained by centrifugation. Urine cytology, including Giemsa staining, p62 immunostaining, and electron microscopic examination, were conducted on cell sediment. Results: The main clinical symptoms of 10 patients included episodic disturbance of consciousness, cognitive impairment, tremor, limb weakness, and so on. Cerebral MRI showed that 9 patients had linear DWI high signal in the corticomedullary junction. Genetic testing found that the number of CGG repeat ranged from 96 to 158 in the NOTCH2NLC gene. Skin biopsy revealed that all patients showed p62-positive intranuclear inclusions in 18.5 ± 6.3% of the duct epithelial cells of sweat gland. In contrast, urine sediment smears revealed that only 3 patients had p62 positive intranuclear inclusions in 3.5 ± 1.2% of the sedimentary cells. Ultrastructural examinations showed that intranuclear inclusions were also identified in the cell sediment of the 3 patients. Conclusion: Urine cytology may be a new and non-invasive pathological diagnosis technique for some NIID patients, although the positive rate is not as high as that of skin biopsy, which is a sensitive and reliable pathological method for NIID.

FUS Mutation Causes Disordered Lipid Metabolism in Skeletal Muscle Associated with ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by dysfunction of the upper and lower motor neurons resulting in muscle weakness and wasting. Recently, several studies on ALS patients and ALS animal models indicated that intramuscular toxicity played a role in ALS disease progression; however, the mechanisms driving this are unknown. In this study, we explored the possible dysfunction of lipid metabolism in myocytes associated with ALS. Initially, skeletal muscle from 41 ALS patients, as well as 53 non-ALS control subjects, was investigated, and we identified that lipid droplet accumulation in the muscle fibers of ALS patients was significantly increased, especially in patients with FUS mutations. A myoblast (C2C12) cell line expressing mutant FUS (FUS-K510Q) was able to induce lipid droplet accumulation and mitochondrial dysfunction. Consistently, transgenic flies expressing FUS-K510Q under a muscle-specific driver showed elevated triglyceride levels in the flight muscles, as well as locomotor defects. Biochemical analysis of C2C12 cells and fly muscle tissues showed upregulation of PLIN2, and downregulation of ATGL and CPT1A, indicating inhibition of lipolysis and fatty acid ß-oxidation in muscle cells with FUS mutations. Our study provided a potential explanation for the pathogenesis associated with lipid droplets accumulating in skeletal muscle in ALS. Our data also suggested that disordered lipid metabolism and mitochondrial dysfunction play a crucial role in intramuscular toxicity in ALS.

DNA2 mutation causing multisystemic disorder with impaired mitochondrial DNA maintenance.

PURPOSE: To describe a novel DNA2 variant contributing to defects in mtDNA maintenance and mtDNA depletion syndrome (MDS), and the clinical and histological findings associated with this variation. METHODS: Herein, we describe the case of a patient who presented with hearing loss and myopathy, given the family history of similar findings in the father, was evaluated by sequencing of the deafness gene panel, mitochondrial genome, and the exome. Furthermore, tissue staining, mtDNA copy number detection, mtDNA sequencing, and long-range polymerase chain reaction tests were also conducted on the muscle biopsy specimen. In vitro experiments, including analyses of the mtDNA copy number; levels of ATP, ATPase, and reactive oxygen species (ROS); and the membrane potential, were performed. RESULTS: The DNA2 heterozygous truncating variant c. 2368C > T (p.Q790X) was identified and verified as the cause of an mtDNA copy number decrement in both functional experiments and muscle tissue analyses. These changes were accompanied by reductions in ATP, ATPase, and ROS levels. CONCLUSION: The DNA2 variant was a likely cause of MDS in this patient. These findings expand the mutational spectrum of MDS and improve our understanding of the functions of DNA2 by revealing its novel role in mtDNA maintenance.

Patterns of myelinated nerve fibers loss in transthyretin amyloid polyneuropathy and mimics.

OBJECTIVE: The present study was intended to analyze the characteristics of myelinated nerve fibers density (MFD) of transthyretin amyloid polyneuropathy (ATTR-PN) and other similar neuropathies. METHODS: A total of 41 patients with ATTR-PN, 58 patients of other common peripheral neuropathies, and 17 age-and gender-matched controls who visited the First Hospital of Peking University and performed sural nerve biopsy between June 2007 and August 2021 were included for analysis of MFD. RESULTS: Except the vasculitic neuropathy group, the total and small MFD of patients in the ATTR-PN group were significantly lower than those of other disease groups. There was an obvious negative correlation between the total MFD and the disease course in the ATTR-PN group. The disease course of early-onset and late-onset symptoms was similar, but the loss of large myelinated nerve fibers (MF) was more severe for the latter. In addition, all late-onset and most early-onset patients had severely reduced MFD after a 2 years' disease course. The MFD in ATTR-PN patients was negatively correlated with Neuropathy Impairment Score (NIS) and Norfolk Quality of life-diabetic neuropathy (Norfolk QOL-DN) score. CONCLUSION: MF is lost differently in ATTR-PN and in other common peripheral neuropathies. The late-onset and early-onset ATTR-PN patients have different patterns of loss of large and small MF.

The polyG diseases: a new disease entity.

Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats in the 5' untranslated region has been found in neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDMs). Although the upstream open reading frame has not been elucidated in OPML and OPDMs, polyglycine (polyG) translated by expanded CGG repeats is reported to be as a primary pathogenesis in FXTAS and NIID. Collectively, these findings indicate a new disease entity, the polyG diseases. In this review, we state the common clinical manifestations, pathological features, mechanisms, and potential therapies in these diseases, and provide preliminary opinions about future research in polyG diseases.

A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.

OBJECTIVE: Spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3) is a very rare autosomal recessive hereditary disease. Mutations in the COA7 gene, which encodes cytochrome c oxidase assembly factor 7, have been recently reported as the causative gene of SCAN3. So far, only five SCAN3 patients with COA7 mutations have been documented. Herein, we report the clinical, electrophysiological, histological, and genetic findings of a Chinese patient with SCAN3. MATERIALS AND METHODS: The patient was a 31-year-old woman who presented with early-onset peripheral neuropathy and progressive ataxia. She was asked about her medical history and underwent electrophysiological examination, nerve and muscle biopsy, and gene detection. RESULTS: Whole exome next-generation sequencing identified a novel compound heterozygous mutation of COA7 (c.17A>G p.D6G; c.554G>A, p.W185*) in this patient. Magnetic resonance imaging showed cerebellum and spinal cord atrophy. Nerve conduction studies and sural nerve biopsies revealed sensorimotor axonal neuropathy. Muscle biopsies showed mitochondrial abnormalities. Respiratory chain enzyme assay of skin fibroblasts showed normal respiratory chain complex activities. Additionally, the clinical data on previously reported SCAN patients with identified genetic causes in PubMed was summarized. Compared with SCAN1 and SCAN2 patients, SCAN3 patients had earlier onset age, less cognitive impairment, and no ocular signs. CONCLUSION: We reported the first patient diagnosed with SCAN3 in China. A novel mutation in the gene COA7 (c.554G>A, p.W185*) expanded the genetic spectrum of the disease.

Skeletal Muscle Involvement Pattern of Hereditary Transthyretin Amyloidosis: A Study Based on Muscle MRI.

Objects: This study was intended to explore the characteristics of muscle magnetic resonance imaging (MRI) of patients with hereditary transthyretin amyloidosis (ATTRv amyloidosis) prospectively. Methods: The clinical data of 20 patients with ATTRv amyloidosis at our hospital between July 2020 and August 2021 were analyzed. MRI of lower limbs including calf muscles was performed in all these 20 patients and MRI of thigh muscles was performed in 16 of them. Results: The mean age of the 20 patients with ATTRv amyloidosis was 44.2 years (ranging from 26 to 60) whose mean duration of weakness was 23.3 ± 23.0 (ranging from 0 to 84) months. All the patients presented with polyneuropathy, and 18 of them with weakness in their lower limbs. Muscle involvement was selective in these patients with ATTRv amyloidosis. The posterior group of muscles was heavily fatty, and the soleus muscle was the most heavily involved. The proportion of fatty infiltration scores at the calf level was higher than at the thigh level with paired comparison for most patients. Three of these patients had more severely fatty infiltration of muscles at the thigh level. The fatty infiltration of posterior compartments at the calf level was highly consistent with neuropathy impairment scores of lower limbs (weakness), the strength of ankle plantar flexion muscles, and the amplitude of the compound muscle action potential of the tibial nerve. Conclusions: It was found that the pattern of muscle fatty infiltration was consistent with a distal-to-proximal gradient on the whole and that proximal involvements in MRI of lower limbs in some patients could also be observed. Selective fatty infiltration of muscles of posterior compartments and fatty infiltration of the soleus muscle might be typical of ATTRv amyloidosis.

Sporadic adult-onset neuronal intranuclear inclusion disease without high-intensity signal on DWI and T2WI: a case report.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in cells in the central and peripheral nervous system. High-intensity signal in the corticomedullary junction on diffusion-weighted imaging (DWI) is supportive to the diagnosis of NIID. We describe a patient with sporadic adult-onset NIID but without any high-intensity signal on DWI and T2-weighted imaging (T2WI). CASE PRESENTATION: A 58-year-old woman without special family history developed mild persistent tremor in the right hand and deteriorated 2 years later. At 60 years of age, the patient began to conceive the bank, police and internet being deceptive, further presented apathy and confusion after two and a half years, as well as fabrication of non-existent things. Despite the treatment of antipsychotic drugs due to a diagnosis of mental disorder, the patient appeared weakness in the right limbs. Neurological examination revealed mutism, resting tremor, cogwheel-like rigidity in upper limbs, and weakness in all limbs. Brain magnetic resonance imaging displayed no cerebral atrophy initially but atrophy of frontal, temporal and parietal lobes 5 years later. No any high-intensity signal on DWI and T2WI was revealed. However, hypometabolism in the cortexes with atrophy and the right putamen nucleus were showed on 18F-fluoro-deoxy-glucose positron emission tomography/magnetic resonance. On the basis of 107 GGC repeats (normal number <40) in NOTCH2NLC gene and intranuclear inclusions with p62 immunoreactivity in the adipocyte of cutaneous sweat duct by skin biopsy, NIID was finally diagnosed. The symptomatic treatment was given but the patient had no evident improvement. CONCLUSIONS: Our case highlights that despite the lack of high-intensity signal on DWI and T2WI, NIID is still considered for patients with parkinsonism and mental impairment.