RESUMEN
Early-onset long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency is a fatty acid ß-oxidation disorder with a poor prognosis. Triheptanoin, an anaplerotic oil with odd-chain fatty acids can improve the disease course. The female patient presented here was diagnosed at the age of 4 months, and treatment was started as fat restriction, frequent feeding, and standard medium-chain triglyceride supplementation. In follow-up, she had frequent rhabdomyolysis episodes (â¼8 per year). At the age of six, she had 13 episodes in 6 months, and triheptanoin was started as part of a compassionate use program. Following unrelated hospital stays due to multisystem inflammatory syndrome in children and a bloodstream infection, she had only 3 rhabdomyolysis episodes, and hospitalized days decreased from 73 to 11 during her first year with triheptanoin. Triheptanoin drastically decreased the frequency and severity of rhabdomyolysis, but progression of retinopathy was not altered.
Asunto(s)
Errores Innatos del Metabolismo Lipídico , Rabdomiólisis , Humanos , Niño , Femenino , Lactante , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Oxidación-Reducción , Triglicéridos/uso terapéutico , Errores Innatos del Metabolismo Lipídico/complicaciones , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Rabdomiólisis/tratamiento farmacológico , Coenzima ARESUMEN
Chanarin-Dorfman syndrome (CDS) is a rare, autosomal recessive disorder of impaired triacylglycerol catabolism leading to cytoplasmic deposition of triglycerides in various cell types. We describe the case of an 8-month-old boy with cataracts, strabismus, motor delays, and an ichthyosiform rash since birth. Genetic testing revealed a pathogenic variant of the ABHD5 gene, suggestive of CDS, and further workup demonstrated hepatic steatosis and myopathy. His ichthyosis improved with initiation of a diet low in very long-chain fatty acids and medium-chain fatty acid supplementation.
Asunto(s)
Catarata , Eritrodermia Ictiosiforme Congénita , Ictiosis Lamelar , Ictiosis , Errores Innatos del Metabolismo Lipídico , Enfermedades Musculares , Masculino , Humanos , Lactante , Eritrodermia Ictiosiforme Congénita/diagnóstico , Eritrodermia Ictiosiforme Congénita/genética , Ictiosis Lamelar/diagnóstico , Ictiosis Lamelar/genética , Ictiosis/diagnóstico , Ictiosis/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/patología , Catarata/diagnóstico , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genéticaRESUMEN
OBJECTIVE: To investigate the incidence, clinical characteristics, gene mutations and prognosis of fatty acid oxidation disorders (FAOD) in newborns in Chongqing. METHODS: Blood samples were collected from 35 374 newborns for screening of FAOD in the Neonatal Screening Center of Women and Children's Hospital of Chongqing Medical University from July 2020 to February 2022. The acylcarnitine spectrum was detected by tandem mass spectrometry, the positive children in primary screening were recalled within 2 weeks, and the diagnosis of FAOD was confirmed by urine organic acid measurement, blood biochemistry testing and genetic analysis. The confirmed children were given early intervention, treatment and followed-up. RESULTS: Among 35 374 newborns, there were 267 positive children in primary screening, with a positive rate of 0.75%. Five children with FAOD were diagnosed by gene detection, with an incidence rate of 1/7075. Among them, there were 3 cases of primary carnitine deficiency (PCD, 1/11 791), 1 case of short-chain acyl-CoA dehydrogenase deficiency (SCADD, 1/35 374) and 1 case of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, 1/35 374). The c.1400C>G and c.338G>A were the common mutations of SLC22A5 gene in 3 children with PCD, while c.621G>T was a novel mutation. There were no clinical manifestations during the follow-up period in 2 children with supplementation of L-carnitine. Another child with PCD did not follow the doctor's advice of L-carnitine treatment, and had acute attack at the age of 6â months. The child recovered after treatment, and developed normally during the follow-up. The detected ACADS gene mutations were c.417G>C and c.1054G>A in child with SCADD, who showed normal intelligence and physical development without any clinical symptoms. The mutations of ACADVL gene were c.1349G>A and c.1843C>T in child with VLCADD, who showed acute attack in the neonatal period and recovered after treatment; the child was fed with milk powder rich in medium-chain fatty acids and had normal development during the follow-up. CONCLUSIONS: The incidence of FAOD in Chongqing area is relatively high. PCD is the most common type, and the clinical phenotype of VLCADD is serious. After early diagnosis through neonatal screening, standardized treatment and management is followed, most of FAOD children can have good prognosis.
Asunto(s)
Errores Innatos del Metabolismo Lipídico , Carnitina , Ácidos Grasos , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/epidemiología , Errores Innatos del Metabolismo Lipídico/genética , Mutación , Tamizaje Neonatal , Polvos , Miembro 5 de la Familia 22 de Transportadores de Solutos/genéticaRESUMEN
Long-chain fatty acid oxidation disorders (LC-FAODs) are rare, life-threatening, autosomal recessive genetic disorders characterized by acute crises of energy production and chronic energy deficiency. Patients may present with rhabdomyolysis induced by exercise; fasting or illness; hepatic dysfunction, including severe hypoglycemia and hyperammonemia; and cardiomyopathy. These clinical manifestations can lead to frequent hospitalizations and premature death. LC-FAODs are caused by mutations in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids (LCFAs) into energy during times of fasting and physiologic stress. Despite newborn screening, current management options leave many patients continuing to experience major clinical events, and mortality rates remain elevated. The current standard therapy for LC-FAODs is avoidance of fasting and supplementation of medium-chain triglyceride oil, an even, medium-chain fatty acid that does not require the typical steps of LC-FAOD for metabolism. Despite this therapy, patients with LC-FAODs continue to experience recurring hospitalizations, and high morbidity and mortality rates. In recent years, the use of medium, odd-chain fatty acids, such as triheptanoin, have been studied as a treatment of LC-FAODs due to its anaplerotic properties. Due to favorable safety and efficacy data from clinical trials, this novel agent has the potential to transform the treatment of LC-FAODs and improve patient outcomes in this patient population. This article provides an overview of the epidemiology, pathophysiology, clinical manifestations, and current management approaches for the diagnosis and management of LC-FAODs. It also provides the most recent clinical safety and efficacy data for triheptanoin and other therapies under investigation.
Asunto(s)
Errores Innatos del Metabolismo Lipídico , Cardiomiopatías , Ejercicio Físico , Ácidos Grasos , Humanos , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/terapia , Oxidación-ReducciónRESUMEN
BACKGROUND: Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency is a fatty acid oxidation disorder that can have variable clinical severity. There is still limited information on its clinical presentation and longitudinal history by genotype, and effectiveness of newborn screening (NBS). METHODS: Retrospective data were collected from 90 patients (44 female, 46 male) to compare biochemical data with clinical outcomes. The frequency of adverse events (number of hypoglycemia-related ER visits and admissions) was assessed by genotype (homozygosity or not for the common pathogenic variant, p.Lys329Glu, in the ACADM gene), and method of diagnosis (NBS vs. clinical). RESULTS: MCAD deficiency in Utah was more frequent compared to the United States average (1: 9266 versus 1:17,759 newborns). With age, C8-carnitine did not change significantly whereas C2-carnitine decreased (p < .001), possibly reflecting reduced carnitine supplementation typically seen with age. Children with MCAD deficiency had normal growth. p.Lys329Glu homozygotes had higher NBS C8-carnitine (23.4 ± 19.6 vs. 6.6 ± 3.0 µmol/L) and lifetime plasma C8-carnitine levels (6.2 ± 5 vs. 3.6 ± 1.9 µmol/L) compared to patients with at least one other pathogenic variant (p < .001 for both) and higher transaminases compared to compound heterozygotes (ALT 41.9 ± 6.2 vs. 31.5 ± 3.7 U/L, AST 63.9 ± 5.8 vs. 45.7 ± 1.8 U/L, p < .05 for both). On average, p.Lys329Glu homozygotes had more hypoglycemic events than compound heterozygotes (1.44 versus 0.49 events/patient) as did patients diagnosed clinically compared to those diagnosed by NBS (2.15 versus 0.62 events/patient), though these differences were not statistically significant. Neonatal death was observed before results of newborn screening were available in one patient homozygous for the common p.Lys329Glu pathogenic variant, but severe neonatal complications (hypoglycemia, cardiac arrhythmia) were also seen in patients with other mutations. No irreversible complications were observed after diagnosis in any patient with MCAD deficiency. DISCUSSION: Homozygosity for the common ACADM p.Lys329Glu pathogenic variant was associated with increased levels of C8-carnitine and transaminases. Newborn screening provides the opportunity to reduce morbidity and post-neonatal mortality in all patients with MCAD deficiency, regardless of genotype.
Asunto(s)
Acil-CoA Deshidrogenasa/deficiencia , Genotipo , Homocigoto , Errores Innatos del Metabolismo Lipídico/diagnóstico , Tamizaje Neonatal , Acil-CoA Deshidrogenasa/genética , Adolescente , Adulto , Carnitina/sangre , Niño , Preescolar , Femenino , Variación Genética , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/mortalidad , Masculino , Mutación , Fenotipo , Estudios Retrospectivos , Transaminasas/sangre , Estados Unidos , Utah , Adulto JovenRESUMEN
Mitochondrial fatty acid oxidation disorders (FAODs) are caused by defects in ß-oxidation enzymes, including very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein (TFP), carnitine palmitoyltransferase-2 (CPT2), carnitine-acylcarnitine translocase (CACT) and others. During prolonged fasting, infection, or exercise, patients with FAODs present with hypoglycemia, rhabdomyolysis, cardiomyopathy, liver dysfunction, and occasionally sudden death. This article describes the diagnosis, newborn screening, and treatment of long-chain FAODs with a focus on VLCAD deficiency. VLCAD deficiency is generally classified into three phenotypes based on onset time, but the classification should be comprehensively determined based on genotype, residual enzyme activity, and clinical course, due to a lack of apparent genotype-phenotype correlation. With the expansion of newborn screening for FAODs, several issues have arisen, such as missed detection, overdiagnosis (including detection of benign/asymptomatic type), and poor prognosis of the neonatal-onset form. Meanwhile, dietary management and restriction of exercise have been unnecessary for patients with the benign/asymptomatic type of VLCAD deficiency with a high fatty acid oxidation flux score. Although L-carnitine therapy for VLCAD/TFP deficiency has been controversial, supplementation with L-carnitine may be accepted for CPT2/CACT and multiple acyl-CoA dehydrogenase deficiencies. Recently, a double-blind, randomized controlled trial of triheptanoin (seven-carbon fatty acid triglyceride) versus trioctanoin (regular medium-chain triglyceride) was conducted and demonstrated improvement of cardiac functions on triheptanoin. Additionally, although the clinical efficacy of bezafibrate remains controversial, a recent open-label clinical trial showed efficacy of this drug in improving quality of life. These drugs may be promising for the treatment of FAODs, though further studies are required.
Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Ácidos Grasos/metabolismo , Hipolipemiantes/uso terapéutico , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Tamizaje Masivo , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/tratamiento farmacológico , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Manejo de la Enfermedad , Humanos , Errores Innatos del Metabolismo Lipídico/enzimología , Enfermedades Mitocondriales/enzimología , Enfermedades Musculares/enzimologíaRESUMEN
Lipid storage myopathies (LSMs) are a heterogeneous group of genetic disorders that present with abnormal lipid storage in multiple body organs, typically muscle. Patients can clinically present with cardiomyopathy, skeletal muscle weakness, myalgia, and extreme fatigue. An early diagnosis is crucial, as some LSMs can be managed by simple nutraceutical supplementation. For example, high dosage l-carnitine is an effective intervention for patients with Primary Carnitine Deficiency (PCD). This review discusses the clinical features and management practices of PCD as well as Neutral Lipid Storage Disease (NLSD) and Multiple Acyl-CoA Dehydrogenase Deficiency (MADD). We provide a detailed summary of current clinical management strategies, highlighting issues of high-risk contraindicated treatments with case study examples not previously reviewed. Additionally, we outline current preclinical studies providing disease mechanistic insight. Lastly, we propose that a number of other conditions involving lipid metabolic dysfunction that are not classified as LSMs may share common features. These include Neurofibromatosis Type 1 (NF1) and autoimmune myopathies, including Polymyositis (PM), Dermatomyositis (DM), and Inclusion Body Myositis (IBM).
Asunto(s)
Errores Innatos del Metabolismo Lipídico/terapia , Metabolismo de los Lípidos , Enfermedades Musculares/terapia , Triglicéridos/metabolismo , Cardiomiopatías/diagnóstico , Cardiomiopatías/metabolismo , Cardiomiopatías/terapia , Carnitina/deficiencia , Carnitina/metabolismo , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/metabolismo , Hiperamonemia/terapia , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/metabolismo , Modelos Biológicos , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/metabolismoRESUMEN
BACKGROUND: The treatment of long-chain mitochondrial ß-oxidation disorders (LC-FOD) with a low fat-high carbohydrate diet, a diet rich in medium-even-chain triglycerides (MCT), or a combination of both has been associated with high morbidity and mortality for decades. The pathological tableau appears to be caused by energy deficiency resulting from reduced availability of citric acid cycle (CAC) intermediates required for optimal oxidation of acetyl-CoA. This hypothesis was investigated by diet therapy with carnitine and anaplerotic triheptanoin (TH). METHODS: Fifty-two documented LC-FOD patients were studied in this investigation (age range: birth to 51 years). Safety monitoring included serial quantitative measurements of routine blood chemistries, blood levels of carnitine and acylcarnitines, and urinary organic acids. RESULTS: The average frequency of serious clinical complications were reduced from ~60% with conventional diet therapy to 10% with TH and carnitine treatment and mortality decreased from ~65% with conventional diet therapy to 3.8%. Carnitine supplementation was uncomplicated. CONCLUSION: The energy deficiency in LC-FOD patients was corrected safely and more effectively with the triheptanoin diet and carnitine supplement than with conventional diet therapy. Safe intervention in neonates and infants will permit earlier intervention following pre-natal diagnosis or diagnosis by expanded newborn screening.
Asunto(s)
Carnitina/uso terapéutico , Ácidos Grasos/metabolismo , Errores Innatos del Metabolismo Lipídico/dietoterapia , Enfermedades Mitocondriales/dietoterapia , Triglicéridos/uso terapéutico , Administración Oral , Adolescente , Adulto , Carnitina/análogos & derivados , Carnitina/sangre , Niño , Preescolar , Ácido Cítrico/orina , Femenino , Humanos , Lactante , Recién Nacido , Ácido Láctico/orina , Errores Innatos del Metabolismo Lipídico/sangre , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/mortalidad , Malatos/orina , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/sangre , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/mortalidad , Oxidación-Reducción , Ácido Succínico/orina , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) is a rare mitochondrial fatty acid ß-oxidation disorder. We aimed to explore the clinical, biochemical, and genetic findings, treatments and outcomes in eight Chinese VLCADD patients. METHODS: Eight patients from six unrelated Chinese families with symptomatic VLCADD were diagnosed in the past 4 years. The clinical features and ACADVL gene mutations were analyzed. RESULTS: One patient underwent newborn screening and has been treated timely, she hardly had any symptoms. The remaining seven patients were found because of edema, diarrhea, coma, liver damage and psychomotor retardation. Seven patients had fatty liver. Five had myopathy. All patients had elevated blood tetradecanoylcarnitine. Nine heterozygous mutations of the ACADVL gene were found. Three (c.1102C > T, c.1795G > A and IVS10, +6T > A) were novel. Seven patients completely recovered after treatment. One patient died before diagnosis due to cardiomyopathy. His mother underwent amniocentesis for prenatal diagnosis. The fetus had the same gene mutation of the proband and markedly elevated tetradecanoylcarnitine in amniotic fluid. The boy has been treated after birth and he is healthy now. CONCLUSIONS: Dietary treatment usually leads to good outcomes to VLCADD patients. Amniocytes ACADVL mutations and amniotic fluid tetradecanoylcarnitine analysis are useful for the prenatal diagnosis.
Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Pueblo Asiatico/genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Tamizaje Neonatal , Diagnóstico Prenatal , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Acil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Acil-CoA Deshidrogenasas/genética , Acil-CoA Deshidrogenasas/metabolismo , Líquido Amniótico/química , Ácido Ascórbico/farmacología , Bezafibrato/farmacología , Carnitina/análogos & derivados , Carnitina/sangre , Carnitina/farmacología , Estudios de Casos y Controles , China , Cromatografía Liquida , Síndromes Congénitos de Insuficiencia de la Médula Ósea , ADN Complementario , Exones , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Lactante , Fórmulas Infantiles/química , Recién Nacido , Errores Innatos del Metabolismo Lipídico/dietoterapia , Masculino , Enfermedades Mitocondriales/dietoterapia , Enfermedades Musculares/dietoterapia , Mutación Missense , Alineación de Secuencia , Análisis de Secuencia de ADN , Espectrometría de Masas en Tándem , Resultado del Tratamiento , Triglicéridos/farmacología , Complejo Vitamínico B/farmacologíaRESUMEN
OBJECTIVES: Ethan B. Russo's paper of December 1, 2003 explored the concept of a clinical endocannabinoid deficiency (CECD) underlying the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome and other functional conditions alleviated by clinical cannabis. METHODS: Available literature was reviewed, including searches via the National Library of medicine database and other sources. RESULTS: A review of the literature indicates that significant progress has been made since Dr. Ethan B. Russo's landmark paper, just ten years ago (February 2, 2004). Investigation at that time suggested that cannabinoids can block spinal, peripheral and gastrointestional mechanisms that promote pain in headache, fibromyalgia, irritable bowel syndrome and muscle spasm. CONCLUSION: Subsequent research has confirmed that underlying endocannabinoid deficiencies indeed play a role in migraine, fibromyalgia, irritable bowel syndrome and a growing list of other medical conditions. Clinical experience is bearing this out. Further research and especially, clinical trials will further demonstrate the usefulness of medical cannabis. As legal barriers fall and scientific bias fades this will become more apparent.
Asunto(s)
Analgésicos/uso terapéutico , Cannabis , Resistencia a Medicamentos , Endocannabinoides/deficiencia , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Marihuana Medicinal/uso terapéutico , Animales , Resistencia a Medicamentos/efectos de los fármacos , Síndrome de Fatiga Crónica/tratamiento farmacológico , Síndrome de Fatiga Crónica/etiología , Fibromialgia/tratamiento farmacológico , Fibromialgia/etiología , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Síndrome del Colon Irritable/etiología , Errores Innatos del Metabolismo Lipídico/complicaciones , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/etiología , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/etiologíaRESUMEN
BACKGROUND: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited defect in the mitochondrial fatty acid oxidation pathway, resulting in significant morbidity and mortality in undiagnosed patients.Newborn screening (NBS) has considerably improved MCADD outcome, but the risk of complication remains in some patients. The aim of this study was to evaluate the relationship between genotype, biochemical parameters and clinical data at diagnosis and during follow-up, in order to optimize monitoring of these patients. METHODS: We carried out a multicenter study in southwest Europe, of MCADD patients detected by NBS. Evaluated NBS data included free carnitine (C0) and the acylcarnitines C8, C10, C10:1 together with C8/C2 and C8/C10 ratios, clinical presentation parameters and genotype, in 45 patients. Follow-up data included C0 levels, duration of carnitine supplementation and occurrence of metabolic crises. RESULTS: C8/C2 ratio and C8 were the most accurate biomarkers of MCADD in NBS. We found a high number of patients homozygous for the prevalent c.985A > G mutation (75%). Moreover, in these patients C8, C8/C10 and C8/C2 were higher than in patients with other genotypes, while median value of C0 was significantly lower (23 µmol/L vs 36 µmol/L).The average follow-up period was 43 months. To keep carnitine levels within the normal range, carnitine supplementation was required in 82% of patients, and for a longer period in patients homozygotes for the c.985A>G mutation than in patients with other genotypes (average 31 vs 18 months). Even with treatment, median C0 levels remained lower in homozygous patients than in those with other genotypes (14 µmol/L vs 22 µmol/L).Two patients died and another three suffered a metabolic crisis, all of whom were homozygous for the c.985 A>G mutation. CONCLUSIONS: Our data show a direct association between homozygosity for c.985A>G and lower carnitine values at diagnosis, and a higher dose of carnitine supplementation for maintenance within the normal range. This study contributes to a better understanding of the relationship between genotype and phenotype in newborn patients with MCADD detected through screening which could be useful in improving follow-up strategies and clinical outcome.
Asunto(s)
Acil-CoA Deshidrogenasa/deficiencia , Cardiomiopatías/epidemiología , Carnitina/sangre , Carnitina/deficiencia , Hiperamonemia/epidemiología , Errores Innatos del Metabolismo Lipídico/diagnóstico , Enfermedades Musculares/epidemiología , Tamizaje Neonatal/métodos , Cardiomiopatías/diagnóstico , Cardiomiopatías/tratamiento farmacológico , Carnitina/administración & dosificación , Carnitina/análogos & derivados , Suplementos Dietéticos , Femenino , Estudios de Asociación Genética , Genotipo , Homocigoto , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/tratamiento farmacológico , Incidencia , Recién Nacido , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Errores Innatos del Metabolismo Lipídico/epidemiología , Masculino , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/tratamiento farmacológico , Fenotipo , Prevalencia , España/epidemiología , Complejo Vitamínico B/administración & dosificación , Complejo Vitamínico B/sangreRESUMEN
Folate and vitamin B(12) metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.
Asunto(s)
Análisis Mutacional de ADN , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Inmunodeficiencia Combinada Grave/genética , 3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , 3-Hidroxiacil-CoA Deshidrogenasas/genética , Anemia Megaloblástica/diagnóstico , Anemia Megaloblástica/tratamiento farmacológico , Anemia Megaloblástica/genética , Examen de la Médula Ósea , Cardiomiopatías/diagnóstico , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/genética , Terapia Combinada , Combinación de Medicamentos , Quimioterapia Combinada , Exoma/genética , Femenino , Tamización de Portadores Genéticos , Humanos , Hidroxocobalamina/uso terapéutico , Inmunización Pasiva , Lactante , Recién Nacido , Leucopenia/diagnóstico , Leucopenia/tratamiento farmacológico , Leucopenia/genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Errores Innatos del Metabolismo Lipídico/genética , Antígenos de Histocompatibilidad Menor , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/tratamiento farmacológico , Infecciones Oportunistas/genética , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/genética , Neumonía por Pneumocystis/diagnóstico , Neumonía por Pneumocystis/tratamiento farmacológico , Neumonía por Pneumocystis/genética , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/tratamiento farmacológico , Retinitis Pigmentosa/genética , Rabdomiólisis , Análisis de Secuencia de ADN , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/tratamiento farmacológico , Sulfadoxina/uso terapéutico , Trimetoprim/uso terapéutico , Vitamina B 12/uso terapéuticoRESUMEN
INTRODUCTION: There is little robust empirical evidence on which to base treatment recommendations for fatty acid oxidation disorders. While consensus guidelines are important, understanding areas where there is a lack of consensus is also critical to inform priorities for future evaluative research. METHODS: We surveyed Canadian metabolic physicians on the treatment of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and mitochondrial trifunctional protein (MTP) deficiency. We ascertained physicians' opinions on the use of different interventions for the long-term management of patients as well as for the management of acute illness, focusing on identifying interventions characterized by high variability in opinions. We also investigated factors influencing treatment decisions. RESULTS: We received 18 responses (response rate 45%). Participants focused on avoidance of fasting and increased meal frequency as interventions for the management of MCAD deficiency. For the long-chain disorders, avoidance of fasting remained the most consistently endorsed intervention, with additional highly endorsed treatments differing for VLCAD versus LCHAD/MTP deficiency. L-carnitine supplementation and restriction of dietary fat were characterized by high variability in physicians' opinions, as were several interventions specific to long-chain disorders. Social factors and patient characteristics were important influences on treatment decisions. CONCLUSIONS: Based on our findings we suggest that high priority treatments for rigorous effectiveness studies could include L-carnitine supplementation (MCAD and LCHAD/MTP deficiencies), restriction of dietary fat, and, for the long-chain disorders, feeding practices for breastfed infants and the use of various supplements (essential fatty acids, carbohydrates, cornstarch, multivitamins).
Asunto(s)
Ácidos Grasos/metabolismo , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/terapia , Oxígeno/química , 3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , Acil-CoA Deshidrogenasa/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Canadá , Carnitina/uso terapéutico , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Grasas de la Dieta , Conocimientos, Actitudes y Práctica en Salud , Humanos , 3-Hidroxiacil-CoA Deshidrogenasa de Cadena Larga , Enfermedades Mitocondriales/terapia , Proteína Trifuncional Mitocondrial , Complejos Multienzimáticos/deficiencia , Enfermedades Musculares/terapia , Encuestas y CuestionariosRESUMEN
Treatment recommendations in mitochondrial fatty acid oxidation (FAO) defects are diverse. With implementation of newborn screening and identification of asymptomatic patients, it is necessary to define whom to treat and how strictly. We here discuss critical questions that are currently under debate. For some asymptomatic long-chain defects, long-chain fat restriction plays a minor role, and a normal diet may be introduced. For patients presenting only with myopathic symptoms, e.g., during exercise, treatment may be adapted to energy demand. As a consequence, patients with exercise-induced myopathy may be able to return to normal activity when provided with medium-chain triglycerides (MCT) prior to exercise. There is no need to limit participation in sports. Progression of retinopathy in disorders of the mitochondrial trifunctional protein complex is closely associated with hydroxyacylcarnitine accumulation. A strict low-fat diet with MCT supplementation is recommended to slow or prevent progression of chorioretinopathy. Additional docosahexanoic acid does not prevent the decline in retinal function but does promote nonspecific improvement in visual acuity and is recommended. There is no evidence that L-carnitine supplementation is beneficial. Thus, supplementation with L-carnitine in a newborn identified by screening with either a medium-chain or long-chain defect is not supported. With respect to the use of the odd-chain medium-chain triglyceride triheptanoin in myopathic phenotypes, randomized trials are needed to establish whether triheptanoin is more effective than even-chain MCT. With increasing pathophysiological knowledge, new treatment options have been identified and are being clinically evaluated. These include the use of bezafibrates in myopathic long-chain defects.
Asunto(s)
Metabolismo Energético , Ácidos Grasos/metabolismo , Errores Innatos del Metabolismo Lipídico/terapia , Mitocondrias/enzimología , Enfermedades Mitocondriales/terapia , Metabolismo Energético/genética , Medicina Basada en la Evidencia , Genotipo , Humanos , Errores Innatos del Metabolismo Lipídico/complicaciones , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/enzimología , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/enzimología , Enfermedades Mitocondriales/genética , Oxidación-Reducción , Fenotipo , Guías de Práctica Clínica como Asunto , Resultado del TratamientoRESUMEN
Evidence-based guidelines for monitoring patients with disorders in fatty acid oxidation (FAO) are lacking, and most protocols are based on expert statements. Here, we describe our protocol for Danish patients. Clinical monitoring is the most important measure and has the main aims of checking growth, development and diet and of bringing families to the clinic regularly to remind them of their child's risk and review how they cope and adjust, e.g. to an acute intercurrent illness. Most of these measures are simple and can be carried out during a routine out-patient visit; we seldom do more complicated assessments by a neuropsychologist, speech therapist, or physical and occupational therapists. Paraclinical measurements are not used for short-chain and medium-chain disorders; electrocardiography (including 24 h monitoring) and echocardiography are done for most patients with long-chain and carnitine transporter deficiencies. Eye examination is done in all, and liver ultrasonography in some patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase/tri-functional protein (LCHAD/TFP) deficiencies. Biochemical follow-up includes determination of free carnitine and acylcarnitines. Free carnitine is measured to monitor carnitine supplementation in patients with multiple acyl-coenzyme A dehydrogenase deficiency (MADD) and carnitine transporter deficiency (CTD) and to follow metabolic control and disclose deficiency states in other FAO disorders. We are evaluating long-chain acylcarnitines in patients with long-chain disorders; so far there does not seem to be any clear-cut benefit in following these levels. An erythrocyte fatty acid profile is done in patients with long-chain disorders to test for essential fatty acid and docosahexanoic acid (DHA) deficiencies. The measurement of creatine kinase is helpful in long-chain disorders. Ongoing follow-up and education of the patient is important throughout life to prevent disease morbidity or death from metabolic crises.
Asunto(s)
Metabolismo Energético , Ácidos Grasos/metabolismo , Errores Innatos del Metabolismo Lipídico/diagnóstico , Mitocondrias/enzimología , Enfermedades Mitocondriales/diagnóstico , Adolescente , Adulto , Biomarcadores/sangre , Niño , Preescolar , Continuidad de la Atención al Paciente , Metabolismo Energético/genética , Genotipo , Conocimientos, Actitudes y Práctica en Salud , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/enzimología , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/terapia , Enfermedades Mitocondriales/enzimología , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/terapia , Oxidación-Reducción , Educación del Paciente como Asunto , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Factores de Tiempo , Adulto JovenRESUMEN
Published data on treatment of fatty acid oxidation defects are scarce. Treatment recommendations have been developed on the basis of observations in 75 patients with long-chain fatty acid oxidation defects from 18 metabolic centres in Central Europe. Recommendations are based on expert practice and are suggested to be the basis for further multicentre prospective studies and the development of approved treatment guidelines. Considering that disease complications and prognosis differ between different disorders of long-chain fatty acid oxidation and also depend on the severity of the underlying enzyme deficiency, treatment recommendations have to be disease-specific and depend on individual disease severity. Disorders of the mitochondrial trifunctional protein are associated with the most severe clinical picture and require a strict fat-reduced and fat-modified (medium-chain triglyceride-supplemented) diet. Many patients still suffer acute life-threatening events or long-term neuropathic symptoms despite adequate treatment, and newborn screening has not significantly changed the prognosis for these severe phenotypes. Very long-chain acyl-CoA dehydrogenase deficiency recognized in neonatal screening, in contrast, frequently has a less severe disease course and dietary restrictions in many patients may be loosened. On the basis of the collected data, recommendations are given with regard to the fat and carbohydrate content of the diet, the maximal length of fasting periods and the use of l-carnitine in long-chain fatty acid oxidation defects.
Asunto(s)
Conferencias de Consenso como Asunto , Directrices para la Planificación en Salud , Errores Innatos del Metabolismo Lipídico/terapia , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Carnitina/uso terapéutico , Preescolar , Dieta con Restricción de Grasas , Suplementos Dietéticos , Ácidos Docosahexaenoicos/uso terapéutico , Ácidos Grasos/metabolismo , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/diagnóstico , Tamizaje Neonatal , Oxidación-ReducciónRESUMEN
At present, long-chain fatty acid oxidation (FAO) defects are diagnosed in a number of countries by newborn screening using tandem mass spectrometry. In the majority of cases, affected newborns are asymptomatic at time of diagnosis and acute clinical presentations can be avoided by early preventive measures. Because evidence-based studies on management of long-chain FAO defects are lacking, we carried out a retrospective analysis of 75 patients from 18 metabolic centres in Germany, Switzerland, Austria and the Netherlands with special regard to treatment and disease outcome. Dietary treatment is effective in many patients and can prevent acute metabolic derangements and prevent or reverse severe long-term complications such as cardiomyopathy. However, 38% of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency had intermittent muscle weakness and pain despite adhering to therapy. Seventy-six per cent of patients with disorders of the mitochondrial trifunctional protein (TFP)-complex including long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, had long-term myopathic symptoms. Of these, 21% had irreversible peripheral neuropathy and 43% had retinopathy. The main principle of treatment was a fat-reduced and fat-modified diet. Fat restriction differed among patients with different enzyme defects and was strictest in disorders of the TFP-complex. Patients with a medium-chain fat-based diet received supplementation of essential long-chain fatty acids. l-Carnitine was supplemented in about half of the patients, but in none of the patients with VLCAD deficiency identified by newborn screening. In summary, in this cohort the treatment regimen was adapted to the severity of the underlying enzyme defect and thus differed among the group of long-chain FAO defects.
Asunto(s)
Congresos como Asunto , Errores Innatos del Metabolismo Lipídico/terapia , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Adolescente , Adulto , Niño , Preescolar , Ácidos Grasos/metabolismo , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/diagnóstico , Persona de Mediana Edad , Tamizaje Neonatal , Oxidación-Reducción , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
A newborn female presented on the first day of life with clinical and biochemical findings consistent with multiple acyl-CoA dehydrogenase deficiency (MADD). Riboflavin supplementation corrected the biochemical abnormalities 24 h after commencing the vitamin. In vitro acylcarnitine profiling in intact fibroblasts both in normal and riboflavin depleted media showed normal oxidation of fatty acids excluding defects in electron transfer flavoprotein (ETF), or ETF ubiquinone oxidoreductase (ETF:QO), or a genetic abnormality in flavin metabolism. In addition, sequencing of the genes encoding ETF and ETF:QO in the proband did not reveal any pathogenic mutations. Determination of the maternal riboflavin status after delivery showed that the mother was riboflavin deficient. Repeat testing done two years after the infant's birth and while on a normal diet showed that the mother was persistently riboflavin deficient and showed a typical MADD profile on plasma acylcarnitine testing. A possible genetic defect in riboflavin transport of metabolism in the mother is postulated to be the cause of the transient MADD seen in the infant. Sequencing of the SLC16A12, RFK and FLAD1 genes encoding key enzymes in riboflavin transport of metabolism in the mother did not identify any pathogenic mutations. The underlying molecular basis of the mother's defect in riboflavin metabolism remains to be established.
Asunto(s)
Acil-CoA Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo Lipídico/diagnóstico , Deficiencia de Riboflavina/genética , Carnitina/análogos & derivados , Carnitina/sangre , Flavoproteínas Transportadoras de Electrones/genética , Femenino , Fibroblastos/citología , Fibroblastos/enzimología , Fibroblastos/patología , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/genética , Desnutrición , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Madres , Oxidación-Reducción , Deficiencia de Riboflavina/metabolismo , Deficiencia de Riboflavina/patología , Piel/enzimología , Piel/patología , Simportadores , Vitaminas/administración & dosificaciónRESUMEN
Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyses the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons. Deficiency of VLCAD activity has been associated with a range of phenotypes, including a severe lethal form presenting in the infantile period and a milder variant with onset in childhood. Varying rates of residual enzyme activity partly explain the heterogeneity in presentations. Here we report the course of disease in a pair of monozygotic twin sisters who were diagnosed in their late forties during an evaluation for rhabdomyolysis and fatigue. Interestingly, the patients' complaints were most severe during puberty and declined significantly after the menopause. The basis for this observation is uncertain, but may be related to hormonally-mediated changes in lipid metabolism that may occur at these times. As metabolic decompensation can be associated with significant morbidity, timely diagnosis of VLCAD deficiency is important. The introduction of appropriate dietary measures (i.e. avoidance of fasting, long-chain fat restriction and supplementation with medium-chain triglycerides) greatly reduces the likelihood of complications.