RESUMEN
A common feature of both congenital and acquired forms of bone marrow failure is an increased risk of developing acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Indeed, the development of MDS or AML is now the major cause of mortality in patients with congenital neutropenia. Thus, there is a pressing clinical need to develop better strategies to prevent, diagnose early, and treat MDS/AML in patients with congenital neutropenia and other bone marrow failure syndromes. Here, we discuss recent data characterizing clonal hematopoiesis and progression to myeloid malignancy in congenital neutropenia, focusing on severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome. We summarize recent studies showing excellent outcomes after allogenic hematopoietic stem cell transplantation for many (but not all) patients with congenital neutropenia, including patients with SCN with active myeloid malignancy who underwent transplantation. Finally, we discuss how these new data inform the current clinical management of patients with congenital neutropenia.
Asunto(s)
Síndromes Congénitos de Insuficiencia de la Médula Ósea/complicaciones , Leucemia Mieloide Aguda/etiología , Síndromes Mielodisplásicos/etiología , Mielopoyesis , Neutropenia/congénito , Preescolar , Hematopoyesis Clonal , Síndromes Congénitos de Insuficiencia de la Médula Ósea/fisiopatología , Síndromes Congénitos de Insuficiencia de la Médula Ósea/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Leucemia Mieloide Aguda/fisiopatología , Leucemia Mieloide Aguda/terapia , Persona de Mediana Edad , Síndromes Mielodisplásicos/fisiopatología , Síndromes Mielodisplásicos/terapia , Neutropenia/complicaciones , Neutropenia/fisiopatología , Neutropenia/terapia , Síndrome de Shwachman-Diamond/complicaciones , Síndrome de Shwachman-Diamond/fisiopatología , Síndrome de Shwachman-Diamond/terapiaRESUMEN
BACKGROUND: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. PATIENTS AND METHODS: We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. RESULTS: The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients' ability to conduct everyday activities was also improved by the treatment. CONCLUSION: Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.
Asunto(s)
Bezafibrato/uso terapéutico , Síndromes Congénitos de Insuficiencia de la Médula Ósea/tratamiento farmacológico , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Musculares/tratamiento farmacológico , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Adulto , Bezafibrato/metabolismo , Niño , Síndromes Congénitos de Insuficiencia de la Médula Ósea/fisiopatología , Femenino , Humanos , Errores Innatos del Metabolismo Lipídico/fisiopatología , Masculino , Enfermedades Mitocondriales/fisiopatología , Enfermedades Musculares/fisiopatologíaRESUMEN
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a genetic disorder of fatty acid beta oxidation that is caused by a defect in ACADVL, which encodes VLCAD. The clinical presentation of VLCAD deficiency is heterogeneous, and either a delayed diagnosis or a misdiagnosis may sometimes occur. We herein describe a difficult-to-diagnose case of the muscle form of adult-onset VLCAD deficiency with compound heterozygous ACADVL mutations including c.790A>G (p.K264E) and c.1246G>A (p.A416T).
Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea/fisiopatología , Síndromes Congénitos de Insuficiencia de la Médula Ósea/terapia , Rabdomiólisis/fisiopatología , Rabdomiólisis/terapia , Adulto , Síndromes Congénitos de Insuficiencia de la Médula Ósea/diagnóstico , Variación Genética , Humanos , Japón , Masculino , Mutación , Rabdomiólisis/diagnóstico , Rabdomiólisis/etiologíaRESUMEN
Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+]i changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+]i in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments.
Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Arritmias Cardíacas/prevención & control , Síndromes Congénitos de Insuficiencia de la Médula Ósea/fisiopatología , Compuestos Epoxi/farmacología , Ácidos Grasos/química , Errores Innatos del Metabolismo Lipídico/fisiopatología , Mitocondrias/fisiología , Enfermedades Mitocondriales/fisiopatología , Enfermedades Musculares/fisiopatología , Miocitos Cardíacos/fisiología , Resveratrol/farmacología , Potenciales de Acción , Arritmias Cardíacas/etiología , Electrofisiología Cardíaca , Síndromes Congénitos de Insuficiencia de la Médula Ósea/complicaciones , Ácidos Grasos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas , Errores Innatos del Metabolismo Lipídico/complicaciones , Enfermedades Mitocondriales/complicaciones , Enfermedades Musculares/complicaciones , Miocitos Cardíacos/efectos de los fármacos , Oxidación-ReducciónRESUMEN
BACKGROUND: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. METHODS: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. RESULTS: We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. CONCLUSIONS: We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.
Asunto(s)
Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Proteínas de Unión al ADN/genética , Pérdida Auditiva Sensorineural/genética , Cadenas Pesadas de Miosina/genética , Neutropenia/congénito , Factores de Transcripción/genética , Adulto , Anciano , Síndromes Congénitos de Insuficiencia de la Médula Ósea/complicaciones , Síndromes Congénitos de Insuficiencia de la Médula Ósea/diagnóstico , Síndromes Congénitos de Insuficiencia de la Médula Ósea/fisiopatología , Exoma/genética , Femenino , Enfermedades Genéticas Congénitas/complicaciones , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/fisiopatología , Pérdida Auditiva Sensorineural/complicaciones , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Neutropenia/complicaciones , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/fisiopatología , Linaje , Fenotipo , Secuenciación del ExomaRESUMEN
Pearson syndrome (PS) is a multisystem mitochondrial respiratory chain disorder typically characterized by sideroblastic anemia and exocrine pancreatic insufficiency. PS is caused by a single large-scale mitochondrial DNA (mtDNA) deletion. PS classically presents in the first year of life and may be fatal in infancy. Children who survive PS may progress to develop Kearns-Sayre syndrome later in life. The full phenotypic spectrum and prognosis of the condition continue to evolve. Here we report five new patients with PS with unique clinical presentations, including four patients with onset later than previously reported in the literature, and one patient with prenatal onset of symptoms. The timing and unique features of these presentations support an expanded phenotypic spectrum of single large-scale mtDNA deletion syndromes (SLSMDS) and reinforce the importance of including SLSMDS in the differential for children with complex multisystem presentations.
Asunto(s)
Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , ADN Mitocondrial/genética , Síndrome de Kearns-Sayre/genética , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Mitocondriales/genética , Enfermedades Musculares/genética , Anemia Sideroblástica/genética , Anemia Sideroblástica/fisiopatología , Niño , Preescolar , Síndromes Congénitos de Insuficiencia de la Médula Ósea/fisiopatología , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/fisiopatología , Femenino , Eliminación de Gen , Humanos , Lactante , Síndrome de Kearns-Sayre/fisiopatología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Masculino , Mitocondrias/genética , Enfermedades Mitocondriales/patología , Enfermedades Mitocondriales/fisiopatología , Enfermedades Musculares/fisiopatología , Fenotipo , Eliminación de Secuencia/genéticaRESUMEN
Pearson marrow-pancreas syndrome (PS), an exceedingly rare mitochondrial disorder, involves multiple systems including hematologic system and pancreas. Other mitochondrial disorders have been associated with progressive infrahisian block but this has not yet been described as a major feature of PS. We report a 7-year-old girl with classical features of PS and cardiac conduction defect. Her electrocardiogram revealed QRS prolongation with right bundle and left anterior fascicular blocks. Follow-up Holter revealed bifascicular block, alternating left and right bundle branch blocks, supraventricular tachycardia (with alternating bundles), and suspicion for nonsustained ventricular tachycardia. She underwent successful transvenous single-chamber ventricular pacemaker.