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1.
JCI Insight ; 9(17)2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39088276

RESUMO

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid ß-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and ß subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.


Assuntos
Cardiolipinas , Metabolismo Energético , Fibroblastos , Erros Inatos do Metabolismo Lipídico , Subunidade alfa da Proteína Mitocondrial Trifuncional , Cardiolipinas/metabolismo , Animais , Humanos , Camundongos , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Subunidade alfa da Proteína Mitocondrial Trifuncional/genética , Metabolismo Energético/genética , Fibroblastos/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Subunidade beta da Proteína Mitocondrial Trifuncional/metabolismo , Subunidade beta da Proteína Mitocondrial Trifuncional/genética , Mitocôndrias/metabolismo , Mutação , Proteína Mitocondrial Trifuncional/deficiência , Proteína Mitocondrial Trifuncional/metabolismo , Proteína Mitocondrial Trifuncional/genética , Rabdomiólise/metabolismo , Rabdomiólise/genética , Rabdomiólise/patologia , Miopatias Mitocondriais/metabolismo , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/patologia , Consumo de Oxigênio , Masculino , Modelos Animais de Doenças , Lisofosfolipídeos , Cardiomiopatias , Doenças do Sistema Nervoso
2.
J Investig Med High Impact Case Rep ; 12: 23247096241267154, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39143735

RESUMO

Here, we report an individual, eventually diagnosed with HMG-CoA synthase deficiency, who presented with a cyclic vomiting phenotype. HMG-CoA synthase deficiency is a rare disorder affecting ketone body synthesis in which affected individuals typically present at a young age with hypoketotic hypoglycemia, lethargy, encephalopathy, and hepatomegaly, usually triggered by catabolism (e.g., infection or prolonged fasting). This individual presented with recurrent episodes of vomiting and lethargy, often associated with hypoglycemia or hyperglycemia, at 3 years of age. Metabolic labs revealed nonspecific abnormalities in her urine organic acids (showing mild elevation of dicarboxylic acids with relatively low excretion of ketones) and a normal acylcarnitine profile. Given her clinical presentation, as well as a normal upper gastrointestinal series, esophagogastroduodenoscopy with biopsies, and abdominal ultrasound, she was diagnosed with cyclic vomiting syndrome at 3 years of age. Molecular testing completed at 7 years of age revealed a previously reported pathogenic sequence variant (c.1016+1G>A) and a novel likely pathogenic deletion (1.57 kB deletion, including exon 1) within HMGCS2 consistent with HMG-CoA synthase deficiency. This individual's presentation, mimicking cyclic vomiting syndrome, widens the clinical spectrum of HMG-CoA synthase deficiency. In addition, this case highlights the importance of molecular genetic testing in such presentations, as this rare disorder lacks specific metabolic markers.


Assuntos
Hidroximetilglutaril-CoA Sintase , Vômito , Humanos , Vômito/etiologia , Feminino , Hidroximetilglutaril-CoA Sintase/genética , Hidroximetilglutaril-CoA Sintase/deficiência , Pré-Escolar , Biomarcadores/urina , Biomarcadores/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/complicações , Diagnóstico Diferencial , Acetil-CoA C-Acetiltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos
3.
Hum Genomics ; 18(1): 85, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090729

RESUMO

Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of ß-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with ß-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies.


Assuntos
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Estudo de Associação Genômica Ampla , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Polimorfismo de Nucleotídeo Único , Sitosteroides , Humanos , Fitosteróis/sangue , Fitosteróis/genética , Fitosteróis/efeitos adversos , Polimorfismo de Nucleotídeo Único/genética , Sitosteroides/sangue , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/sangue , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Masculino , Feminino , Enteropatias/genética , Enteropatias/sangue , Adulto , Colesterol/sangue , Colesterol/análogos & derivados , Hipercolesterolemia/genética , Hipercolesterolemia/sangue , Pessoa de Meia-Idade , Lipoproteínas/sangue , Lipoproteínas/genética , Transportadores de Cassetes de Ligação de ATP/genética
4.
Orphanet J Rare Dis ; 19(1): 315, 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39210374

RESUMO

BACKGROUND: Fatty acid oxidation defects are rare autosomal recessive disorders with variable clinical manifestations and outcome. Early detection by systematic neonatal screening may improve their prognosis. Long-term outcome studies of these disorders in the Middle East and North Africa region are limited. The purpose of this study is to report the diagnostic challenges and outcome of fatty acid oxidation defects in a major tertiary care center in Lebanon, a resource-constrained country in the Middle East. METHODS: A retrospective review of charts of all fatty acid oxidation defects sequential patients diagnosed and followed at our center was conducted. Collected data included: parental consanguinity, age at diagnosis, clinical presentation, biochemical profile, confirmatory diagnosis, treatment and outcome. A genotype-phenotype correlation was also performed, when available. RESULTS: Seven types of fatty acid oxidation defects were identified in a total of 34 patients from 21 families. Most families (79%) were consanguineous (first-degree cousins). The majority were diagnosed when clinically symptomatic (78%), at various ages between 10 days and 19 years (average: 2 years). Follow-up duration spanned between 2 months and 15 years (average: 5 years). The remainder of the patients were detected while still asymptomatic by systematic neonatal screening (9%) or due to positive family history (9%). The most common defect was carnitine transporter deficiency (50%) with an exclusive cardiac presentation related to a founder variant c.981C > T, (p.Arg254*) in the SLC22A5 gene. Medium chain acyl-CoA dehydrogenase deficiency was found in 13% only, which could be explained by the absence of systematic neonatal screening. Rare gene variants were detected in very long chain and multiple acyl-CoA dehydrogenase deficiency. The worse prognosis was observed in very long chain acyl-CoA dehydrogenase deficiency. The overall survival at last follow-up reached 75% with a complete reversal of symptoms with treatment in most patients (63%), despite their late diagnosis. CONCLUSIONS: Our experience highlights the diagnostic challenges and outcome of fatty acid oxidation defects in a resource-constrained country with high consanguinity rates. Physicians' awareness and systematic neonatal screening are key for diagnosis. Larger genotype-phenotype studies are still needed to understand the natural history of these rare diseases and possibly improve their outcome.


Assuntos
Ácidos Graxos , Erros Inatos do Metabolismo Lipídico , Centros de Atenção Terciária , Humanos , Líbano , Feminino , Masculino , Lactente , Recém-Nascido , Estudos Retrospectivos , Pré-Escolar , Criança , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Adolescente , Ácidos Graxos/metabolismo , Adulto Jovem
5.
Nutrients ; 16(16)2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39203843

RESUMO

Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible. Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake. In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy (total MCT+LCT ratio = 20-35%). Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise. In medium- and short-chain deficits, dietary modifications are not advised (except during exacerbations), with MCT contraindicated and slow sugars recommended 20 min before any significant physical exertion. Parents should be alerted to the need to increase the amount and frequency of carbohydrate intake in stressful situations. The main measure in emergency hospital treatment is the administration of IV glucose. The use of carnitine remains controversial and new therapeutic options are under investigation.


Assuntos
Ácidos Graxos , Humanos , Ácidos Graxos/administração & dosagem , Oxirredução , Carboidratos da Dieta/administração & dosagem , Erros Inatos do Metabolismo Lipídico/dietoterapia , Triglicerídeos/sangue , Carnitina/administração & dosagem , Suplementos Nutricionais , Rabdomiólise
6.
BMC Musculoskelet Disord ; 25(1): 661, 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39174932

RESUMO

BACKGROUND: Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare lipid metabolism disorder caused by PNPLA2 gene mutations. Clinical manifestations are heterogeneous, and diagnosis is often delayed, usually gaining patients' attention due to the increased risk of cardiomyopathy. CASE PRESENTATION: We herein report a 36-year-old Asian male presenting with progressive limb weakness, muscle atrophy of limbs and trunk, dysarthria, and heart failure. Electromyography indicated myogenic changes, and muscle biopsy results revealed characteristics of lipid storage myopathy. Genetic analysis of PNPLA2 revealed two heterozygous mutations: c.757 + 1G > T (chr11-823588, splice-5) on intron 6 and c.919delG (chr11-823854, p.A307Pfs*13) on exon 7. The patient improved limb strength, and dysarthria disappeared after the Medium Chain Fatty Acids diet. CONCLUSIONS: In conclusion, we report for the first time that the two heterozygous mutations PNPLA2 c.919delG and c.757 + 1G > T together induced NLSDM, which was confirmed by muscle biopsy.


Assuntos
Heterozigoto , Lipase , Erros Inatos do Metabolismo Lipídico , Doenças Musculares , Mutação , Humanos , Masculino , Lipase/genética , Adulto , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Musculares/genética , Doenças Musculares/diagnóstico , Músculo Esquelético/patologia , Aciltransferases
7.
Lipids Health Dis ; 23(1): 222, 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39039599

RESUMO

BACKGROUND: Sitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage. METHODS: This study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted. RESULTS: The index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient. CONCLUSION: This study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation.


Assuntos
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Humanos , Feminino , Fitosteróis/efeitos adversos , Idoso , Hipercolesterolemia/genética , Hipercolesterolemia/patologia , Hipercolesterolemia/complicações , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Erros Inatos do Metabolismo Lipídico/diagnóstico por imagem , Enteropatias/genética , Enteropatias/patologia , Enteropatias/diagnóstico por imagem , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Sequenciamento do Exoma , Xantomatose/patologia , Xantomatose/genética , Xantomatose/diagnóstico por imagem , Linhagem , Colesterol/sangue , Masculino , Sitosteroides , Lipoproteínas
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(7): 840-843, 2024 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-38946369

RESUMO

OBJECTIVE: To explore the clinical phenotype and genetic basis of a child with Neutral lipid storage disease with myopathy (NLSDM). METHODS: A child who was admitted to the First Affiliated Hospital of Zhengzhou University in February 2021 for a history of elevated creatine kinase (CK) for over 2 months was selected as the study subject. Clinical and laboratory examinations were carried out, and the child was subjected to whole exome sequencing. Candidate variants were validated by Sanger sequencing of her family members. RESULTS: The patient, a 9-year-old female, had exhibited weakness in the lower limbs, elevated CK level, and refractory cardiomyotrophy. Genetic testing revealed that she has harbored c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene, which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PM1+PM2_Supporting+PP3+PP4). CONCLUSION: The c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene probably underlay the myasthenia gravis and elevated creatine kinase in this child.


Assuntos
Lipase , Erros Inatos do Metabolismo Lipídico , Doenças Musculares , Humanos , Feminino , Criança , Doenças Musculares/genética , Erros Inatos do Metabolismo Lipídico/genética , Lipase/genética , Mutação , Testes Genéticos , Sequenciamento do Exoma , Creatina Quinase/sangue , Linhagem , Fenótipo , Aciltransferases
9.
Clin Chim Acta ; 562: 119886, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39053727

RESUMO

BACKGROUND: Sitosterolemia is a rare inherited lipid metabolic disorder characterized by increased levels of plant sterols and accelerated atherosclerosis. Although early detection is beneficial for the prevention of disease progression, it is largely underdiagnosed by routine screening based on conventional lipid profiles. MATERIALS AND METHODS: A gas chromatography-mass spectrometry (GC-MS)-based profiling has been developed and validated to measure the levels of biologically active free sterols, including five endogenous sterols and three plant sterols (sitosterol, campesterol, and stigmasterol) in dried blood spot (DBS). RESULTS: Within- and between-run precisions were 1.4-11.1 % and 2.2-14.1 %, respectively, while the accuracies were all 86.3 âˆ¼ 121.9 % with the correlation coefficients (r2) > 0.988 for all the sterols. In the patients (four girls and two boys, 6.5 ± 2.8 years), sitosterol levels were significantly increased, with an optimal cut-off value of 2.5 µg/mL distinguishing them from ninety-three age-matched healthy children. A cut-off value of 31.9 µg/mL differentiated the patients from six ABCG5/ABCG8 heterozygous carriers. In addition, the molecular ratios of sitosterol to cholesterol, desmosterol, and 7-dehydrocholesterol provided excellent cut-off values of 26.3, 67.6, and 21.6, respectively, to distinguish patients from both healthy controls and heterozygous carriers. CONCLUSIONS: The novel DBS-based GC-MS profiling of free sterols accurately identified patients with sitosterolemia, with a performance comparable to that of a serum assay. The DBS profiling could be more feasible method in clinical practice as well as population screening programs, and it can provide diagnostic cut-off values for individual plant sterols.


Assuntos
Teste em Amostras de Sangue Seco , Cromatografia Gasosa-Espectrometria de Massas , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Humanos , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Feminino , Masculino , Enteropatias/sangue , Enteropatias/diagnóstico , Criança , Fitosteróis/sangue , Fitosteróis/efeitos adversos , Teste em Amostras de Sangue Seco/métodos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Pré-Escolar , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Esteróis/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Lipoproteínas/sangue
10.
Front Biosci (Schol Ed) ; 16(2): 12, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38939976

RESUMO

Several inherited metabolic fatty acid disorders present with myopathies. Skeletal muscle accounts for 40% of the body and is important for metabolism, exercise, and movement. Muscle energy failure is manifested by metabolic crises with muscle weakness, sometimes associated with muscle fatigue and failure resulting in acute necrosis or rhabdomyolysis/myoglobinuria episodes. Lack of energy leads to muscle necrosis. Other presentations are weakness and myalgias with lipid storage myopathies in the biopsy. The biomarkers of such disorders are acyl-carnitine with various profiles and need to be carefully evaluated to plan supplementary therapy and specific diets. If red flags are not distinctly followed and diagnosed in time they might lead to a metabolic or cardiac failure.


Assuntos
Carnitina , Erros Inatos do Metabolismo Lipídico , Doenças Musculares , Humanos , Doenças Musculares/metabolismo , Doenças Musculares/terapia , Doenças Musculares/genética , Carnitina/metabolismo , Carnitina/análogos & derivados , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Erros Inatos do Metabolismo Lipídico/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofias Musculares
11.
Orphanet J Rare Dis ; 19(1): 202, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760795

RESUMO

BACKGROUND: There is a notable lack of harmonisation in newborn screening (NBS) programmes worldwide. The Galician programme for early detection of inborn errors of metabolism (IEM) was one of the first NBS programmes in Europe to incorporate mass spectrometry (July 2000). This programme currently screens for 26 IEMs in dried blood and urine samples collected 24-72 h after birth. RESULTS: In its 22-year history, this programme has analysed samples from 440,723 neonates and identified 326 cases of IEM with a prevalence of 1:1351. The most prevalent IEMs were hyperphenylalaninaemia (n = 118), followed by medium chain acyl-CoA dehydrogenase deficiency (MCADD, n = 26), galactosaemia (n = 20), and cystinurias (n = 43). Sixty-one false positives and 18 conditions related to maternal pathologies were detected. Urine samples have been identified as a useful secondary sample to reduce the rate of false positives and identify new defects. There were 5 false negatives. The overall positive value was 84.23%. The fatality rate over a median of 12.1 years of follow-up was 2.76%. The intelligence quotient of patients was normal in 95.7% of cases, and school performance was largely optimal, with pedagogic special needs assistance required in < 10% of cases. Clinical onset of disease preceded diagnosis in 4% of cases. The age at which first NBS report is performed was reduced by 4 days since 2021. CONCLUSIONS: This study highlights the benefits of collecting urine samples, reduce NBS reporting time and expanding the number of IEMs included in NBS programmes.


Assuntos
Erros Inatos do Metabolismo , Triagem Neonatal , Humanos , Triagem Neonatal/métodos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Feminino , Masculino , Galactosemias/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/epidemiologia , Seguimentos , Espanha , Acil-CoA Desidrogenase/deficiência
12.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732138

RESUMO

D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.


Assuntos
Proteína Mitocondrial Trifuncional/deficiência , Proteína Multifuncional do Peroxissomo-2 , Humanos , Proteína Multifuncional do Peroxissomo-2/deficiência , Proteína Multifuncional do Peroxissomo-2/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Recém-Nascido , Lactente , Masculino , Feminino , Sequenciamento do Exoma , Mutação da Fase de Leitura , 17-Hidroxiesteroide Desidrogenases/deficiência , 17-Hidroxiesteroide Desidrogenases/genética , Região de Recursos Limitados , Miopatias Mitocondriais , Cardiomiopatias , Doenças do Sistema Nervoso , Rabdomiólise
14.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1869(5): 159491, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38565373

RESUMO

Inborn errors of metabolism (IEM) represent a heterogeneous group of more than 1800 rare disorders, many of which are causing significant childhood morbidity and mortality. More than 100 IEM are linked to dyslipidaemia, but yet our knowledge in connecting genetic information with lipidomic data is limited. Stable isotope tracing studies of the lipid metabolism (STL) provide insights on the dynamic of cellular lipid processes and could thereby facilitate the delineation of underlying metabolic (patho)mechanisms. This mini-review focuses on principles as well as technical limitations of STL and describes potential clinical applications by discussing recently published STL focusing on IEM.


Assuntos
Metabolismo dos Lipídeos , Lipidômica , Humanos , Lipidômica/métodos , Metabolismo dos Lipídeos/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/genética , Animais , Lipídeos/genética , Marcação por Isótopo/métodos
15.
Mymensingh Med J ; 33(2): 636-642, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38557550

RESUMO

Renal cell carcinoma (RCC) is derived from renal tubular epithelial cells and is among the 10 most common cancers worldwide. Incidence of renal cell carcinoma is 400,000 individuals worldwide per year. The age of diagnosis is approximately 60years, and twice as many men are diagnosed as women. African Americans have a slightly higher rate of RCC than do White peoples. The reasons for this are not clear. Inherited syndromes in family, long term dialysis, smoking individuals who had quit smoking >10 years prior had a lower risk when compared to those who had quit <10 years. 22.5 pack-year smokers had a more than 50.0% increased RCC risk compared to nonsmokers, high body mass index i.e. 5kg/m2 increase in body mass index (BMI) was found to be strongly associated with RCC. BMI >35kg/m2 is associated with higher incidence of Cancer raise blood pressure- Higher BMI and hypertension were independently shown to increase the long-term risk of RCC in men. A rise of blood pressure of 10mmHg is associated with 10-22 percent risk of RCC. Clear cell carcinoma is the most common variety of renal cell carcinoma as compared to other varieties of renal cell carcinomas (68.0-75.0%). It has also been found that CAIX is positive for all papillary renal cell carcinoma and negative for CK7, AMACR & TEF. We also found that CK7, EMA, CD117 and CAIX are most commonly positive for all chromophobe renal cell carcinoma. It has been found that clear cell carcinoma is the most common variety of renal cell carcinoma as compared to other varieties of renal cell carcinomas (68.0-75.0%). Again it has also been found that CAIX is positive for all papillary renal cell carcinoma and negative for CK7, AMACR and TEF. Here it has been found that chromophobe carcinoma is most commonly positive for CK7, EMA, CD117 and CAIX. In a patient coming with signs and symptoms of renal cell carcinoma can be confirmed with the help of histoimmunological markers and in that case one can plan for a proper planning of management.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Erros Inatos do Metabolismo Lipídico , Doenças do Sistema Nervoso , Racemases e Epimerases/deficiência , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Biomarcadores Tumorais , Diálise Renal , Diagnóstico Diferencial
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(4): 467-472, 2024 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-38565514

RESUMO

OBJECTIVE: To analyze the clinical phenotype and genotypes of two children with Carnitine-acylcarnitine translocase deficiency (CACTD). METHODS: Two children diagnosed with CACTD at the Gansu Provincial Maternal and Child Health Care Hospital respectively on January 3 and November 19, 2018 were selected as the study subjects. Trio-whole exome sequencing (trio-WES) was carried out, and candidate variants were validated through Sanger sequencing and pathogenicity analysis. RESULTS: Both children were males and had manifested mainly with hypoglycemia. Trio-WES and Sanger sequencing showed that child 1 had harbored compound heterozygous variants of the SLC25A20 gene, namely c.49G>C (p.Gly17Arg) and c.106-2A>G, which were inherited from his father and mother, respectively. Child 2 had harbored homozygous c.199-10T>G variants of the SLC25A20 gene, which were inherited from both of his parents. Among these, the c.106-2A>G and c.49G>C variants were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.49G>C (p.Gly17Arg), c.106-2A>G, and c.199-10T>G variants were classified as likely pathogenic (PM2_supporting+PP3+PM3_strong+PP4), pathogenic (PVS1+PM2_supporting+PM5+PP3), and pathogenic (PVS1+PM2_supporting+PP3+PP5), respectively. CONCLUSION: Combined with their clinical phenotype and genetic analysis, both children were diagnosed with CACTD. Above finding has provided a basis for their treatment as well as genetic counseling and prenatal diagnosis for their families.


Assuntos
Carnitina Aciltransferases/deficiência , Aconselhamento Genético , Genômica , Erros Inatos do Metabolismo Lipídico , Criança , Masculino , Feminino , Gravidez , Humanos , Linhagem , Mães , Mutação , Proteínas de Membrana Transportadoras
17.
J Inherit Metab Dis ; 47(4): 746-756, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38623632

RESUMO

Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.


Assuntos
Diagnóstico Precoce , Erros Inatos do Metabolismo Lipídico , Proteína Mitocondrial Trifuncional , Triagem Neonatal , Doenças Retinianas , Acuidade Visual , Humanos , Masculino , Feminino , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Criança , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Proteína Mitocondrial Trifuncional/deficiência , Adulto , Lactente , Pré-Escolar , Adolescente , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Adulto Jovem , Carnitina/análogos & derivados , Carnitina/uso terapêutico , Eletrorretinografia , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , 3-Hidroxiacil-CoA Desidrogenases/deficiência , 3-Hidroxiacil-CoA Desidrogenases/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Resultado do Tratamento , Rabdomiólise/diagnóstico , Rabdomiólise/genética , Doenças do Sistema Nervoso
19.
Clin Investig Arterioscler ; 36(4): 229-233, 2024.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-38443216

RESUMO

Sitosterolemia is an autosomal recessive and very rare disease. Its main characteristic is that there is a greater absorption and a decrease in the excretion of sterols, which leads to them being deposited in tissues. It is given by mutations in the ABCG5 or ABCG8 genes found on chromosome 2p21. In this clinical note, we describe the first two patients with familial sitosterolemia described in Colombia, brothers, one of them with xanthomas in extremities as the only symptom, and the other, completely asymptomatic. Genetic studies were performed as a diagnostic test in both patients, where a pathogenic homozygous variant could be identified in the ABCG8 gene in the first case (symptomatic), and a heterozygous variant in the ABCG8 gene in the second case (asymptomatic); the first patient has responded to treatment with ezetimibe. In conclusion, xanthomas should be studied in depth in pediatric age as they may be the only visible sign of such complex and hereditary diseases as familial sitosterolemia, which can be controlled and prevent cardiovascular complications of the disease.


Assuntos
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Ezetimiba , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Masculino , Colômbia , Fitosteróis/efeitos adversos , Fitosteróis/genética , Enteropatias/genética , Enteropatias/diagnóstico , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Hipercolesterolemia/genética , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/diagnóstico , Ezetimiba/uso terapêutico , Xantomatose/genética , Xantomatose/patologia , Xantomatose/diagnóstico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Mutação , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Homozigoto , Criança , Heterozigoto , Lipoproteínas/genética
20.
Forensic Sci Int Genet ; 71: 103028, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38518711

RESUMO

INTRODUCTION: Sudden Unexplained Death in Childhood (SUDC) needs to be fully assessed considering its impact on the family, parents and siblings. Inborn Errors of Metabolism (IEM) such as Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) should be taken into consideration when SUDC occurres. Our aim is to present a family with two successive SUDC and to discuss the post-mortem genetics investigations revealing an IEM implication. CASES REPORT: A complete autopsy with genetic testing was performed when the proband, a 4-year-old girl, died. A few years previously, her older brother had died at the same age and off the same condition. Years later, his exhumation was necessary in order to perform a post-mortem diagnosis.The two siblings were revealed to have had the same pathogenic genotype of the ACADM gene, heterozygous substitutions in ACADM (NM_000016.5): c.985 A>G p.(Lys329Glu) and c.347 G>A p.(Cys116Tyr). In addition, they also both carried a VUS in TECRL, a gene implicated in Catecholaminergic Polymorphic Tachycardia Ventricular (CPVT) and SUDC. CONCLUSION: We illustrate the importance of exome analyses for investigating unexplained sudden death, especially in children, with the possible impact for genetic counselling in the family. The finding of the implication of ACADM gene in this case, raises likely responsibility of the public health system in countries such as France, who delayed implementation of new born screening for these conditions. Exome analyses in this case detected unexpected complexity in interpretation linked to the identification of a second candidate gene for SUDC.


Assuntos
Acil-CoA Desidrogenase , Morte Súbita , Humanos , Feminino , Pré-Escolar , Morte Súbita/etiologia , Masculino , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo Lipídico/genética , Linhagem , Genótipo , Testes Genéticos , Irmãos , Recidiva
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