Effects of mesenchymal stem cell culture on radio sterilized human amnion or radio sterilized pig skin in burn wound healing.

Deep second and third degree burns treatment requires fibroblasts, keratinocytes and other skin cells in order to grow new dermis and epidermis. Cells can proliferate, secrete growth factors and extracellular matrix required to repair the damaged tissue. Radiosterilized human amnion and radiosterilized pig skin have been used as natural origin skin dressings for burned patients. Adipose-derived mesenchymal stem cells can differentiate into fibroblasts and keratinocytes and improve wound-healing progress. These cells can stimulate vascular tissue formation, release growth factors, synthetize new extracellular matrix and immunoregulate other cells. In this study, we developed mesenchymal stem cells-cellularized skin substitutes based from radiosterilized human amnion or pig skin. Third-degree burns were induced in mice animal models to evaluate the effect of cellularized skin substitutes on burn wound healing. Mesenchymal phenotype was immunophenotypically confirmed by flow cytometry and cell viability was close to 100%. Skin recovery was evaluated in burned mice after seven and fourteen days post-coverage with cellularized and non-cellularized sustitutes. Histological techniques and immunofluorescence were used to evaluate re-epithelization and type I collagen deposition. We determined that cellularized-human amnion or cellularized-pig skin in combination with mesenchymal stem cells improve extracellular matrix deposition. Both cellularized constructs increase detection of type I collagen in newly formed mouse skin and can be potentially used as skin coverage for further clinical treatment of burned patients.

Silver-pig skin nanocomposites and mesenchymal stem cells: suitable antibiofilm cellular dressings for wound healing.

BACKGROUND: Treatment of severe or chronic skin wounds is an important challenge facing medicine and a significant health care burden. Proper wound healing is often affected by bacterial infection; where biofilm formation is one of the main risks and particularly problematic because it confers protection to microorganisms against antibiotics. One avenue to prevent bacterial colonization of wounds is the use of silver nanoparticles (AgNPs); which have proved to be effective against non-multidrug-resistant and multidrug-resistant bacteria. In addition, the use of mesenchymal stem cells (MSC) is an excellent option to improve wound healing due to their capability for differentiation and release of relevant growth factors. Finally, radiosterilized pig skin (RPS) is a biomatrix successfully used as wound dressing to avoid massive water loss, which represents an excellent carrier to deliver MSC into wound beds. Together, AgNPs, RPS and MSC represent a potential dressing to control massive water loss, prevent bacterial infection and enhance skin regeneration; three essential processes for appropriate wound healing with minimum scaring. RESULTS: We synthesized stable 10 nm-diameter spherical AgNPs that showed 21- and 16-fold increase in bacteria growth inhibition (in comparison to antibiotics) against clinical strains Staphylococcus aureus and Stenotrophomonas maltophilia, respectively. RPS samples were impregnated with different AgNPs suspensions to develop RPS-AgNPs nanocomposites with different AgNPs concentrations. Nanocomposites showed inhibition zones, in Kirby-Bauer assay, against both clinical bacteria tested. Nanocomposites also displayed antibiofilm properties against S. aureus and S. maltophilia from RPS samples impregnated with 250 and 1000 ppm AgNPs suspensions, respectively. MSC were isolated from adipose tissue and seeded on nanocomposites; cells survived on nanocomposites impregnated with up to 250 ppm AgNPs suspensions, showing 35% reduction in cell viability, in comparison to cells on RPS. Cells on nanocomposites proliferated with culture days, although the number of MSC on nanocomposites at 24 h of culture was lower than that on RPS. CONCLUSIONS: AgNPs with better bactericide activity than antibiotics were synthesized. RPS-AgNPs nanocomposites impregnated with 125 and 250 ppm AgNPs suspensions decreased bacterial growth, decreased biofilm formation and were permissive for survival and proliferation of MSC; constituting promising multi-functional dressings for successful treatment of skin wounds.

Actividad de la Unidad de Enfermedades Metabólicas del Hospital Universitario Ramón y Cajal / Activity of the metabolic diseases unit of the Hospital Universitario Ramón y Cajal

Los errores innatos del metabolismo comprenden un amplio grupo de patologías, habitualmente con una alta morbimortalidad. Son poco conocidas por parte de la comunidad médica debido a su baja prevalencia, y las dificultades en su diagnóstico y tratamiento hacen que sea imprescindible su manejo en Unidades especializadas. La Unidad de Enfermedades Metabólicas del Hospital Ramón y Cajal fue pionera en el estudio de estos pacientes, y es hoy un referente ¡mundial en la asistencia e investigación en este campo (AU)

Inborn errors of metabolism are an extensive group of diseases that usually have high morbility and mortality. They are little known within the medical community due to their low prevalence, which coupled with the difficulties in their diagnosis and treatment make it indispensable for them to be handled in specialized units. The Metabolic Department of the Ramón y Cajal was a pioneer in the study of these patients and is nowadavs a worldwide recognized center in the treatment and investigation in this field (AU)

Importancia del diagnóstico precoz de fenilcetonuria en la mujer y del control de los niveles de fenilalanina en la gestación / Importance of early diagnosis of phenylketonuria in women and control of phenylalanine levels during pregnancy

La Fenilalanina Hidroxilasa (PAH) hidroxila a nivel hepático la fenilalanina proveniente de la dieta. Los fetos dependen para la hidroxilación de fenilalanina de la función materna, ya que por inmadurez fetal esta función no se adquiere hasta la semana 26. Los pacientes con deficiencia de PAH (Fenilcetonuria, PKU) no hidroxilan adecuadamente la fenilalanina de la dieta por lo que sus niveles en sangre estan elevados. Los niveles de fenilalaninemia se consideran teratogénicos y neurotóxicos por encima de 360 umol/L (N < 120). Las mujeres PKU embarazadas deberán seguir estrictamente un tratamiento dietético y/o farmacológico para mantener niveles de fenilalaninemia < 180 umol/L y evitar las posibles complicaciones teratogénicas en el feto (Sindrome Fetal de Hiperfenilalaninemia Materna), como el caso que presentamos. Recomendamos descartar Fenilcetonuria en mujeres en quienes no se haya realizado un despistaje neonatal y/o tengan abortos, hijos con microcefalia, cardiopatía o malformaciones renales (AU)

The phenylalanine hydroxylase (PAH) in the liver hydroxylates phenylalanine from the diet. Fetuses depend for the hydroxylation of phenylalanine the maternal metabolism , fetal maturity does not come until week 26. Though the women with PAH deficiency (phenylketonuria, PKU) not adequately hydroxylate phenylalanine diet so their blood levels are high. Fenilalaninemia levels are considered neurotoxic teratogenic and above 360 umol/L (N < 120). Pregnant women should strictly follow PKU dietary treatment and/or drug to maintain levels of fenilalaninemia < 180 umol/L and avoid the teratogenic complications in the fetus (Hyperphenylalaninaemias Maternal Fetal Syndrome), as the case presented. We recommend discarding Phenylketonuria in women who have not been done a neonatal screening and/or have abortions, children with microcephaly, cardiac or renal malformations (AU)

Estudio epidemiológico de las enfermedades metabólicas con homocistinuria en España / Epidemiological study of the metabolic diseases with homocystinuria in Spain

Objetivos: Conocer la prevalencia en España de los diferentes errores congénitos del metabolismo que presentan homocistinuria y establecer las medidas oportunas para garantizar su prevención, diagnóstico y tratamiento, en aquellos casos posibles. Material y métodos: En abril 2009 se realizó una encuesta nacional de carácter transversal mediante cuestionario enviado a 35 centros, en los que se atiende a pacientes infantiles y adultos. La finalidad de la encuesta era establecer la prevalencia en ese momento recogiendo el histórico de pacientes que cada centro tuviera documentados. Resultados: A través de los cuestionarios respondidos por 25 médicos de 16 centros, se han identificado 75 pacientes: 41 defectos de transulfuración (uno fallecido), 27 de remetilación (6 fallecidos) y 7 sin diagnóstico etiológico definitivo. La edad de diagnóstico muestra una amplia variación, en 18 casos había más de un hermano afectado. Las manifestaciones clínicas más graves inciden en el grupo de los pacientes afectados de trastornos de la remetilación. Destaca el alto porcentaje de déficit cognitivo, seguido de la patología de cristalino; casi la mitad de los pacientes presentan trastornos neurológicos, es elevada la afectación vascular en los adultos con deficiencia de CBS; las opciones terapéuticas más utilizadas han sido el ácido fólico, la hidroxicobalamina y la betaína. Conclusiones: A la vista de estos resultados, y en especial del escaso número de deficiencias de CBS detectadas, se concluye la necesidad de implantar el cribado neonatal para la homocistinuria clásica y asegurar la puesta en marcha del proceso diagnóstico oportuno en todos los pacientes de riesgo(AU)

Objectives: To determine the prevalence of homocystinuria in Spain and to establish the measures and mechanisms to ensure its prevention, diagnosis and treatment. Material and methods: A national cross-sectional survey was conducted by means of a questionnaire sent to 35 hospitals in which children and adult patients are treated. Results: Using the questionnaires submitted by 25 physicians from 16 centres, 75 patients were identified: 41 transsulphuration defects (one deceased), 27 remethylation (six deaths) and 7 without a syndromic diagnosis. The age at diagnosis varied widely, and 18 cases had more than one sibling affected. The more severe clinical manifestations involved the patients with remethylation defects. There was a high percentage of cognitive impairment, followed by lens diseases. Almost half of the patients had neurological disorders. There was increased vascular involvement in CBS-deficient adults. The therapeutic options most used were, folic acid, hydroxycobalamin and betaine. Conclusions: In view of these results and especially the small number of CBS deficiencies detected, we conclude that there is a need to introduce newborn screening for classical homocystinuria and ensure implementation of an appropriate diagnostic workup in all patients at risk(AU)

[Epidemiological study of the metabolic diseases with homocystinuria in Spain]. / Estudio epidemiológico de las enfermedades metabólicas con homocistinuria en España.

OBJECTIVES: To determine the prevalence of homocystinuria in Spain and to establish the measures and mechanisms to ensure its prevention, diagnosis and treatment. MATERIAL AND METHODS: A national cross-sectional survey was conducted by means of a questionnaire sent to 35 hospitals in which children and adult patients are treated. RESULTS: Using the questionnaires submitted by 25 physicians from 16 centres, 75 patients were identified: 41 transsulphuration defects (one deceased), 27 remethylation (six deaths) and 7 without a syndromic diagnosis. The age at diagnosis varied widely, and 18 cases had more than one sibling affected. The more severe clinical manifestations involved the patients with remethylation defects. There was a high percentage of cognitive impairment, followed by lens diseases. Almost half of the patients had neurological disorders. There was increased vascular involvement in CBS-deficient adults. The therapeutic options most used were, folic acid, hydroxycobalamin and betaine. CONCLUSIONS: In view of these results and especially the small number of CBS deficiencies detected, we conclude that there is a need to introduce newborn screening for classical homocystinuria and ensure implementation of an appropriate diagnostic workup in all patients at risk.

[Importance of early diagnosis of phenylketonuria in women and control of phenylalanine levels during pregnancy]. / Importancia del diagnóstico precoz de fenilcetonuria en la mujer y del control de los niveles de fenilalanina en la gestación.

The phenylalanine hydroxylase (PAH) in the liver hydroxylates phenylalanine from the diet. Fetuses depend for the hydroxylation of phenylalanine the maternal metabolism , fetal maturity does not come until week 26. Though the women with PAH deficiency (phenylketonuria, PKU) not adequately hydroxylate phenylalanine diet so their blood levels are high. Fenilalaninemia levels are considered neurotoxic teratogenic and above 360 umol/L (N < 120). Pregnant women should strictly follow PKU dietary treatment and/or drug to maintain levels of fenilalaninemia < 180 umol/L and avoid the teratogenic complications in the fetus (Hyperphenylalaninaemias Maternal Fetal Syndrome), as the case presented. We recommend discarding Phenylketonuria in women who have not been done a neonatal screening and/or have abortions, children with microcephaly, cardiac or renal malformations.

[A guide to the clinical diagnosis and urgent treatment of neonatal hyperammonaemia]. / Guía clínica de diagnóstico y tratamiento urgente de hiperamonemia neonatal.

Symptomatic hyperammonaemia in newborn is a medical emergency that should be recognised in its early stages, specifically diagnosed and aggressively treated to improve the immediate and long-term prognosis of these children. The paediatrician and the neonatal doctor should have a diagnosis-therapy scheme for its urgent management.

Guía clínica de diagnóstico y tratamiento urgente de hiperamonemia neonatal / A guide to the clinical diagnosis and urgent treatment of neonatal hyperammonaemia

La hiperamonemia sintomática en el recién nacido es una urgencia médica que debe reconocerse de manera precoz, diagnosticarse de manera específica y tratarse de forma intensiva para mejorar el pronóstico inmediato y a largo plazo de estos niños. Para esto, es necesario que el pediatra en general y el neonatólogo en particular tengan presente una secuencia diagnostico terapéutica de actitud inmediata que contribuya a una adecuada actuación (AU)

Symptomatic hyperammonaemia in newborn is a medical emergency that should be recognised in its early stages, specifically diagnosed and aggressively treated to improve the immediate and long-term prognosis of these children. The paediatrician and the neonatal doctor should have a diagnosis-therapy scheme for its urgent management (AU)

Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group.

Methylmalonic acidaemia (MMA) is a genetic disorder caused by defects in methylmalonyl-CoA mutase or in any of the different proteins involved in the synthesis of adenosylcobalamin. The aim of this work was to examine the biochemical and clinical phenotype of 32 MMA patients according to their genotype, and to study the mutant mRNA stability by real-time PCR analysis. Using cellular and biochemical methods, we classified our patient cohort as having the MMA forms mut (n = 19), cblA (n = 9) and cblB (n = 4). All the mut (0) and some of the cblB patients had the most severe clinical and biochemical manifestations, displaying non-inducible propionate incorporation in the presence of hydroxocobalamin (OHCbl) in vitro and high plasma odd-numbered long-chain fatty acid (OLCFA) concentrations under dietary therapy. In contrast, mut (-) and cblA patients exhibited a milder phenotype with propionate incorporation enhanced by OHCbl and normal OLCFA levels under dietary therapy. No missense mutations identified in the MUT gene, including mut (0) and mut (-) changes, affected mRNA stability. A new sequence variation (c.562G>C) in the MMAA gene was identified. Most of the cblA patients carried premature termination codons (PTC) in both alleles. Interestingly, the transcripts containing the PTC mutations were insensitive to nonsense-mediated decay (NMD).

Prevención de riesgos y responsabilidad profesional en Anestesiología / Prevention of risks and professional liability in anesthesiology

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Persistent increase of plasma butyryl/isobutyrylcarnitine concentrations as marker of SCAD defect and ethylmalonic encephalopathy.

High concentrations of butyryl/isobutyrylcarnitine (C(4)-carnitine) in plasma with increase of ethylmalonic acid (EMA) in urine point to different genetic entities, and further investigations are required to differentiate the possible underlying defect. Here we report three unrelated cases, two neurologically affected and one asymptomatic, with this abnormal metabolite pattern due either to mutations in the ETHE1 gene or to a short-chain acyl-CoA dehydrogenase (SCAD) defect.

Dificultad diagnóstica del insulinoma en una paciente con epilepsia mioclónica juvenil / Diagnostic difficulty of insulinoma in a female patient with juvenile myoclonic epilepsyil

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[Macrocephaly the first manifestation of glutaric aciduria type I: the importance of early diagnosis]. / Macrocefalia como forma de presentación de la aciduria glutárica tipo 1. Importancia de un diagnóstico precoz.

INTRODUCTION: The clinical manifestations of glutaric aciduria type I (GA-I) usually develop during the first two years of life as acute encephalopathic crisis leading to irreversible dystonic. Progressive macrocephaly can be an early clinical sign. We report a 9 month old patient with macrocephaly diagnosed of GA-I in the presyntomatic stage. This early diagnosis and treatment avoided the irreversible neurologic damage associated to this disease. CASE REPORT: A 9 month old male referred to the pediatrics neurology clinic because of macrocephaly with a head circumference of 51 cm (> 97th percentle). At birth this head circumference was 37.5 cm (97th percentile) and showed rapid growth during the first 4 months of life. In the physical exam there was mild hypotonia and no other neurologic alterations with normal psychomotor development. In the work up for macrocephaly urinary organic acids were determined showing a glutaric acid: 78,000 mmol/mol creatinine (normal values: 2-10); 3-hydroxyglutaric acid: 250 mmol/mol creatinine (normal values: 1-12). Cerebral magnetic resonance (MR) performed at 12 months of age showed frontotemporal atrophy with enlargement of subarachnoid spaces, a high signal in T2 in the pallidus nucleus and subdural hematomas. Genetic analysis showed a mutation S 305 L/Q 352 X in GCDH gene. L-carnitine and riboflavin supplementation and a diet with restriction of lysine and tryptophan was started. Intercurrent illnesses were treated with intravenous fluid, glucose and L-carnitine. At 3 years and 6 month of age, he had not shown any encephalopathic crisis, he had a normal psychomotor development and no dystonia. MR shows mild temporal lobe atrophy without basal ganglia alterations. CONCLUSIONS: In GA-I, macrocephaly is an early sign before other neurologic alterations. In patients with little or no neurological symptoms, early treatment may prevent the acute encephalopathic crisis and neurological deterioration, improving the prognosis and may also normalize the basal ganglia neuroradiological alterations. Urinary organic acid analysis should be performed in the work up of macrocephaly of unknown aetiology.

Macrocefalia como forma de presentación de la aciduria glutárica tipo 1. Importancia de un diagnóstico precoz / Macrocephaly in the first manifestation of glutaric aciduria type I: the importance of early diagnosis

Introducción. La aciduria glutárica tipo I (AG-I) habitualmente se presenta con un deterioro neurológico agudo en los primeros 2 años de vida con secuelas irreversibles. La macrocefalia progresiva puede ser una manifestación precoz de la enfermedad. Presentamos un caso diagnosticado en la fase presintomática, por estudio de macrocefalia, en el cual el tratamiento instaurado precozmente evitó las crisis encefalopáticas y el deterioro neurológico. Caso clínico. Varón de 9 meses de edad remitido por macrocefalia de 51 cm (> p97). El perímetro cefálico al nacimiento era de 37,5 cm (p97) y presentó un incremento acelerado durante los primeros 4 meses de vida. En la exploración física presentaba una discreta hipotonía axial sin otros hallazgos y desarrollo psicomotor normal. Exploraciones complementarias: ácidos orgánicos (o): glutárico: 78.000 mmolfmol creatinina (normal: 2-10); 3-hidroxiglutárico: 250 mmolfmol creatinina (normal: 1-12). Resonancia magnética (RM) cerebral a los 12 meses: atrofia frontotemporal con aumento del espacio subaracnoideo de predominio bitemporal, hiperintensidad en T2 en núcleos pálidos y hematomas subdurales bilaterales. Estudio genético: mutación S 305 L/Q 352 X. Se inició tratamiento con carnitina y riboflavina y dieta restringida en lisina y triptófano. Los procesos intercurrentes infecciosos o de intolerancia oral fueron tratados con aportes intravenosos de líquidos, glucosa y carnitina. Con 3 años y 6 meses no ha presentado crisis encefalopáticas y el desarrollo es normal sin distonías. La RM muestra atrofia de predominio temporal, sin alteraciones de núcleos de la base. Conclusiones. En la AG-I la macrocefalia con frecuencia precede al resto de las manifestaciones neurológicas. El tratamiento en la fase presintomática puede prevenir las crisis encefalopáticas, mejorar el pronóstico e incluso mantener al paciente asintomático. También las alteraciones neurorradiológicas de los núcleos de la base pueden desaparecer con el tratamiento precoz. Ante una macrocefalia de diagnóstico incierto debe realizarse un estudio de ácidos orgánicos en orina

Introduction. The clinical manifestations of glutaric aciduria type 1 (GA-I) usually develop during the first two years of life as acute encephalopathic crisis leading to irreversible dystonic. Progressive macrocephaly can be an early clinical signo We report a 9 month old patient with macrocephaly diagnosed of GA-I in the presyntomatic stage. This early diagnosis and treatment avoided the irreversible neurologic damage associated to this disease. Case report. A 9 month old male referred to the pediatrics neurology clinic because of macrocephaly with a head circumference of 51 cm (> 97th percentle). At birth this head circumference was 37.5 cm (97th percentile) and showed rapid growth during the first 4 months of life. In the physical exam there was ínild hypotonia and no other neurologic alterations with normal psychomotor development. In the work up for macrocephaly urinary organic acids were determined showing a glutaric acid: 78,000 mmolfmol creatinine (normal values: 2-10); 3-hydroxyglutaric acid: 250 mmolfmol creatinine (normal values: 1-12). Cerebral magnetic resonance (MR) performed at 12 months of age showed frontotemporal atrophy with enlargement of subarachnoid spaces, a high signal in T2 in the pallidus nucleus and subdural hematomas. Genetic analysis showed a mutation S 305 LfQ 352 X in GCDH gene. L-camitine and riboflavin supplementation and a diet with restriction of lysine and tryptophan was started. Intercurrent illnesses were treated with intravenous fluid, glucose and L-camitine. At 3 years and 6 month of age, he had not shown any encephalopathic crisis, he had a normal psychomotor development and no dystonia. MR shows mild temporal lobe atrophy without basal ganglia alterations. Conclusions. In GA-I, macrocephaly is an early sign before other neurologic alterations. In patients with little or no neurological symptoms, early treatment may prevent the acute encephalopathic crisis and neurological deterioration, improving the prognosis and may also normalize the basal ganglia neuroradiological alterations. Urinary organic acid analysis should be performed in the work up of macrocephaly of unknown aetiology

Enfermedad celíaca en paciente con ataxia de origen desconocido / Celiac disease in a patient with ataxia of unknown origin

La sensibilidad al gluten es un estado de hiperrespuestainmunológica desencadenada por la ingestade gluten en sujetos con predisposición genética.Esta alteración inmunológica viene expresadapor la determinación de anticuerpos antitransglutaminasay antigliadina. Aunque las alteraciones neurológicas,sobre todo la ataxia, son frecuentes enestos pacientes, sólo el 16% tienen síntomas digestivos.Se recoge el caso de una niña de dos añoscon ataxia desde las semanas previas. No se encontraronalteraciones en las pruebas de neuroimagen,ni en las neurofisiológicas ni en las metabólicas.Se encontraron autoanticuerpos antigliadina yantitransglutaminasa positivos y se inició una dietasin gluten. En las semanas posteriores se produjouna mejoría clínica y los niveles de autoanticuerposeran más bajos

Gluten sensitivity is a state of hightened inmunologicalresponsiveness triggered by the ingestion ofgluten in genetically susceptible individuals. This inmunologicaldisorder is expressed by the finding ofantitransglutaminase and antigliadin autoantibodies.Although neurological disorders, mainly ataxia, arecommon in this patients, only 16% of them havegastrointestinal symptoms. We report a case of a2year-old child with ataxia for the previous weeks.No neuroimaging, neurophysiological nomnetabolicaldisorders were found. Nevertheless antigliadinand antitransglutaminase autoantibodies were detectedand a gluten-free diet was introduced. ln thefollowing weeks was noticed a clinical improvementand the autoantibodies levels were lower

[Glutaric aciduria type I: diagnosis in adulthood and phenotypic variability]. / Aciduria glutárica tipo I: diagnóstico en el adulto y variabilidad fenotípica.

Glutaric aciduria typo I (GA I) is an uncommon metabolic disease with autosomal recessive inheritance. It usually presents in the first years of life and frequently causes movement disorders. Only a few cases have been diagnosed in adulthood. Two siblings who were diagnosed of GA I after a course of more than 20 years are reported here. The elder brother, after 9 months of normal psychomotor development, suffered from an acute encephalopathy with generalized hypotonia and, later on, dyskinetic movements. Throughout the following years severe generalized dystonia developed. The younger brother presented at 16 months with acute encephalopathy, hypotonia and generalized choreoathetoid movements. Cranial computed tomography showed in both patients an slight enlargement of Silvian cisures and diffuse white matter hypodensities. Magnetic resonance imaging performed in the second case disclosed in addition bilateral hyperintensities in putamen and caudate nucleous. At 29 and 24 years of age, respectively, an increased urinary excretion of glutaric and 3-hydroxiglutaric acids was detected in both patients. Glutaryl-CoA deshidrogenase activity in fibroblasts was absent in both. The patients were treated with carnitine and riboflavine, with no response. The present report shows that diagnosis of GA I should be considered in adults presenting a range of movement disorders from childhood.

[Orphan drugs and metabolic disorders]. / Medicamentos huérfanos y enfermedades metabólicas.

INTRODUCTION: Over the past twenty years the legal and philosophical concept of orphan diseases has developed to include the diseases with an incidence in the general population of less than 1/5,000. Treatment of these conditions, which is very specific, requires drugs which will be used by a very small number of patients and are therefore not profitable from the financial point of view. This gives rise to the concept of orphan drugs which lack sponsorship, are expensive to investigate and develop, are little used and therefore there is little incentive to market them. All metabolic disorders due to genetic defects may be considered to be orphan diseases , since their incidence in the population is less than 1/5,000 and there may be only a negligible incidence of 1/37,000,000. DEVELOPMENT: In this study we discuss the treatment of three orphan metabolic diseases, which severely affect the central nervous system by different mechanisms, by three orphan drugs which solve the problems of only a few patients. We describe the treatment of: (1) the deficiency of the synthesis of tetrahydrobiopterin, which causes neurotransmitter deficiency, with tetrahydrobiopterin, (2) N acetylglutamate sythetase deficiency, which causes severe hyperammonaemia and cerebral oedema, with N carbamyl glutamate (3) cystathionine synthetase deficiency which causes hyperhomocyteinaemia and a high risk of thromboembolic accidents, with Betaine.