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1.
Hum Genet ; 142(1): 59-71, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36048237

RESUMEN

Dystrophinopathy is caused by alterations in DMD. Approximately 1% of patients remain genetically undiagnosed, because intronic variations are not detected by standard methods. Here, we combined laboratory and in silico analyses to identify disease-causing genomic variants in genetically undiagnosed patients and determine the regulatory mechanisms underlying abnormal DMD transcript generation. DMD transcripts from 20 genetically undiagnosed dystrophinopathy patients in whom no exon variants were identified, despite dystrophin deficiency on muscle biopsy, were analyzed by transcriptome sequencing. Genome sequencing captured intronic variants and their effects were interpreted using in silico tools. Targeted long-read sequencing was applied in cases with suspected structural genomic abnormalities. Abnormal DMD transcripts were detected in 19 of 20 cases; Exonization of intronic sequences in 15 cases, exon skipping in one case, aberrantly spliced and polyadenylated transcripts in two cases and transcription termination in one case. Intronic single nucleotide variants, chromosomal rearrangements and nucleotide repeat expansion were identified in DMD gene as pathogenic causes of transcript alteration. Our combined analysis approach successfully identified pathogenic events. Detection of diseasing-causing mechanisms in DMD transcripts could inform the therapeutic options for patients with dystrophinopathy.


Asunto(s)
Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Distrofina/genética , Empalme del ARN/genética , Intrones/genética , Nucleótidos , Análisis de Secuencia de ARN
2.
No To Hattatsu ; 48(3): 199-203, 2016 May.
Artículo en Japonés | MEDLINE | ID: mdl-27349083

RESUMEN

A 10-year-old boy developed bilateral optic neuritis and myelitis after a suspected viral infection and appendicitis. Magnetic resonance imaging (MRI) showed multiple lesions in both optic nerves, the optic chiasm, and the spinal cord. Several small lesions were also observed in the cerebellum and cerebral white matter. The serum tested negative for anti-aquaporin (AQP)-4 antibody and positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibody. The diagnosis was neuromyelitis optica spectrum disorder (NMOSD). Two courses of high-dose methylprednisolone were administered; however, only a small improvement in his visual acuity was achieved. He underwent 3 courses of plasma exchange to achieve sufficient visual acuity. After the serum anti-MOG antibody titer decreased to the cut-off level, oral prednisolone and azathioprine administration were also stopped, 10 months after onset. Recently, NMO and NMOSD cases positive for anti-MOG antibodies have been reported, which showed clinical features different from those of NMO cases positive for anti-AQP4 antibody. Although most of the reported cases responded to steroid therapy, plasma exchange was required in our case. Further analysis on larger numbers of cases is needed to establish treatments for anti-MOG antibody-positive NMO and NMOSD.


Asunto(s)
Autoanticuerpos , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/terapia , Plasmaféresis , Azatioprina/administración & dosificación , Niño , Humanos , Masculino , Metilprednisolona/administración & dosificación , Prednisolona/administración & dosificación , Quimioterapia por Pulso , Resultado del Tratamiento
3.
Pediatr Neurol ; 157: 29-38, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38848614

RESUMEN

BACKGROUND: Six percent of patients with Leigh syndrome (LS) present with infantile epileptic spasms syndrome (IESS). However, treatment strategies for IESS with LS remain unclear. This retrospective study aimed to evaluate the efficacy and safety of treatment strategies in patients with IESS complicated by LS and Leigh-like syndrome (LLS). METHODS: We distributed questionnaires to 750 facilities in Japan, and the clinical data of 21 patients from 15 hospitals were collected. The data comprised treatment strategies, including adrenocorticotropic hormone (ACTH) therapy, ketogenic diet (KD) therapy, and antiseizure medications (ASMs); effectiveness of each treatment; and the adverse events. RESULTS: The median age at LS and LLS diagnosis was 7 months (range: 0 to 50), whereas that at the onset of epileptic spasms was 7 (range: 3 to 20). LS was diagnosed in 17 patients and LLS in four patients. Seven, two, five, and seven patients received ACTH + ASMs, ACTH + KD + ASMs, KD + ASMs, and ASMs only, respectively. Four (44%) of nine patients treated with ACTH and one (14%) of seven patients treated with KD achieved electroclinical remission within one month of treatment. No patients treated with only ASMs achieved electroclinical remission. Seven patients (33%) achieved electroclinical remission by the last follow-up. Adverse events were reported in four patients treated with ACTH, none treated with KD therapy, and eight treated with ASMs. CONCLUSION: ACTH therapy shows the best efficacy and rapid action in patients with IESS complicated by LS and LLS. The effectiveness of KD therapy and ASMs in this study was insufficient.

4.
Hum Genome Var ; 9(1): 9, 2022 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-35361766

RESUMEN

We describe the case of a male patient with orofaciodigital (OFD) syndrome type XVI with a homozygous variant of TMEM107 (p.Phe106del) and the additional findings of tibial dysplasia, which is a pivotal finding of OFD syndrome type IV. His family history included two fetuses with anencephaly with or without cleft lip/palate and polydactyly with no genetic information. Careful attention should be given to the interpretation of this rare pattern.

5.
Child Neurol Open ; 9: 2329048X221111716, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35936110

RESUMEN

The neurological symptoms of pediatric mild encephalopathy/encephalitis with a reversible splenial lesion (MERS) are mild and have a good prognosis. However, some aspects of neonatal MERS are unclear due to a lack of clinical knowledge. We present a neonatal case of MERS with features of poor activity and prolonged poor oxygenation after birth without asphyxia. He was diagnosed with MERS by brain magnetic resonance imaging (MRI) on day10, because the diffusion restriction of the splenium of the corpus callosum (SCC) seen on diffusion-weighted MRI on day 5 was attenuating. He was discharged due to good progress on day 26, but growth issues and developmental delay were observed in the follow up from 1-10 months. In rare neonatal cases, many aspects of the clinical course and prognosis are thus unclear. MERS should be considered in newborns who show unexplained non-neural or other encephalopathic symptoms.

6.
Eur J Med Genet ; 63(11): 104057, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32877735

RESUMEN

Here, we present the case of a 15-year-old Japanese girl with Dystonia 28, childhood-onset; DYT28 (MIM#606834) showing early-onset generalized progressive dystonia and status dystonicus. The patient was genetically undiagnosed and had not responded to various medications. By trio-based whole exome sequencing and in silico analyses, we identified a de novo heterozygous variant of KMT2B: NM_014727.2: c.7828C > T, p(Arg2610Cys). Globus pallidus internus deep brain stimulation (GPi-DBS) therapy was considered; however, the therapy could not be performed due to the patient's poor nutritional status and repeated infections. GPi-DBS is considered to be an effective treatment for patients with KMT2B mutations, and genetic diagnosis is important before progression to status dystonicus.


Asunto(s)
Distonía/genética , N-Metiltransferasa de Histona-Lisina/genética , Niño , Distonía/patología , Femenino , Humanos , Mutación Missense , Fenotipo
7.
Hum Genome Var ; 7: 11, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32337051

RESUMEN

Carnitine-acylcarnitine translocase (CACT) deficiency is a fatty acid ß-oxidation disorder of the carnitine shuttle in mitochondria, with a high mortality rate in childhood. We evaluated three patients, including two siblings, with neonatal-onset CACT deficiency and revealed identical homozygous missense mutations of p.Arg275Gln within the SLC25A20 gene. One patient died from hypoglycemia and arrhythmia at 26 months; his pathological autopsy revealed increased and enlarged mitochondria in the heart but not in the liver.

8.
J Occup Health ; 62(1): e12144, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32713100

RESUMEN

OBJECTIVES: The aim of this study was to develop and validate a simple and reliable gas chromatography-mass spectrometry (GC-MS) method to simultaneously determine urinary 1-naphthol (1-NAP) and 2-naphthol (2-NAP) for biological monitoring of occupational exposure to naphthalene. METHODS: NAPs were derivatized in situ with acetic anhydride after enzymatic hydrolysis, extracted with n-hexane, and analyzed using GC-MS. Validation of the proposed method was conducted in accordance with US Food and Drug Administration guidance. A final validation was performed by analyzing a ClinChek® -Control for phenolic compounds. RESULTS: The linearity of calibration curves was indicated by a high correlation coefficient (>0.999) in the concentration range 1-100 µg/L for each NAP. The limits of detection and quantification for each NAP were 0.30 and 1.00 µg/L, respectively. The recovery was 90.8%-98.1%. The intraday and interday accuracies, expressed as the deviation from the nominal value, were 92.2%-99.9% and 93.4%-99.9%, respectively. The intraday and interday precision, expressed as the relative standard deviation, was 0.3%-3.9% and 0.4%-4.1%, respectively. The ClinChek® values obtained using our method were sufficiently accurate. CONCLUSIONS: The proposed method is simple, reliable, and appropriate for routine analyses, and is useful for biological monitoring of naphthalene exposure in occupational health practice.


Asunto(s)
Monitoreo Biológico/métodos , Cromatografía de Gases y Espectrometría de Masas/métodos , Naftoles/orina , Exposición Profesional/análisis , Humanos , Naftoles/química
9.
Hum Genome Var ; 6: 23, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31098032

RESUMEN

Cornelia de Lange syndrome (CdLS) is a cohesinopathy caused by genetic variations. We present a female with SMC1A-associated CdLS with a novel SMC1A truncation mutation (p. Arg499Ter), transposition of the great arteries, and periodic intractable seizures from 40 months of age. A review of the literature revealed that a seizure-free period after birth of at least 15 months is required for these patients to be able to walk, irrespective of the epileptic course.

10.
Clin Case Rep ; 6(2): 330-336, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29445472

RESUMEN

A Japanese boy aged 7 years with Bainbridge-Ropers syndrome (BRPS) had a prominent domed forehead without metric ridge, mild prominence of the Sylvian fissure with bitemporal hollowing, and a heterozygous de novo novel variant "p.P1010Lfs*14" in ASXL3 gene in addition to typical findings of BRPS.

11.
Hum Genome Var ; 4: 17002, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28224042

RESUMEN

A pilot study of newborn screening for Fabry disease was performed in Okinawa, Japan. A total of 2,443 neonates were screened using dried blood spot samples over 7 years starting in 2007. Of 13 neonates determined to have low α-galactosidase A (GLA) activity, one boy had a new missense mutation, p.G144D of the GLA gene. This mutation was considered to be a late-onset type, as evaluated based on plasma globotriaosylsphingosine levels and family history.

12.
Mol Genet Metab Rep ; 11: 2-5, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30547004

RESUMEN

Isovaleric acidemia (IVA) is an organic acid disease caused by a deficiency of isovaleryl-CoA dehydrogenase. Deficiency of this enzyme leads to accumulation of organic acids, such as isovalerylcarnitine and isovalerylglycine. The proposed IVA treatments include leucine restriction and l-carnitine and/or glycine supplementation, which convert isovaleric acid into non-toxic isovalerylcarnitine and isovalerylglycine, respectively. We examined the therapeutic response using the leucine load test and performed a 10-year follow-up in the patient. METHODS: We evaluated the patient with IVA beginning at 5 years of age, when he presented with a mild to intermediate metabolic phenotype. Ammonia, free carnitine, isovalerylcarnitine, and isovalerylglycine were analyzed in the urine and blood after a meal consisting of 1600 mg leucine with glycine alone (250 mg/kg/day), l-carnitine alone (100 mg/kg/day), or both glycine and l-carnitine for four days each. RESULTS: (Leucine load test) Three hours after the meal, serum ammonia levels increased most dramatically with glycine treatment alone, then with both in combination, and least with l-carnitine alone. Urinary isovalerylglycine levels increased 2-fold more with glycine supplementation than those following supplementation with both agents or with l-carnitine alone. Treatment with both agents resulted in a gradual increase in urinary acylcarnitine levels during the 6-h period following the leucine load, reaching concentrations comparable to those observed with l-carnitine alone. (Clinical course) After initiation of both glycine (200 mg/kg/day) and l-carnitine (100 mg/kg/day) supplementation at 5 years of age, doses were gradually reduced to 111.7 mg/kg/day and 55.8 mg/kg/day, respectively, at 15 years of age. His mind and body had developed without any sequelae. DISCUSSION: We concluded that l-carnitine conjugated isovaleric acid earlier than glycine. Additionally, during the 10-year follow-up period, the patient displayed no clinical deterioration.

13.
Brain Dev ; 37(1): 101-6, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24534057

RESUMEN

AIM: To clarify the evolution of an augmented startle reflex in Tay-Sachs disease and compare the temporal relationship between this reflex and brainstem evoked potentials. SUBJECTS AND METHODS: Clinical and electrophysiological data from 3 patients with Tay-Sachs disease were retrospectively collected. RESULTS: The augmented startle reflex appeared between the age of 3 and 17 months and disappeared between the age of 4 and 6 years. Analysis of brainstem auditory evoked potentials revealed that poor segregation of peak I, but not peak III, coincided with the disappearance of the augmented startle reflex. A blink reflex with markedly high amplitude was observed in a patient with an augmented startle reflex. CONCLUSION: The correlation between the augmented startle reflex and the preservation of peak I but not peak III supports the theory that the superior olivary nucleus is dispensable for this reflex. The blink reflex with high amplitudes may represent augmented excitability of reticular formation at the pontine tegmentum in Tay-Sachs disease, where the pattern generators for the augmented startle and blink reflexes may functionally overlap.


Asunto(s)
Tronco Encefálico/fisiopatología , Potenciales Evocados Auditivos/fisiología , Reflejo de Sobresalto/fisiología , Enfermedad de Tay-Sachs/fisiopatología , Niño , Preescolar , Humanos , Lactante , Masculino
14.
J Chromatogr A ; 1038(1-2): 291-4, 2004 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-15233544

RESUMEN

A method for the determination of seven alkylphenols and bisphenol A by stir bar sorptive extraction (SBSE) with in situ derivatization-thermal desorption (TD)-gas chromatography (GC)-mass spectrometry (MS) is described. SBSE was performed with in situ acetylation and without derivatization for comparison. For 4-tert-butylphenol and bisphenol A, in situ acetylation improved the responses in SBSE-TD-GC-MS. The method detection limits ranged from 0.1 to 3.2 ng/l. The recoveries of the analytes from a river water sample spiked with standards at 10 and 100 ng/l were 85.3-105.9% (R.S.D., 3.0-11.0%) and 88.3-105.8% (R.S.D., 1.6-8.3%), respectively.


Asunto(s)
Cromatografía de Gases y Espectrometría de Masas/métodos , Fenoles/análisis , Contaminantes Químicos del Agua/análisis , Acetilación , Compuestos de Bencidrilo , Agua Dulce , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
15.
Anal Sci ; 28(7): 669-73, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22790368

RESUMEN

Fenthion, fenthion sulfoxide, fenthion oxon sulfoxide and fensulfothion showed two different mass spectra in GC/MS, depending on their concentrations. The base peaks shifted to lower levels by 1 m/z at lower concentration, and no retention time shifts were observed. The "shifted base peaks" were not obtained by a general EI fragmentation. The product ion scan spectra of the "shifted base peaks" were coincident with those of molecular ions of their corresponding sulfides. These phenomena can be ascribed to the conversion of sulfoxide into sulfide by the dominant deoxidation reaction than EI fragmentation in an ion source. Adding polyethylene glycol 300 (PEG300) into a test solution prevented sulfoxide deoxidation.


Asunto(s)
Fentión/química , Cromatografía de Gases y Espectrometría de Masas/métodos , Compuestos Organotiofosforados/química , Polietilenglicoles/química , Safrol/análogos & derivados , Inyecciones , Oxidación-Reducción , Safrol/química , Solventes/química , Temperatura
16.
J Agric Food Chem ; 60(41): 10226-34, 2012 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-22985413

RESUMEN

The detailed matrices and their behaviors during pesticide residue analyses were clarified using a metabolomics analysis approach. The matrix profile was investigated using two different extraction solvents, acetone and acetonitrile. Acetone extracted the matrix components with a wide range of log P(O/W) values. Components with log P(O/W) values >10, such as sterols and tocopherols, and components with log P(O/W) values <3.2 were more extracted by acetone than by acetonitrile. In contrast, components with log P(O/W) values in the range from 3.2 to 10 were extracted by both acetone and acetonitrile at the same concentration level. The study also examined the difference in the column cleanup efficiency using a solid phase extraction (SPE). Florisil, silica gel, NH(2), PSA, and GCB were selected as representative columns for pesticide residue analysis, and acetone extraction of brown rice was selected in this experiment. Most of the matrix components were removed by either column, whereas monoacylglycerols, which are the components causing the matrix effect, were not removed by any column. Understanding such a detailed matrix behavior helps to develop a better analytical method for pesticide analysis using GC-MS.


Asunto(s)
Productos Agrícolas/química , Cromatografía de Gases y Espectrometría de Masas/métodos , Metabolómica/métodos , Residuos de Plaguicidas/análisis , Acetona , Acetonitrilos , Oryza/química , Extractos Vegetales/química , Extracción en Fase Sólida
18.
J Chromatogr A ; 1130(1): 83-90, 2006 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-16814312

RESUMEN

A method for fast screening of pesticide multiresidues in aqueous samples using dual stir bar sorptive extraction-thermal desorption-low thermal mass gas chromatography-mass spectrometry (dual SBSE-TD-LTM-GC-MS) has been developed. Recovery of 82 pesticides - organochlorine, carbamate, organophosphorous, pyrethroid and others - for the SBSE was evaluated as a function of octanol-water distribution coefficients (log K(o/w): 1.7-8.35), sample volume (2-20 mL), salt addition (0-30% NaCl), and methanol addition (0-20%). The optimized method consists of a dual SBSE performed simultaneously on respectively a 20-mL sample containing 30% NaCl and a 20-mL sample without modifier (100% sample solution). One extraction with 30% NaCl is mainly targeting solutes with low K(o/w) (log K(o/w)<3.5) and another extraction with unmodified sample solution is targeting solutes with medium and high K(o/w) (log K(o/w)>3.5). After extraction, the two stir bars are placed in a single glass desorption liner and are simultaneously desorbed. The desorbed compounds are analyzed by use of LTM-GC-MS with fast temperature programming (75 degrees C min(-1)) using a 0.18 mm i.d. narrow-bore capillary column and fast scanning (10.83 scan s(-1)) using quadrupole MS. The method showed good linearity (r(2)>0.9900) and high sensitivity (limit of detection: <10 ng L(-1)) for most of the target pesticides. The method was applied to the determination of pesticides at nanograms per liter levels in river water and brewed green tea.


Asunto(s)
Bebidas/análisis , Fraccionamiento Químico/métodos , Agua Dulce/análisis , Cromatografía de Gases y Espectrometría de Masas/métodos , Residuos de Plaguicidas/análisis , Reproducibilidad de los Resultados , Cloruro de Sodio/química , Temperatura
19.
Anal Bioanal Chem ; 382(1): 99-107, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15900458

RESUMEN

A method for determining 68 pesticides in river water using stir bar sorptive extraction (SBSE)-thermal desorption (TD)-gas chromatography-mass spectrometry (GC-MS) is described. SBSE sampling was optimized for sample solution pH, salting-out and methanol addition. Although salting-out enhanced the ability of the method to extract most of the pesticides with low absolute recoveries, the absolute recoveries of four pesticides were not improved by salting-out. The detection limits of the method for the pesticides ranged from 0.2 to 20 ng/l. Analyte recoveries from a river water sample spiked with standards at 10 and 100 ng/l were 58.5-132.0% (RSD: 1.8-15.8%) and 61.0-121.3% (RSD: 1.4-20.2%), respectively.


Asunto(s)
Cromatografía de Gases y Espectrometría de Masas/métodos , Plaguicidas/análisis , Contaminantes Químicos del Agua/análisis , Agua Dulce , Concentración de Iones de Hidrógeno , Reproducibilidad de los Resultados
20.
J Sep Sci ; 28(18): 2511-6, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16405182

RESUMEN

A method for determining the earthy and musty odors 2-methylisoborneol (2-MIB) and geosmin in drinking water using static headspace-GC-MS is described. To achieve lower detection limits, split ratio was optimized with ramped inlet pressure for large headspace sampling volume. The ramped inlet pressure, which held higher pressure (higher column flow rate) only during injection, allowed us to inject 3-mL volume to GC with very low split ratio (2:1). Although sequential analysis with a stainless steel ion source often changed the mass spectrum of 2-MIB, this spectral change was eliminated by using an inert ion source with a 6 mm drawout plate. The detection limits of this method were 0.36 and 0.14 ng/L, respectively, for 2-MIB and geosmin. The repeatabilities (n = 30) were 6.6 and 4.8%, respectively, at 1 ng/L for 2-MIB and geosmin.

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