Detección prenatal y seguimieto postnatal de las anomalías congénitas del sistema nervioso central.

215 p.Las anomalías congénitas del Sistema Nervioso Central (ACSNC) se dan en el 1% de los nacimientos y suponen una causa importante de muerte neonatal y discapacidad a largo plazo. El diagnóstico suele realizarse a nivel prenatal, el pronóstico puede ser variable y la decisión supone continuar o terminar el embarazo. El objetivo de este estudio es describir las características clínicas, epidemiológicas y pronóstico de las ACSNC en el País Vasco y principalmente en Gipuzkoa, a través de los datos recogidos en el registro de anomalías congénitas del País Vasco (RACAV) durante los años 1990 a 2011. Se ha observado un aumento de la prevalencia de las ACSNC a lo largo de este periodo, principalmente por el aumento de los casos detectados prenatalmente. Los defectos del tubo neural (DNT) son los más prevalentes, seguidos de la hidrocefalia. La prevalencia de DTN no ha disminuido a pesar de la instauración oficial de la recomendación de la toma de ácido fólico periconcepcional en el 2001. Se conoce la etiología en el 22% de los casos, 14% son debidas a anomalías cromosómicas, 5% se engloban dentro de un síndrome concreto y 3% son secundarias a factores ambientales. De manera global, el 60% de las malformaciones acaban en interrupción voluntaria del embarazo (IVE), 38% nacen vivos y 2% nacen muertos. El factor más importante para decidir seguir o no con el embarazo es el momento de detección de la anomalía. De los casos nacidos vivos, la supervivencia depende de las anomalías asociadas en otros órganos

Detección prenatal y seguimieto postnatal de las anomalías congénitas del sistema nervioso central.

215 p.Las anomalías congénitas del Sistema Nervioso Central (ACSNC) se dan en el 1% de los nacimientos y suponen una causa importante de muerte neonatal y discapacidad a largo plazo. El diagnóstico suele realizarse a nivel prenatal, el pronóstico puede ser variable y la decisión supone continuar o terminar el embarazo. El objetivo de este estudio es describir las características clínicas, epidemiológicas y pronóstico de las ACSNC en el País Vasco y principalmente en Gipuzkoa, a través de los datos recogidos en el registro de anomalías congénitas del País Vasco (RACAV) durante los años 1990 a 2011. Se ha observado un aumento de la prevalencia de las ACSNC a lo largo de este periodo, principalmente por el aumento de los casos detectados prenatalmente. Los defectos del tubo neural (DNT) son los más prevalentes, seguidos de la hidrocefalia. La prevalencia de DTN no ha disminuido a pesar de la instauración oficial de la recomendación de la toma de ácido fólico periconcepcional en el 2001. Se conoce la etiología en el 22% de los casos, 14% son debidas a anomalías cromosómicas, 5% se engloban dentro de un síndrome concreto y 3% son secundarias a factores ambientales. De manera global, el 60% de las malformaciones acaban en interrupción voluntaria del embarazo (IVE), 38% nacen vivos y 2% nacen muertos. El factor más importante para decidir seguir o no con el embarazo es el momento de detección de la anomalía. De los casos nacidos vivos, la supervivencia depende de las anomalías asociadas en otros órganos

Collaborative model for diagnosis and treatment of very rare diseases: experience in Spain with thymidine kinase 2 deficiency

Malaltia mitocondrial; Medicina mitocondrial; Deficiència de timidina cinasa 2 (TK2d)Mitochondrial disease; Mitochondrial medicine; Thymidine kinase 2 deficiency (TK2d)Enfermedad mitocondrial; Medicina mitocondrial; Deficiencia de timidina cinasa 2 (TK2d)Background Mitochondrial diseases are difficult to diagnose and treat. Recent advances in genetic diagnostics and more effective treatment options can improve patient diagnosis and prognosis, but patients with mitochondrial disease typically experience delays in diagnosis and treatment. Here, we describe a unique collaborative practice model among physicians and scientists in Spain focused on identifying TK2 deficiency (TK2d), an ultra-rare mitochondrial DNA depletion and deletions syndrome. Main Body This collaboration spans research and clinical care, including laboratory scientists, adult and pediatric neuromuscular clinicians, geneticists, and pathologists, and has resulted in diagnosis and consolidation of care for patients with TK2d. The incidence of TK2d is not known; however, the first clinical cases of TK2d were reported in 2001, and only ~ 107 unique cases had been reported as of 2018. This unique collaboration in Spain has led to the diagnosis of more than 30 patients with genetically confirmed TK2d across different regions of the country. Research affiliate centers have led investigative treatment with nucleosides based on understanding of TK2d clinical manifestations and disease mechanisms, which resulted in successful treatment of a TK2d mouse model with nucleotide therapy in 2010. Only 1 year later, this collaboration enabled rapid adoption of treatment with pyrimidine nucleotides (and later, nucleosides) under compassionate use. Success in TK2d diagnosis and treatment in Spain is attributable to two important factors: Spain’s fully public national healthcare system, and the designation in 2015 of major National Reference Centers for Neuromuscular Disorders (CSURs). CSUR networking and dissemination facilitated development of a collaborative care network for TK2d disease, wherein participants share information and protocols to request approval from the Ministry of Health to initiate nucleoside therapy. Data have recently been collected in a retrospective study conducted under a Good Clinical Practice–compliant protocol to support development of a new therapeutic approach for TK2d, a progressive disease with no approved therapies. Conclusions The Spanish experience in diagnosis and treatment of TK2d is a model for the diagnosis and development of new treatments for very rare diseases within an existing healthcare system.This study was sponsored by Zogenix, Inc., and ERN EURO-NMD. The sponsors reviewed the drafts and provided medical writing support for draft preparation

Noves aportacions al coneixement del medi vegetal i l'explotació del combustible durant el bronze final a partir de l'anàlisi antracològica de Sta. Digna III (Llerona, Les Franqueses del Vallès)

El objetivo del estudio antracológico del yacimiento del Bronce final de Sta. Digna III es el de aportar nuevos datos al conocimiento del medio vegetal y su explotación. Los resultados obtenidos, aunque son reducidos, muestran datos que puede correlacionarse con otras secuencias de cronologías similares, durante las cuales los taxones del ambiente del encinar toman en este período una gran importancia. Edad del bronce, antracología, medio vegetal, recursos forestales.The aim of these charcoal analyses from the Upper Bronze Age site of Sta Digna III has yielded new data to the knowledge of the landscape and its exploitations. The obtained results, even though they are scarce, show data that can be related to other sequences with similar chronologies. During this period evergreen oaks forests taxa have a major importance.L’objective de l’analyse anthracologique du site du Bronze final de Sta Digna III a apportée des nouveaux donnée pour la connaissance du milieu végétal et son exploitation. Les résultats obtenus, même si réduits, montrent données qui peuvent se comparer avec d’autres séquences de chronologies similaires, pendant les quelles les taxons des ambiants de la chênaie verte prennent la majeure importance

Small for gestational age moderate to late preterm children: a neuropsychological follow-up

[EN] Determine whether SGA constitutes a neurodevelopmental risk-factor of MLP, exploring if potential developmental difficulties at toddlerhood persist and are related to school-age performance. 109 SGA and 109 adequate for gestational age MLP children were evaluated at 2 and at 6.5 y.o. SGA children obtained poorer results in several areas at both timepoints; and their development at toddlerhood strongly correlated with only some results at school-age. SGA confers vulnerability to MLP, evolving from global/unspecific difficulties in toddlerhood to a domain-specific profile (attentional/dysexecutive) at 6.5. Findings claim the need for neuropsychological follow-up in MLP to identify emerging difficulties

The use of lower of higher than recommended doses of folic acid supplements during pregnancy is associated with child attentional dysfunction at 4-5 years of age in the INMA Project

We assessed the association between the use of lower- and higher-than-recommended doses of folic acid supplements (FAs) during pregnancy and attentional function in boys and girls at age of 4-5. We analyzed data from 1329 mother-child pairs from the mother-child cohort INfancia y Medio Ambiente Project (INMA) study. Information on FAs use during pregnancy was collected in personal interviews at weeks 12 and 30, and categorized in <400, 400-999 (recommended dose), and ≥1000 μg/day. Child attentional function was assessed by Conners' Kiddie Continuous Performance Test. Multivariable regression analyses were used to estimate incidence rate ratios (IRR) and beta coefficients with 95% confidence intervals (CI). Compared to recommended FAs doses, the periconceptional use of <400 and ≥1000 μg/day was associated with higher risk of omission errors-IRR = 1.14 (95% CI: 1.01; 1.29) and IRR = 1.16 (95% CI: 1.02; 1.33), respectively. The use of FAs < 400 μg/day and ≥1000 μg/day was significantly associated with deficits of attentional function only in boys. FAs use < 400 μg/day was associated with higher omission errors with IRR = 1.22 and increased hit reaction time (HRT) β = 34.36, and FAs use ≥ 1000 μg/day was associated with increased HRT β = 33.18 and HRT standard error β = 3.31. The periconceptional use of FAs below or above the recommended doses is associated with deficits of attentional function in children at age of 4-5, particularly in boys

Collaborative model for diagnosis and treatment of very rare diseases: experience in Spain with thymidine kinase 2 deficiency

Background Mitochondrial diseases are difficult to diagnose and treat. Recent advances in genetic diagnostics and more effective treatment options can improve patient diagnosis and prognosis, but patients with mitochondrial disease typically experience delays in diagnosis and treatment. Here, we describe a unique collaborative practice model among physicians and scientists in Spain focused on identifying TK2 deficiency (TK2d), an ultra-rare mitochondrial DNA depletion and deletions syndrome. Main Body This collaboration spans research and clinical care, including laboratory scientists, adult and pediatric neuromuscular clinicians, geneticists, and pathologists, and has resulted in diagnosis and consolidation of care for patients with TK2d. The incidence of TK2d is not known; however, the first clinical cases of TK2d were reported in 2001, and only ~ 107 unique cases had been reported as of 2018. This unique collaboration in Spain has led to the diagnosis of more than 30 patients with genetically confirmed TK2d across different regions of the country. Research affiliate centers have led investigative treatment with nucleosides based on understanding of TK2d clinical manifestations and disease mechanisms, which resulted in successful treatment of a TK2d mouse model with nucleotide therapy in 2010. Only 1 year later, this collaboration enabled rapid adoption of treatment with pyrimidine nucleotides (and later, nucleosides) under compassionate use. Success in TK2d diagnosis and treatment in Spain is attributable to two important factors: Spain’s fully public national healthcare system, and the designation in 2015 of major National Reference Centers for Neuromuscular Disorders (CSURs). CSUR networking and dissemination facilitated development of a collaborative care network for TK2d disease, wherein participants share information and protocols to request approval from the Ministry of Health to initiate nucleoside therapy. Data have recently been collected in a retrospective study conducted under a Good Clinical Practice–compliant protocol to support development of a new therapeutic approach for TK2d, a progressive disease with no approved therapies. Conclusions The Spanish experience in diagnosis and treatment of TK2d is a model for the diagnosis and development of new treatments for very rare diseases within an existing healthcare system

Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T&gt;C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity

Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy

GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1–49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age

Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy

GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1-49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age