New variants expand the neurological phenotype of COQ7 deficiency.

The protein encoded by COQ7 is required for CoQ synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients.

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.

The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency.

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.

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.

Mutations of GEMIN5 are associated with coenzyme Q deficiency: long-term follow-up after treatment.

GEMIN5 exerts key biological functions regulating pre-mRNAs intron removal to generate mature mRNAs. A series of patients were reported harboring mutations in GEMIN5. No treatments are currently available for this disease.

Metabolic characterization of neurogenetic disorders involving glutamatergic neurotransmission.

The study of inborn errors of neurotransmission has been mostly focused on monoamine disorders, GABAergic and glycinergic defects. The study of the glutamatergic synapse using the same approach than classic neurotransmitter disorders is challenging due to the lack of biomarkers in the CSF. A metabolomic approach can provide both insight into their molecular basis and outline novel therapeutic alternatives.

ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures.

Purpose: ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders.

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.

Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity.

Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404).

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

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.

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

Purpose: Inborn errors of neurotransmitters are rare monogenic diseases. In general, conventional neuroimaging is not useful for diagnosis. Nevertheless, advanced neuroimaging techniques could provide novel diagnosis and prognosis biomarkers.

Paradigmatic De Novo Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum.

Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting genes (mostly , and genes), which encode for the GluN subunit of the -methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present.

Methods: In this study, we aimed to delineate the structural and functional alterations of disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH deficiency (mean IQ 84, range 40-129).

U-IMD: the first Unified European registry for inherited metabolic diseases.

Background: Following the broad application of new analytical methods, more and more pathophysiological processes in previously unknown diseases have been elucidated. The spectrum of clinical presentation of rare inherited metabolic diseases (IMDs) is broad and ranges from single organ involvement to multisystemic diseases. With the aim of overcoming the limited knowledge about the natural course, current diagnostic and therapeutic approaches, the project has established the first unified patient registry for IMDs that fully meets the requirements of the European Infrastructure for Rare Diseases (ERDRI).

GRIN database: A unified and manually curated repertoire of GRIN variants.

Glutamatergic neurotransmission is crucial for brain development, wiring neuronal function, and synaptic plasticity mechanisms. Recent genetic studies showed the existence of autosomal dominant de novo GRIN gene variants associated with GRIN-related disorders (GRDs), a rare pediatric neurological disorder caused by N-methyl- d-aspartate receptor (NMDAR) dysfunction. Notwithstanding, GRIN variants identification is exponentially growing and their clinical, genetic, and functional annotations remain highly fragmented, representing a bottleneck in GRD patient's stratification.

Disease-associated GRIN protein truncating variants trigger NMDA receptor loss-of-function.

De novo GRIN variants, encoding for the ionotropic glutamate NMDA receptor subunits, have been recently associated with GRIN-related disorders, a group of rare paediatric encephalopathies. Current investigational and clinical efforts are focused to functionally stratify GRIN variants, towards precision therapies of this primary disturbance of glutamatergic transmission that affects neuronal function and brain. In the present study, we aimed to comprehensively delineate the functional outcomes and clinical phenotypes of GRIN protein truncating variants (PTVs)-accounting for ~20% of disease-associated GRIN variants-hypothetically provoking NMDAR hypofunctionality.