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1.
Eur J Med Genet ; 65(5): 104478, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35395430

RESUMO

Mandibulofacial dysostosis with microcephaly (MFDM, OMIM#610536) is an extremely rare genetic syndrome characterised by microcephaly, external ear deformity, hearing loss, and distinct facial appearance, including zygomatic hypoplasia and micrognathia. Occasionally, various malformations in other internal organs, including oesophageal atresia or tracheoesophageal fistula, may lead to life-threatening situations. Haploinsufficiency of EFTUD2 is responsible for MFDM. Here, we present the phenotypic and genetic characteristics of six Korean children who were diagnosed with MFDM by molecular genetic testing. All but one patient had occipitofrontal circumferences below the -2.0 standard deviation score. Micrognathia was identified in all patients. A cleft palate (66.7%) and other facial dysmorphisms, including facial asymmetry (50%) and malar hypoplasia (50%), were also frequently observed. Hearing loss was observed in all patients along with one or more internal and external ear deformities, including ossicular anomalies, auditory canal stenosis, and microtia. Two patients (33.3%) had undergone surgery for tracheoesophageal fistula type C. Most patients were initially misdiagnosed as other better-known syndromes with overlapping characteristics, such as Treacher Collins or CHARGE syndrome. The first three patients were diagnosed using exome sequencing. However, after increased awareness of MFDM in the first three patients, MFDM was considered one of the initial differential diagnoses and could be diagnosed by target gene analysis in the remaining three cases. Thus, we recommend targeted EFTUD2 analysis as the initial workup for the rapid diagnosis of MFDM in patients with facial dysostosis, microcephaly, and otologic problems.


Assuntos
Anormalidades Múltiplas , Perda Auditiva , Disostose Mandibulofacial , Microcefalia , Micrognatismo , Fístula Traqueoesofágica , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Criança , Humanos , Disostose Mandibulofacial/genética , Microcefalia/diagnóstico , Microcefalia/genética , Fatores de Alongamento de Peptídeos/genética , República da Coreia , Ribonucleoproteína Nuclear Pequena U5/genética , Fístula Traqueoesofágica/genética
2.
J Med Genet ; 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35387801

RESUMO

BACKGROUND: Whole-exome sequencing-based diagnosis of rare diseases typically yields 40%-50% of success rate. Precise diagnosis of the patients with neuromuscular disorders (NMDs) has been hampered by locus heterogeneity or phenotypic heterogeneity. We evaluated the utility of transcriptome sequencing as an independent approach in diagnosing NMDs. METHODS: The RNA sequencing (RNA-Seq) of muscle tissues from 117 Korean patients with suspected Mendelian NMD was performed to evaluate the ability to detect pathogenic variants. Aberrant splicing and CNVs were inspected to identify additional causal genetic factors for NMD. Aberrant splicing events in Dystrophin (DMD) were investigated by using antisense oligonucleotides (ASOs). A non-negative matrix factorisation analysis of the transcriptome data followed by cell type deconvolution was performed to cluster samples by expression-based signatures and identify cluster-specific gene ontologies. RESULTS: Our pipeline called 38.1% of pathogenic variants exclusively from the muscle transcriptomes, demonstrating a higher diagnostic rate than that achieved via exome analysis (34.9%). The discovery of variants causing aberrant splicing allowed the application of ASOs to the patient-derived cells, providing a therapeutic approach tailored to individual patients. RNA-Seq data further enabled sample clustering by distinct gene expression profiles that corresponded to clinical parameters, conferring additional advantages over exome sequencing. CONCLUSION: The RNA-Seq-based diagnosis of NMDs achieves an increased diagnostic rate and provided pathogenic status information, which is not easily accessible through exome analysis.

3.
Int J Mol Sci ; 23(5)2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35270040

RESUMO

Dystrophinopathy is caused by mutations in the dystrophin gene, which lead to progressive muscle degeneration, necrosis, and finally, death. Recently, golden retrievers have been suggested as a useful animal model for studying human dystrophinopathy, but the model has limitations due to difficulty in maintaining the genetic background using conventional breeding. In this study, we successfully generated a dystrophin mutant dog using the CRISPR/Cas9 system and somatic cell nuclear transfer. The dystrophin mutant dog displayed phenotypes such as elevated serum creatine kinase, dystrophin deficiency, skeletal muscle defects, an abnormal electrocardiogram, and avoidance of ambulation. These results indicate that donor cells with CRISPR/Cas9 for a specific gene combined with the somatic cell nuclear transfer technique can efficiently produce a dystrophin mutant dog, which will help in the successful development of gene therapy drugs for dogs and humans.


Assuntos
Distrofina , Distrofia Muscular de Duchenne , Animais , Sistemas CRISPR-Cas/genética , Cães , Distrofina/genética , Distrofina/metabolismo , Edição de Genes , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Técnicas de Transferência Nuclear
4.
Neuromuscul Disord ; 32(2): 176-184, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35165004

RESUMO

Nemaline myopathies are clinically and genetically heterogeneous disorders caused by several different genes. One of them is TNNT1, which was initially described in Amish families and has not been reported in Asian populations. Although most TNNT1 myopathies are caused by loss-of-function mutations, several recent studies have shown that missense mutations can also be pathogenic. A 16-year-old Korean boy with progressive muscle weakness visited the Seoul National University Hospital. He showed generalized myopathy, which was predominant in the paraspinal and neck muscles. Moreover, nemaline rods were observed in a muscle biopsy. Whole-exome sequencing of DNA samples of the patient and his younger brother, who had a similar phenotype, revealed novel compound heterozygous mutations in TNNT1 (c.724G>C (p.Ala242Pro) and c.611+1G>A). Sanger sequencing of cDNA extracted from muscle samples of the patient confirmed partial or total skipping of exon 11 in the splicing variant. The impact of the missense variant on muscle integrity and locomotor activity was verified using a zebrafish loss-of-function model. Here, we reported novel familial cases of TNNT1 myopathy with intermediate clinical presentations caused by compound heterozygous mutations and demonstrated their functional defects using an animal model.


Assuntos
Miopatias da Nemalina , Troponina T/genética , Peixe-Zebra , Adolescente , Animais , Humanos , Masculino , Músculo Esquelético/patologia , Mutação , Miopatias da Nemalina/genética , Fenótipo
5.
Int J Stem Cells ; 2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35220279

RESUMO

BACKGROUND AND OBJECTIVES: Menkes disease (MNK) is a rare X-linked recessive disease, caused by mutations in the copper transporting ATP7A gene that is required for copper homeostasis. MNK patients experience various clinical symptoms including neurological defects that are closely related to the prognosis of MNK patients. Neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) produce new neurons throughout life, and defects in DG neurogenesis are often correlated with cognitive and behavioral problems. However, neurodevelopmental defects in the DG during postnatal period in MNK have not been understood yet. METHODS AND RESULTS: Mottled-brindled (MoBr/y) mice (MNK mice) and littermate controls were used in this study. In vivo microCT imaging and immunohistochemistry results demonstrate that blood vasculatures in hippocampus are abnormally decreased in MNK mice. Furthermore, postnatal establishment of NSC population and their neurogenesis are severely compromised in the DG of MNK mice. In addition, in vitro analyses using hippocampal neurosphere culture followed by immunocytochemistry and immunoblotting suggest that neurogenesis from MNK NSCs is also significantly compromised, corresponding to defective neurogenic gene expression in MNK derived neurons. CONCLUSIONS: Our study is the first reports demonstrating that improper expansion of the postnatal NSC population followed by significant reduction of neurogenesis may contribute to neurodevelopmental symptoms in MNK. In conclusion, our results provide new insight into early neurodevelopmental defects in MNK and emphasize the needs for early diagnosis and new therapeutic strategies in the postnatal central nerve system damage of MNK patients.

6.
Dev Med Child Neurol ; 2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35106761

RESUMO

AIM: To investigate the clinical characteristics and prevalence of paediatric anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis. METHOD: A total of 94 paediatric patients (46 males, 48 females, median age 9 years 5 months, range: 8 months-17 years 8 months) with autoimmune encephalitis were recruited at Seoul National University Children's Hospital. We evaluated autoantibody status and identified patients with anti-MOG antibody-associated autoimmune encephalitis. Retrospective reviews of medical records were performed to describe clinical presentations, laboratory findings, treatments, and outcomes. RESULTS: Eight patients (five males, three females, median age 11 years 9 months) with anti-MOG antibody-associated encephalitis were identified (8.5% of those with autoimmune encephalitis), one of whom was copositive for anti-N-methyl-d-aspartate receptor (NMDAR) antibodies. Anti-NMDAR antibodies were identified in 23 patients (23 out of 94, 24.5%). Unilateral or bilateral cortical involvement was identified in five patients. Focal contrast enhancement was also identified in three of the five patients with cortical lesions. All patients showed favourable response to immunotherapy with a Modified Rankin Scale ≤2 at the last follow-up. Relapse was found in one patient and clinico-radiological remission was achieved with cyclic intravenous immunoglobulin therapy. INTERPRETATION: Anti-MOG antibody-associated encephalitis accounts for a significant proportion of clinically defined paediatric patients with autoimmune encephalitis. Anti-MOG antibody-associated encephalitis should be included in the clinical spectrum of anti-MOG-associated diseases.

7.
Mult Scler Relat Disord ; 60: 103709, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35220001

RESUMO

PURPOSE: To investigate the ophthalmic and neurological features of myelin oligodendrocyte glycoprotein antibody seropositive optic neuritis (MOG-ON) in pediatric patients. METHODS: We analyzed the clinical data and orbital magnetic resonance images of patients aged below 15 years, diagnosed with MOG-ON at our institution (n = 40). RESULTS: The mean age at first ON onset was 7.7 ± 3.1 years, and 26 (65.0%) patients were girls. Twenty-three patients (57.5%) experienced bilateral ON, and ten (25.0%) had recurrent ON. Pain on eye movement was present in 30.6% of the eyes. In the acute stage, optic disk swelling and peripapillary hemorrhage was found in 82.6% and 15.2% of the eyes, respectively. In the chronic stage, optic atrophy was noted in 91.5% of the eyes. Although mean visual acuity (VA) at nadir was 1.72 ± 0.66 logMAR, all patients experienced visual improvement of ≥0.3 logMAR, and the mean final VA was 0.05 ± 0.14 logMAR. Twenty-one patients (52.5%) had other demyelinating diseases during the disease course (ON plus group), while 18 patients (45.0%) had experienced ON without other demyelinating disease (isolated ON group). Pain (19.4% vs. 38.5%, p = 0.098) and perineural enhancement (3.3% vs. 21.7%, p = 0.036) were less frequently observed in ON plus group. CONCLUSIONS: Pediatric MOG-ON has distinct clinical features, such as infrequent pain and perineural enhancement. Although optic atrophy is commonly observed, visual function is retained in most patients. A multidisciplinary approach and long-term follow-up are required for pediatric MOG-ON, since CNS involvement is more common than ON recurrence.

8.
Brain Dev ; 44(4): 287-293, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35033405

RESUMO

INTRODUCTION: Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder long recognized as the most common genetic cause of infantile mortality described so far. However, the emergence of some innovative therapies, such as nusinersen and onasemnogene abeparvovec (AVXS-101), have made it possible to change the disease course of SMA. METHODS: In this study, five SMA type 1 and one SMA type 2 patients who received AVXS-101 were enrolled (7-24 months of age when administered). They were all previously treated with nusinersen, 4-5 times including loading doses, but stopped nusinersen maintenance after injection of AVXS-101. Patients were regularly followed up with laboratory tests and functional assessments after administration. RESULTS: Liver enzymes (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase) and monocyte count tended to be elevated but normalized after several weeks. Platelets and white blood cells were transiently decreased for a few weeks after injection. Prolonged elevation of liver enzymes was associated with steroid tapering earlier than 1 month post treatment. During the follow-up period (ranging from 5 to 17 months after injection), all patients showed improved motor function and there was no case of mortality or requirement for permanent ventilatory support. For one patient, use of bilevel positive airway pressure could be reduced from 16 h to 8 h a day during sleep at 6 months post treatment. CONCLUSION: Our experience of AVXS-101 treatment has shown that a single intravenous dose could be safe and effective for SMA patients without the need for any maintenance treatment.


Assuntos
Produtos Biológicos/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Atrofias Musculares Espinais da Infância/terapia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Avaliação de Resultados em Cuidados de Saúde , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos
9.
Ann Lab Med ; 42(1): 79-88, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34374352

RESUMO

BACKGROUND: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genomic imprinting disorders that are mainly caused by a deletion on 15q11-q13, the uniparental disomy of chromosome 15, or an imprinting defect. We evaluated the utility of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a diagnostic tool and for demonstrating the relationship between molecular mechanisms and clinical presentation. METHODS: We performed MS-MLPA using DNA samples from 93 subjects (45 PWS, 24 AS, and 24 non-PWS/AS controls) who had previously undergone MS-PCR for the diagnosis of PWS/AS. We compared the results of both assays, and patients' clinical phenotypes were reviewed retrospectively. RESULTS: MS-MLPA showed a 100% concordance rate with MS-PCR. Among the 45 PWS patients, 26 (57.8%) had a deletion of 15q11-q13, and the others (42.2%) had uniparental disomy 15 or an imprinting defect. Among the 24 AS patients, 16 (66.7%) had a deletion of 15q11-q13, 7 AS patients (29.2%) had uniparental disomy 15 or an imprinting defect, and one AS patient (4.2%) showed an imprinting center deletion. CONCLUSIONS: MS-MLPA has clinical utility for the diagnosis of PWS/AS, and it is superior to MS-PCR in that it can identify the molecular mechanism underlying the disease.


Assuntos
Síndrome de Angelman , Síndrome de Prader-Willi , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Cromossomos Humanos Par 15/genética , Metilação de DNA , Humanos , Metilação , Reação em Cadeia da Polimerase Multiplex , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Estudos Retrospectivos
10.
Genet Med ; 24(3): 663-672, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34906491

RESUMO

PURPOSE: Despite the importance of exonic copy number variations (CNVs) in human genetic diseases, reliable next-generation sequencing-based methods for detecting them are unavailable. We developed an expandable and robust exonic CNV detection tool called consistent count region (CCR)-CNV. METHODS: In total, about 1000 samples of the truth set were used for validating CCR-CNV. We compared CCR-CNV performance with 2 well-known CNV tools. Finally, to overcome the limitations of CCR-CNV, we devised a combined approach. RESULTS: The mean sensitivity and specificity of CCR-CNV alone were above 95%, which was superior to that of other CNV tools, such as DECoN and Atlas-CNV. However, low covered region and positive predictive value and high false discovery rate act as obstacles to its use in clinical settings. The combined approach showed much improved performance than CCR-CNV alone. CONCLUSION: In this study, we present a novel diagnostic tool that allows the identification of exonic CNVs with high confidence using various reagents and clinical next-generation sequencing platforms. We validated this method using the largest multiple ligation-dependent probe amplification-confirmed data set, including sufficient copy normal control data. The approach, combined with existing CNV tools, allows the implementation of CCR-CNV in clinical settings.


Assuntos
Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Variações do Número de Cópias de DNA/genética , Éxons/genética , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
11.
Sci Rep ; 11(1): 23347, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34857824

RESUMO

It is challenging to extract the brain region from T2-weighted magnetic resonance infant brain images because conventional brain segmentation algorithms are generally optimized for adult brain images, which have different spatial resolution, dynamic changes of imaging intensity, brain size and shape from infant brain images. In this study, we propose a brain extraction algorithm for infant T2-weighted images. The proposed method utilizes histogram partitioning to separate brain regions from the background image. Then, fuzzy c-means thresholding is performed to obtain a rough brain mask for each image slice, followed by refinement steps. For slices that contain eye regions, an additional eye removal algorithm is proposed to eliminate eyes from the brain mask. By using the proposed method, accurate masks for infant T2-weighted brain images can be generated. For validation, we applied the proposed algorithm and conventional methods to T2 infant images (0-24 months of age) acquired with 2D and 3D sequences at 3T MRI. The Dice coefficients and Precision scores, which were calculated as quantitative measures, showed the highest values for the proposed method as follows: For images acquired with a 2D imaging sequence, the average Dice coefficients were 0.9650 ± 0.006 for the proposed method, 0.9262 ± 0.006 for iBEAT, and 0.9490 ± 0.006 for BET. For the data acquired with a 3D imaging sequence, the average Dice coefficient was 0.9746 ± 0.008 for the proposed method, 0.9448 ± 0.004 for iBEAT, and 0.9622 ± 0.01 for BET. The average Precision was 0.9638 ± 0.009 and 0.9565 ± 0.016 for the proposed method, 0.8981 ± 0.01 and 0.8968 ± 0.008 for iBEAT, and 0.9346 ± 0.014 and 0.9282 ± 0.019 for BET for images acquired with 2D and 3D imaging sequences, respectively, demonstrating that the proposed method could be efficiently used for brain extraction in T2-weighted infant images.


Assuntos
Algoritmos , Encéfalo/anatomia & histologia , Lógica Fuzzy , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Humanos , Lactente
12.
Ann Neurol ; 90(5): 738-750, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34564892

RESUMO

OBJECTIVE: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation. METHODS: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. INTERPRETATION: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.


Assuntos
Mutação/genética , Paraplegia Espástica Hereditária/genética , alfa Carioferinas/genética , Adulto , Pré-Escolar , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
13.
Mol Genet Genomic Med ; 9(10): e1791, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34427995

RESUMO

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a rare congenital malformation syndrome with clinical characteristics such as hypertrichosis, high arched eyebrows, large beaked nose, and broad thumbs and halluces. RSTS patients showed intellectual disability and health problems such as short stature, ophthalmologic abnormalities, congenital heart defects, genitourinary defects, and variable types of tumors. Although mutations in CREBBP and EP300 genes are associated with RSTS features, genetic causation is still unknown in 30% of patients. METHODS: We present clinical and molecular genetic characteristics of 25 unrelated Korean patients clinically diagnosed with RSTS. Sanger sequencing analysis and multiplex ligation-dependent probe amplification for CREBBP in 25 patients and exome sequencing of CREBBP-negative cases were performed in nine patients successively. RESULTS: Causative variants were identified in 20 (80%) patients: 16 (64%) in CREBBP and 4 (16%) in EP300. All the identified variants predict protein truncation (11 frameshift, 2 nonsense, 1 splicing-site, and 6 large intragenic deletions); there are no repeatedly identified sequence variants. Four of the CREBBP and all four EP300 variants are novel. Intellectual disability was noted in 24/25 patients (96%); no difference was found between CREBBP and EP300 groups. One patient with a CREBBP variant (4%) had malignant tumor. CONCLUSIONS: To date, this is the largest cohort of patients with RSTS including EP300-related patients in Korea. Future large-scale studies to find genetic mutation of molecularly unsolved patients and long-term prospective studies are required to validate our results.


Assuntos
Variação Biológica da População , Estudos de Associação Genética , Predisposição Genética para Doença , Fenótipo , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Proteína de Ligação a CREB/genética , Criança , Pré-Escolar , Proteína p300 Associada a E1A/genética , Feminino , Seguimentos , Humanos , Lactente , Masculino , República da Coreia , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
14.
J Clin Endocrinol Metab ; 106(9): 2678-2689, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34406393

RESUMO

CONTEXT: Individuals with monogenic diabetes due to inactivating glucokinase (GCK) variants typically do not require treatment, except potentially during pregnancy. In pregnancy, fetal GCK genotype determines whether treatment is indicated, but noninvasive methods are not clinically available. OBJECTIVE: This work aims to develop a method to determine fetal GCK genotype noninvasively using maternal cell-free fetal DNA. METHODS: This was a proof-of-concept study involving 3 pregnant women with a causal GCK variant that used information from 1) massive parallel sequencing of maternal plasma cell-free DNA, 2) direct haplotype sequences of maternal genomic DNA, and 3) the paternal genotypes to estimate relative haplotype dosage of the pathogenic variant-linked haplotype. Statistical testing of variant inheritance was performed using a sequential probability ratio test (SPRT). RESULTS: In each of the 3 cases, plasma cell-free DNA was extracted once between gestational weeks 24 and 36. The fetal fraction of cell-free DNA ranged from 21.8% to 23.0%. Paternal homozygous alleles that were identical to the maternal GCK variant-linked allele were not overrepresented in the cell-free DNA. Paternal homozygous alleles that were identical to the maternal wild-type-linked allele were significantly overrepresented. Based on the SPRT, we predicted that all 3 cases did not inherit the GCK variant. Postnatal infant genotyping confirmed our prediction in each case. CONCLUSION: We have successfully implemented a noninvasive method to predict fetal GCK genotype using cell-free DNA in 3 pregnant women carrying an inactivating GCK variant. This method could guide tailoring of hyperglycemia treatment in pregnancies of women with GCK monogenic diabetes.


Assuntos
Ácidos Nucleicos Livres/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/genética , Feto/enzimologia , Glucoquinase/genética , Análise de Sequência de DNA , Adulto , Ácidos Nucleicos Livres/química , Feminino , Genótipo , Haplótipos , Humanos , Gravidez
15.
Neuromuscul Disord ; 31(11): 1194-1198, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34454814

RESUMO

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a heterogeneous group of inborn error of metabolic disease affecting the oxidation of fatty acids and amino acids, and choline metabolism. Genes involved in electrons transfer to the mitochondrial respiratory chain typically induce MADD. Recently, FLAD1, which encodes flavin adenine dinucleotide synthase, has also been reported as a cause of MADD. Here, we present a case of a 28-month girl with progressive weakness in facial and bulbar muscle. She has been suffering from feeding difficulty and recurrent respiratory distress. Lipid storage myopathy was evident from muscle biopsy. Furthermore, whole exome sequencing identified homozygous variant of c.745C > T (p.Arg249*) in FLAD1, confirming the diagnosis of FLAD1-related MADD. The patient showed improvements in her symptoms and exhibited catch-up growth following the supplementation of riboflavin. Lipid storage myopathy with FLAD1-related MADD is potentially treatable. Therefore, we should have high clinical suspicion, even though the diagnosis is challenging.


Assuntos
Deficiência Múltipla de Acil Coenzima A Desidrogenase/tratamento farmacológico , Debilidade Muscular/etiologia , Riboflavina/uso terapêutico , Complexo Vitamínico B/uso terapêutico , Pré-Escolar , Códon sem Sentido , Feminino , Homozigoto , Humanos , Músculo Esquelético , Mutação
16.
Eur J Med Genet ; 64(10): 104295, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34371190

RESUMO

Defects in the PIEZO1 gene cause lymphatic dysplasia in an autosomal recessive manner, mostly by loss-of-function variants. Moreover, since 2019, the role of PIEZO1 in bone formation has been established, but there have been no PIEZO1-related cases presenting definite skeletal involvement to date. A 21-year-old male with primary lymphatic dysplasia had some other distinctive clinical features, including multiple fracture history during infancy, thoracolumbar scoliosis, short stature, and left-sided facial bone hypoplasia. We analyzed the whole exome of the patient and found two novel pathogenic variants of PIEZO1 in trans: a 93.7 kb heterozygous deletion (chr16:88,782,477-88,876,207; exon 1-50) and c.2858G>A (p.Arg953His). Sanger sequencing validated the deletion with breakpoints, and each variant was inherited from a different parent. This study presented an extremely rare case of a patient with lymphatic dysplasia caused by compound heterozygous variants of PIEZO1, along with additional clinical manifestations including several skeletal phenotypes.


Assuntos
Anormalidades Craniofaciais/genética , Fraturas Ósseas/genética , Canais Iônicos/genética , Linfangiectasia Intestinal/genética , Linfedema/genética , Mutação , Fenótipo , Escoliose/genética , Anormalidades Craniofaciais/patologia , Fraturas Ósseas/patologia , Heterozigoto , Humanos , Linfangiectasia Intestinal/patologia , Linfedema/patologia , Masculino , Escoliose/patologia , Adulto Jovem
17.
JACC Case Rep ; 3(5): 795-800, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34317628

RESUMO

We encountered siblings with familial Majewski osteodysplastic primordial dwarfism type II (MOPD II) with acute myocardial infarction in adolescence and in their early 20s. We successfully performed percutaneous and surgical coronary interventions. From these cases, we were able to better understand coronary artery disease of MOPD II and provide better management. (Level of Difficulty: Intermediate.).

18.
Pediatr Allergy Immunol Pulmonol ; 34(2): 83-87, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34143683

RESUMO

Background: Myhre syndrome is a rare connective tissue disorder caused by heterozygous pathogenic variants in the SMAD4 gene. Although recognizing Myhre syndrome in early childhood is challenging, it is important to manage airway stenosis in patients with Myhre syndrome. Case Presentation: We report the case of a 2-month-old boy who initially presented with severe multilevel airway stenosis, dysmorphic face, and multiple abnormalities. Lung fibrosis and mild aortic valve stenosis were additionally observed on follow-up examinations. A heterozygous missense variant, c.1499T>C (p.Ile500Thr), in SMAD4 was identified through exome sequencing. Tracheostomy was performed, and the patient has maintained stable respiration through a customized tracheostomy tube with a home ventilator. Conclusions: Patients who have dysmorphic face, airway stenosis, and cardiovascular anomalies that do not fit the diagnosis of common syndromes should be evaluated for rare diseases, including Myhre syndrome. Since respiratory complications can be life threatening, early diagnosis and suitable intervention are necessary.


Assuntos
Deformidades Congênitas da Mão , Traqueostomia , Pré-Escolar , Constrição Patológica , Criptorquidismo , Facies , Transtornos do Crescimento , Humanos , Lactente , Deficiência Intelectual , Masculino
19.
Brain Dev ; 43(9): 912-918, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34116881

RESUMO

BACKGROUND: PURA-related neurodevelopmental disorders (PURA-NDDs) include 5q31.3 deletion syndrome and PURA syndrome. PURA-NDDs are characterized by neonatal hypotonia, moderate to severe global developmental delay/intellectual disability (GDD/ID), facial dysmorphism, epileptic seizures, nonepileptic movement disorders, and ophthalmological problems. PURA-NDDs have recently been identified and underestimated in neurodevelopmental cohorts, but their diagnosis is still challenging. METHODS: We retrospectively reviewed the clinical characteristics, genetic spectrum, and diagnostic journey of patients with PURA-NDDs. RESULTS: We report 2 patients with 5q31.3 microdeletion and 5 with PURA pathogenic variants. They demonstrated hypotonia (7/7, 100%), feeding difficulties (4/5, 80%), and respiratory problems (4/7, 57%) in the neonatal period. All of them had severe GDD/ID and could not achieve independent walking and verbal responses. Distinctive facial features of open-tented upper vermilion, long philtrum, and anteverted nares and poor visual fixation and tracking with or without nystagmus were most commonly found (5/7, 71.4%). There were no significant differences in clinical phenotypes between 5q31.3 microdeletion syndrome and PURA syndrome. PURA-NDDs need to be considered as a differential diagnosis in individuals who show severe hypotonia, including feeding difficulties since birth and severe developmental retardation with distinctive facial and ophthalmological features. CONCLUSIONS: Our data expands the phenotypic and genetic spectrum of PURA-NDD. Next-generation sequencing methods based on the detailed phenotypic evaluation would shorten the diagnostic delay and would help this rare disorder become a recognizable cause of neurodevelopmental delay.


Assuntos
Proteínas de Ligação a DNA/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Face , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/genética , Fenótipo , Estudos Retrospectivos
20.
Nat Commun ; 12(1): 2558, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33963192

RESUMO

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Neurônios/metabolismo , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Proteínas do Complexo SMN/genética , Alelos , Sequência de Aminoácidos , Animais , Pré-Escolar , Deficiências do Desenvolvimento/genética , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Feminino , Técnicas de Silenciamento de Genes , Ontologia Genética , Células HEK293 , Humanos , Mutação com Perda de Função , Masculino , Hipotonia Muscular/genética , Dissinergia Cerebelar Mioclônica/genética , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Polimorfismo de Nucleotídeo Único , RNA-Seq , Ribonucleoproteínas Nucleares Pequenas/genética , Rigor Mortis/genética , Proteínas do Complexo SMN/metabolismo
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