Elisenda Cortès‐Saladelafont

Hospital Sant Joan de Déu Barcelona

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ÀG

Àngels García‐Cazorla

Hospital Sant Joan de Déu Barcelona

Rafael Artuch

Hospital Sant Joan de Déu Barcelona

ÁG

Ángeles García‐Cazorla

Hospital Sant Joan de Déu Barcelona

Sven F. Garbade

University Hospital Heidelberg

Georg F. Hoffmann

University Hospital Heidelberg

Thomas Opladen

University Hospital Heidelberg

Kathrin Jeltsch

University Hospital Heidelberg

Oya Kuseyri Hübschmann

Heidelberg University

Alberto Burlina

University of Padua

Gabriella Horváth

British Columbia Children's Hospital

Cooperative Institutions

Centre for Biomedical Network Research on Rare Diseases

Instituto de Salud Carlos III

Hospital Sant Joan de Déu Barcelona

Universitat de Barcelona

Centro de Investigación Biomédica en Red

University Hospital Heidelberg

Heidelberg University

Instituto de Investigación de Enfermedades Raras

Institut de Recerca Sant Joan de Déu

University College London

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Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

Orphanet Journal of Rare Diseases (2020)

Thomas Opladen Eduardo López‐Laso Elisenda Cortès‐Saladelafont Toni S. Pearson Serap Sivri

Abstract Background Tetrahydrobiopterin (BH 4 ) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH 4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH 4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH 4 deficiencies. Conclusion Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH 4 deficient patients.

Hyperphenylalaninemia

Guideline

Biopterin

10.1186/s13023-020-01379-8

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Citations (111)

From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria

Human Mutation (2020)

Matthias Zielonka Sven F. Garbade Florian Gleich Jürgen G. Okun Sandesh C.S. Nagamani

Argininosuccinic aciduria (ASA) is an inherited urea cycle disorder and has a highly variable phenotypic spectrum ranging from individuals with lethal hyperammonemic encephalopathy, liver dysfunction, and cognitive deterioration, to individuals with a mild disease course. As it is difficult to predict the phenotypic severity, we aimed at identifying a reliable disease prediction model. We applied a biallelic expression system to assess the functional impact of pathogenic argininosuccinate lyase (ASL) variants and to determine the enzymatic activity of ASL in 58 individuals with ASA. This cohort represented 42 ASL gene variants and 42 combinations in total. Enzymatic ASL activity was compared with biochemical and clinical endpoints from the UCDC and E-IMD databases. Enzymatic ASL activity correlated with peak plasma ammonium concentration at initial presentation and with the number of hyperammonemic events (HAEs) per year of observation. Individuals with ≤9% of enzymatic activity had more severe initial decompensations and a higher annual frequency of HAEs than individuals above this threshold. Enzymatic ASL activity also correlated with the cognitive outcome and the severity of the liver disease, enabling a reliable severity prediction for individuals with ASA. Thus, enzymatic activity measured by this novel expression system can serve as an important marker of phenotypic severity.

Argininosuccinate lyase

Hyperammonemia

Liver disease

10.1002/humu.23983

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Citations (19)

Gamma‐aminobutyric acid levels in cerebrospinal fluid in neuropaediatric disorders

Developmental Medicine & Child Neurology (2018)

Elisenda Cortès‐Saladelafont Marta Molero‐Luis Daniel Cuadras Mercedes Casado Judith Armstrong

Aim Gamma‐aminobutyric acid ( GABA ) is a major modulator in brain maturation and its role in many different neurodevelopmental disorders has been widely reported. Although the involvement of GABA in different disorders has been related to its regulatory function as an inhibitory neurotransmitter in the mature brain, co‐transmitter, and signalling molecule, little is known about its role as a clinical biomarker in neuropaediatric disorders. The aim of this study is to report the cerebrospinal fluid ( CSF ) free‐ GABA concentrations in a large cohort of patients ( n =85) with different neurological disorders. Method GABA was measured in the CSF of neuropaediatric patients using capillary electrophoresis with laser‐induced fluorescence detection. Other neurotransmitters (amino acids and monoamines) were also analysed. Results GABA concentrations in CSF were abnormal, with a greater frequency (44%) than monoamines (20%) in neuropaediatric patients compared with our reference values. Although we included a few patients with inborn errors of metabolism, GABA levels in CSF were more frequently abnormal in metabolic disorders than in other nosological groups. Interpretation Our work suggests further research into brain GABA ergic status in neuropaediatric disorders, which could also lead to new therapeutic strategies. What this paper adds Homeostasis of GABA seems more vulnerable than that of monoamines in the developing brain. The highest GABA levels are found in the primary GABA neurotransmitter disorder SSADH deficiency. GABA alterations are not specific for any clinical or neuroimaging presentation.

Gamma-Aminobutyric Acid

10.1111/dmcn.13746

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Citations (9)

Metabolopathy with characteristic clinical triad: Sengers syndrome

Anales de Pediatría (English Edition) (2024)

Laura Naqui Xicota Elisenda Cortès‐Saladelafont Elena Berrocal Acevedo Andrea Ros Peña Berta Brussosa Ventura

Triad (sociology)

10.1016/j.anpede.2024.11.001

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Citations (0)

Volumetric study of brain MRI in a cohort of patients with neurotransmitter disorders

Neuroradiology (2022)

Chiara Alfonsi Christian Stephan‐Otto Elisenda Cortès‐Saladelafont Natalia Juliá Palacios Inés Podzamczer‐Valls

Gyrus

Neuropsychiatry

Neurochemistry

10.1007/s00234-022-02989-8

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Citations (2)

Correction to: Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

Orphanet Journal of Rare Diseases (2020)

Thomas Opladen Eduardo López‐Laso Elisenda Cortès‐Saladelafont Toni S. Pearson Serap Sivri

An amendment to this paper has been published and can be accessed via the original article.

Guideline

Human genetics

10.1186/s13023-020-01464-y

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Citations (20)

Monoamine neurotransmitters in early epileptic encephalopathies: New insights into pathophysiology and therapy

Developmental Medicine & Child Neurology (2022)

Natalia Juliá‐Palacios Cristina Molina‐Anguita María Sigatulina Bondarenko Elisenda Cortès‐Saladelafont Javier Aparicio

Aim To study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients. Method Two hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0–3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non‐progressive disorders, infantile spasms, Doose syndrome, Lennox–Gastaut syndrome, Landau–Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments. Results Abnormal neurotransmitter values were identified in 68 (33%) patients. 5‐Hydroxyindoleacetic acid (5‐HIAA) deficit was the most prevalent alteration (91%). Low CSF 5‐HIAA levels were significantly higher in 1‐ to 3‐year‐old children. A negative significant correlation was found between 5‐HIAA levels and epilepsy duration before CSF study (Spearman's ρ =−0.191, p =0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5‐HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills. Interpretation A considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy. What this paper adds 5‐Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.

10.1111/dmcn.15140

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Citations (7)

Unraveling Molecular Pathways Altered in MeCP2-Related Syndromes, in the Search for New Potential Avenues for Therapy

Biomedicines (2021)

A Castells Rafel Balada Alba Tristán‐Noguero Mar O’Callaghan Elisenda Cortès‐Saladelafont

Methyl-CpG-binding protein 2 (MeCP2) is an X-linked epigenetic modulator whose dosage is critical for neural development and function. Loss-of-function mutations in MECP2 cause Rett Syndrome (RTT, OMIM #312750) while duplications in the Xq28 locus containing MECP2 and Interleukin-1 receptor-associated kinase 1 (IRAK1) cause MECP2 duplication syndrome (MDS, OMIM #300260). Both are rare neurodevelopmental disorders that share clinical symptoms, including intellectual disability, loss of speech, hand stereotypies, vasomotor deficits and seizures. The main objective of this exploratory study is to identify novel signaling pathways and potential quantitative biomarkers that could aid early diagnosis and/or the monitoring of disease progression in clinical trials. We analyzed by RT-PCR gene expression in whole blood and microRNA (miRNA) expression in plasma, in a cohort of 20 females with Rett syndrome, 2 males with MECP2 duplication syndrome and 28 healthy controls, and correlated RNA expression with disease and clinical parameters. We have identified a set of potential biomarker panels for RTT diagnostic and disease stratification of patients with microcephaly and vasomotor deficits. Our study sets the basis for larger studies leading to the identification of specific miRNA signatures for early RTT detection, stratification, disease progression and segregation from other neurodevelopmental disorders. Nevertheless, these data will require verification and validation in further studies with larger sample size including a whole range of ages.

Rett Syndrome

MeCP2

10.3390/biomedicines9020148

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Citations (2)

The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency

Journal of Inherited Metabolic Disease (2024)

Natalia Juliá‐Palacios Oya Kuseyri Hübschmann Mireia Olivella Roser Pons Gabriella Horváth

Abstract The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long‐term follow‐up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8–33.4 years) showed a diversifying course in follow‐up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.

Movement Disorders

Choreoathetosis

10.1002/jimd.12723

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Citations (3)

Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Genetics in Medicine (2023)

Roland Posset Sven F. Garbade Florian Gleich Svenja Scharre Jürgen G. Okun

Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed.

10.1016/j.gim.2023.101039

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Citations (4)