Case report: Muscle involvement in a Chinese patient with TRNT1-related disorder.

The TRNT1 gene encodes tRNA nucleotidyltransferase 1, which catalyzes the addition of cytosine-cytosine-adenosine (CCA) to the ends of cytoplasmic and mitochondrial tRNAs. The most common clinical phenotype associated with TRNT1 is autosomal recessive sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD). Muscle involvement has rarely been reported in TRNT1-related disorders. Here we report a Chinese patient with incomplete SIFD and hyperCKemia, and explored the skeletal muscle pathological changes. The patient was a 3-year-old boy with sensorineural hearing loss, sideroblastic anemia, and developmental delay since infancy. At the age of 11 months, significantly increased levels of creatine kinase were noted, accompanied by mild muscle weakness. Whole-exome sequencing revealed compound heterozygous variants of the TRNT1 gene, c.443C > T (p.Ala148Val) and c.692C > G (p.Ala231Gly), in the patient. Western blot showed a decreased expression of TRNT1 and cytochrome c oxidase subunit IV (COX IV) in the skeletal muscle of the patient. Electron microscopy observation of skeletal muscle pathology revealed abnormal mitochondria of various sizes and shapes, supporting a diagnosis of mitochondrial myopathy. The present case indicates that in addition to the classic SIFD phenotype, TRNT1 mutations can cause mitochondrial myopathy, a rare clinical phenotype of TRNT1-related disorders.

Characteristics and feasibility of ambulatory respiratory assessment of paediatric neuromuscular disease: an observational retrospective study.

PURPOSE: To investigate the characteristics of respiratory involvement in Chinese paediatric neuromuscular disease (NMD) at early stage and to explore convenient monitoring methods. MATERIALS AND METHODS: Children with NMD (age < 18) diagnosed at a multidisciplinary joint NMD clinic at Peking University First Hospital from January 2016 to April 2021 were included. Overnight polysomnography (PSG) and pulmonary function test (PFT) data were analysed, and the characteristics of four groups: congenital muscular dystrophy (CMD), congenital myopathy, spinal muscular atrophy, and Duchenne muscular dystrophy (DMD) were compared. RESULTS: A total of 83 children with NMD were referred for respiratory assessment, of who 80 children underwent PSG; 41 performed spirometry and 38, both. The duration of pulse oxygen saturation (SpO2) <90% over apnoea and hypopnoea index (AHI) was lowest in DMD and significantly different from CMD (p = 0.033). AHI was positively correlated with the oxygen desaturation index (ODI) (r = 0.929, p = 0.000). The peak expiratory flow (PEF) were positively correlated with forced vital capacity (FVC), both as actual values and percent pred, respectively (r = 0.820, 0.719, p = 0.000). ROC derived sensitivity and specificity of prediction of AHI > 15/h or duration of SpO2<90% ≥ 60 min from FVC <51% pred was 75.8% and 85.7%, respectively. CONCLUSIONS: AHI and hypoxia burden were independent factors in children with NMD in PSG and attention needed to be paid in both. FVC might be a daytime predictor for significant sleep-disordered breathing or hypoxia. Nocturnal consecutive oximetry with diurnal peak flow measurement may be convenient and effective for home monitoring at early stage of respiratory involvement.

Structurally Diverse Indole Alkaloids with Vasorelaxant Activity from Melodinus hemsleyanus.

Six new structurally diverse indole alkaloids, melohemsines J-M (1-4), 11-hydroxy-Δ14-vincamine (5), and 11-hydroxy-16-epi-Δ14-vincamine (6), and 15 known alkaloids were isolated from the leaves and twigs of Melodinus hemsleyanus Diels. These new compounds and their absolute configurations were determined through spectroscopic data analyses, X-ray diffraction, and computational methods. Melohemsine J (1) is the first example of a melodinus-type alkaloid possessing a 6/6/5/5/6/5 hexacyclic skeleton and containing a tetrahydrofuro[2,3-b]pyridine-2(3H)-one unit. Melohemsine K (2) is an unusual aspidosperma-type alkaloid possessing a 6/5/6/5/5 pentacyclic architecture with a contracted E ring (loss of CH2). Compounds 5-10 and 16 exhibited vasorelaxant activities with EC50 values of 0.8-3.8 µM. In addition, compound 4 displayed moderate cytotoxicity toward the tumor cell lines HepG2 and A-549 with EC50 values of 18.7 and 28.7 µM, respectively.

Hunterines A-C, Three Unusual Monoterpenoid Indole Alkaloids from Hunteria zeylanica.

Three new monoterpenoid indole alkaloids (MIAs), hunterines A-C (1-3), were isolated from Hunteria zeylanica. Compound 1 possesses a unique skeleton with an unprecedented azabicyclo[4.3.1]decane ring system. Compounds 2 and 3 are a pair of epimeric vobasinylindole alkaloid heterodimers. Their structures including absolute configurations were established by spectroscopic analyses, X-ray diffraction, computational calculation, and the modified Mosher's method. Plausible biogenetic pathways of 1-3 were also proposed. Alkaloid 1 showed moderate cytotoxic activity against the HepG2 cell line.

[Value of muscle enzyme analysis in differential diagnosis of childhood myopathic hyper-creatine kinase-emia].

OBJECTIVE: To summarize the etiology and clinical characteristics of children with myopathic elevated creatine kinase (CK) levels. The degrees of elevated CK as well as lactic dehydrogenase (LDH) and aspartate aminotransferase (AST) levels in different myopathy were analyzed. METHODS: The clinical data of 235 cases characterized as myopathic hyper-CK-emia from January 2004 to December 2011 were collected and analyzed. A retrospective analysis of LDH and AST levels according to CK in part of the patients were reviewed. RESULTS: Of the 235 cases, 180 were male and 55 female. According to the age at which hyper-CK-emia was diagnosed, 64 cases were under 6 months, 90 between 6 months and 3 years, 50 between 3 and 6 years and 31 between 6 and 14 years. Their CK levels significantly increased in 162 cases, moderately increased in 31 cases, and slightly increased in 42 cases. The age at which hyper-CK-emia was diagnosed and the CK level had no correlation with muscle weakness and the severity. As to CK levels: Duchenne muscular dystrophy (DMD) > inflammatory myopathies > congenital muscular dystrophy (CMD) > metabolic myopathies. LDH and AST levels: DMD > inflammatory myopathies > metabolic myopathies > CMD. CONCLUSION: Unlike adults, the etiology of myopathic hyper-CK-emia in children is complicated and diverse. The onset type, the degree and duration of hyper-CK-emia are helpful to make the diagnosis. CK increases most significantly in DMD, then in inflammatory myopathies, CMD, and metabolic myopathies. Diagnostic flowchart of myogenic hyper-CK-emia should follow a certain process, and the indications of biochemical tests, metabolic screening, electrophysiological examination, muscle biopsy and genetic testing should be made. Finally, different treatments should be designed according to the etiology.

[Clinical and molecular genetic analysis of a family with normokalemic periodic paralysis].

OBJECTIVE: Periodic paralysis (PP) is one type of skeletal muscle channelopathies characterized by episodic attacks of weakness. It is usually classified into hyperkalemic periodic paralysis (HyperPP), hypokalemic periodic paralysis (HypoPP) and normokalemic periodic paralysis (NormoPP) based on the blood potassium levels. HypoPP is the most common type of these three and NormoPP is the rarest one. The aim of this study was to explore the clinical and genetic features of a Chinese family with normokalemic periodic paralysis (NormoKPP). METHOD: Clinical features of all patients in the family with NormoKPP were analyzed. Genomic DNA was extracted from peripheral blood leukocytes and amplified with PCR. We screened all 24 exons of SCN4A gene and then sequence analysis was performed in those who showed heteroduplex as compared with unaffected controls. RESULT: (1) Fifteen members of the family were clinically diagnosed NormoKPP, and their common features are: onset within infacy, episodic attacks of weakness, the blood potassium levels were within normal ranges, high sodium diet or large dosage of normal saline could attenuate the symptom. One muscle biopsy was performed and examination of light and electronic microscopy showed occasionally degenerating myofibers. (2) Gene of 12 patients were screened and confirmed mutations of SCN4A genes--c. 2111 T > C/p. Thr704Met. CONCLUSION: The study further defined the clinical features of patients with NormoKPP, and molecular genetic analysis found SCN4A gene c. 2111 T > C/p. Thr704Met point mutation contributed to the disease. In line with the autosomal dominant inheritance laws, this family can be diagnosed with periodic paralysis, and be provided with genetic counseling. And the study may also help the clinical diagnosis, guide treatment and genetic counseling of this rare disease in China.

Genotype/phenotype of 6 Chinese cases with Niemann-Pick disease type C.

UNLABELLED: Niemann-Pick disease type C (NP-C), caused by mutations of either NPC1 or NPC2 gene, is an inherited lysosomal lipid storage disorder that is difficult to be diagnosed and treated. NP-C is rarely reported in China and so far very few literatures are available for Chinese clinical workers. To better characterize this disease in China and improve genetic counseling, mutational analyses of NPC1 gene were carried out in 6 unrelated Chinese patients. METHODS: Clinical data of the probands from 2007 to 2010 were collected and analyzed. All exons of NPC1 were analyzed by direct sequencing. RESULTS: The six cases, four males and two females, included three cases of late infantile subtype and three cases of juvenile subtype. Case one and case six had siblings who suffered from the same disease. The onset of clinical symptoms varied from three to ten years old, and they included progressive cognitive and language impairment, and motion retrogradation. All were caught by focal or generalized seizures from one to four years after the onset. Vertical supranuclear gaze palsy, dysarthria, dysphagia, internal rotation and adduction of bilateral hands and splenomegaly occurred gradually during the disease progression. Five patients had laughter-cataplexy. MRI indicated mild brain atrophy. Sea blue cells and Niemann-Pick cells were presented in bone marrow smears. Activity of acid sphingomyelinase was normal or only slightly lower than controls. Supporting and symptomatic treatments could improve some of the clinical signs. We identified 10 different NPC1 mutations were identified in 12/12 alleles, 3 of which are described for the first time. All mutations were missense mutations, which located throughout the gene with five clustering in the cysteine-rich luminal domain. Homozygous mutation of S865L correlated with a relatively severe juvenile neurological form. CONCLUSIONS: NP-C is a rare autosomal recessive lysosomal storage disease that affects intellectual development of children, causing dementia, vegetative state and eventual death. The awareness of NP-C should be raised in the Chinese population. The typical clinical features of this disease include vertical supranuclear gaze palsy, seizures and cataplexy. Laboratory features include the presence of sea blue cells and Niemann-Pick cells in bone marrow smears. NPC1 mutation can be identified in most of these patients and most of them are missense mutations.