Recomendaciones para el diagnóstico y el tratamiento de la enfermedad de Gaucher durante la infancia / Recommendations for diagnosis and treatment of pediatric Gaucher disease

El diagnóstico y el tratamiento de la enfermedad de Gaucher infantil presentan dificultades debido a su variabilidad clínica. Tres pediatras expertos en la enfermedad han propuesto una serie de recomendaciones generales al respecto. El paciente debe ser asistido por un equipo multidisciplinario, en un centro pediátrico con experiencia en el tratamiento de enfermedades metabólicas. El diagnóstico del paciente sintomático se garantiza con la anamnesis, el examen físico (afectación visceral, hematológica, esquelética y/o del sistema nervioso central), los exámenes complementarios y la confirmación mediante un estudio enzimático y genético. Los objetivos terapéuticos son recuperar al paciente de los síntomas que presenta, modificar beneficiosamente la evolución natural de la enfermedad y evitar el desarrollo de asociaciones patológicas. En los pacientes sin patología neurológica menores de 20 años de edad es obligado el tratamiento enzimático sustitutivo i.v., pero en patología neurológica no ejerce efecto sobre el sistema nervioso central, aunque puede utilizarse en la forma tipo III para mejorar las manifestaciones viscerales y óseas (AU)

The diagnosis and treatment of pediatric Gaucher disease is difficult due to its clinical variability. Three pediatricians, experts in the disease, have proposed a series of recommendations regarding the subject. The patient must be taken care of by a multidisciplinary team, in a pediatric center with experience in metabolic diseases. The diagnosis of the symptomatic patient is guaranteed by the anamnesis, physical exam (visceral, hematologic, skeletal and/or CNS involvement), complementary exams and confirmation by means of enzymatic and genetic studies. The therapeutic objectives are recovery from exhibited symptoms, beneficial modification of the natural course of the disease and avoidance of development of associated pathology. In patients with no neurologic pathology <20 years old, iv enzymatic replacement therapy is mandatory but in case of neurologic pathology it does not exert an effect on SNC, although it may be used in type III to improve visceral and bone manifestations (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.

Recomendaciones y manejo de la tirosinemia hereditaria Tipo I o Tirosinemia hepatorrenal / Recommendations and management of Type I hereditary or hepatorenal Tyrosinemia

La Tirosinemia tipo I es una enfermedad potencialmente letal si no se diagnostica y trata adecuadamente. Los avances diagnóstico terapéuticos en los últimos años han mejorado ostensiblemente el pronóstico de estos pacientes. Por ello es importante que el pediatra disponga de una guía de práctica clínica con recomendaciones para el diagnóstico, y manejo terapéutico de esta enfermedad que contribuya a una adecuada actuación (AU)

Tyrosinemia type I is a potentially lethal disease if not diagnosed and treated properly. Diagnostic and therapeutic advances in recent years have significantly improved the prognosis for these patients. It is therefore important that the pediatrician has a clinical practice guideline with recommendations for diagnosis and treatment of this disease that leads to the appropriate intervention (AU)

[Recommendations and management of type I hereditary or hepatorenal tyrosinemia]. / Recomendaciones y manejo de la tirosinemia hereditaria Tipo I o Tirosinemia hepatorrenal.

Tyrosinemia type I is a potentially lethal disease if not diagnosed and treated properly. Diagnostic and therapeutic advances in recent years have significantly improved the prognosis for these patients. It is therefore important that the pediatrician has a clinical practice guideline with recommendations for diagnosis and treatment of this disease that leads to the appropriate intervention.

Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency.

Methylenetetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism. Disturbed function of the enzyme results in hyperhomocysteinemia and causes severe vascular and neurological disorders and developmental delay. Five patients suspected of having non-classical homocystinuria due to MTHFR deficiency were examined with respect to their symptoms, MTHFR enzyme activity and genotypes of the MTHFR gene. All patients presented symptoms of severe central nervous system disease. Two patients died, at the ages of 15 months and 14 years. One patient is currently 32 years old, and is being treated with betaine and folinic acid. The other two patients, with an early diagnosis and a severe course of the disease, are currently improving under treatment. MTHFR enzyme activity in the fibroblasts of four of the patients was practically undetectable. We found four novel mutations, three of which were missense changes c.664G> T (p.V218L), c.1316T> C (p.F435S) and c.1733T> G (p.V574G), and the fourth was the 1-bp deletion c.1780delC (p.L590CfsX72). We also found the previously reported nonsense mutation c.1420G> T (p.E470X). All the patients were homozygous. Molecular modelling of the double mutant allele (p.V218L; p.A222V) revealed that affinity for FAD was not affected in this mutant. For the p.E470X mutation, the evidence pointed to nonsense-mediated mRNA decay. In general, genotype-phenotype analysis predicts milder outcomes for patients with missense changes than for those in which mutations led to severe alterations of the MTHFR protein.

[Inborn errors of metabolism as rare diseases with a specific global situation]. / Los errores congénitos del metabolismo como enfermedades raras con un planteamiento global específico.

So-called congenital metabolic diseases (CMD) are a consequence of biochemical alterations originating in the genes that result in the alteration of a protein. Depending on this protein's function - whether as an enzyme, a hormone, a receiver-transporter of a cellular membrane or forming part of a cellular organelle (lysosome, peroxysome) - different groups of diseases emerge, which cause the most outstanding characteristic of inborn errors of metabolism (IEM): their clinical heterogeneity. The majority of these diseases are autosomal recessive, with a limited number of asymptomatic carriers, but there are also those ruled by an autonomous, dominant character inheritance or linked to the X chromosome. Taken individually, CMDs are highly infrequent, but taken as a whole CMDs (of which over 500 have been described to date) can affect 1/500 of the newborn. A common characteristic of many CMDs is the possibility of dietary treatment and treatment with enzymatic replacement. For essentially didactic purposes the following groups should be considered: CMDs of the intermediary metabolism (whose types are intoxication and energy deficit), CMDs of cellular organelles, complex CMDs due to cycle alterations and others. A summary is presented of the clinical, diagnostic and therapeutic aspects of one disease of each type of those previously described: hyperphenylalaninemias, deficiencies of the mitochondrial oxidative phosphorilation (OXPHOS) and lysosomal storage diseases.

Los defectos del ciclo de la urea en el neonato: una urgencia vital / Defects of urea cycle in newborn: a life-threatening emergency

Los defectos congénitos del ciclo de la urea son urgencias vitales en el recién nacido. El diagnóstico precoz y el tratamiento adecuado en cada caso son imprescindibles para asegurar la supervivencia y el mejor desarrollo posible de los niños afectados. Desde esta perspectiva es muy importante que los médicos responsables de la atención de los recién nacidos tengan los conocimientos y habilidades necesarios para ello (AU)

Inherited disorders of the urea cycle are life-treating emergencies in the newborn. Early diagnosis and proper treatment in each case essential to ensure the survival and the best possible development of children affected. From this perspective it is very important that doctors responsible for the medical care of newborns have the knowledge and skills necessary to do so (AU)

Los errores congénitos del metabolismo como enfermedades raras con un planteamiento global específico / Inborn errors of metabolism as rare diseases with a specific global situation

Las llamadas enfermedades congénitas del metabolismo(ECM) son consecuencia de alteraciones bioquímicasde origen génico que tienen como consecuencia la alteraciónde una proteína. Dependiendo de la función de estaproteína, ya sea como un enzima; como una hormona; comoun receptor-transportador de membrana celular; o formandoparte de una organela celular (lisosoma, peroxisoma)surgen diferentes grupos de enfermedades, lo cual originala característica más destacada de los errores innatos delmetabolismo (EIM) que es su gran heterogeneidad clínica.La mayoría de estas enfermedades son autosómico-recesivas,con un número limitado de portadores asintomáticos,pero también las hay regidas por una herencia de carácterautonómica dominante o ligada al cromosoma X. Uno a uno,realmente los ECM son muy poco frecuentes pero en suconjunto los ECM (de los cuales hay descritos en el momentoactual más de 500) pueden afectar al 1/500 recién nacidos.Una característica común a muchos ECM es la posibilidadde tratamiento dietético y el tratamiento con sustituciónenzimática.Desde el punto de vista práctico es útil considerar suclasificacion atendiendo al momento de inicio de los síntomasy a la forma de presentación de las manifestaciones clínicas.Desde esta perspectiva y con fines fundamentalmentedidácticos se deben considerar los siguientes grupos:ECM del metabolismo intermediario, (tipo intoxicación, ytipo déficit energético). Errores congénitos del metabolismode las organelas celulares, y EMCM complejos por alteraciónde ciclos y otros. Se presentan de forma resumidalos aspectos clínicos, diagnósticos y terapéuticos de unaenfermedad de cada tipo de las descritas anteriormente:hiperfenilalaninemias, deficiencias de la fosforilación oxidativamitocondrial (OXPHOS) y enfermedades lisosomales

So-called congenital metabolic diseases (CMD) are aconsequence of biochemical alterations originating in thegenes that result in the alteration of a protein. Dependingon this protein’s function - whether as an enzyme, a hormone,a receiver-transporter of a cellular membrane orforming part of a cellular organelle (lysosome, peroxysome)– different groups of diseases emerge, which cause the mostoutstanding characteristic of inborn errors of metabolism(IEM): their clinical heterogeneity. The majority of these diseasesare autosomal recessive, with a limited number ofasymptomatic carriers, but there are also those ruled by anautonomous, dominant character inheritance or linked tothe X chromosome. Taken individually, CMDs are highlyinfrequent, but taken as a whole CMDs (of which over 500have been described to date) can affect 1/500 of the newborn.A common characteristic of many CMDs is the possibilityof dietary treatment and treatment with enzymaticreplacement.For essentially didactic purposes the following groupsshould be considered: CMDs of the intermediary metabolism(whose types are intoxication and energy deficit),CMDs of cellular organelles, complex CMDs due to cyclealterations and others. A summary is presented of the clinical,diagnostic and therapeutic aspects of one disease ofeach type of those previously described: hyperphenylalaninemias,deficiencies of the mitochondrial oxidative phosphorilation(OXPHOS) and lysosomal storage diseases

Guía clínica para el diagnóstico, tratamiento y seguimiento de la enfermedad de Gaucher en la infancia / Clinical guidelines for the diagnostic, treatment and follow-up of pediatric Gaucher disease

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Genetic and phenotypic aspects of phenylalanine hydroxylase deficiency in Spain: molecular survey by regions.

We present an extensive study of the genetic diversity of phenylalanine hydroxylase deficiency in the Spanish phenylketonuria population. We have analysed 195 PKU patients by DGGE analysis identifying 67 different mutations which represent 89% of the total mutant chromosomes. Seventeen mutations first described in Spain have not yet been detected elsewhere; ten of these are reported here for the first time. The clinical significance of this high genetic heterogeneity was examined by analysing the genotype-phenotype correlations, mainly focusing on the mild hyperphenylalaninaemia (MHP) phenotype. The genotypes found in a group of 93 MHP patients, the largest analysed so far, are described in detail, as well as the relative frequencies of the MHP mutations identified. From the total pool of mutations, 27 can be considered severe, 18 can be defined as mild and 13 as associated with MHP. The prevalent mutations correspond to one severe mutation (IVS10nt-11), one MHP mutation (A403V) and two mild mutations (165T and V388M). The high frequency of mutations with a low degree of severity can explain the relatively higher prevalence of MHP and mild PKU phenotypes in Spain compared with NOrthern European populations. We have looked at the geographical distribution in Spain of the more common mutations, finding evidence of local mutation clustering, which could be the result of differences in the ethnic background and/or of genetic drift within each region.

High risk of medium chain acyl-coenzyme A dehydrogenase deficiency among gypsies.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is recognized as the most common hereditary defect of fatty acid oxidation in humans. Death is the outcome of the first attack in about 25% of cases. A point mutation (A to G [corrected] at position 985) of the MCAD gene represents more than 90% of alleles causing MCAD deficiency. The frequency of this allelic variant exhibits considerable geographical variations. In Spain, where the few diagnosed patients are mostly of Gypsy origin, the frequency is low as occurs in other Southern European countries (1 heterozygote among 200 individuals). Here we have analyzed the frequency of the G985 allele among Spanish gypsies. Heterozygotes were detected at a frequency of 1/17, with a 95% confidence interval ranging from 1/11 to 1/39. This represents the highest G985 rate described so far and calls for preventive measures, such as selective screening in this population.

[Demand for neuropediatric care in a regional general hospital. V. Complementary tests]. / Estudio de la demanda asistencial de Neuropediatría en un hospital de referencia regional V. Exámenes complementarios.

INTRODUCTION: Complementary tests orientated by the clinical findings and correctly interpreted, are useful in some cases in order to exclude certain pathologies and on other occasions to help to orientate towards or to confirm diagnoses. Material and methods. In this paper we analyze the complementary tests most often used in children evaluated during a five year period, from May 1990 to May 1995, by a neuropaediatrician who recently joined the staff of the Hospital Miquel Servet in Zaragoza (which had no neuropaediatrician before then). RESULTS AND CONCLUSIONS: Neuroimaging is the technique which was most often useful in establishing the diagnosis. CT or MR orientated or established the diagnosis in 21% of the total number of children evaluated and in 39% of the children in whom this investigation was carried out. The EEG contributed to the diagnosis of epilepsy in 11% of the children. In 16% of the cases of epilepsy the EEG was normal or with nonspecific changes and diagnosis was made on clinical grounds alone. Biochemical tests enabled some pathologies to be ruled out, but contributed to diagnosis on few occasions, most frequently the CSF (basically in meningitis and encephalitis) and muscle enzyme tests were also useful. Routinely used investigations such as those involving amino acids, ammonia, lactate and pyruvate established the diagnosis in a smaller proportion of cases than those used more selectively. Genetics were not found to be very useful in diagnosis. Reallocation of resources is necessary to permit the population as a whole to benefit from the continuous advances being made in techniques of direct study of molecular genetics.

[Acute presentation of leukodystrophy due to mitochondrial cytopathology and multiple deletions of mitochondrial DNA]. / Leucodistrofia de presentación aguda por citopatía mitocondrial y deleciones múltiples del ADN mitocondrial.

INTRODUCTION: Deletions of mitochondrial DNA (mtDNA) are a known cause of various mitochondrial cytopathies, which are sporadic and usually not due to maternal transmission. The multiple deletions are usually transmitted on a Mendelian pattern, and are frequently of autosomal dominant character. Leukodystrophy may be part of the picture, or even the form of presentation, of some mitochondrial cytopathies. Thus, in a case of leukoencephaly of unknown origin, mitochondrial cytopathy should be considered in the differential diagnosis. CLINICAL CASE: We present the case of a boy with no previous clinical abnormalities who, at the age of 13, suddenly fell to the floor with an encephalopathy which required aggressive treatment, needing mechanical ventilation and prolonged sedation. Following partial recovery spastic-dystonic quadriplegia remained. Neuroimaging showed advanced leukodystrophy with small hemorrhages in the white matter, which later disappeared. After rejecting other aetiologies, mitochondrial cytopathies in muscle were studied. A partial defect of the I and IV complexes of the respiratory chain and two deletions of mtDNA were shown. CONCLUSIONS: This case is another example of the variable clinical presentation of mitochondrial cytopathies and yet another argument for their inclusion in the diagnosis of leukodystrophy of unknown origin.

Relationship between mutation genotype and biochemical phenotype in a heterogeneous Spanish phenylketonuria population.

Genotyping of the phenylalanine hydroxylase (PAH) gene offers a new tool for characterizing patients with phenylketonuria (PKU), refining the diagnosis and aiding in the prediction of the clinical outcome and in the implementation of a more adequate treatment. The primary goal of this work was the detailed study of the different allele combinations and the metabolic phenotypes in Spanish PKU patients in order to understand better the clinical heterogeneity of PAH deficiency in our population. The results show that the disease phenotype is a consequence of a combination of mutations at the PAH locus and this observation is valid throughout the spectrum of clinical and biochemical varieties found in Spanish PKU patients. A stronger correlation was found between the predicted residual activity, when known from previous in vitro studies of the mutant proteins, and the Phe tolerance than between the predicted residual activity and the inverse of Phe levels at diagnosis. The observed genotype-phenotype correlations and the available data on the in vitro residual activity of the mutant proteins has enabled the estimation of the severity of most of the mutations found in Spain. This study includes relevant data for clinicians and pediatricians adding to the present knowledge which relates allelic PAH genotypes to biological phenotypes.

[Demand for neuropediatric services in a general referral hospital. III. Diagnosis]. / Estudio de la demanda asistencial de Neuropediatría en un hospital de referencia regional. III. Diagnósticos.

INTRODUCTION AND OBJECTIVES: In order to determine the requirements for neuropaediatric attention in the Hospital Miguel Servet of Zaragoza, we studied the diagnoses of the 2,046 children evaluated during the 5 year period-May 1990 to May 1995-, when a neuropediatrician was appointed to the hospital (which previously did not have such a specialist). RESULTS: The most frequent problems were non-epileptic paroxystic disorders, epilepsies and febrile crises. The following is a list in descending order, of diseases affecting these children: Prenatal encephalopathies, disorders of development and behaviour, head injury (TCE), peripheral nervous system and cranial nerve disorders (which were neither traumatic nor secondary to space-occupying lesions), headaches, perinatal encephalopathies, infections and para-infectious diseases of the nervous system, cardiovascular problems, hydrocephalus, metabolic disorders, hypovision and eye disorders, neuromuscular disorders, tumours, dyskinesias, medulla problems and neurocutaneous syndromes. CONCLUSIONS: The frequency and diversity of the neurological pathology seen in childhood and the continual advances in knowledge and the related sciences are more than a single professional person can be expected to cope with. Experts are required in areas such as electroencephalography and epilepsy, neonatal neurology, the neurological aspects of intensive care, neuropsychology, neuro-oncology, neurometabolic disorders, neurogenetics and neuromuscular disorders. Neuropediatricians are required to control illnesses with great personal, family and social impact, such as the neurocutaneous syndromes and myelomeningocoele. Neuropaediatric services working in close inter-disciplinary collaboration with other specialists are necessary.

[Demand for neuropediatric services at a general referral hospital. IV. Psychomotor development and physical examination]. / Estudio de la demanda asistencial de Neuropediatría en un hospital de referencia regional. IV. Desarrollo psicomotor y examen físico.

INTRODUCTION AND OBJECTIVE: Diagnosis in neuropediatrics requires a detailed personal and family history and thorough physical examination. In this paper we study the psychomotor development and physical examination of children evaluated during a 5 year period, from May 1990 to May 1995 by a neuropediatrician newly appointed to the Hospital Miguel Servet in Zaragoza, which previously did not have such a specialist. RESULTS: Psychomotor retardation was seen in 19% of the children. In 50% of the children evaluated, significant data was obtained from the physical examination. The commonest finding, observed in 14% of the children, was of anomalous behaviour or an impression of mental deficiency. In decreasing order of frequency other data were: Diffuse pyramidal involvement, cranial nerve involvement, anomalous phenotype, microcephaly, microsomy, signs of neuromuscular involvement, hemiparesia, macrocephaly, skin markings, scoliosis, signs of extrapyramidal involvement, signs of cerebellar involvement, macrosomy and sensory disorders. CONCLUSIONS: Diagnosis in neuropediatrics is directed or established, sometimes exclusively, by an extensive personal and family history and adequate interpretation of this, which in the end depends on the skill of the clinician.

[A study of the demand for neuropediatrics care at a regional hospital. I. Presentation of the study and general results]. / Estudio de la demanda asistencial de Neuropediatría en un hospital de referencia regional. I. Presentación del trabajo y resultados generales.

INTRODUCTION AND OBJECTIVE: The need for healthcare in neuropediatric pathology has always existed. It increases with changes in the needs of the population determined by medical scientific and social advances. These needs, together with the frequency and diversity of the neurological pathology of infancy justify the existence of neuropediatricians and neuropediatric services in regional reference hospitals. To organize a regional neuropediatric service, it is first necessary to know the real needs of the population. The objective of this study was to determine the need for neuropediatric care in the Pediatric Department of the Hospital Miguel Servet in Zaragoza, the regional reference centre for Aragón, La Rioja and Soria. MATERIAL AND METHODS: We studied the work carried out over 5 years by a neuropediatrician, newly arrived in a department which did not formerly have such a specialist, principally evaluating diagnostic work. In this first part we describe the material and methods used and the general results obtained. RESULTS: We analyzed the children studied during a 5 year period (May 1990 to May 1995). We evaluated 1,294 children seen in the Outpatient department and 752 during hospital admission (not followed up in Outpatients). This gave an annual average of 409 new patients in neuropediatrics. CONCLUSIONS: There is a great demand for neuropediatric attention. Its importance is due to the great frequency, diversity and the complexity of many of these conditions.