On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next-generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and provide new genes for NBIAs, which are investigated according to 2 main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving toward a new age of precision medicine.

Proteomic analysis of platelet N-glycoproteins in PMM2-CDG patients.

UNLABELLED: PMM2-CDG, the most frequent congenital disorder of N-glycosylation, is an autosomal recessive disease with a multisystem presentation. PMM2-CDG patients show an increased risk for thrombosis, which might be in part due to spontaneous platelet aggregations as previously described. A potential hypoglycosylation of platelet proteins in these patients might explain this increased reactivity, as removal of sialic acid from platelets, particularly of GPIbα, leads to enhance platelet aggregation and clearance from the circulation. This study is the first one that has evaluated the glycosylation status of platelet proteins in 6 PMM2-CDG patients using different approaches including immunoblot, RCA120 lectin binding to platelets and expression of different membrane platelet N-glycoproteins by flow cytometry, as well as by platelet N-glycoproteome analysis. RCA120 lectin binding to the platelet membrane of PMM2-CDG patients showed evidence for decreased sialic acid content. However, immunoblot and flow cytometric analysis of different platelet N-glycoproteins, together with the more sensitive 2D-DIGE analysis, suggest that platelet N-glycoproteins, including GPIbα, seem to be neither quantitatively nor qualitatively significantly affected. The increased binding of RCA120 lectin could be explained by the abnormal glycosylation of hepatic proteins being attached to the platelets. CONCLUSIONS: This is the first study that has evaluated the platelet N-glycoproteome. Our findings suggest that platelet proteins are not significantly affected in PMM2-CDG patients. Further studies are still warranted to unravel the mechanism(s) that increase(s) the risk of thrombosis in these patients.

Opsoclonus-mioclonus-ataxia en el contexto de infección aguda por Mycoplasma pneumoniae / Acute Mycoplasma pneumoniae infection-associated opsoclonus-myoclonus-ataxia syndrome

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[Medication-related oculogyric crises: a description of four cases and a review of the literature]. / Crisis oculogiras asociadas a farmacos: descripcion de cuatro casos y revision de la bibliografia.

INTRODUCTION: Oculogyric crises are considered to be a form of focal dystonia and can be observed as reactions to pharmaceuticals. The signs and symptoms may be confused with epileptic crises. AIMS: To describe the clinical features and progress of patients with pharmaceutical-related oculogyric crises and to carry out a review of the topic. CASE REPORTS: We conducted a retrospective, descriptive study of four patients evaluated in the neurology service due to oculogyric crises. The patients had been diagnosed with an associated conduct disorder requiring treatment with antipsychotic drugs. The episodes of oculogyric crises did not correlate with the findings in the electroencephalogram. They responded well to the reduction in dosage or to withdrawal of the apparent causing agent. CONCLUSIONS: The clinical picture does not present only in patients treated with antipsychotics but is also linked with other pharmaceuticals that are frequently used in daily paediatric practice. When oculogyric crises are the reason for visiting, differential diagnoses must be taken into account in order to avoid unnecessary studies and to carry out an appropriate therapeutic management.

Hypokinetic-rigid syndrome in children and inborn errors of metabolism.

Hypokinetic-rigid syndrome (HRS) or "parkinsonism" is rare in children. From a clinical point of view it is characterised by a group of signs in which hypokinesia (decreased number of movements), bradykinesia (slowness of movements), rigidity and rest tremor are the fundamental traits. Nervous system infections, immunomediated encephalitis, hypoxia and some drugs have been described as acquired or secondary causes of HRS in the paediatric age. Inborn errors of metabolism (IEM) comprise and important group regarding genetic causes. Main diseases causing HRS in children are neurotransmitter (biogenic amines) defects, metal storage diseases, energy metabolism disorders and lysosomal diseases. In general, in IEM, the HRS is associated to other neurological signs such as dykinesias, pyramidal signs, and psychomotor delay, is very rare in the neonatal period, tends to be more frequent in advanced stages of progressive diseases, and may respond to specific therapies. In particular, l-dopa + carbidopa can be a very effective treatment in neurotransmitter defects, whereas other disorders such as Wilson disease and some particular lysosomal disorders have different therapeutic possibilities. Furthermore, other genetic conditions in dopa-responsive and non-responsive HRS should be also considered, especially in juvenile parkinsonism. Through this review, a practical orientation for paediatric neurologists concerning clinical clues, diagnostic procedure and treatment of metabolic HRS will be provided.

Assessment of plasma ammonia and glutamine concentrations in urea cycle disorders.

OBJECTIVES: To analyze the association between ammonia and glutamine used for metabolic control in inherited urea cycle disorders (UCD) in a large series of patients. DESIGN AND METHODS: Paired plasma amino acid-ammonia data from 26 UCD patients were analyzed (n=921). RESULTS: Increased plasma glutamine values were consistently observed in UCD patients, despite normal plasma ammonia concentrations, especially for mitochondrial UCD. CONCLUSIONS: Further therapeutic efforts are probably needed to control increased glutamine values, considering their potentially neurotoxic effect.

Ancient origin of the CTH alelle carrying the c.200C>T (p.T67I) variant in patients with cystathioninuria.

Hereditary cystathioninuria is due to mutations in the CTH gene that encodes for cystathionase, a pyridoxal-5'-phosphate (PLP) dependent enzyme. To date, mutations in this gene have been described in 10 unrelated cystathioninuric patients. Enzyme assays have showed that mutated cystathionase exhibits lower activity than controls. As cystathioninuria is usually accompanied by a wide variety of symptoms, it has been questioned whether it is a disease or just a biochemical finding not associated with the clinical picture of these patients. This is the first report of Spanish patients with cystathioninuria and mild to severe neurological symptoms in childhood. After oral pyridoxine therapy biochemical parameters have normalized but clinical amelioration was not evident. All patients were homozygotes for the c.200C>T (p.T67I) variant which is the most prevalent inactivating mutation in the CTH gene. To further investigate the history of the alleles carrying the c.200C>T transition in Europe, we also constructed the haplotypes on the CTH locus in our Spanish patients as well as in a clinical series of cystathioninuric patients from the Czech Republic harboring the same nucleotide change. We suggest that the CTH p.T67I substitution could have an ancient common origin, which probably occurred in the Neolithic Era and spread throughout Europe.

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 and motor disturbances in children.

Motor disturbances are very common in paediatric neurology. Often families can be reassured that these are just variants of normal development. However, abnormal movements can also be the hallmark of severe brain dysfunction of different and complex origins. This review concentrates on motor disturbances as frequent and important symptoms of inborn errors of metabolism. A structured diagnostic approach is developed taking into account age-dependent physiological developments and pathophysiological responses of gross and fine motor functions. A series of investigations are presented with the primary aim of early diagnosis of treatable conditions. The correct recognition and differentiation of movement disorders (ataxia, rigid akinetic syndrome (Fparkinsonism_), dystonia, athetosis, tremor,and others), spasticity, and neuromuscular disorders, requires profound neurological expertise. A high level of suspicion and close interaction between paediatric neurologists and specialists in inborn errors of metabolism are indispensable to effectively and timely identify patients in whom motor disturbances are the presenting and/or main symptom of an inborn error.

Mental retardation and inborn errors of metabolism.

In countries where clinical phenylketonuria is detected by newborn screening inborn errors of metabolism are rare causes of isolated mental retardation. There is no international agreement about what type of metabolic tests must be applied in patients with unspecific mental retardation. However, and although infrequent, there are a number of inborn errors of metabolism that can present in this way. Because of the high recurrence risk and the possibility of specific therapies, guidelines need to be developed and adapted to different populations. The application of a universal protocol may result in a low diagnostic performance in individual ethnic populations. Consideration of associated signs (extraneurological manifestations, psychiatric signs, autistic traits, cerebellar dysfunction, epilepsy or dysmorphic traits) greatly improves the diagnostic fulfilment.

Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations.

Congenital disorder of glycosylation Ia (CDG-Ia) is a metabolic disease with a broad spectrum of clinical signs, including recently described mild phenotypes. Our aim was to describe the clinical presentation and follow-up of eight CDG-Ia patients highlighting atypical features and aspects of evolution of the disease. CDG diagnosis was confirmed by enzymatic analysis of phosphomannomutase (PMM2) and molecular studies of the PMM2 gene. Four neonates presented with cerebral haemorrhage (1), failure to thrive (2) and non-immune hydrops (1) and a fatal course to death (2); pathological examination of the brain in one case revealed olivopontocerebellar atrophy of prenatal origin. During infancy failure to thrive, coagulopathy and hepatopathy were the most significant causes of morbidity, but these disappeared after the first years of life in most patients. Three patients are currently in their 20s; they present mental retardation and severe motor impairment but no acute decompensations were noticed after the first decade of life. They do not present spinal or thoracic deformities otherwise observed in patients from northern countries. A 10-year-old patient who manifested gastrointestinal dysfunction in early childhood showed normal neurodevelopment. Mutation analysis of the PMM2 gene showed great variability, with all patients being compound heterozygous for two different mutations. Long-term evolution in our patients indicates that CDG-Ia is a stable systemic and neurological condition after the first decade of life. The diverse phenotypes and atypical manifestations in our series may be due to their genetic heterogeneity.

Secondary abnormalities of neurotransmitters in infants with neurological disorders.

Neurotransmitters are essential in young children for differentiation and neuronal growth of the developing nervous system. We aimed to identify possible factors related to secondary neurotransmitter abnormalities in pediatric patients with neurological disorders. We analyzed cerebrospinal fluid (CSF) and biogenic amine metabolites in 56 infants (33 males, 23 females; mean age 5.8mo [SD 4.1mo] range 1d-1y) with neurological disorders whose aetiology was initially unknown. Patients were classified into three clinical phenotypes: epileptic encephalopathy, severe motor impairment, and non-specific manifestations. All patients showed normal results for screening of inborn errors of metabolism. We report clinical, neuroimaging, and follow-up data. Among the patients studied, 10 had low homovanillic acid (HVA) levels and in four patients, 5-hydroxyindoleacetic acid (5-HIAA) was also reduced. Patients with neonatal onset had significantly lower levels of HVA than a comparison group. HVA deficiency was also associated with severe motor impairment and the final diagnosis related to neurodegenerative disorders. 5-HIAA values tended to be decreased in patients with brain cortical atrophy. The possibility of treating patients with L-Dopa and 5-hydroxytryptophan, in order to improve their neurological function and maturation, may be considered.

[Orientation of mental retardation from neurometabolic diseases]. / Orientación del retraso mental desde las enfermedades neurometabólicas.

INTRODUCTION AND DEVELOPMENT: Isolated mental retardation is rarely caused by metabolic factors. The application of a standardised protocol offers low diagnostic performance. There is no international agreement about what type of metabolic examination must be applied in patients with unspecific mental retardation. Nevertheless, and although they are infrequent, there are a number of inborn errors of metabolism that can present in this way. Urea cycle disorders, different forms of homocystinuria, creatine transport deficiency, 4-hydroxybutyric aciduria, Sanfilippo disease, adenylosuccinate lyase deficit and certain extraordinarily rare congenital disorders of the glycosylation of proteins are some examples of them. It is important first to consider those for which treatment is available and that could be diagnosed genetically for possible family counselling. CONCLUSIONS: Rather than applying a standardised study protocol it is essential is to perform a thorough appraisal of the signs and symptoms associated with the mental retardation (psychiatric disorders, autistic traits, predominant compromise of language, signs of cerebellar dysfunction, epilepsy, dysmorphic traits), since in most disorders it is necessary to apply specific analyses, which are not included in conventional metabolic studies and are only available in certain reference centres.

Orientación del retraso mental desde las enfermedades neurometabólicas / Orientation of mental retardation from neurometabolic diseases

Introducción y desarrollo. El retraso mental aislado raramentees de origen metabólico. La aplicación de un protocoloestandarizado ofrece un rendimiento diagnóstico bajo. No existe unconsenso internacional sobre qué tipo de exámenes metabólicos sehan de aplicar en pacientes con retraso mental inespecífico. Apesar de ello, y aunque es infrecuente, existen algunos errores congénitosdel metabolismo que pueden presentarse de este modo. Lostrastornos del ciclo de la urea, diferentes formas de homocistinuria,el déficit del transportador de creatina, la aciduria 4-hidroxibutírica,la enfermedad de Sanfilippo, el déficit de adenilosuccinatoliasa y algunas formas extraordinariamente infrecuentes deerrores congénitos de la glucosilación de las proteínas están entreellos. Es importante considerar en primer lugar aquellos que tienentratamiento y posibilidades de diagnóstico genético para unposible consejo familiar. Conclusiones. Más que la aplicación de unprotocolo de estudio estandarizado es imprescindible valorar meticulosamentela sintomatología asociada al retraso mental (trastornospsiquiátricos, rasgos autistas, afectación predominante del lenguaje,signos de disfunción cerebelosa, epilepsia, rasgos dismórficos),ya que en la mayoría de los trastornos se han de aplicar análisisespecíficos, no incluidos en los estudios metabólicos convencionalesy solamente disponibles en algunos centros de referencia

Introduction and development. Isolated mental retardation is rarely caused by metabolic factors. The applicationof a standardised protocol offers low diagnostic performance. There is no international agreement about what type ofmetabolic examination must be applied in patients with unspecific mental retardation. Nevertheless, and although they areinfrequent, there are a number of inborn errors of metabolism that can present in this way. Urea cycle disorders, differentforms of homocystinuria, creatine transport deficiency, 4-hydroxybutyric aciduria, Sanfilippo disease, adenylosuccinate lyasedeficit and certain extraordinarily rare congenital disorders of the glycosylation of proteins are some examples of them. It isimportant first to consider those for which treatment is available and that could be diagnosed genetically for possible familycounselling. Conclusions. Rather than applying a standardised study protocol it is essential is to perform a thorough appraisal ofthe signs and symptoms associated with the mental retardation (psychiatric disorders, autistic traits, predominant compromiseof language, signs of cerebellar dysfunction, epilepsy, dysmorphic traits), since in most disorders it is necessary to applyspecific analyses, which are not included in conventional metabolic studies and are only available in certain reference centres

Aplicación del protocolo de actuación para embarazadas con fenilcetonuria clásica: tres gestaciones con éxito / Application of a protocol for pregnant women with classic phenylketonuria: three successful pregnancies

El síndrome de fenilcetonuria materna (SFM) aparece en hijos de madres afectadas por hiperfenilalaninemia grave o moderada con concentraciones plasmáticas elevadas de fenilalanina(Phe) durante los meses previos y/o la gestación. Cursa con malformaciones similares al síndrome alcoholico fetal y es especialmente frecuente la aparición de microcefalia y retardomental y del desarrollo. La planificación y los controles estrictos de Phe durante el embarazo son fundamentales para evitar la aparición de SFM. Presentamos un protocolo de seguimiento y nuestra experiencia en tres embarazos que han finalizado con éxito

Maternal phenylketonuria syndrome(MPS)occurs in children whose mothers have severe or moderate hyperphenylalaninemia and present high plasma phenylalanine levels during the months prior to and/or throughout pregnancy. MPS presents with malformations similar to those associated with fetal alcohol syndrome, the most common of which are microcephaly, congenital heart defects and mental and developmental retardation. Planning and strict control of phenylalanine levels during pregnancy are essential for the prevention of the development of MPS. We present a follow-up protocol and our experience with three successful pregnancies in women with phenylketonuria