REVEAL-CP: Selective Screening of Pediatric Patients for Aromatic L-Amino Acid Decarboxylase Deficiency with a Guthrie Card and Structural Modeling of One Index Case.

The main objective of this prospective, multicenter study (REVEAL-CP) was to test children with cerebral palsy-like signs and symptoms for raised 3--methyldopa (3-OMD) blood levels, a biomarker for aromatic L-amino acid decarboxylase deficiency (AADCd). A secondary objective was to characterize the molecular basis for the defective aromatic L-amino acid decarboxylase (AADC) gene product. Patients were identified in pediatric secondary and tertiary care hospitals through database searches and personal communication.

A crucial active site network of titratable residues guides catalysis and NAD binding in human succinic semialdehyde dehydrogenase.

Human succinic semialdehyde dehydrogenase is a mitochondrial enzyme fundamental in the neurotransmitter γ-aminobutyric acid catabolism. It catalyzes the NAD-dependent oxidative degradation of its derivative, succinic semialdehyde, to succinic acid. Mutations in its gene lead to an inherited neurometabolic rare disease, succinic semialdehyde dehydrogenase deficiency, characterized by mental and developmental delay.

Mild/moderate phenotypes in AADC deficiency: Focus on the aromatic amino acid decarboxylase protein.

AADC deficiency is a severe neurometabolic inherited rare disorder due to the absence or decrease of dopamine and serotonin levels, causing deep motor and neurodevelopmental impairments. The disease is often fatal in the first decade of life, and pharmacological treatments (dopamine agonists, pyridoxine, and monoamine oxidase inhibitors as the first-line choices) can only alleviate the symptoms. Gene therapy surgery is now available for severe patients in the European Union and the United Kingdom, and follow-up data witness encouraging improvements.

Functional Characterization of a Spectrum of Genetic Variants in a Family with Succinic Semialdehyde Dehydrogenase Deficiency.

Succinic semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter γ-amino butyric acid. Pathogenic variants in the gene encoding this enzyme cause SSADH deficiency, a developmental disease that manifests as hypotonia, autism, and epilepsy. SSADH deficiency patients usually have family-specific gene variants.

Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder.

Background: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy.

Methods: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy.

Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency.

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction.

An attenuated, adult case of AADC deficiency demonstrated by protein characterization.

A case of an adult with borderline AADC deficiency symptoms is presented here. Genetic analysis revealed that the patient carries two AADC variants (NM_000790.3: c.

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits.

Case report: Childhood epilepsy and borderline intellectual functioning hiding an AADC deficiency disorder associated with compound heterozygous gene pathogenic variants.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder leading to severe combined serotonin, dopamine, norepinephrine, and epinephrine deficiency. We report on a female patient with borderline functioning and sporadic clear-cut focal to bilateral seizures from age 10 years. A neuropsychological assessment highlighted a mild impairment in executive functions, affecting attention span and visual-spatial abilities.

Acceptability of Switching to Long-Acting Cabotegravir and Rilpivirine Among People Living with HIV on Dolutegravir/Rilpivirine Combination: A Single-Center Experience.

The availability of long-acting cabotegravir and rilpivirine injection combination requires some changes in service delivery of outpatient HIV clinics; it is therefore important for clinicians to know the potential number of people living with HIV (PLWH) who are interested in a long-acting antiretroviral treatment. We aimed to determine in an outpatient clinic the number of PLWH, on dolutegravir/rilpivirine, accepting a switch to an injectable long-acting antiretroviral treatment, and the reasons underlying this choice. In our single-center study, in this subset of HIV-infected patients, the main cause for refusal of a long-acting injectable regimen was the need for the administration to be done in hospital, as required in Italy, suggesting that current regulations about this aspect must be changed.

Active site serine-193 modulates activity of human aromatic amino acid decarboxylase.

Aromatic amino acid decarboxylase is a pyridoxal 5'-phosphate-dependent enzyme responsible for the synthesis of the neurotransmitters, dopamine and serotonin. Here, by a combination of bioinformatic predictions and analyses, phosphorylation assays, spectroscopic investigations and activity measurements, we determined that Ser-193, a conserved residue located at the active site, can be phosphorylated, increasing catalytic efficiency. In order to determine the molecular basis for this functional improvement, we determined the structural and kinetic properties of the site-directed variants S193A, S193D and S193E.

Phenotypic Correlates of Structural and Functional Protein Impairments Resultant from ALDH5A1 Variants.

Objective: To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism.

Methods: Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics.

Human aromatic amino acid decarboxylase is an asymmetric and flexible enzyme: Implication in aromatic amino acid decarboxylase deficiency.

Human aromatic amino acid decarboxylase (AADC) is a pyridoxal 5'-phosphate-dependent enzyme responsible for the biosynthesis of dopamine and serotonin, essential neurotransmitters involved in motor and cognitive abilities. Mutations in its gene lead to AADC deficiency, a monogenic rare neurometabolic childhood parkinsonism characterized by severe motor and neurodevelopmental symptoms. Here, for the first time, we solved the crystal structure of human holoAADC in the internal aldimine (1.

Exome sequencing data screening to identify undiagnosed Aromatic l-amino acid decarboxylase deficiency in neurodevelopmental disorders.

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in the DDC gene and mainly characterized by developmental delay, hypotonia, and oculogyric crises. Early diagnosis is crucial for correct patient management; however, many patients remain misdiagnosed or undiagnosed due to the rarity and clinical heterogeneity of the disorder especially in the milder forms. Here, we applied exome sequencing approach by screening 2000 paediatric patients with neurodevelopmental disorders to identify possible new AADC variants and AADC deficiency patients.

The presence and severity of epilepsy coincide with reduced γ-aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency.

Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation.

Validation of CORE-MD PMS Support Tool: A Novel Strategy for Aggregating Information from Notices of Failures to Support Medical Devices' Post-Market Surveillance.

Introduction: The EU Medical Device Regulation 2017/745 defines new rules for the certification and post-market surveillance of medical devices (MD), including an additional review by Expert Panels of clinical evaluation data for high-risk MD if reports and alerts suggest possibly associated increased risks. Within the EU-funded CORE-MD project, our aim was to develop a tool to support such process in which web-accessible safety notices (SN) are automatically retrieved and aggregated based on their specific MD categories and the European Medical Device Nomenclature (EMDN) classification by applying an Entity Resolution (ER) approach to enrich data integrating different sources. The performance of such approach was tested through a pilot study on the Italian data.

The Integrated Approach to Inherited Disorders in Neurotransmitters from Molecules to Systems.

This Special Issue focusses on monoamine neurotransmitters responsible for mediating neuronal transmission [...

Compound Heterozygosis in AADC Deficiency and Its Complex Phenotype in Terms of AADC Protein Population.

Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease due to mutations in the gene producing AADC, a homodimeric pyridoxal 5'-phosphate-dependent enzyme. The disorder is often fatal in the first decade and is characterized by profound motor impairments and developmental delay. In the last two years, there has been a net rise in the number of patients and variants identified, maybe also pushed by the ongoing gene therapy trials.