ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization.

BACKGROUND: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) have become indispensable tools to solve rare Mendelian genetic conditions. Nevertheless, there is still an urgent need for sensitive, fast algorithms to maximise WES/WGS diagnostic yield in rare disease patients. Most tools devoted to this aim take advantage of patient phenotype information for prioritization of genomic data, although are often limited by incomplete gene-phenotype knowledge stored in biomedical databases and a lack of proper benchmarking on real-world patient cohorts. METHODS: We developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient's standardized phenotypic features (in Human Phenotype Ontology (HPO) terms). The algorithm propagates the data through an interactome network-based prioritization approach. This algorithm was thoroughly benchmarked using a synthetic patient cohort and was subsequently tested on a heterogeneous prospective, real-world series of 135 families affected by hereditary spastic paraplegia (HSP) and/or cerebellar ataxia (CA). RESULTS: ClinPrior successfully identified causative variants achieving a final positive diagnostic yield of 70% in our real-world cohort. This includes 10 novel candidate genes not previously associated with disease, 7 of which were functionally validated within this project. We used the knowledge generated by ClinPrior to create a specific interactome for HSP/CA disorders thus enabling future diagnoses as well as the discovery of novel disease genes. CONCLUSIONS: ClinPrior is an algorithm that uses standardized phenotype information and interactome data to improve clinical genomic diagnosis. It helps in identifying atypical cases and efficiently predicts novel disease-causing genes. This leads to increasing diagnostic yield, shortening of the diagnostic Odysseys and advancing our understanding of human illnesses.

Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.

BACKGROUND AND OBJECTIVES: Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes. METHODS: A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient. RESULTS: We evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B, EIF2B5, POLR3A, and PLP1, and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD. DISCUSSION: Our strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel disease-causing genes and phenotypes, and predicts novel putative candidate genes, shedding light on etiopathogenic mechanisms that are pivotal for myelin generation and maintenance.

Early detection of lysosomal diseases by screening of cases of idiopathic splenomegaly and/or thrombocytopenia with a next-generation sequencing gene panel.

Lysosomal diseases (LD) are a group of about 70 rare hereditary disorders (combined incidence 1:5000) in which diverse lysosomal functions are impaired, impacting multiple organs and systems. The first clinical signs and symptoms are usually unspecific and shared by hundreds of other disorders. Diagnosis of LD traditionally relies on performing specific enzymatic assays, if available, upon clinical suspicion of the disorder. However, the combination of the insidious onset of LD and the lack of awareness on these rare diseases among medical personnel results in undesirable diagnostic delays, with unchecked disease progression, appearance of complications and a worsened prognosis. We tested the usefulness of a next-generation sequencing-based gene panel for quick, early detection of LD among cases of idiopathic splenomegaly and/or thrombocytopenia, two of the earliest clinical signs observed in most LD. Our 73-gene panel interrogated 28 genes for LD, 1 biomarker and 44 genes underlying non-LD differential diagnoses. Among 38 unrelated patients, we elucidated eight cases (21%), five with LD (GM1 gangliosidosis, Sanfilippo disease A and B, Niemann-Pick disease B, Gaucher disease) and three with non-LD conditions. Interestingly, we identified three LD patients harboring pathogenic mutations in two LD genes each, which may result in unusual disease presentations and impact treatment. Turnaround time for panel screening and genetic validation was 1 month. Our results underline the usefulness of resequencing gene panels for quick and cost-effective screening of LDs and disorders sharing with them early clinical signs.

Clinical Assessment of Dysarthria in Children with Cerebellar Syndrome Associated with PMM2-CDG.

Phosphomannomutase deficiency (PMM2-CDG) causes a cerebellar syndrome that has been evaluated using the International Cooperative Ataxia Rating Scale (ICARS). However, no particular dysarthria tests have been used. Speech ICARS subscore subjectively assesses fluency and clarity of speech with two items. Repetition of syllables, traditionally used for characterization of ataxic speech, was validated in early-onset ataxia conditions. We assess the validity of the PATA test (SCA Functional Index [SCAFI]) in PMM2-CDG patients.PATA rates from 20 patients were compared with a control population were and correlated with ICARS and neuroimaging.There was a difference between the PATA rate in patients and controls. PATA rate increased with age in controls. In patients, the improvement of PATA rate with age was not significant. In patients, the PATA rate was negatively correlated with the total ICARS score and the Speech ICARS subscore. Regarding neuroimaging, midsaggital vermis relative diameter was positively correlated with PATA results. These last differences were also significant when the results are corrected by age.PATA rate provides an easy measure for a quantitative assessment of dysarthria that may help clinicians to monitor patients' evolution in a regular consultation. It could also be used in PMM2-CDG clinical trials implementing ICARS speech subscore information.

Elosulfase alfa for mucopolysaccharidosis type IVA: Real-world experience in 7 patients from the Spanish Morquio-A early access program.

There is a growing interest in evaluating the effectiveness of enzyme replacement therapy (ERT) with elosulfase alfa in patients with mucopolysaccharidosis type IVA (MPS-IVA) under real-world conditions. We present the experience of seven pediatric MPS-IVA patients from the Spanish Morquio-A Early Access Program. Efficacy was evaluated based on the distance walked in the 6-min walking test (6-MWT) and the 3-min-stair-climb-test (3-MSCT) at baseline and after 8 months of ERT treatment. Additionally, urinary glycosaminoglycans were measured, and a molecular analysis of a GALNS mutation was performed. The health-related quality of life was evaluated using the EuroQoL (EQ)-5D-5 L. The distance walked according to the 6-MWT ranged from 0 to 325 m at baseline and increased to 12-300 m after 8 months with elosulfase alfa (the walked distance improved in all patients except one). An increase was observed for the two patients who had to use a wheelchair. Improvements were also observed for the 3-MSCT in four patients, whereas two patients showed no changes. Three patients showed an improvement in the EQ-VAS score, whereas the scores of three patients remained stable. Regarding urinary glycosaminoglycans measurements, an irregular response was observed. Our results showed overall improvement in endurance and functionality after 8 months of elosulfase alfa treatment in a heterogeneous subset of MPS IVA patients with severe clinical manifestations managed in a real-world setting.

Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy.

Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients' group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.

A quantitative assessment of the evolution of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG).

BACKGROUND: We aim to delineate the progression of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG) using the International Cooperative Ataxia Rating Scale (ICARS). We sought correlation between cerebellar volumetry and clinical situation. We prospectively evaluated PMM2-CDG patients aged from 5 to 18 years through ICARS at two different time points set apart by at least 20 months. We reviewed available MRIs and performed volumetric analysis when it was possible. RESULTS: From the eligible 24, four patients were excluded due to severe mental disability (n = 2) and supratentorial lesions (n = 2). Two different ICARS evaluations separated by more than 20 months were available for 14 patients showing an improvement in the cerebellar syndrome: ICARS1: 35.71 versus ICARS2: 30.07 (p < 0.001). When we considered time, we saw an improvement of 2.64 points in the ICARS per year with an SD of 1.97 points (p < 0.001). The ICARS subscales results improved with time, reaching statistical significance in "Posture and gait" (p < 0.001), "Kinetic functions" (p = 0.04) and "Speech abnormalities" (p = 0.045). We found a negative correlation between the ICARS results and total cerebellar volume (r = -0.9, p = 0.037) in a group of five patients with available volumetric study, meaning that the higher the ICARS score, the more severe was the cerebellar atrophy. CONCLUSIONS: Our study shows a stabilization or mild improvement in the cerebellar functions of paediatric PMM2-CDG patients despite cerebellar volume loss. ICARS is a valid scale to quantify the evolution of cerebellar syndrome in PMM2-CDG patients. The availability of ICARS and other reliable and sensitive follow-up tools may prove essential for the evaluation of potential therapies.

A selective screening program for the early detection of mucopolysaccharidosis: Results of the FIND project - a 2-year follow-up study.

The mucopolysaccharidoses (MPSs) are underdiagnosed but they are evaluated in few newborn screening programs, probably due to the many challenges remaining, such as the identification of late-onset phenotypes. Systematic screening at the onset of clinical symptoms could help to early identify patients who may benefit from specific treatments. The aim of this prospective study was to assess a novel selective screening program, the FIND project, targeting patients aged 0 to 16 years with clinical manifestations of MPS. The project was designed to increase awareness of these diseases among pediatricians and allow early diagnosis.From July 2014 to June 2016, glycosaminoglycan (GAG) levels normalized to creatinine levels were determined in urine-impregnated analytical paper submitted by pediatricians who had patients with clinical signs and/or symptoms compatible with MPS. When high GAG concentrations were detected, a new liquid urine sample was requested to confirm and identify the GAG present. When a specific form of MPS was suspected, enzyme activity was analyzed using blood-impregnated paper to determine MPS type (I, IIIB, IIIC, IVA, IVB, VI, or VII). Age-specific reference values for GAG were previously established using 145 urine samples from healthy children.GAG levels were normal in 147 (81.7%) of the 180 initial samples received. A liquid sample was requested for the other 33 cases (18.3%); GAG levels were normal in 13 of these and slightly elevated in 12, although the electrophoresis study showed no evidence of MPS. Elevated levels with corresponding low enzymatic activity were confirmed in 8 cases. The mean time from onset of clinical symptoms to detection of MPS was 22 months, and just 2 cases were detected at the beginning of the project were detected with 35 and 71 months of evolution of clinical symptoms. Our screening strategy for MPS had a sensitivity of 100%, a specificity of 85%, and a positive predictive value of 24%.The FIND project is a useful and cost-effective screening method for increasing awareness of MPS among pediatricians and enabling the detection of MPS at onset of clinical symptoms.

Clinical and genetic features of 13 Spanish patients with KCNQ2 mutations.

The KCNQ2 gene codifies a subunit of the voltage-gated potassium M channel underlying the neuronal M-current. Classically, mutations in this gene have been associated with benign familial neonatal seizures, however, in recent years KCNQ2 mutations have been reported associated to early-onset epileptic encephalopathy. In this work, detailed familiar, clinical and genetic data were collected for 13 KCNQ2-positive patients revealed among a cohort of 80 epileptic pediatric probands from Spain who were analyzed through a targeted next-generation sequencing assay for 155 epilepsy-associated genes. This work shows for the first time the association between KCNQ2 mutations and startle attacks in 38% of patients, which opens the possibility to define electroclinical phenotypes associated to KCNQ2 mutations. It also demonstrates that KCNQ2 mutations contribute to an important percentage of Spanish patients with epilepsy. The study confirm the high genetic heterogeneity of this gene with 13 different mutations found, 10 of them novel and the better outcome of patients treated with sodium channel blockers.

Terapias novedosas en enfermedades neurometabólicas: importancia de una intervención precoz / Novel therapies in neurometabolic diseases: the importance of early intervention

Introducción. Las enfermedades neurometabólicas son individualmente ultrarraras, pero algunas de ellas tienen un tratamiento eficaz. Desarrollo. Se revisan algunas novedades terapéuticas. Las enfermedades lisosomales tienen actualmente mejores posibilidades de tratamiento. En los últimos años se ha extendido el uso de la terapia enzimática sustitutiva a la mucopolisacaridosis tipo IVA (Morquio A), a la mucopolisacaridosis tipo VII (enfermedad de Sly), al déficit de lipasa ácida lisosomal y a la alfa-manosidosis. Se ha constatado que un tratamiento muy precoz de las mucopolisacaridosis puede cambiar su historia natural. Se está probando la terapia enzimática sustitutiva intratecal en algunas mucopolisacaridosis con afectación cognitiva, en el intento de frenar la neurodegeneración. Se han obtenido resultados muy positivos con autotrasplante modificado genéticamente en leucodistrofia metacromática infantil tardía y se está trabajando en otras patologías (mucopolisacaridosis tipo III, adrenoleucodistrofia ligada a X). También hay novedades en la terapia de algunas encefalopatías sensibles a vitaminas o cofactores: la triple terapia en la dependencia de piridoxina, el tratamiento con tiamina de algunas encefalopatías subagudas con afectación de ganglios basales, el tratamiento con ácido folínico de niños con deficiencia de folato cerebral, o el tratamiento con monofosfato de piranopterina cíclico en los defectos de cofactor de molibdeno de tipo A. Conclusiones. Los neuropediatras debemos actualizar nuestro conocimiento especialmente en aquellas patologías neurometabólicas tratables, dado que una terapia precoz puede cambiar de forma significativa su pronóstico (AU)

Introduction. Individually, neurometabolic diseases are ultra rare, but for some of them there is an effective treatment. Development. Several recent therapeutic advances are reviewed. Today, the possibilities of treatment for lysosomal diseases have improved. In recent years the use of enzyme replacement therapy has become more widely extended to treat mucopolysaccharidosis type IVA (Morquio A), mucopolysaccharidosis type VII (Sly syndrome), lysosomal acid lipase deficiency and alpha-mannosidosis. It has been proven that very early treatment of mucopolysaccharidoses can change their natural course. Intrathecal enzyme replacement therapy is being tried in some mucopolysaccharidoses with cognitive involvement, in an attempt to halt neurodegeneration. Very positive results have been obtained with genetically modified autotransplants in late-onset infantile metachromatic leukodystrophy and research is being conducted on other pathologies (mucopolysaccharidosis type III, X-linked adrenoleukodystrophy). Novel outcomes are also being achieved in the treatment of some encephalopathies that are sensitive to vitamins or cofactors: triple therapy in pyridoxine dependency, treatment with thiamine for some subacute encephalopathies with involvement of the basal ganglia, treatment with folinic acid for children with cerebral folate deficiency, or treatment with cyclic pyranopterin monophosphate in molybdenum cofactor deficiency type A. Conclusions. As neuropaediatricians we must update our knowledge, especially in the case of treatable neurometabolic pathologies, since early treatment can change their prognosis significantly (AU)

Utilización de bromuros en cinco pacientes epilépticos / Use of bromides in five epileptic patients

No disponible

Guía de práctica clínica para el tratamiento del síndrome de Hunter / Clinical practice guideline for the management of Hunter syndrome

El síndrome de Hunter (SH), o mucopolisacaridosis tipo ii , es una enfermedad producida por la deficiencia o ausencia de la enzima iduronato-2-sulfatasa (I2S) debida a mutaciones en el gen IDS. La deficiencia de la I2S ocasiona un bloqueo en el proceso de degradación de glucosaminoglucanos (GAG) en los lisosomas citoplasmáticos, lo que da lugar a su acumulación en las células. Esto provoca una alteración celular generalizada, y una eliminación aumentada de estos GAG en orina. El SH es una enfermedad hereditaria recesiva ligada al cromosoma X, que afecta a uno de cada 49.000-526.000 recién nacidos vivos varones. Su carácter multisistémico y progresivo hace que en algún momento de la evolución sea necesario el abordaje por distintas especialidades médicas. Recientemente se dispone de tratamiento de sustitución enzimática con I2S recombinante que mejora y ralentiza la evolución de la enfermedad, por lo que resulta clave el diagnóstico y tratamiento precoz. Por estas razones, se ha elaborado esta guía de práctica clínica (GPC), que pretende ayudar a los diferentes especialistas que están en contacto con pacientes que padecen el SH en la detección precoz, y en el seguimiento y tratamiento. La guía ha sido elaborada por un grupo de trabajo constituido por el Grupo Español de Hunter (equipo multidisciplinar formado por médicos especialistas expertos en el diagnóstico y tratamiento del SH) e investigadores con experiencia metodológica en el desarrollo de GPC. Las recomendaciones se basan en la síntesis de la evidencia científica disponible y en la experiencia de los expertos (AU)

The Hunter syndrome (HS), or mucopolysaccharidosis type II, is a disease caused by a deficiency or absence of the enzyme iduronate-2-sulfatase (I2S) due to mutations in the IDS gene. I2S deficiency causes a block in the degradation of glycosaminoglycans (GAG) in cytoplasmic lysosomes which leads to their accumulation in cells. This causes a generalized cellular disorder and increased elimination of these GAG in urine. The HS is an inherited X-linked recessive disease, which affects one in 49,000 to 526,000 male live births. The HS progressive and multisystem involvement usually causes the need of various medical specialties for managing the disease. Recently a new enzyme replacement therapy with recombinant I2S is available, which improves and slows the disease progression. Thus, early diagnosis and treatment are key factors for managing HS. For these reasons, this clinical practice guideline (CPG) has been developed. This CPG aims to help the different specialists who manage patients with SH in the early detection, follow-up and treatment. This guide has been developed by a working group set up by the Spanish Hunter Group multidisciplinary team of physician specialists in the diagnosis and management of HS) and researchers with methodological experience in developing GPC. The recommendations are based on the synthesis of the best available scientific evidence and the experience of experts (AU)

[Analysis of a series of cases with an initial diagnosis of acute disseminated encephalomyelitis over the period 2000-2010]. / Análisis de una serie de casos con diagnostico inicial de encefalomielitis aguda diseminada en el periodo 2000-2010.

INTRODUCTION: Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease that essentially affects the white matter of the central nervous system. The diagnosis is based on clinical-imaging and developmental findings. Magnetic resonance imaging of the brain is the most useful diagnostic tool. The disease course is usually monophasic and the preferred initial treatment is with corticoids. PATIENTS AND METHODS: We conducted a retrospective study of 18 patients with a presumptive diagnosis of ADEM. Symptoms, imaging findings, progress and treatment were analysed. The definitive diagnosis was established in 12 patients, excluding one patient with positive polymerase chain reaction for herpes simplex virus in cerebrospinal fluid, one with a clinical picture that was consistent but normal magnetic resonance imaging of the brain, and four with an onset that was similar to ADEM whose definitive diagnoses were: Rassmusen's syndrome, haemophagocytic syndrome, brain tumour, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). RESULTS: The median age was 31 months with no predominance of either sex. Infection of the upper respiratory tract was the most frequent cause in children over 2 years of age and of the gastrointestinal tract in those under the age of 2. All of them presented altered levels of consciousness and multifocal neurological deficits. The most frequent imaging finding was multifocal alteration of the white matter in both hemispheres. Corticoids were the preferred treatment in most cases. Progression was favourable in nearly all patients except for two, who were left with important sequelae. CONCLUSIONS: ADEM may present at any age, including in infants. There are a number of conditions that can mimic ADEM in the early stages.

TITLE: Analisis de una serie de casos con diagnostico inicial de encefalomielitis aguda diseminada en el periodo 2000-2010.Introduccion. La encefalomielitis aguda diseminada (EMAD) es una enfermedad desmielinizante que afecta fundamentalmente a la sustancia blanca del sistema nervioso central. El diagnostico se basa en hallazgos clinicorradiologicos y evolutivos. La resonancia magnetica cerebral es la herramienta diagnostica mas util. El curso suele ser monofasico y el tratamiento inicial de eleccion, los corticoides. Pacientes y metodos. Estudio retrospectivo de 18 pacientes con diagnostico de sospecha inicial de EMAD. Se analizo la sintomatologia, los hallazgos radiologicos, la evolucion y el tratamiento. El diagnostico definitivo se establecio en 12 pacientes, excluyendo un paciente con reaccion en cadena de la polimerasa positiva para el virus herpes simple en el liquido cefalorraquideo, uno con clinica compatible pero resonancia magnetica cerebral normal, y cuatro con inicio similar a EMAD cuyos diagnosticos definitivos fueron: sindrome de Rassmusen, sindrome hemofagocitico, tumor cerebral y MELAS (encefalomiopatia mitocondrial con acidosis lactica y accidentes cerebrovasculares). Resultados. La mediana de edad fue de 31 meses, sin predominio de sexo. La infeccion de la via respiratoria superior fue la causa mas frecuente en niños mayores y la gastrointestinal, en menores de 2 años. Todos presentaron alteracion en el nivel de conciencia y deficits neurologicos multifocales. El hallazgo radiologico mas frecuente fue la alteracion multifocal bihemisferica de la sustancia blanca. Los corticoides fueron el tratamiento de eleccion en la mayoria. La evolucion fue favorable en casi todos los pacientes excepto en dos, que tuvieron secuelas importantes. Conclusiones. La EMAD puede presentarse a cualquier edad, incluyendo lactantes. Hay multiples entidades que pueden simular una EMAD en un inicio.

[MCT8-specific thyroid hormone cell transporter deficiency: a case report and review of the literature]. / Deficiencia del transportador celular de hormona tiroidea MCT8: caso clinico y revision de la bibliografia.

INTRODUCTION: MCT8 is a specific transporter for the T4 and T3 thyroid hormones that allows their entry in the brain and other organs. Mutations in MCT8 (Allan-Herndon-Dudley syndrome) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma T3 and low T4. AIM: We describe the first case diagnosed in Spain with this syndrome and review the published literature about this topic. We both review the various clinical presentations, genetic advances, differential diagnosis and therapeutic perspectives of this syndrome and propose a diagnostic algorithm for it. CASE REPORT: A 5 year-old boy, with a clinical picture compatible with Pelizaeus-Merzbacher disease. PLP1 gene sequencing showed no abnormalities. All the genetic and metabolic studies conducted were normal. Finally, a complete study of thyroid profile revealed abnormalities that were consistent with MCT8 transporter deficiency. The sequencing of the SLC16A2 gene (MCT8) showed a mutation in exon 3 and the study made at a cellular level, has confirmed that this mutation changes the properties of the protein. CONCLUSIONS: In the last five years, there have been many publications about this syndrome, with the identification of more than 50 families worldwide. It is important to both know and suspect this syndrome, because the diagnosis is easy, cheap and accessible (thyroid profile) and, although it has no specific treatment, early diagnosis prevents unnecessary testing and allows to offer genetic counseling to the families affected by it.

TITLE: Deficiencia del transportador celular de hormona tiroidea MCT8: caso clinico y revision de la bibliografia.Introduccion. El MCT8 es un transportador especifico para las hormonas tiroideas T4 y T3, que permite su entrada en el cerebro y otros organos. La deficiencia de MCT8, o sindrome de Allan-Herndon-Dudley, es un trastorno ligado a X que, generalmente, se presenta como un cuadro neurologico grave de inicio precoz, con un perfil tiroideo caracteristico (aumento de T3 y disminucion de T4 y rT3). Objetivo. Se presenta el primer caso diagnosticado en España con este sindrome y se revisa la bibliografia publicada, las distintas formas de presentacion clinica, los avances geneticos, el diagnostico diferencial y las perspectivas terapeuticas, y se propone un algoritmo diagnostico. Caso clinico. Varon de 5 años con un cuadro clinico compatible con una enfermedad de Pelizaeus-Merzbacher. La secuenciacion del gen PLP1 no mostro alteraciones. Todos los estudios metabolicos y geneticos realizados fueron normales. Finalmente, un estudio completo del perfil tiroideo revelo alteraciones compatibles con una deficiencia del transportador MCT8. La secuenciacion del gen SLC16A2 (MCT8) mostro una mutacion en el exon 3 y el estudio celular confirmo que esta mutacion cambia las propiedades de la proteina. Conclusiones. En los ultimos años se han multiplicado las publicaciones sobre este sindrome, con la identificacion de mas de 50 familias en el mundo. Es importante conocer este sindrome y sospecharlo, porque el diagnostico es facil, economico y accesible (perfil tiroideo), y, aunque no tiene tratamiento especifico, el diagnostico precoz evita pruebas innecesarias y permite ofrecer consejo genetico a las familias afectadas.

Deficiencia del transportador celular de hormona tiroidea MCT8: caso clínico y revisión de la bibliografía / MCT8-specific thyroid hormone cell transporter deficiency: a case report and review of the literature

Introducción. El MCT8 es un transportador específico para las hormonas tiroideas T4 y T3, que permite su entrada en elcerebro y otros órganos. La deficiencia de MCT8, o síndrome de Allan-Herndon-Dudley, es un trastorno ligado a X que, generalmente, se presenta como un cuadro neurológico grave de inicio precoz, con un perfil tiroideo característico (aumento de T3 y disminución de T4 y rT3). Objetivo. Se presenta el primer caso diagnosticado en España con este síndrome y se revisa la bibliografía publicada, las distintas formas de presentación clínica, los avances genéticos, el diagnóstico diferencial y las perspectivas terapéuticas, y se propone un algoritmo diagnóstico. Caso clínico. Varón de 5 años con un cuadro clínico compatible con una enfermedad de Pelizaeus-Merzbacher. La secuenciación del gen PLP1 no mostró alteraciones. Todos los estudios metabólicos y genéticos realizados fueron normales. Finalmente, un estudio completo del perfil tiroideo reveló alteraciones compatibles con una deficiencia del transportador MCT8. La secuenciación del gen SLC16A2 (MCT8) mostró una mutación en el exón 3 y el estudio celular confirmó que esta mutación cambia las propiedades de la proteína. Conclusiones. En los últimos años se han multiplicado las publicaciones sobre este síndrome, con la identificación de más de 50 familias en el mundo. Es importante conocer este síndrome y sospecharlo, porque el diagnóstico es fácil, económico y accesible (perfil tiroideo), y, aunque no tiene tratamiento específico, el diagnóstico precoz evita pruebas innecesarias y permite ofrecer consejo genético a las familias afectadas (AU)

Introduction. MCT8 is a specific transporter for the T4 and T3 thyroid hormones that allows their entry in the brain and other organs. Mutations in MCT8 (Allan-Herndon-Dudley syndrome) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma T3 and low T4. Aim. We describe the first case diagnosed in Spain with this syndrome and review the published literature about this topic. We both review the various clinical presentations, genetic advances, differential diagnosis and therapeutic perspectives of this syndrome and propose a diagnostic algorithm for it. Case report. A 5 year-old boy, with a clinical picture compatible with Pelizaeus-Merzbacher disease. PLP1 gene sequencing showed no abnormalities. All the genetic and metabolic studies conducted were normal. Finally, a complete study of thyroid profile revealed abnormalities that were consistent with MCT8 transporter deficiency. The sequencing of the SLC16A2 gene (MCT8) showed a mutation in exon 3 and the study made at a cellular level, has confirmed that this mutation changes the properties of the protein. Conclusions. In the last five years, there have been many publications about this syndrome, with the identification ofmore than 50 families worldwide. It is important to both know and suspect this syndrome, because the diagnosis is easy, cheap and accessible (thyroid profile) and, although it has no specific treatment, early diagnosis prevents unnecessary testing and allows to offer genetic counseling to the families affected by it (AU)

Detection by Urinary GAG Testing of Mucopolysaccharidosis Type II in an At-Risk Spanish Population.

Hunter syndrome (Mucopolysaccharidosis type II) is an inherited lysosomal storage disorder with potentially severe degenerative consequences. Clinical diagnosis is not easy, although biochemical confirmation is straightforward, and sometimes patients are diagnosed at a late age. It is widely believed, for inborn errors of metabolism in general, that early diagnosis and management is of paramount importance for improving the prognosis of the disease. The objective of this study was to identify specific populations at risk of suffering from Hunter syndrome. Urine samples were obtained from children between the ages of 0 to 18, belonging to known risk groups of mucopolysaccharidosis (MPS) type II, for the semi-quantitative (GAG test) and quantitative determination of glycosaminoglycans (GAG). One case of Hunter syndrome was found among the 130 samples that were collected and analysed. This study supports the feasibility of early diagnosis and the usefulness of screening tests for MPS II in specific paediatric populations.

Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy.

OBJECTIVE: Sepiapterin reductase deficiency (SRD) is an under-recognized levodopa-responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms. METHODS: Forty-three individuals with SRD were identified from 23 international medical centers. The phenotype and treatment response were assessed by chart review using a detailed standardized instrument and by literature review for cases for which records were unavailable. RESULTS: In most cases, motor and language delays, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit become evident in infancy or childhood. Average age of onset is 7 months, with delay to diagnosis of 9.1 years. Misdiagnoses of cerebral palsy (CP) are common. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Cerebrospinal fluid findings are distinctive. Diagnosis is confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts. INTERPRETATION: Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction.

Hunter syndrome: resolution of extensive typical skin lesions after 9 months of enzyme replacement therapy with idursulfase.

A 10-year-old boy with Hunter syndrome and extensive typical skin lesions underwent 9 months of enzyme replacement therapy, after which the skin lesions disappeared. We believe that treatment with idursulfase probably removes the cutaneous storage of glucosaminoglycans in Hunter syndrome.