Introduction: Hypothyroidism is the most common outcome following radioiodine (RAI) therapy for Graves’ disease, affecting up to 80% of patients, usually within 6 months. While symptoms are often nonspecific, musculoskeletal complaints may be the predominant or sole manifestation. Hypothyroid myopathy occurs in 30–80% of patients, typically causing myalgias, cramps, fatigue, and slowly progressive, symmetric proximal weakness with delayed reflex relaxation. We report an atypical case with subacute and evolving weakness after levothyroxine initiation. Case: A 43-year-old female with Graves’ disease underwent RAI therapy (25 mCi) and developed hypothyroidism 7 weeks later. She was started on levothyroxine 50 mcg daily. Two weeks into treatment, she presented with progressive proximal lower limb weakness (power 4/5), while distal strength and reflexes remained intact. Labs revealed elevated creatine kinase (259 U/L), hypokalemia (3.3 mmol/L), creatinine (57 µmol/L), and severe hypothyroidism (thyroid-stimulating hormone [TSH] 52.88 mIU/L, free thyroxine 4 [FT4] 7.79 pmol/L). Levothyroxine was increased to 100 mcg daily. Two weeks later, she developed proximal upper limb weakness (power 4/5), while lower limb strength had normalized. Nerve conduction studies and electromyography were unremarkable. Labs showed creatine kinase (244 U/L) and creatinine (58 µmol/L). As she remained hypothyroid (TSH 20.85 mIU/L, FT4 11.61 pmol/L), levothyroxine 100 mcg daily was continued. Her symptoms gradually improved alongside biochemical recovery (TSH 8.83 mIU/L, FT4 15.90 pmol/L) after 4 weeks, consistent with hypothyroid myopathy. Conclusion This case highlights an atypical subacute presentation of hypothyroid myopathy following RAI, with evolving weakness and transient worsening after starting thyroid hormone therapy. Although other serious causes should be excluded, clinicians must maintain a high index of suspicion to avoid unnecessary investigations and ensure timely optimization of thyroid hormone therapy, as clinical improvement parallels biochemical recovery.
Iodine Radioisotopes ; Muscular Diseases

Introduction: Muscle weakness in thyroid disease is commonly attributed to thyrotoxic myopathy or hypokalemic periodic paralysis. Nevertheless, autoimmune conditions such as idiopathic inflammatory myopathies (IIM) and myasthenia gravis (MG) should be considered, as they may coexist with Graves’ disease. Case: A 54-year-old female with hypertension and Graves’ disease, treated with carbimazole for 2 years, had her therapy discontinued after remission. She was restarted on low-dose carbimazole following symptom recurrence. Three weeks later, she developed progressive proximal weakness, dysphagia, hoarseness, anorexia, and weight loss. On examination, body mass index was 22 kg/m² with mild proptosis, symmetrical proximal weakness (MRC 4/5), and erythematous rashes on thighs and shins. Otorhinolaryngology evaluation confirmed bilateral vocal cord palsy. Investigations revealed markedly elevated creatine kinase (7,950 U/L), aspartate aminotransferase (349 U/L), and alanine aminotransferase (179 U/L), with euthyroid biochemistry (thyroid-stimulating hormone 5.21 mIU/L, free thyroxine 4 16.6 pmol/L). Hypokalemia correction failed to improve symptoms, excluding periodic paralysis. ANA, C3, and C4 were normal. Myositis panel showed strong anti-Cytosolic 5’-nucleotidase 1A positivity with borderline anti-Ro-52. A diagnosis of IIM with bulbar involvement was made. She was treated with intravenous methylprednisolone and intravenous immunoglobulin, with clinical improvement. Conclusion This case highlights the diagnostic challenge of muscle weakness in thyroid disease. While thyrotoxic myopathy is often presumed, markedly elevated creatinine kinase, rash, and bulbar involvement should prompt suspicion of IIM. Early immunosuppressive therapy is essential to achieve favorable outcomes.
Muscle Weakness ; Thyroid Diseases ; Muscular Diseases

OBJECTIVE: Based on the PTEN-induced hypothetical kinase 1 (PINK1)/Parkin pathway, the effect of acupuncture pretreatment on the expression of mitochondrial autophagy-related proteins in gastrocnemius muscle tissue of rats with exercise-induced muscle damage (EIMD) was observed, and the underlying mechanism of acupuncture pretreatment for the prevention and treatment of EIMD was explored. METHODS: Of 88 SD male rats, aged 6 weeks, 8 rats were randomly selected as a blank group, and the remaining 80 rats were randomized into a model group and an acupuncture pretreatment group, with 40 rats in each group. Either the model group or the acupuncture pretreatment group was subdivided randomly into 5 subgroups with 8 rats in each one according to the time points of sample collection, 0 h, 12 h, 24 h, 48 h and 72 h after modeling. An intermittent downhill running centrifugal exercise was carried out on an animal experimental treadmill to establish the EIMD model in the model group and the acupuncture pretreatment group. The rats in the acupuncture pretreatment group received acupuncture at "Guanyuan" (CV6) and bilateral "Zusanli" (ST36), once a day for 20 min each time, for 7 consecutive days before EIMD model preparation. Transmission electron microscopy was used to observe the ultrastructure of gastrocnemius muscle tissue in each group. The contents of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) in serum were detected by ELISA. Western blot was used to detect the protein expression of PINK1, Parkin, sequestosome 1 (p62) and microtubule-associated protein light chain 3B (LC3B) in rat gastrocnemius muscle tissue. Real-time PCR was adopted to detect the mRNA expression of PINK1, Parkin, p62 and LC3B in rat gastrocnemius muscle tissue. RESULTS: Compared with the blank group, the mitochondria of gastrocnemius muscles showed obvious swelling in the 0 h, 12 h, 24 h, and 48 h model subgroups , autophagosomes were formed in the 12 h and 24 h model subgroups, and the mitochondrial morphology returned to normal gradually in the 72 h model subgroup. The serum MDA contents of rats in 5 model subgroups increased (P<0.01, P<0.05). The contents of SOD and CAT in the subgroups of 0 h, 12 h, 24 h and 48 h decreased (P<0.05, P<0.01). The protein and mRNA expression levels of PINK1, Parkin and LC3B in gastrocnemius muscle tissue of rats in 0 h, 12 h and 24 h subgroups were elevated (P<0.01); and the protein and mRNA expression levels of p62 in the 0 h, 12 h, 24 h and 48 h subgroups were reduced (P<0.01, P<0.05). Compared with the model subgroup at the same time point, the myofibril damage and the degree of mitochondrial swelling were mild in each acupuncture pretreatment subgroup, and the numbers of autophagosomes were fewer. The contents of MDA in the acupuncture pretreatment subgroups decreased at 0 h, 12 h, 24 h, and 48 h (P<0.05, P<0.01). The contents of SOD and CAT in the 12 h acupuncture pretreatment subgroup increased (P<0.05, P<0.01). The protein and mRNA expression levels of PINK1 and Parkin in the 0 h, 12 h, and 24 h acupuncture pretreatment subgroups decreased (P<0.01, P<0.05). The protein and mRNA expression levels of LC3B in the 12 h acupuncture pretreatment subgroup decreased (P<0.01), and that of p62 in the 0 h and 24 h acupuncture pretreatment subgroups increased (P<0.01, P<0.05). CONCLUSION The intermittent downhill running centrifugal exercise induces the excessive mitochondrial autophagy. Acupuncture pretreatment may attenuate EIMD, and the underlying mechanism is related to the regulation of PINK1/Parkin signaling pathway expression, reducing oxidative stress damage in skeletal muscle cells, and inhibiting mitochondrial autophagy overactivation.
Animals ; Ubiquitin-Protein Ligases/genetics* ; Male ; Rats ; Acupuncture Therapy ; Protein Kinases/genetics* ; Rats, Sprague-Dawley ; Mitophagy ; Humans ; Muscle, Skeletal/metabolism* ; Physical Conditioning, Animal ; Muscular Diseases/physiopathology* ; Signal Transduction

The SMPX (small muscle protein X-linked) gene encodes a small-molecular-weight protein that is mainly expressed in skeletal and cardiac muscles and is involved in cytoskeletal dynamics and mechanical stress responses. In recent years, missense variants of the SMPX gene have been identified as the cause of a novel X-linked distal myopathy (Distal myopathy 7). This article has systematically reviewed the molecular functions, variant types, and pathological mechanisms of the SMPX gene by integrating its clinical classification, molecular pathological evidence, and experimental model data, and revealed its pathgenetic mechanism through protein aggregation, dynamic dysregulation of stress granules, abnormal Rac1/p38 signaling pathways, and future research directions.
Humans ; Mutation ; Muscle Proteins/metabolism* ; Deafness/genetics* ; Animals ; Muscular Diseases/genetics* ; Genes, X-Linked

OBJECTIVE: To explore the genetic basis of a child with Chanarin-Dorfman syndrome (CDS) manifesting as ichthyosis. METHODS: A child who had presented at Henan Provincial People's Hospital in June 2023 was selected as study subject. Clinical data of the child was collected. Peripheral blood samples were collected from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing. Relevant literature was searched in databases using key words "Chanarin-Dorfman syndrome" and "ABHD5 gene". The clinical manifestations and variant sites of previously reported cases were compiled and analyzed for correlations. This study was approved by the Medical Ethics Committee of Henan Provincial People's Hospital [Ethics No.: (2019) Jun Shen No. (134)]. RESULTS: WES revealed that the child has harbored compound heterozygous variants of the ABHD5 gene, namely c.99_103del (p.H34*) in exon 2 and c.770C>G (p.P257R) in exon 5, which were inherited from her father and mother, respectively. Bioinformatic analysis suggested that both variants were pathogenic. Literature review indicated that the affected organs in CDS are ranked from most to least including liver, eyes, ears, nervous system, muscles, spleen, and kidneys. The c.594insC and c.594dupC variants are most common. CONCLUSION The identification of the two novel ABHD5 gene variants has enriched the mutation spectrum of CDS. c.594insC or c.594dupC are hotspot mutations of this disease, albeit with no definitive correlation between the genotype and phenotype.
Humans ; Female ; Ichthyosiform Erythroderma, Congenital/genetics* ; Lipid Metabolism, Inborn Errors/genetics* ; Phenotype ; 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics* ; Mutation ; Muscular Diseases/genetics* ; Exome Sequencing ; Child ; Male ; Child, Preschool

OBJECTIVE: To investigate the results of preimplantation genetic testing for monogenic diseases (PGT-M) in a Chinese pedigree affected with Primary carnitine deficiency (PCD). METHODS: A pedigree affected with PCD who visited Hainan Women and Children's Medical Center in April 2023 due to "SLC22A5 gene mutation found in offspring genetic testing and preparing for a second child" was selected as the study subject. Pathogenicity of the proband's variant sites was determined by referring to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG). Sanger sequencing was used to verify the variant sites of SLC22A5 gene in the proband and her parents, and the single nucleotide polymorphism (SNP) haplotype of the family was constructed by SNP microarray (SNP array) method to determine the carrier status of pathogenic genes. After fertilization via assisted reproductive technology, whole genome amplification (WGA) was performed on the biopsied trophoblastic cells. Sanger sequencing, next-generation sequencing (NGS), and SNP array techniques were then used to detect the variants in the SLC22A5 gene and chromosome copy number variation (CNV) in the embryos. Embryos without the variants were selected for transferring. After the successful pregnancy of the proband's mother, amniocentesis was not performed for prenatal diagnosis due to repeated vaginal bleeding. After delivery, neonatal peripheral blood sample was collected to verify the results of PGT-M, and follow-up was conducted. This study was reviewed and approved by the Medical Ethics Committee of Hainan Women and Children's Medical Center (Ethics No. HNWCMC-2022-178). RESULTS: In this study, the c.338G>A and c.760C>T variants in SLC22A5 gene were evaluated as pathogenic variants. Sanger sequencing results of this family showed that the c.338G>A and c.760C>T variants of the proband were inherited from his father and mother, respectively. Haplotypes of c.338G>A and c.760C>T variants of SLC22A5 gene were successfully constructed. PGT-M results showed that 2 of the 8 blastulas biopsied failed WGA, and the CNV detection results of the remaining 6 blastocysts were all euploid: 2 had no mutations in the SLC22A5 gene, 3 were single heterozygous carriers of paternal or maternal origin, and 1 was compound heterozygous carriers of paternal and maternal origin. Combined with the embryo morphology score, an intrauterine singleton pregnancy was achieved after the successful transfer of an optimal embryo with no CNV abnormalities and no paternal or maternal SLC22A5 gene mutations, resulting in the birth of a healthy female baby at 38⁺³ weeks of gestation. The results of peripheral blood chromosomal karyotyping analysis, CNV detection and SLC22A5 gene c.338G>A and c.760C>T site variant detection of the infant were consistent with those of PGT-M, and no abnormality was found. CONCLUSION PGT-M had helped the couple carrying SLC22A5 gene variant to have a healthy offspring and effectively blocked the transmission of PCD in this family.
Adult ; Female ; Humans ; Male ; Pregnancy ; Cardiomyopathies ; China ; East Asian People/genetics* ; Genetic Testing/methods* ; High-Throughput Nucleotide Sequencing ; Hyperammonemia/genetics* ; Mutation ; Pedigree ; Polymorphism, Single Nucleotide ; Preimplantation Diagnosis/methods* ; Solute Carrier Family 22 Member 5/genetics* ; Carnitine/deficiency* ; Muscular Diseases

Objective: To summarize the clinical characteristics and gene variants of 2 pedigrees of non-muscle myosin heavy chain 9 related diseases (MYH9-RD) in children. Methods: The basic information, clinical features, gene variants and laboratory tests of MYH9-RD patients from 2 pedigrees confirmed in the First Affiliated Hospital of Zhengzhou University in November 2021 and July 2022 were analyzed retrospectively. "Non-muscle myosin heavy chain 9 related disease" "MYH9" and "children" were used as key words to search at Pubmed database, CNKI and Wanfang database up to February 2023. The MYH9-RD gene variant spectrum and clinical data were analyzed and summarized. Results: Proband 1 (male, 11 years old) sought medical attention due to epistaxis, the eldest sister and second sister of proband 1 only showed excessive menstrual bleeding, the skin and mucous membrane of the their mother were prone to ecchymosis after bumping, the uncle of proband 1 had kidney damage, and the maternal grandmother and maternal great-grandmother of proband 1 had a history of cataracts. There were 7 cases of phenotypic abnormalities in this pedigree. High-throughput sequencing showed that the proband 1 MYH9 gene had c.279C>G (p.N93K) missense variant, and family verification analysis showed that the variant was inherited from the mother. A total of 4 patients including proband 1 and family members were diagnosed with MYH9-RD. The proband 2 (female, 1 year old) sought medical attention duo to fever and cough, and the father's physical examination revealed thrombocytopenia. There were 2 cases of phenotypic abnormalities in this pedigree. High-throughput sequencing showed that there was a c.4270G>A (p.D1424N) missense variant in the proband 2 MYH9 gene, and family verification analysis showed that the variant was inherited from the father. A total of 2 patients including proband 2 and his father were diagnosed with MYH9-RD. A total of 99 articles were retrieved, including 32 domestic literatures and 67 foreign literatures. The MYH9-RD cases totaled 149 pedigrees and 197 sporadic patients, including 2 pedigrees in our study. There were 101 cases with complete clinical data, including 62 sporadic cases and 39 pedigrees. There were 56 males and 45 females, with an average age of 6.9 years old. The main clinical manifestations were thrombocytopenia, skin ecchymosis, and epistaxis. Most patients didn't receive special treatment after diagnosis. Six English literatures related to MYH9-RD caused by c.279C>G mutation in MYH9 gene were retrieved. Italy reported the highest number of cases (3 cases). Twelve literatures related to MYH9-RD caused by c.4270G>A mutation in MYH9 gene were retrieved. China reported the highest number of cases (9 cases). Conclusions: The clinical manifestations of patients in the MYH9-RD pedigrees varied greatly. MYH9 gene c.279C>G and c.4270G>A mutations are the cause of MYH9-RD.
Infant ; Humans ; Female ; Male ; Child ; Myosin Heavy Chains/genetics* ; Ecchymosis ; Epistaxis ; Pedigree ; Retrospective Studies ; Muscular Diseases ; Thrombocytopenia ; Cytoskeletal Proteins

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.
Humans ; Abnormalities, Multiple ; Retrospective Studies ; Intellectual Disability/genetics* ; Bone Diseases, Developmental/complications* ; Tooth Abnormalities/complications* ; Facies ; Muscular Dystrophy, Duchenne/complications* ; Muscular Atrophy, Spinal/complications* ; Carrier Proteins ; Nuclear Proteins

The patient was a 55-year-old man who was admitted to hospital with "progressive myalgia and weakness for 4 months, and exacerbated for 1 month". Four months ago, he presented with persistent shoulder girdle myalgia and elevated creatine kinase (CK) at routine physical examination, which fluctuated from 1 271 to 2 963 U/L after discontinuation of statin treatment. Progressive myalgia and weakness worsened seriously to breath-holding and profuse sweating 1 month ago. The patient was post-operative for renal cancer, had previous diabetes mellitus and coronary artery disease medical history, had a stent implanted by percutaneous coronary intervention and was on long-term medication with aspirin, atorvastatin and metoprolol. Neurological examination showed pressure pain in the scapularis and pelvic girdle muscles, and V- grade muscle strength in the proximal extremities. Strongly positive of anti-HMGCR antibody was detected. Muscle magnetic resonance imaging (MRI) T2-weighted image and short time inversion recovery sequences (STIR) showed high signals in the right vastus lateralis and semimembranosus muscles. There was a small amount of myofibrillar degeneration and necrosis, CD4 positive inflammatory cells around the vessels and among myofibrils, MHC-Ⅰ infiltration, and multifocal lamellar deposition of C5b9 in non-necrotic myofibrils of the right quadriceps muscle pathological manifestation. According to the clinical manifestation, imageological change, increased CK, blood specific anti-HMGCR antibody and biopsy pathological immune-mediated evidence, the diagnosis of anti-HMGCR immune-mediated necrotizing myopathy was unequivocal. Methylprednisolone was administrated as 48 mg daily orally, and was reduced to medication discontinuation gradually. The patient's complaint of myalgia and breathlessness completely disappeared after 2 weeks, the weakness relief with no residual clinical symptoms 2 months later. Follow-up to date, there was no myalgia or weakness with slightly increasing CK rechecked. The case was a classical anti-HMGCR-IMNM without swallowing difficulties, joint symptoms, rash, lung symptoms, gastrointestinal symptoms, heart failure and Raynaud's phenomenon. The other clinical characters of the disease included CK as mean levels >10 times of upper limit of normal, active myogenic damage in electromyography, predominant edema and steatosis of gluteus and external rotator groups in T2WI and/or STIR at advanced disease phase except axial muscles. The symptoms may occasionally improve with discontinuation of statins, but glucocorticoids are usually required, and other treatments include a variety of immunosuppressive therapies such as methotrexate, rituximab and intravenous gammaglobulin.
Male ; Humans ; Middle Aged ; Autoantibodies ; Myositis/diagnosis* ; Autoimmune Diseases ; Muscle, Skeletal/pathology* ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use* ; Necrosis/pathology* ; Muscular Diseases/drug therapy*

OBJECTIVE: To explore the molecular pathological mechanism of liver metabolic disorder in severe spinal muscular atrophy (SMA). METHODS: The transgenic mice with type Ⅰ SMA (Smn^-/- SMN2^0tg/2tg) and littermate control mice (Smn^+/- SMN2^0tg/2tg) were observed for milk suckling behavior and body weight changes after birth. The mice with type Ⅰ SMA mice were given an intraperitoneal injection of 20% glucose solution or saline (15 μL/12 h), and their survival time was recorded. GO enrichment analysis was performed using the RNA-Seq data of the liver of type Ⅰ SMA and littermate control mice, and the results were verified using quantitative real-time PCR. Bisulfite sequencing was performed to examine CpG island methylation level in Fasn gene promoter region in the liver of the neonatal mice. RESULTS: The neonatal mice with type Ⅰ SMA showed normal milk suckling behavior but had lower body weight than the littermate control mice on the second day after birth. Intraperitoneal injection of glucose solution every 12 h significantly improved the median survival time of type Ⅰ SMA mice from 9±1.3 to 11± 1.5 days (P < 0.05). Analysis of the RNA-Seq data of the liver showed that the expression of the target genes of PPARα related to lipid metabolism and mitochondrial β oxidation were down-regulated in the liver of type Ⅰ SMA mice. Type Ⅰ SMA mice had higher methylation level of the Fasn promoter region in the liver than the littermate control mice (76.44% vs 58.67%). In primary cultures of hepatocytes from type Ⅰ SMA mice, treatment with 5-AzaC significantly up-regulated the expressions of the genes related to lipid metabolism by over 1 fold (P < 0.01). CONCLUSION Type Ⅰ SMA mice have liver metabolic disorder, and the down-regulation of the target genes of PPARα related to lipid and glucose metabolism due to persistent DNA methylation contributes to the progression of SMA.
Mice ; Animals ; PPAR alpha ; Liver Diseases ; Muscular Atrophy, Spinal/genetics* ; Mice, Transgenic ; Body Weight ; Glucose