RESUMEN
BACKGROUND: Rare diseases (RDs) are often complex, serious, chronic and multi-systemic conditions, associated with physical, sensory and intellectual disability. Patients require follow-up management from multiple medical specialists and health and social care professionals involving a high level of integrated care, service coordination and specified care pathways. METHODS AND OBJECTIVES: This pilot study aimed to explore the best approach for developing national RD care pathways in the Irish healthcare system in the context of a lack of agreed methodology. Irish clinical specialists and patient/lived experience experts were asked to map existing practice against evidence-based clinical practice guidelines (CPGs) and best practice recommendations from the European Reference Networks (ERNs) to develop optimal care pathways. The study focused on the more prevalent, multisystemic rare conditions that require multidisciplinary care, services, supports and therapeutic interventions. RESULTS: 29 rare conditions were selected across 18 ERNs, for care pathway development. Multidisciplinary input from multiple specialisms was relevant for all pathways. A high level of engagement was experienced from clinical leads and patient organisations. CPGs were identified for 26 of the conditions. Nurse specialist, Psychology, Medical Social Work and Database Manager roles were deemed essential for all care pathways. Access to the therapeutic Health Service Professionals: Physiotherapy, Occupational Therapy, and Speech and Language Therapy were seen as key requirements for holistic care. Genetic counselling was highlighted as a core discipline in 27 pathways demonstrating the importance of access to Clinical Genetics services for many people with RDs. CONCLUSIONS: This study proposes a methodology for Irish RD care pathway development, in collaboration with patient/service user advocates. Common RD patient needs and health care professional interventions across all pathways were identified. Key RD stakeholders have endorsed this national care pathway initiative. Future research focused on the implementation of such care pathways is a priority.
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Vías Clínicas , Enfermedades Raras , Atención a la Salud , Humanos , Irlanda , Proyectos Piloto , Enfermedades Raras/terapiaRESUMEN
BACKGROUND: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. METHODS: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. RESULTS: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. CONCLUSION: This study describes the natural history of classic galactosemia based on the hitherto largest data set.
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Galactosemias/patología , UTP-Hexosa-1-Fosfato Uridililtransferasa/genética , Adolescente , Adulto , Estudios de Cohortes , Femenino , Galactosemias/genética , Homocigoto , Humanos , Recién Nacido , Masculino , Mutación/genética , Tamizaje Neonatal , Sistema de Registros , Estudios Retrospectivos , Adulto JovenRESUMEN
Adherence to dietary and treatment recommendations is a long-standing concern for adults and adolescents with PKU and treating clinicians. In about 20-30% of PKU patients, Phe levels may be controlled by tetrahydrobiopterin (BH4) therapy. The European PKU 2017 Guidelines recommends treatment with BH4 for cases of proven long-term BH4 responsiveness, with a recommended dosage of Sapropterin 10-20 mg/kg/day.We report four young Irish patients with mild PKU, known to be BH4 responsive, who were treated with lower doses of Sapropterin for over 7 years.Case 1: Female, currently age 20. Genotype p. 165T/p/F39L, c.[194T>C]; [117C>G]. Newborn Phe: 851 µmol/L. Pre-Sapropterin Phe tolerance: 600 mg Phe/day to maintain Phe levels <400 µmol/L. Commenced on Sapropterin 400 mg (6.5 mg/kg/day) with increase in Phe tolerance to 800 mg/day.Case 2: Female, currently age 23. Genotype p. 165T/pF39L; c.[194T>C]; [117C>G]. Newborn Phe: 714 µmol/L. Pre-Sapropterin Phe tolerance: 700 mg Phe/day. Commenced on Sapropterin 400 mg (8 mg/kg/day) with increase in Phe tolerance to 800 mg/day.Case 3: Male, currently age 22. Genotype p. 165T/p.S349P; c.[194T>C][1045T>C]. Newborn Phe: 1,036 µmol/L. Pre-Sapropterin Phe tolerance: 600 mg Phe/day. Commenced on Sapropterin 400 mg (5.4 mg/kg/day). Increased to 1,600 mg Phe/day.Case 4: Female, currently age 29. Genotype p.R408W/p/p.Y414C; c.[1222C>T], [1241A>G]. Newborn Phe: 1,600 µmol/L. Pre-Sapropterin tolerance: 450 mg/day. Commenced on Sapropterin 400 mg (5.0 mg/kg/day). Increased to 900 mg Phe/day.Almost 7 years of surveillance for these four patients has shown that this dose of Sapropterin (range 5-8 mg/kg day) was well tolerated and effective with a significant response to treatment and a marked improvement in quality of life at these lower Sapropterin doses.
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Investigación Biomédica , Bases de Datos Factuales , Galactosemias , Cooperación Internacional , Sistema de Registros , Investigación Biomédica/economía , Bases de Datos Factuales/economía , Medicina Basada en la Evidencia , Galactosemias/diagnóstico , Galactosemias/epidemiología , Galactosemias/terapia , Humanos , Guías de Práctica Clínica como Asunto , Apoyo a la Investigación como AsuntoRESUMEN
BACKGROUND: Investigation of patients, particularly children, with unexplained global developmental delay (GDD)/learning disability (LD) has been challenging due to a lack of clear guidance from specialised centres. Limited knowledge of rare diseases and a poor understanding of the purpose or limitations of appropriate investigations have been some of the principal reasons for this difficulty. AIMS: A guideline development group was formed to recommend on appropriate, first line metabolic, genetic and radiological investigations for children and adults with unexplained GDD/ID. METHODS AND RECOMMENDATIONS: A comprehensive literature search was conducted, evaluated and reviewed by the guideline committee and a best practice protocol for first line assessment and genetic, metabolic and radiological investigations was decided upon after considering diagnostic yield, practicality, treatability and costs. CONCLUSION: It is hoped that these recommendations will become national guidelines for the first line metabolic, genetic and radiological investigation of patients presenting with unexplained GDD/ID.
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Discapacidades del Desarrollo/diagnóstico , Discapacidades para el Aprendizaje/diagnóstico , Errores Innatos del Metabolismo/diagnóstico , Adulto , Niño , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/metabolismo , Humanos , Discapacidades para el Aprendizaje/genética , Discapacidades para el Aprendizaje/metabolismo , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Enfermedades RarasRESUMEN
Classical Galactosaemia is a rare disorder of carbohydrate metabolism caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT). The disease is life-threatening in the neonate, and the only treatment option is life-long dietary restriction of galactose. However, long-term complications persist in treated patients including cognitive impairments, speech and language abnormalities and premature ovarian insufficiency in females. Microarray analysis of T-lymphocytes from treated adult patients identified systemic dysregulation of numerous gene pathways, including the glycosylation, inflammatory and inositol pathways. Analysis of gene expression in patient-derived dermal fibroblasts of patients exposed to toxic levels of galactose, with immunostaining, has further identified the susceptibility of the glycosylation gene alpha-1,2-mannosyltransferase (ALG9) and the inflammatory gene annexin A1 (ANXA1) to increased galactose concentrations. These data suggest that Galactosaemia is a multi-system disorder affecting numerous signalling pathways.
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Galactosemias/genética , Transcriptoma , Adolescente , Adulto , Anexina A1/genética , Anexina A1/metabolismo , Estudios de Casos y Controles , Línea Celular , Femenino , Galactosemias/metabolismo , Redes Reguladoras de Genes , Humanos , Masculino , Manosiltransferasas/genética , Manosiltransferasas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Linfocitos T/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Hereditary metabolic diseases (HMDs) are almost all rare diseases, many of which, if ascertained are treatable and preventable causes of intellectual and general disability. The improved detection and treatment of HMDs in paediatric practice has resulted in increased survival into adult life. The identification of adult patients with HMDs who may benefit from new emerging treatments is challenging. As for many rare diseases, there are difficulties tracing patients for many of these conditions in current Irish coding systems and lack of established patient Registries. METHODS: In this study, we describe the efforts made to trace Irish adult patients with potentially treatable HMDs using (1) a mailed questionnaire sent to all currently registered adult Medical Specialists practising in Ireland requesting details of all cases seen over the 4-year period 2007-2010, (2) the analysis of HIPE in-patient data during this time and (3) analysis of the database held at NCIMD. CONCLUSIONS: The current systems in place for identification and coding of potentially treatable HMDs are very deficient. This emphasizes the need to prioritize the development of a National HMD Registry.
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Enfermedades Metabólicas/epidemiología , Enfermedades Metabólicas/genética , Enfermedades Raras/epidemiología , Enfermedades Raras/genética , Adulto , Predisposición Genética a la Enfermedad , Encuestas Epidemiológicas , Humanos , Irlanda/epidemiología , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/terapia , Fenotipo , Prevalencia , Pronóstico , Enfermedades Raras/diagnóstico , Sistema de Registros , Encuestas y CuestionariosRESUMEN
Newborn screening for the inborn error of metabolism, classical galactosaemia prevents life-threatening complications in the neonatal period. It does not however influence the development of long-term complications and the complex pathophysiology of this rare disease remains poorly understood. The objective of this study was to report the development of a healthcare database (using Distiller Version 2.1) to review the epidemiology of classical galactosaemia in Ireland since initiation of newborn screening in 1972 and the long-term clinical outcomes of all patients attending the National Centre for Inherited Metabolic Disorders (NCIMD). Since 1982, the average live birth incidence rate of classical galactosaemia in the total Irish population was approximately 1:16,476 births. This reflects a high incidence in the Irish 'Traveller' population, with an estimated birth incidence of 1:33,917 in the non-Traveller Irish population. Despite early initiation of treatment (dietary galactose restriction), the long-term outcomes of classical galactosaemia in the Irish patient population are poor; 30.6 % of patients ≥ 6 yrs have IQs <70, 49.6 % of patients ≥ 2.5 yrs have speech or language impairments and 91.2 % of females ≥ 13 yrs suffer from hypergonadotrophic hypogonadism (HH) possibly leading to decreased fertility. These findings are consistent with the international experience. This emphasizes the requirement for continued clinical research in this complex disorder.
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Galactosemias/complicaciones , Galactosemias/epidemiología , Adolescente , Adulto , Niño , Preescolar , Femenino , Galactosemias/diagnóstico , Galactosemias/tratamiento farmacológico , Humanos , Incidencia , Lactante , Recién Nacido , Irlanda/epidemiología , Masculino , Persona de Mediana Edad , Tamizaje Neonatal/métodos , Estudios Retrospectivos , Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
N-glycan processing and assembly defects have been demonstrated in untreated and partially treated patients with Classical Galactosaemia. These defects may contribute to the ongoing pathophysiology of this disease. The aim of this study was to develop an informative method of studying differential galactose tolerance levels and diet control in individuals with Galactosaemia, compared to the standard biochemical markers. Ten Galactosaemia adults with normal intellectual outcomes were analyzed in the study. Five subjects followed galactose liberalization, increments of 300 mg to 4000 mg/day over 16 weeks, and were compared to five adult Galactosaemia controls on a galactose restricted diet. All study subjects underwent clinical and biochemical monitoring of red blood cell galactose-1-phosphate (RBC Gal-1-P) and urinary galactitol levels. Serum N-glycans were isolated and analyzed by normal phase high-performance liquid chromatography (NP-HPLC) with galactosylation of IgG used as a specific biomarker of galactose tolerance. IgG N-glycan profiles showed consistent individual alterations in response to diet liberalization. The individual profiles were improved for all, but one study subject, at a galactose intake of 1000 mg/day, with decreases in agalactosylated (G0) and increases in digalactosylated (G2) N-glycans. We conclude that IgG N-glycan profiling is an improved method of monitoring variable galactosylation and determining individual galactose tolerance in Galactosaemia compared to the standard methods.
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Galactosa/administración & dosificación , Galactosa/metabolismo , Galactosemias/metabolismo , Inmunoglobulina G/metabolismo , Polisacáridos/metabolismo , Adulto , Biomarcadores Farmacológicos , Dieta , Tolerancia a Medicamentos , Femenino , Galactosemias/economía , Galactosemias/terapia , Glicosilación , Humanos , Inmunoglobulina G/inmunología , Masculino , Polisacáridos/inmunologíaRESUMEN
OBJECTIVES: Homoplasmic maternally inherited, m.14674T>C or m. 14674T>G mt-tRNA(Glu) mutations have recently been identified in reversible infantile cytochrome c oxidase deficiency (or 'benign COX deficiency'). This study sought other genetic defects that may give rise to similar presentations. PATIENTS: Eight patients from seven families with clinicopathological features of infantile reversible cytochrome c oxidase deficiency were investigated. METHODS: The study reviewed the diagnostic features and performed molecular genetic analyses of mitochondrial DNA and nuclear encoded candidate genes. RESULTS: Patients presented with subacute onset of profound hypotonia, feeding difficulties and lactic acidosis within the first months of life. Although recovery was remarkable, a mild myopathy persisted into adulthood. Histopathological findings in muscle included increased lipid and/or glycogen content, ragged-red and COX negative fibres. Biochemical studies suggested more generalised abnormalities than pure COX deficiency. Clinical improvement was reflected by normalisation of lactic acidosis and histopathological abnormalities. The m.14674T>C mt-tRNA(Glu) mutation was identified in four families, but none had the m. 14674T>G mutation. Furthermore, in two families pathogenic mutations were also found in the nuclear TRMU gene which has not previously been associated with this phenotype. In one family, the genetic aetiology still remains unknown. CONCLUSIONS: Benign COX deficiency is better described as 'reversible infantile respiratory chain deficiency'. It is genetically heterogeneous, and patients not carrying the m.14674T>C or T>G mt-tRNA(Glu) mutations may have mutations in the TRMU gene. Diagnosing this disorder at the molecular level is a significant advance for paediatric neurologists and intensive care paediatricians, enabling them to select children with an excellent prognosis for continuing respiratory support from those with severe mitochondrial presentation in infancy.
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Deficiencia de Citocromo-c Oxidasa/genética , Acidosis Láctica/genética , Acidosis Láctica/metabolismo , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Encéfalo/patología , Niño , Preescolar , Deficiencia de Citocromo-c Oxidasa/metabolismo , Deficiencia de Citocromo-c Oxidasa/patología , Complejo IV de Transporte de Electrones/genética , Cara/patología , Familia , Femenino , Heterogeneidad Genética , Histocitoquímica , Humanos , Lactante , Recién Nacido , Hígado/patología , Imagen por Resonancia Magnética , Masculino , Proteínas Mitocondriales/genética , Datos de Secuencia Molecular , Hipotonía Muscular , Músculo Esquelético/patología , Mutación/genética , Alineación de Secuencia , ARNt Metiltransferasas/genéticaRESUMEN
The aim was to determine the rate of varicella infection and complications in children with disorders of intermediary metabolism (IEM) between the ages of 1 and 16 years attending our national metabolic referral centre. Of 126 children identified, a response was received from 122. A history of previous varicella infection was identified in 64 cases (53%) and of varicella vaccination in 5 (4%). Fifty-three (43%) patients apparently did not have a history of clinical varicella infection. Of the 64 children with a history of varicella infection, five required hospitalisation for complications, including life-threatening lactic acidosis in one patient with mitochondrial disease and metabolic decompensation in four patients. In conclusion, varicella infection may cause an increased risk of metabolic decompensation in patients with IEMs. We propose that a trial of varicella vaccination be considered for this cohort of patients with monitoring of its safety and efficacy.
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Vacuna contra la Varicela/administración & dosificación , Varicela/epidemiología , Errores Innatos del Metabolismo/epidemiología , Adolescente , Varicela/complicaciones , Varicela/prevención & control , Niño , Preescolar , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Irlanda/epidemiología , Errores Innatos del Metabolismo/complicaciones , Vacunación/estadística & datos numéricosRESUMEN
Classical galactosaemia is relatively common in Ireland due to a high carrier rate of the Q188R GALT mutation. It is screened for using a bacterial inhibition assay (BIA) for free galactose. A Beutler assay on day one of life is performed only in high risk cases (infants of the Traveller community and relatives of known cases). A 16-month-old Irish-born boy of Nigerian origin was referred for investigation of developmental delay, and failure to thrive. He had oral aversion to solids and his diet consisted of cow's milk and milk-based cereal mixes. He was found to have microcephaly, weight <2nd percentile, hepatomegaly and bilateral cataracts. Coagulation screen was normal and transaminases were slightly elevated. His original newborn screen was reviewed and confirmed to have been negative; urinary reducing substances on three separate occasions were negative. Beutler assay demonstrated "absent" red cell galactose-1-phosphate uridyltransferase (GALT) activity. GALT enzyme activity was <0.5 gsubs/h per gHb confirming classical galactosaemia. Gal-1-P was elevated at 1.88 micromol/gHb. Mutation analysis of the GALT gene revealed S135L homozygosity. S135L/S135L galactosaemia is associated with absent red cell GALT activity but with approximately 10% activity in other tissues such as the liver and intestines, probably explaining the negative screening tests and the somewhat milder phenotype associated with this genotype. The patient was commenced on galactose-restricted diet; on follow-up at 2 years of age, growth had normalized but there was global developmental delay. In conclusion, galactosaemia must be considered in children who present with poor growth, hepatomegaly, developmental delay and cataracts and GALT enzyme analysis should be a first line test in such cases. Non-enzymatic screening methods such as urinary reducing substances and BIA for free galactose are not reliable in S135L homozygous galactosaemia.
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Galactosemias/diagnóstico , Galactosemias/genética , Tamizaje Neonatal , UDP-Glucosa-Hexosa-1-Fosfato Uridiltransferasa/genética , Sustitución de Aminoácidos/genética , Sustitución de Aminoácidos/fisiología , Reacciones Falso Negativas , Homocigoto , Humanos , Lactante , Recién Nacido , Leucina/genética , Masculino , Serina/genéticaRESUMEN
Mucopolysaccharidosis type 1 (MPS1) is an autosomal recessive disorder with severe, moderate and mild phenotypes: Hurler, Hurler-Scheie and Scheie syndromes. We estimated incidence (2001-2006) and prevalence (2002 census) of MPS1 in the Irish Republic (ROI) using population data, database and chart review of all live MPS1 patients attending two specialised centres. Patient genotypes, ethnicity, province of origin, age at diagnosis and presenting features were recorded. Thirty-one patients (14 females, 17 males) were alive, 27 of whom were <15 years. Twenty-six patients had Hurler syndrome, four had Hurler-Scheie and one had Scheie syndrome. The birth incidence was 1 in 26 206 births with a carrier frequency of 1 in 81. Of note, 19/26 (73%) Hurler patients were Irish Travellers. Amongst Irish Travellers the incidence was 1 in 371 with a carrier frequency of 1 in 10. This is the highest recorded incidence worldwide. Given the morbidity and mortality associated with delayed treatment we recommend targeted newborn screening for this population.
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Trasplante de Células Madre Hematopoyéticas/métodos , Iduronidasa/uso terapéutico , Mucopolisacaridosis I/epidemiología , Sistema de Registros/estadística & datos numéricos , Migrantes , Edad de Inicio , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Irlanda/epidemiología , Masculino , Mucopolisacaridosis I/enzimología , Mucopolisacaridosis I/terapia , Tamizaje Neonatal , Fenotipo , Prevalencia , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Maple syrup urine disease (MSUD; OMIM 248600) results from an inherited deficiency of the branched-chain ketoacid dehydrogenase (BCKD) complex. Approximately 20% of patients with BCKD deficiency are non-classic variants of MSUD with differing clinical severity. Outcomes for this cohort are generally favourable; episodes of metabolic decompensation do not appear to correlate with adverse events if acute management is promptly provided. A case of predominantly axonal sensory-motor neuropathy following metabolic decompensation which persisted for a number of months is presented in an adolescent girl with variant (intermediate type) MSUD. EMG and nerve conduction studies suggested a pre-existent asymptomatic chronic neuropathy, exacerbated by the acute decompensation. Peak leucine concentration at decompensation was 1083 µmol/L. The patient had laboratory signs of secondary mitochondrial respiratory chain dysfunction at presentation. She had been on a moderate dose of thiamine prior to decompensation; thiamine and pyridoxine blood concentrations were normal. This, to our knowledge, is the first report of a neuropathy presenting in a patient with a decompensation of variant MSUD. We propose that this presentation resembles the intermittent neuropathy observed in pyruvate dehydrogenase deficiency and may reflect secondary inhibition of pyruvate dehydrogenase activity by MSUD metabolites.
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Enfermedad de la Orina de Jarabe de Arce/complicaciones , Conducción Nerviosa , Nervios Periféricos/fisiopatología , Polineuropatías/etiología , Desempeño Psicomotor , Adolescente , Biomarcadores/sangre , Biomarcadores/orina , Electromiografía , Femenino , Humanos , Leucina/sangre , Enfermedad de la Orina de Jarabe de Arce/sangre , Enfermedad de la Orina de Jarabe de Arce/diagnóstico , Enfermedad de la Orina de Jarabe de Arce/tratamiento farmacológico , Enfermedad de la Orina de Jarabe de Arce/fisiopatología , Enfermedades Mitocondriales/etiología , Enfermedades Mitocondriales/fisiopatología , Examen Neurológico , Polineuropatías/sangre , Polineuropatías/diagnóstico , Polineuropatías/fisiopatología , Recurrencia , Factores de TiempoRESUMEN
BACKGROUND: Mitochondrial DNA (mtDNA) mutations are important causes of human genetic disease, with mutations in tRNA genes particularly prevalent. In many patients, mutations are heteroplasmic, affecting a population of mtDNA molecules. Establishing the pathogenicity of homoplasmic mitochondrial tRNA (mt-tRNA) mutations, in which the mutation is present in every mtDNA molecule, is extremely difficult. These mutations must conform to specific pathogenic criteria, documenting unequivocally a functional defect of the mutant mt-tRNA. AIMS: To investigate the pathogenic nature of two homoplasmic mt-tRNA(Thr) deletions, m.15940delT (previously reported as pathogenic) and m.15937delA, by assessing the steady state levels of the mutant mt-tRNA in tissue and cell-line samples from six unrelated families, in which affected individuals were thoroughly investigated for mitochondrial DNA disease on the basis of clinical presentations. Rates of de novo mitochondrial protein synthesis were also examined in control and m.15937delA mutant fibroblasts. RESULTS: Our data strongly suggest that both single nucleotide deletions are neutral polymorphisms; no obvious defects were apparent in either steady state mt-tRNA(Thr) levels or rates of mitochondrial protein synthesis. CONCLUSIONS: These findings have important implications for the investigation of other families with suspected mtDNA disease, in particular the requirement to fulfil strict and established pathogenic criteria in order to avoid misattribution of pathogenicity to mt-tRNA variants.
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ADN Mitocondrial/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Mutación , ARN de Transferencia de Treonina/genética , ARN/genética , Adulto , Biopsia , Células Cultivadas , Niño , Análisis Mutacional de ADN , Femenino , Fibroblastos , Humanos , Lactante , Masculino , Mitocondrias Cardíacas/genética , Mitocondrias Musculares/genética , Enfermedades Mitocondriales/fisiopatología , Músculo Esquelético , Polimorfismo Genético , ARN Mitocondrial , Piel/citologíaRESUMEN
BACKGROUND: Mitochondrial beta oxidation plays a major role in energy production. Long chain fatty acid oxidation defects include deficiency of the trifunctional protein (rare) or more commonly defects of the long chain 3-hydroxy acyl-CoA dehydrogenase enzyme (LCHAD). These long chain defects have variable presentations, they may present in the neonate or infant with sudden death, hepatopathy (Reyes disease), hypoketotic hypoglycaemia, rhabdomyolysis, myopathy, cardiomyopathy and with late complications such as peripheral neuropathy, pigmentary retinopathy, retinal degeneration and progressive visual loss. The correct diagnosis at presentation is not only life saving but also allows for the appropriate dietary and other intervention, which may have major effects on outcome. AIM: Three case reports of patients with long chain fatty acid oxidation defects who have shown significant benefits from treatment are reported. CONCLUSIONS: These paediatric presentations illustrate the clinical heterogeneity of long chain fatty acid oxidation defects and opportunities for effective management if correctly diagnosed.
Asunto(s)
Ácidos Grasos/metabolismo , Errores Innatos del Metabolismo/diagnóstico , Femenino , Humanos , Lactante , Masculino , Errores Innatos del Metabolismo/terapia , Proteína Trifuncional Mitocondrial , Complejos Multienzimáticos/metabolismoRESUMEN
Mitochondrial respiratory chain disorders account for significant and varied presentations in paediatric practice. The true prevalence of these disorders in the paediatric population is still not well documented with predicted geographic variation. We report a retrospective analysis over a seven year period of cases presenting to a tertiary care centre and associated clinical features. The overall prevalence of mitochondrial disorders in our population is higher than expected (1/9,000 births), explained in part by multiple presentations in a consanguineous subgroup of the population (Irish travellers).
Asunto(s)
Enfermedades Mitocondriales/epidemiología , Humanos , Incidencia , Irlanda/epidemiología , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , FenotipoRESUMEN
Ornithine transcarbamylase deficiency (OTCD) resulting from deficiency of the mitochondrial enzyme OTC shows extensive phenotypic heterogeneity influenced by allelic heterogeneity and modifying environmental influences such as protein intake. We report the fatal late-onset presentation of OTCD in a 62-year-old man with the V337L mutation, a previous presentation in his grandson and negative clinical and biochemical screening of the proband's three daughters.
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Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/diagnóstico , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/genética , Salud de la Familia , Resultado Fatal , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Linaje , Mutación PuntualRESUMEN
In 1988 we reported two sisters with bilateral Coats' disease, sparse hair, dystrophic nails, and primeval splashes of intracranial calcification. We now provide an update on this family documenting the occurrence of skeletal defects comprising abnormal bone marrow, osteopenia, and sclerosis with a tendency to fractures, a mixed cerebellar and extrapyramidal movement disorder, infrequent epileptic seizures, leukodystrophic changes, and postnatal growth failure. Additionally, we present two previously unreported individuals from Ireland and Switzerland with the identical disorder which we designate Coats' plus. Since our original publication a number of other authors have described, frequently as a "new" syndrome, cases with a variable combination of the same features observed in our patients. We review this literature and suggest that the phenotypic overlap with dyskeratosis congenita may provide a clue to the molecular aetiology of this multisystem disorder.