RESUMEN
Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results, and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions, and translations. Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128 (42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration < 3.9 mmol/L) was reported in only 15% of hospital admissions and was uncommon in patients with ketotic GSD and patients with FAOD aged >5 years. Convulsions, coma, or death was not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in nine different languages. Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD.
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Tratamiento de Urgencia/métodos , Enfermedad del Almacenamiento de Glucógeno Tipo I/metabolismo , Hipoglucemia/terapia , Errores Innatos del Metabolismo Lipídico/metabolismo , Telemedicina , Adolescente , Adulto , Niño , Preescolar , Ayuno , Ácidos Grasos/metabolismo , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo I/fisiopatología , Humanos , Hipoglucemia/etiología , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/fisiopatología , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Estudios Retrospectivos , Adulto JovenRESUMEN
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.
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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
Fatty acid oxidation disorders (FAOD) are a group of rare, autosomal recessive, metabolic disorders caused by variants of the genes for the enzymes and proteins involved in the transport and metabolism of fatty acids in the mitochondria. Those affected by FAOD are unable to convert fatty acids into tricarboxylic acid cycle intermediates such as acetyl-coenzyme A, resulting in decreased adenosine triphosphate and glucose for use as energy in a variety of high-energy-requiring organ systems. Signs and symptoms may manifest in infants but often also appear in adolescents or adults during times of increased metabolic demand, such as fasting, physiologic stress, and prolonged exercise. Patients with FAOD present with a highly heterogeneous clinical spectrum. The most common clinical presentations include hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Despite efforts to detect FAOD through newborn screening and manage patients early, symptom onset can be sudden and serious, even resulting in death. Therefore, it is critical to identify quickly and accurately the key signs and symptoms of patients with FAOD to manage metabolic decompensations and prevent serious comorbidities.
Asunto(s)
Ácidos Grasos/metabolismo , Cardiopatías , Errores Innatos del Metabolismo Lipídico , Hepatopatías , Enfermedades Musculares , Enfermedades del Sistema Nervioso , Enfermedades de la Retina , Cardiopatías/etiología , Cardiopatías/fisiopatología , Cardiopatías/terapia , Humanos , Errores Innatos del Metabolismo Lipídico/complicaciones , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/fisiopatología , Errores Innatos del Metabolismo Lipídico/terapia , Hepatopatías/etiología , Hepatopatías/fisiopatología , Hepatopatías/terapia , Enfermedades Musculares/etiología , Enfermedades Musculares/fisiopatología , Enfermedades Musculares/terapia , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/fisiopatología , Enfermedades del Sistema Nervioso/terapia , Enfermedades de la Retina/etiología , Enfermedades de la Retina/fisiopatología , Enfermedades de la Retina/terapiaRESUMEN
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.
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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
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.
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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.
Asunto(s)
Trastorno del Sistema de Conducción Cardíaco/complicaciones , Trastorno del Sistema de Conducción Cardíaco/diagnóstico , Trastorno del Sistema de Conducción Cardíaco/terapia , Síndromes Congénitos de Insuficiencia de la Médula Ósea/complicaciones , Electrocardiografía/métodos , Sistema de Conducción Cardíaco/fisiopatología , Errores Innatos del Metabolismo Lipídico/complicaciones , Enfermedades Mitocondriales/complicaciones , Enfermedades Musculares/complicaciones , Marcapaso Artificial , Niño , Síndromes Congénitos de Insuficiencia de la Médula Ósea/fisiopatología , Femenino , Humanos , Errores Innatos del Metabolismo Lipídico/fisiopatología , Enfermedades Mitocondriales/fisiopatología , Enfermedades Musculares/fisiopatologíaRESUMEN
Multiple acyl-CoA dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism. The late-onset multiple acyl-CoA dehydrogenase deficiency is frequently caused by mutations in ETFDH gene. Because of its clinical heterogeneity, diagnosis and treatment of late-onset multiple acyl-CoA dehydrogenase deficiency are often delayed. The authors described a previously healthy 40-yr-old Thai woman presenting with subacute severe weakness of bulbar-limb muscles and elevated serum creatine kinase. The authors emphasized the importance of needle EMG and prompt muscle histopathological evaluation, which rapidly led to the diagnosis and riboflavin therapy, resulting in a dramatic and rapid improvement before genetic study disclosed mutation in ETFDH gene.
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Electromiografía/métodos , Errores Innatos del Metabolismo Lipídico/etiología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/complicaciones , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/fisiopatología , Distrofias Musculares/etiología , Distrofias Musculares/fisiopatología , Adulto , Femenino , Humanos , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Errores Innatos del Metabolismo Lipídico/genética , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/tratamiento farmacológico , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/genética , Distrofias Musculares/tratamiento farmacológico , Distrofias Musculares/genética , Riboflavina/uso terapéuticoRESUMEN
BACKGROUND In this study, we investigated the clinical and pathological features of patients with lipid storage myopathy (LSM) complicated with hyperuricemia, to improve clinicians' understanding of metabolic multi-muscular disorder with metabolic disorders, and to reduce the risk of missed diagnosis of LSM. MATERIAL AND METHODS From January 2005 to December 2017, 8 patients underwent muscle biopsy and diagnosed by muscle pathology and genetic testing in our hospital. All 8 patients were in compliance with LSM diagnosis. We collected data on the patient's clinical performance, adjuvant examination, treatment, and outcomes to provide a comprehensive report and description of LSM patients with hyperuricemia. RESULTS All patients were diagnosed as having ETFDH gene mutations. The main clinical manifestations of patients were chronic limb and trunk weakness, limb numbness, and muscle pain. The serum creatine kinase (CK) values in all patients were higher than normal values. Electromyography showed 3 cases of simple myogenic damage and 3 cases of neurogenic injury. Hematuria metabolic screening showed that 2 patients had elevated glutaric aciduria, and 1 patient had elevated fatty acyl carnitine in the blood. All patients were given riboflavin treatment, and the clinical symptoms were significantly improved, and 3 patients returned to normal uric acid levels after treatment. Pathological staining showed an abnormal deposition of lipid droplets in muscle fibers. CONCLUSIONS If an adolescent hyperuricemia patient has abnormal limb weakness, exercise intolerance, and elevated serum CK values, clinicians need to be highly alert to the possibility of LSM. Early diagnosis and treatment of LSM should improve the clinical symptoms and quality of life and reduce complications.
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Hiperuricemia/fisiopatología , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/fisiopatología , Distrofias Musculares/genética , Distrofias Musculares/fisiopatología , Adolescente , Adulto , Carnitina/análogos & derivados , Carnitina/metabolismo , Niño , China , Flavoproteínas Transportadoras de Electrones/genética , Flavoproteínas Transportadoras de Electrones/metabolismo , Femenino , Humanos , Hiperuricemia/metabolismo , Proteínas Hierro-Azufre/genética , Proteínas Hierro-Azufre/metabolismo , Errores Innatos del Metabolismo Lipídico/metabolismo , Masculino , Debilidad Muscular , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares/genética , Distrofias Musculares/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Calidad de Vida , Riboflavina/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Chanarin-Dorfman syndrome (CDS) is a rare syndromic disease related to an accumulation of triacylglycerol in most organs. The aim of our study was to investigate various organs in a large series of CDS patients. RESULTS: We report for the first time thyroid function impairment in CDS. Among 12 investigated patients, 7 showed thyroid function impairment. All of them were over 30 of age. The 5 remaining investigated patients with normal thyroid function were under 30. Thyroid loss of function is an unknown clinical feature of CDS that could gradually develop with age. Thyroid ultrasound showed an abnormal aspect in all investigated patients (6 with thyroid impairment and 3 with normal thyroid function). Cervical MRI done in 2 patients with thyroid impairment showed fat infiltration of thyroid parenchyma. Audiogram carried out in 8 of our patients showed sensorineural hearing impairment in all patients, although only 2 patients suffered from clinical hypoacusia. We also demonstrated that kidney could be a more commonly involved organ than previously reported in the literature. A poorly differentiated kidney parenchyma is a common feature in our series. One patient showed cerebellar atrophy and T2 hypersignal of brain's white matter in MRI. All patients carried the same founder mutation c.773(- 1)G > A in the ABDH5 gene. DISCUSSION: Aside from the congenital ichthyosiform erythroderma, the most common symptom of CDS, in addition to other organs involvement frequently reported in the literature, we described thyroid dysfunction, an unreported feature, probably related to the lipid infiltration of the thyroid parenchyma. The association found between age and hypothyroidism in CDS patients could explain the gradually development of thyroid disease with age. CONCLUSION: We reported a thyroid dysfunction and unreported ultrasonographic aspects of kidneys and cerebral MRI in CDS patients. METHODS: We performed clinical analyses in 15 patients in whom thyroid, liver, ocular, kidney, skeletal muscle and neurological involvement were explored. Genetic and molecular explorations were performed by direct sequence analysis. Software SPSS, Fisher's exact test and ANOVA were used for statistical analyses.
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1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética , Eritrodermia Ictiosiforme Congénita/metabolismo , Eritrodermia Ictiosiforme Congénita/fisiopatología , Errores Innatos del Metabolismo Lipídico/metabolismo , Errores Innatos del Metabolismo Lipídico/fisiopatología , Enfermedades Musculares/metabolismo , Enfermedades Musculares/fisiopatología , Glándula Tiroides/metabolismo , Glándula Tiroides/fisiopatología , Adulto , Exones/genética , Femenino , Homocigoto , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Mutación/genética , Estudios RetrospectivosRESUMEN
RATIONALE: Sitosterolemia is a rare autosomal recessive disorder of dyslipidemia due to mutations of genes ABCG5 and ABCG8, leading to highly elevated plasma levels of plant sterols and expanded body pools of cholesterol. PATIENT CONCERNS: We present a 9-year-old and a 7-year-old Chinese boy with hypercholesterolemia and xanthomas of sitosterolemia due to ABCG5 gene mutations. We also make a literature review of another 30 sitosterolemic children cases that have been reported with virulence ABCG5 gene mutations. DIAGNOSIS: We took peripheral blood samples from 2 patients and their parents to conduct genetic analysis by next-generation sequencing (NGS) technologies. INTERVENTIONS: The 2 patients received dietary modifications without pharmaceuticals treatment. OUTCOMES: A c.1166G>A (Arg389His) homozygosis mutation in exon 9 was observed in case 1, whereas a c.751C>T (Gln251*) homozygosis mutation in exon 6 was found in case 2. Literature review found another 30 pediatric cases with sitosterolemia due to ABCG5 gene mutation. The lipid profile was normalized and xanthomas got smaller with combined therapy of a combined low-cholesterol and low-phytosterols diet. LESSONS: These suggested that in patients (especially Asian patients) with multiple xanthomas, severe hypercholesterolemia, or elevated low-density lipoprotein-cholesterol, sitosterolemia should be considered in the differential diagnosis. Early diagnosis is important, and restriction of both cholesterol and phytosterols diet should suggested for these patients.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Hipercolesterolemia/genética , Enfermedades Intestinales/genética , Errores Innatos del Metabolismo Lipídico/genética , Lipoproteínas/genética , Fitosteroles/efectos adversos , Niño , Diagnóstico Diferencial , Humanos , Hipercolesterolemia/dietoterapia , Hipercolesterolemia/patología , Hipercolesterolemia/fisiopatología , Enfermedades Intestinales/dietoterapia , Enfermedades Intestinales/patología , Enfermedades Intestinales/fisiopatología , Errores Innatos del Metabolismo Lipídico/dietoterapia , Errores Innatos del Metabolismo Lipídico/patología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Masculino , Fenotipo , Fitosteroles/genéticaAsunto(s)
Eritrodermia Ictiosiforme Congénita/tratamiento farmacológico , Ictiosis Lamelar/tratamiento farmacológico , Queratolíticos/uso terapéutico , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Enfermedades Musculares/tratamiento farmacológico , Ácidos Nicotínicos/uso terapéutico , Adolescente , Femenino , Humanos , Eritrodermia Ictiosiforme Congénita/fisiopatología , Ictiosis Lamelar/fisiopatología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Enfermedades Musculares/fisiopatología , Crema para la Piel/uso terapéutico , Tomografía de Coherencia Óptica , Pérdida Insensible de AguaRESUMEN
Muscle weakness is a nonspecific finding of myopathy of any etiology that include iatrogenic, toxic, endocrinological, infectious, immunologic, and metabolic disorders. Among the metabolic myopathies glutaric aciduria type II (GAII) is an autosomal recessively inherited rare disorder of fatty acid and amino acid metabolisms. The late onset form is heterogeneous in terms of symptomatology and severity and for the cases that chronic manifestations of lipid storage myopathy are the only clues for the disease, differential diagnosis can be challenging. Here we report two cases of GAII: the first one was 18-year old boy who presented with proximal muscle weakness and in another center, he was diagnosed as polymyositis and treated with immunosuppressive therapies. He admitted to our clinic with ongoing muscle weakness and symptoms that were related to the side effects of immunosuppressive therapies. The second case was also presented with muscle weakness. For both cases, muscle biopsies and urinary organic acid analyses were consistent with the diagnosis of GAII. To differentiate inflammatory myositis from non-inflammatory myopathies; rheumatic symptoms, accompanying complaints of the patient and autoantibody positivity can be helpful. To our knowledge this is the first report to underline the differential diagnosis of inflammatory myopathies from metabolic myopathies.
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Acil-CoA Deshidrogenasa/deficiencia , Enfermedades de Inicio Tardío , Errores Innatos del Metabolismo Lipídico , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa , Músculo Esquelético/patología , Distrofias Musculares , Miositis/diagnóstico , Adolescente , Biopsia/métodos , Carnitina/administración & dosificación , Diagnóstico Diferencial , Femenino , Humanos , Enfermedades de Inicio Tardío/diagnóstico , Enfermedades de Inicio Tardío/fisiopatología , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/etiología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Masculino , Micronutrientes/administración & dosificación , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/diagnóstico , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/metabolismo , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/fisiopatología , Debilidad Muscular/diagnóstico , Debilidad Muscular/etiología , Distrofias Musculares/diagnóstico , Distrofias Musculares/etiología , Distrofias Musculares/fisiopatología , Riboflavina/administración & dosificación , Índice de Severidad de la Enfermedad , Urinálisis/métodos , Adulto JovenRESUMEN
Neutral lipid storage disease with myopathy (NLSDM) is characterized by the accumulation of cytoplasmic triglyceride droplets in various tissues; this very rare condition is caused by mutations in the PNPLA2 gene, susceptible to specific pharmacological management that decreases clinical progression. We describe the clinical and biochemical characteristics of a Colombian patient with a previously unreported homozygous mutation in the PNPLA2 gene with a difficult to manage disease, who was diagnosed late by advances in molecular techniques.
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Lipasa/genética , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Musculares/genética , Diagnóstico Tardío , Progresión de la Enfermedad , Femenino , Humanos , Errores Innatos del Metabolismo Lipídico/fisiopatología , Persona de Mediana Edad , Enfermedades Musculares/fisiopatología , Mutación MissenseAsunto(s)
Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Hipercolesterolemia/fisiopatología , Enfermedades Intestinales/metabolismo , Enfermedades Intestinales/patología , Enfermedades Intestinales/fisiopatología , Errores Innatos del Metabolismo Lipídico/metabolismo , Errores Innatos del Metabolismo Lipídico/patología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Fitosteroles/efectos adversos , Esteroles/metabolismo , Humanos , Fitosteroles/metabolismoRESUMEN
PURPOSE: Pulmonary function abnormalities and sleep-related breathing disorders (SRBD) are frequent in subjects with several neuromuscular diseases but there is no data about lipid storage diseases (LSD). Therefore, we aimed to evaluate pulmonary functions and SRBD in adults with LSD. METHODS: Pulmonary functions (forced expiratory volume (FEV1), forced vital capacity (FVC), supine FVC, upright-supine FVC% change, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), peak cough flow (PCF)), arterial blood gases, and polysomnographic data of all subjects were evaluated. RESULTS: Twenty-five subjects with LSD were evaluated [17 males, 8 females; age 34.9 ± 15 years; BMI 26.5 ± 3.4 kg/m2]. MIP was - 72.2 ± 32.7 cmH2O (< - 80 cmH2O in 13 subjects), MEP was 80.9 ± 39.1 cmH2O (< 80 cmH2O in 9 subjects, < 40 cmH2O in 6 subjects), and PCF was 441.3 ± 190.9 L/min (< 360 L/min in 11 subjects). FVC was 87.8% ± 25.7 and 6 subjects had FVC < 80%. Seven subjects had diaphragm dysfunction (four upright-supine FVC% ≥ 15, three dyspnea in supine position with paradoxical abdominal respiration). Five subjects had hypoxemia (PaO2 < 80 mmHg) and 8 subjects had hypercapnia (PaCO2 > 45 mmHg). REM sleep had decreased in all subjects (10.2% ± 6.1). Obstructive sleep apnea (OSA) was found in 80% of the subjects (n = 20; 9 mild, 9 moderate, 2 severe). For subjects with OSA, apnea-hypopnea index (AHI) was 20.8 ± 15.9/h, oxygen desaturation index (ODI) was 11.9 ± 15.4/h, AHIREM was 30.6 ± 19.7/h, AHINREM was 19.7 ± 16.6/h, ODIREM was 27.2 ± 26.1/h, and ODINREM was 11.4 ± 15/h. Five subjects (20%) diagnosed as REM-related OSA. Nocturnal mean SpO2 was 94.9% ± 1.7, lowest SpO2 was 73.3% ± 13.9, and time spent with SpO2 < 90% was 2.4% ± 7.2. CONCLUSION: In subjects with LSD, pulmonary function impairment, daytime hypercapnia and hypoxemia, and OSA, especially REM-related OSA, are frequent. Therefore, pulmonary functions and polysomnography should be performed routinely.
Asunto(s)
Errores Innatos del Metabolismo Lipídico/fisiopatología , Enfermedades Musculares/fisiopatología , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/fisiopatología , Adulto , Índice de Masa Corporal , Presión de las Vías Aéreas Positiva Contínua/métodos , Femenino , Volumen Espiratorio Forzado , Humanos , Errores Innatos del Metabolismo Lipídico/complicaciones , Masculino , Persona de Mediana Edad , Enfermedades Musculares/complicaciones , Polisomnografía , Respiración con Presión Positiva , Insuficiencia Respiratoria/etiología , Capacidad VitalRESUMEN
Mitochondria regulate the balance between lipid metabolism and storage in the skeletal muscle. Altered lipid transport, metabolism and storage influence the bioenergetics, redox status and insulin signalling, contributing to cardiac and neurological diseases. Lipid storage disorders (LSDs) are neurological disorders which entail intramuscular lipid accumulation and impaired mitochondrial bioenergetics in the skeletal muscle causing progressive myopathy with muscle weakness. However, the mitochondrial changes including molecular events associated with impaired lipid storage have not been completely understood in the human skeletal muscle. We carried out morphological and biochemical analysis of mitochondrial function in muscle biopsies of human subjects with LSDs (n = 7), compared to controls (n = 10). Routine histology, enzyme histochemistry and ultrastructural analysis indicated altered muscle cell morphology and mitochondrial structure. Protein profiling of the muscle mitochondria from LSD samples (n = 5) (vs. control, n = 5) by high-throughput mass spectrometric analysis revealed that impaired metabolic processes could contribute to mitochondrial dysfunction and ensuing myopathy in LSDs. We propose that impaired fatty acid and respiratory metabolism along with increased membrane permeability, elevated lipolysis and altered cristae entail mitochondrial dysfunction in LSDs. Some of these mechanisms were unique to LSD apart from others that were common to dystrophic and inflammatory muscle pathologies. Many differentially regulated mitochondrial proteins in LSD are linked with other human diseases, indicating that mitochondrial protection via targeted drugs could be a treatment modality in LSD and related metabolic diseases. Cover Image for this Issue: doi: 10.1111/jnc.14177.
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Errores Innatos del Metabolismo Lipídico/patología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Mitocondrias Musculares/patología , Adolescente , Adulto , Biopsia , Femenino , Humanos , Masculino , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/ultraestructura , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Músculo Esquelético/ultraestructura , Adulto JovenRESUMEN
The Native American Pima population has the highest incidence of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) of any reported population, but the pathophysiologic mechanism is unknown. Genetic studies in Pima Indians have linked acyl-CoA dehydrogenase 10 (ACAD10) gene polymorphisms, among others, to this predisposition. The gene codes for a protein with a C-terminus region that is structurally similar to members of a family of flavoenzymes-the acyl-CoA dehydrogenases (ACADs)-that catalyze α,ß-dehydrogenation reactions, including the first step in mitochondrial FAO (FAO), and intermediary reactions in amino acids catabolism. Dysregulation of FAO and an increase in plasma acylcarnitines are recognized as important in the pathophysiology of IR and T2DM. To investigate the deficiency of ACAD10 as a monogenic risk factor for T2DM in human, an Acad-deficient mouse was generated and characterized. The deficient mice exhibit an abnormal glucose tolerance test and elevated insulin levels. Blood acylcarnitine analysis shows an increase in long-chain species in the older mice. Nonspecific variable pattern of elevated short-terminal branch-chain acylcarnitines in a variety of tissues was also observed. Acad10 mice accumulate excess abdominal adipose tissue, develop an early inflammatory liver process, exhibit fasting rhabdomyolysis, and have abnormal skeletal muscle mitochondria. Our results identify Acad10 as a genetic determinant of T2DM in mice and provide a model to further investigate genetic determinants for insulin resistance in humans.
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Acil-CoA Deshidrogenasa/genética , Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina , Errores Innatos del Metabolismo Lipídico/enzimología , Grasa Abdominal/enzimología , Grasa Abdominal/fisiopatología , Adiposidad , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Insulina/sangre , Resistencia a la Insulina/genética , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/patología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Hígado/enzimología , Hígado/patología , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias Musculares/enzimología , Mitocondrias Musculares/patología , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Enfermedad del Hígado Graso no Alcohólico/enzimología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad Abdominal/enzimología , Obesidad Abdominal/genética , Obesidad Abdominal/fisiopatología , Fenotipo , Rabdomiólisis/enzimología , Rabdomiólisis/genética , Rabdomiólisis/patologíaRESUMEN
Fatty acid oxidation disorders presenting as primary myopathy is relatively rare and also diagnostically challenging. Its association with "dropped head syndrome" is reported till date in single cases of carnitine deficiency and multiple acyl CoA dehydrogenase deficiency (MADD).We studied nineteen cases of primary progressive myopathy confirmed to have fatty acid oxidation defects by Tandem Mass Spectrometry. The detailed clinical, muscle histopathology, tandem mass spectrometry and muscle magnetic resonance imaging (MRI) findings are presented here. The fatty acid oxidation defects identified were sub-grouped into: medium chain acyl CoA dehydrogenase deficiency (MCAD) = 4; very long chain acyl CoA dehydrogenase deficiency (VLCAD) = 7; MADD = 6; carnitine uptake defect and short chain acyl CoA dehydrogenase (SCAD) deficiency = 1 each. The age at onset for MCAD, VLCAD and MADD ranged from 11.5 to 15, 8 to 17 and 10 to 38 years respectively. The patients with carnitine uptake defect and SCAD had onset at 29 and 15 years of age. The dominant symptoms were exertion induced myalgia and progressive proximal limb weakness in all. 12/19 (63.2%) had classical dropped head syndrome. Ptosis and bulbar weakness were present in a few cases. This study emphasizes that fatty acid oxidation disorders presenting as primary myopathy are probably under diagnosed and should be entertained in the differential diagnosis of acute or chronic limb girdle syndromes. Hitherto, unreported we describe "dropped head syndrome" as a prominent phenomenon in MCAD and VLCAD. The presence of ptosis and bulbar weakness in fatty acid oxidation defects expands the clinical spectrum.
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Acil-CoA Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo Lipídico/diagnóstico , Enfermedades Musculares/diagnóstico , Adolescente , Adulto , Edad de Inicio , Niño , Estudios de Cohortes , Femenino , Cabeza , Humanos , Errores Innatos del Metabolismo Lipídico/patología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Enfermedades Musculares/patología , Enfermedades Musculares/fisiopatología , Síndrome , Adulto JovenRESUMEN
Sitosterolemia is a metabolic disorder characterized by increased intestinal absorption and tissue accumulation of phytosterols. Although sitosterolemia is considered a rare disease, its prevalence may be significantly higher than initially thought. Indeed, accumulating evidence suggests that patients with unexplained hematologic abnormalities or premature cardiovascular disease in the absence of classic risk factors may exhibit disordered phytosterol metabolism. In this review, we present a patient with sitosterolemia, describe the pathophysiology and the clinical picture of this disorder, and discuss the clinical value of phytosterol supplementation in patients with primary dyslipidemias.
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Hipercolesterolemia/metabolismo , Enfermedades Intestinales/metabolismo , Errores Innatos del Metabolismo Lipídico/metabolismo , Fitosteroles/efectos adversos , Femenino , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/patología , Hipercolesterolemia/fisiopatología , Enfermedades Intestinales/diagnóstico , Enfermedades Intestinales/patología , Enfermedades Intestinales/fisiopatología , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/patología , Errores Innatos del Metabolismo Lipídico/fisiopatología , Persona de Mediana Edad , Fitosteroles/metabolismoRESUMEN
Neutral lipid storage disease with myopathy (NLSDM) presents with skeletal muscle myopathy and severe dilated cardiomyopathy in nearly 40% of cases. NLSDM is caused by mutations in the PNPLA2 gene, which encodes the adipose triglyceride lipase (ATGL). Here we report clinical and genetic findings of a patient carrying two novel PNPLA2 mutations (c.696+4A>G and c.553_565delGTCCCCCTTCTCG). She presented at age 39 with right upper limb abduction weakness slowly progressing over the years with asymmetric involvement of proximal upper and lower limb muscles. Cardiological evaluation through ECG and heart echo scan was normal until the age 53, when mild left ventricular diastolic dysfunction was detected. Molecular analysis revealed that only one type of PNPLA2 transcript, with exon 5 skipping, was expressed in patient cells. Such aberrant mRNA causes the production of a shorter ATGL protein, lacking part of the catalytic domain. This is an intriguing case, displaying severe PNPLA2 mutations with clinical presentation characterized by slight cardiac impairment and full expression of severe asymmetric myopathy.