A Missense Variant in HACE1 Is Associated with Intellectual Disability, Epilepsy, Spasticity, and Psychomotor Impairment in a Pakistani Kindred.

Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person's intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.

Phosphoserine aminotransferase deficiency diagnosed by whole-exome sequencing and LC-MS/MS reanalysis: A case report and review of literature.

BACKGROUND: Phosphoserine aminotransferase deficiency (PSATD) is an autosomal recessive disorder associated with hypertonia, psychomotor retardation, and acquired microcephaly. Patients with PSATD have low concentrations of serine in plasma and cerebrospinal fluid. METHODS: We reported a 2-year-old female child with developmental delay, dyskinesia, and microcephaly. LC-MS/MS was used to detect amino acid concentration in the blood and whole-exome sequencing (WES) was used to identify the variants. PolyPhen-2 web server and PyMol were used to predict the pathogenicity and changes in the 3D model molecular structure of protein caused by variants. RESULTS: WES demonstrated compound heterozygous variants in PSAT1, which is associated with PSATD, with a paternal likely pathogenic variant (c.235G>A, Gly79Arg) and a maternal likely pathogenic variant (c.43G>C, Ala15Pro). Reduced serine concentration in LC-MS/MS further confirmed the diagnosis of PSATD in this patient. CONCLUSIONS: Our findings demonstrate the importance of WES combined with LC-MS/MS reanalysis in the diagnosis of genetic diseases and expand the PSAT1 variant spectrum in PSATD. Moreover, we summarize all the cases caused by PSAT1 variants in the literature. This case provides a vital reference for the diagnosis of future cases.

Transcriptional and metabolic effects of aspartate-glutamate carrier isoform 1 (AGC1) downregulation in mouse oligodendrocyte precursor cells (OPCs).

Aspartate-glutamate carrier isoform 1 (AGC1) is a carrier responsible for the export of mitochondrial aspartate in exchange for cytosolic glutamate and is part of the malate-aspartate shuttle, essential for the balance of reducing equivalents in the cells. In the brain, mutations in SLC25A12 gene, encoding for AGC1, cause an ultra-rare genetic disease, reported as a neurodevelopmental encephalopathy, whose symptoms include global hypomyelination, arrested psychomotor development, hypotonia and seizures. Among the biological components most affected by AGC1 deficiency are oligodendrocytes, glial cells responsible for myelination processes, and their precursors [oligodendrocyte progenitor cells (OPCs)]. The AGC1 silencing in an in vitro model of OPCs was documented to cause defects of proliferation and differentiation, mediated by alterations of histone acetylation/deacetylation. Disrupting AGC1 activity could possibly reduce the availability of acetyl groups, leading to perturbation of many biological pathways, such as histone modifications and fatty acids formation for myelin production. Here, we explore the transcriptome of mouse OPCs partially silenced for AGC1, reporting results of canonical analyses (differential expression) and pathway enrichment analyses, which highlight a disruption in fatty acids synthesis from both a regulatory and enzymatic stand. We further investigate the cellular effects of AGC1 deficiency through the identification of most affected transcriptional networks and altered alternative splicing. Transcriptional data were integrated with differential metabolite abundance analysis, showing downregulation of several amino acids, including glutamine and aspartate. Taken together, our results provide a molecular foundation for the effects of AGC1 deficiency in OPCs, highlighting the molecular mechanisms affected and providing a list of actionable targets to mitigate the effects of this pathology.

SBP lança tradução de Cartilha de Desenvolvimento, elaborada pelo Centers of Disease Control and Prevention

A Sociedade Brasileira de Pediatria (SBP), em parceria com a Sociedade Paraibana de Pediatria (SPP), lança nesta semana a “Cartilha de Desenvolvimento – 2 meses a 5 anos”. O conteúdo – elaborado pelo Centers of Disease Control and Prevention (CDC), dos Estados Unidos – foi oficialmente traduzido para o Português por pediatra com expertise em Desenvolvimento Infantil e apresenta o programa “Act Early”, cujo intuito é auxiliar na identificação precoce de atrasos do neurodesenvolvimento.

Psychomotor Slowing in Psychosis and Inhibitory Repetitive Transcranial Magnetic Stimulation: A Randomized Clinical Trial.

Importance: Psychomotor slowing is a frequent symptom of psychosis, impairing gross and fine motor behavior. It is associated with poor outcomes and functioning, and no treatment is available. Objective: To investigate whether 15 sessions of inhibitory repetitive transcranial magnetic stimulation (rTMS) may reduce psychomotor slowing. Design, Setting, and Participants: This was a 4-arm, double-blind, randomized, sham-controlled trial at a university hospital in Switzerland. Enrollment took place from March 2019 to August 2022. Adults aged 18 to 60 years with schizophrenia spectrum disorders and severe psychomotor slowing were eligible. All patients continued existing medications, including antipsychotics and benzodiazepines. Those with substance misuse (other than nicotine), conditions associated with impaired or aberrant movement, convulsions, history of hearing problems, other conditions typically excluded from magnetic resonance imaging or TMS, any TMS treatment in the past 3 months, or those who were pregnant or breastfeeding were excluded. Of 615 patients screened for eligibility, 103 were randomized and 88 received at least 1 session of rTMS: 22 were assigned to 1-Hz rTMS, 22 to iTBS, 22 to sham, and 22 to the waiting group. Follow-up was conducted at 6 weeks and 24 weeks following the week 3 assessments including clinical, functional, and motor measures. Interventions: Fifteen sessions of rTMS in 3 weeks over the supplementary motor area: 1-Hz rTMS, iTBS, sham, or no treatment (waiting). After 3 weeks, the waiting group received 15 sessions of 1-Hz rTMS over the supplementary motor area. Main Outcomes and Measures: The main outcome was the proportion of responders at week 3 in the Salpêtrière Retardation Rating Scale (SRRS) defined as a 30% or greater reduction from baseline (last-observation-carried-forward). The SRRS has 15 items and a maximum total score of 60. Results: Of the 88 participants analyzed, 45 were men and 43 were women. The mean (SD) age was 36.3 (12.4) years and the mean (SD) SRRS score was 24.0 (5.9). A total of 69 participants completed the study. At week 3, response rates differed between groups: 15 of 22 (68%) in the 1-Hz rTMS group, 8 of 22 (36%) in the iTBS group, 7 of 22 (32%) in the sham group, and 4 of 22 (18%) in the waiting group (χ23 = 12.1; P = .007). The 1-Hz rTMS group had more responders than sham (odds ratio [OR], 0.13; 95% CI, 0.02-0.65; P = .03), iTBS (OR, 0.12; 95% CI, 0.02-0.61; P = .02), and waiting (OR, 0.04; 95% CI, 0.01-0.22; P = .003). In the waiting group, 10 of 16 participants (63%) responded after receiving 15 sessions of 1-Hz rTMS. No serious adverse events occurred. Conclusions and Relevance: In this study, inhibitory add-on rTMS safely alleviated psychomotor slowing in psychosis compared with iTBS, sham, and no treatment. The treatment was also effective with delayed onset. Future studies need to explore the neural changes associated with supplementary motor area rTMS in psychosis. Trial Registration: ClinicalTrials.gov Identifier: NCT03921450.

Fumarate Hydratase-Deficient Leiomyoma of the Uterine Corpus: Comparative Morphologic Analysis of Protein-Deficient Tumors With and Without Pathogenic Germline Fumarate Hydratase Gene Mutations.

Deficiency of fumarate hydratase (FH) protein expression in uterine corpus leiomyomas may be attributable to either germline or somatic mutations of the FH gene, the former being definitional for the hereditary leiomyomatosis and renal cell cancer syndrome. The authors assess whether, using previously reported FH-associated morphologic features, FH protein-deficient uterine corpus leiomyomas associated with a pathogenic germline mutations of the FH gene (group 1) are distinguishable from FH protein-deficient uterine corpus leiomyomas without such mutations (and whose FH protein loss is presumed to be attributable to somatic/epigenetic inactivation or other unknown phenomena: group 2). Groups 1 and 2 were compared regarding a variety of clinicopathologic features, including 7 core "FH-associated" tumoral morphologic features: staghorn vasculature; alveolar-type edema; bizarre nuclei; chain-like tumor nuclei; hyaline cytoplasmic globules; prominent nucleoli, intranuclear inclusions, and perinucleolar halos; and prominent eosinophilic/fibrillary cytoplasm. Among 2418 patients diagnosed with uterine corpus leiomyoma during the study period, FH-associated morphologic features were reported in 1.5% (37 patients), and FH immunohistochemistry was performed in 29 (1.19%). Fourteen (48.27%) of the 29 patients showed FH protein deficiency by immunohistochemistry. Twelve patients underwent germline testing, of which 8 (66.7%) were classified as group 1 and 4 (33.3%) as group 2. FH protein-deficient tumors were larger (10.44 vs 4.08 cm, P = 0.01) and associated with younger patients (42.05 vs 47.97, P = 0.004) than 370 randomly selected uterine leiomyoma controls. Groups 1 and 2 showed no significant differences in patient age and tumor size. In group 1 tumors, the FH-associated morphologic features were generally present diffusely; all group 1 tumors displayed ≥5 FH-associated features, whereas all group 2 tumors displayed <5 FH-associated features (means 6.5 ± 0.53 vs 3.5 ± 1.00, P < 0.001). Notably, eosinophilic/fibrillary cytoplasm and alveolar-type edema were each significantly more prevalent in group 1 tumors than group 2 tumors (P = 0.018 for both). No single morphologic feature was found to be completely sensitive and specific in making the distinction between group 1 and 2 tumors. Our findings suggest that groups 1 and 2 are unlikely to be morphologically distinguishable by individual morphologic features. Whether there is a combination of features that can reliably make this distinction is unclear and will require additional studies with larger cohorts.

Ketamine in DUID cases in the greater Cologne area.

INTRODUCTION: Ketamine is primarily used as an anaesthetic or for analgesics in medical treatment, but due to its dissociative and hallucinogenic effects, abuse has increased in the past years leading to several drug impaired driving cases. METHODS: Eight DUID (driving under the influence of drugs) cases involving ketamine from two institutes of legal medicine over a period from January 2021 to January 2023 were evaluated. The cases were compared with regard to psychomotor impairments, adverse effects on driving performance and co-consumption of drugs. Analyses of ketamine were carried out by high performance liquid chromatography with diode array detection (HPLC-DAD). Other drugs of abuse were either detected via liquid chromatography with tandem mass spectromety (LC-MS/MS) and/or gas chromatography with (tandem) mass spectrometry (GC-MS(/MS)). RESULTS: Ketamine plasma concentrations in a range of approx. 100-1200 ng/mL (mean: 510 ng/mL, median: 370 ng/mL) were detected. Co-consumption of at least one substance was ascertained in all cases. Besides driving impairments, recorded psychomotor impairments of the drivers comprised e.g. dilated pupils, missing or delayed pupil reactions, a slurred or decelerated speech, delayed reaction, lack of concentration, vertigo or agitation. DISCUSSION: The observed peculiarities were in-line with literature data. However, the assessment and differentiation of ketamine-induced impairments was aggravated due to co-consumption of other drugs of abuse or pharmaceuticals in the herein investigated cases. Nevertheless, in two cases impairments can be attributed mainly to ketamine consumption since the co-consumed substances were only detected in low concentrations. CONCLUSION: The presented cases provide additional data on psychomotor impairments observed in ketamine-related DUID cases. Limiting factors are co-consumption of substances, unknown habituation to drugs and the limited case number. Nevertheless, the results of this study are comparable with existing literature data. Since the abuse of ketamine has increased in the past years, these data will support forensic casework.

Prevalencia de alteraciones en el neurodesarrollo en niños de población rural de Oaxaca evaluados mediante la prueba Evaluación de Desarrollo Infantil / Prevalence of neurodevelopmental disorders in children from the rural population of Oaxaca evaluated by means of the Child Development Evaluation test

Introducción: Durante el desarrollo del niño, el acceso a la salud, la nutrición, las oportunidades de estimulación y el aprendizaje temprano son necesarios para un óptimo desarrollo del sistema nervioso central. En zonas rurales se denota la falta de acceso a ellas, y esto repercute en el neurodesarrollo de los niños. Objetivo: Identificar la prevalencia de rezago o retraso en el desarrollo de niños de población rural.Sujetos y métodos: Estudio descriptivo, transversal y prospectivo, con muestreo no probabilístico de conveniencia, en el que a 97 niños a partir de 1 mes de edad y hasta un día antes de cumplir los 5 años, pertenecientes a comunidades rurales del estado de Oaxaca, México, se les aplicó la Evaluación de Desarrollo Infantil, diseñada y validada para la población mexicana en la detección de problemas del neurodesarrollo. Resultados: La prevalencia de las alteraciones del desarrollo fue del 43%, con predominio en el sexo masculino. El área de desarrollo con mayor afectación fue el lenguaje, con un 29%, y en segundo lugar la motricidad gruesa, con un 18%; sin embargo, las afectaciones neurológicas sólo se presentaron en el 2% de los participantes. Los factores de riesgo de mayor prevalencia fueron las infecciones de las vías urinarias, presentes en el 56% de las madres. Conclusión: Existe un porcentaje mayor del 30% de alteraciones en el neurodesarrollo en comunidades rurales debido a los factores de riesgo social que viven los niños, como el difícil acceso a la atención médica, un ambiente poco estimulante y una mala nutrición.(AU)

Introduction: During child’s growth, access to health, nutrition, opportunities for stimulation, and early learning are necessary for an optimal development of the central nervous system. In rural areas there is a lack of access to them, and this has an impact on children’s neurodevelopment. Objective: To identify the prevalence of lag or delay in the development of children in rural areas. Subjects and methods: A descriptive, cross-sectional and prospective study, with non-probabilistic convenience sampling, where 97 infants from 1 month of age to one day before their 5th birthday, all belonging to rural communities in the state of Oaxaca, Mexico, were applied the Child Development Evaluation, designed and validated for the Mexican population in the early detection of neurodevelopmental problems. Results: The prevalence of developmental disorders was 43%, with predominance in the male sex. The area of development with the greatest affectation was language, with a total of 29%, and in second place gross motor skills, with 18%; however, neurological affectation as the only one occurred in 2% of the participants, the most prevalent risk factors were the urinary tract infections in 56% of mothers. Conclusion: There is a percentage greater than 30% of neurodevelopmental disorders in rural communities due to social risk factors that infants face, such as the difficult access to medical care, a poorly stimulating environment and bad nutrition.(AU)

The Behavioral Mapping of Psychomotor Slowing in Psychosis Demonstrates Heterogeneity Among Patients Suggesting Distinct Pathobiology.

OBJECTIVES: Psychomotor slowing (PS) occurs in up to half of schizophrenia patients and is linked to poorer outcomes. As standard treatment fails to improve PS, novel approaches are needed. Here, we applied the RDoC framework using 3 units of analysis, ie, behavior, self-report, and physiology to test, whether patients with PS are different from patients without PS and controls. METHODS: Motor behavior was compared between 71 schizophrenia patients with PS, 25 without PS, and 42 healthy controls (HC) using 5 different measures: (1) for behavior, an expert rating scale: Motor score of the Salpêtrière Retardation Rating Scale, (2) for self-report, the International Physical Activity Questionnaire; and for physiology, (3) Actigraphy, which accounts for gross motor behavior, (4) Gait velocity, and (5) coin rotation task to assess manual dexterity. RESULTS: The ANCOVAs comparing the 3 groups revealed differences between patients with PS and HC in expert ratings, self-report, and instrumental measures (all P ≤ .001). Patients with PS also scored higher in expert ratings and had lower instrumental activity levels compared to patients without PS (all P ≤ .045). Instrumental activity levels correlated with an expert rating of PS (rho = -0.51, P-fdr corrected <.001) and classified similarly at 72% accuracy. CONCLUSIONS: PS is characterized by slower gait, lower activity levels, and slower finger movements compared to HC. However, only actigraphy and observer ratings enable to clearly disentangle PS from non-PS patients. Actigraphy may become the standard assessment of PS in neuroimaging studies and clinical trials.

Percepções de familiares sobre uma rede de cuidados de saúde mental infantojuvenil / Family perceptions about a children's mental health network / Percepciones familiares sobre una red de atención de salud mental infantojuvenil

Este artigo pretende conhecer como a rede de cuidados em saúde tem se operacionalizado a partir da percepção de familiares de crianças com demanda de cuidado em saúde mental (SM). Foram realizados dois grupos focais, um com familiares da Atenção Básica (AB) e outro com familiares do Centro de Atenção Psicossocial Infantojuvenil (CAPSij), totalizando 15 participantes. Seguiu-se com a análise lexical do tipo classificação hierárquica descendente, com o auxílio do software R Interface, a fim de análises multidimensionais de textos e questionários (IRaMuTeQ), resultando em cinco classes: A Pílula Mágica; Forças e Fraquezas dos serviços; Procurando por ajuda; Aceitando o diagnóstico da criança e Onde procurei ajuda. Os resultados apontam para dificuldades presentes na AB em identificar e manejar situações de Saúde Mental Infantojuvenil (SMIJ), por meio de uma lógica ainda medicalizante. Ressalta-se que a escola é apresentada como lugar de destaque na produção da demanda por cuidado e a família ainda é pouco convocada à construção das ações. Conclui-se, então, que avanços ainda são necessários para operacionalização de um cuidado pautado nas diretrizes da política de SMIJ.(AU)

This article aims to know how the healthcare network has been operationalized from the perception of family members of children with demand for mental health care (MH). Two focus groups were held, one with family members from Primary Care (PC) and the other with family members from the Child Psychosocial Care Center (CAPSij), totaling 15 participants. A lexical analysis of the descending hierarchical classification type was performed with the help of the software R Interface for multidimensional analyzes of texts and questionnaires (IRAMUTEQ), resulting in five classes: The Magic Pill; Strengths and Weaknesses of services; Looking for help; Accepting the child's diagnosis; and Where did I look for help. The results point to difficulties present in PC in identifying and managing situations of mental health in children and adolescents (MHCA), with a medicalization logic. Note that the school is presented as a prominent place in producing the demand for care, and the family is still not very much involved in the actions. It is, thus, concluded that advances are still needed for operationalization of care guided by MHCA policy guidelines.(AU)

Este artículo tuvo por objetivo conocer cómo opera una red asistencial a partir de la percepción de familiares de niños con demanda de atención en salud mental (SM). Se realizaron dos grupos focales, uno con familiares de Atención Primaria (AP) y otro con familiares del Centro de Atención Psicosocial Infantojuvenil (CAPSij), totalizando 15 participantes. Se realizó análisis léxico del tipo clasificación jerárquica descendente con la ayuda del software Interface de R pour les Analyses Multidimensionnelles de Textes et de Questionnaires (IRAMUTEQ), lo que resultó en cinco clases: "La píldora mágica"; "Fortalezas y debilidades de los servicios"; "En busca de ayuda"; "Aceptar el diagnóstico del niño" y "¿Dónde busqué ayuda?". Los resultados apuntan las dificultades presentes en AP para identificar y manejar situaciones de salud mental infantojuvenil (SMIJ) mediante una lógica aún medicalizante. La escuela tiene un lugar destacado en la producción de la demanda de cuidados y la familia aún no está muy involucrada en la construcción de acciones. Se concluye que se necesitan avances para ofertar una atención guiada por lineamientos de la política del SMIJ.(AU)

Os sentidos produzidos por cuidadoras escolares de crianças com SCZV / Los sentidos producidos por cuidadores escolares de niños con SCZV / The senses produced by school caregivers of children with SCZV

RESUMO. Este estudo, fundamentado na perspectiva da psicologia cultural-histórica sobre a pessoa com deficiência, teve por objetivo apreender a dimensão subjetiva da realidade (ou as mediações) das crianças com a Síndrome Congênita do Zika Vírus (SCZV) no contexto escolar de desenvolvimento e aprendizagem a partir dos sentidos produzidos por cuidadoras escolares. Para tal, foram realizadas entrevistas semiestruturadas com três cuidadoras escolares que trabalham em três creches pertencentes ao sistema de educação de ensino de Campina Grande/PB. Para análise dos dados, foi realizado o procedimento dos Núcleos de Significação, que visa à apreensão das contradições que constituem as produções de significação discursiva dos sujeitos participantes. Os resultados indicaram que as cuidadoras escolares priorizam a mediação pedagógica na relação estabelecida com as crianças com SCZV, embora não desconsiderem a instância do cuidado em termos das necessidades especiais relacionadas à integridade psicomotora que essas crianças apresentam. Ademais, foi evidenciado que as participantes salientam as potencialidades das crianças em detrimento da falta ou lesão gerada pela deficiência.

RESUMEN. Este estudio, basado en la perspectiva de la psicología cultural-histórica sobre las personas con discapacidad, tenía como objetivo apreciar la dimensión subjetiva de la realidad de los niños con Síndrome Congénito del Virus del Zika (SCVZ). en el contexto escolar del desarrollo y el aprendizaje de los significados producidos por los cuidadores escolares. Para ello, se realizaron entrevistas semiestructuradas con tres cuidadores escolares de guarderías diferentes que pertenecen al sistema educativo de Campina Grande/PB. Para el análisis de datos, se realizó el procedimiento de los núcleos de significación, cuyo objetivo es aprehender las contradicciones que constituyen las producciones de significado discursiva de los participantes. Los resultados indicaron que los cuidadores de la escuela dan prioridad a la mediación pedagógica en la relación establecida con los niños con SCVZ, aunque no descuidan la instancia de cuidado en cuanto a las necesidades especiales relacionadas con la integridad psicomotora que tienen estos niños. Además, se destacó que los participantes ponen de relieve el potencial de los niños en detrimento de la falta o lesión generada por la discapacidad.

ABSTRACT This study is based by the perspective of the cultural-historical psychology on people with disabilities, aimed to apprehend the subjective dimension of the reality (or mediations) of children with Congenital Zika Virus Syndrome (CZVS) on the school context development and learning from the senses produced by school children caregivers. For this reason, semi-structured interviews were conducted with three caregivers working in three daycare centers belonging to the teaching system of education in Campina Grande/PB. For data analysis, was performed the meaning core, which aims to apprehend the contradictions that constitute the productions of discursive meaning in the participating subjects. The results indicated that school caregivers prioritize the mediation in the relationship established with children CZVS, though not disregard the instance of care in terms of the special needs related to psychomotor integrity that these children have. Furthermore, it was evidenced that the participants emphasize the children's potentialities to the detriment of the lack or injury generated by the disability.

Determinants of the psychomotor development delay in children aged 12 to 59 months infected with HIV in Yaounde, Cameroon.

Introduction: children infected with HIV are at increased risk of impaired neurodevelopmental, due to several environmental factors. Methods: we conducted a cross-sectional analytical study on HIV-infected children aged 12 to 59 months, followed up in five hospitals in Yaounde, Cameroon. Sociodemographic, clinical, and biological variables as well as the antecedents were collected. Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 25 software. The Denver test was used to assess the psychomotor development of these children. Global psychomotor delay, defined as a global development quotient of less than 70 with an alteration in at least two of the four domains of the test, was retained as the primary endpoint. The significance threshold was set at 5%. Results: one hundred and eighty-one children were included in the study. The sex ratio was 0.6. The age range 48-59 months was the most represented. None of these children had a known chronic pathology other than HIV infection. The proportion of global psychomotor delay was 11.04%, with language (16%) and fine motor skills (16%) being the most affected domains of psychomotor development. The independent factors significantly associated with global psychomotor delay were birth weight below 2500 grams (OR= 17.61 [1.76-181.39], p= 0.022), growth retardation (OR= 17.64 [1.63-190.24], p= 0.018) and elevated viral load (OR= 22.75 [2.78-186.02], p= 0.004). Conclusion: psychomotor delay affects about one out of ten children living with HIV. Its occurrence is linked to various factors that must be taken into account in the development of public health policies in connection with the management of HIV infection in children.

Simultaneous assay of urine sepiapterin and creatinine in patients with sepiapterin reductase deficiency.

OBJECTIVES: Sepiapterin reductase deficiency (SRD) causes central nervous system symptoms due to dopamine and serotonin depletion because sepiapterin reductase plays an important role in tetrahydrobiopterin biosynthesis. SRD cannot be detected by newborn screening because of the absent hyperphenylalaninemia. To diagnose SRD biochemically, confirmation of reduced monoamine metabolites and elevated sepiapterin in the cerebrospinal fluid (CSF) has been considered necessary, because a past study showed no elevation of urine sepiapterin. Recently, however, the elevation of urine sepiapterin in SRD was reported. METHODS: We developed a fast method to measure sepiapterin and creatinine simultaneously using high-performance liquid chromatography with fluorescence and ultraviolet detection. Urine sepiapterin and creatinine were measured in three SRD patients, two SRD carriers, four SRD siblings, and 103 non-SRD patients. RESULTS: In the three SRD cases, concentrations of urine sepiapterin were 1086, 914, and 575 µmol/mol creatinine (upper limit: 101.7 µmol/mol creatinine), and were markedly higher than those in other groups. CSF sepiapterin concentration was also measured in one SRD case and it was 4.1 nmol/L (upper limit: 0.5 nmol/L). CONCLUSIONS: The simultaneous determination of urine sepiapterin and creatinine appears helpful for the diagnosis of SRD. This assay system can also be used to measure sepiapterin in the CSF.

[Multicenter retrospective study of 38 cases with fumarate hydratase deficiency uterine leiomyoma].

Objective: To investigate the clinicopathological features of fumarate hydratase (FH) deficiency uterine leiomyoma. Methods: The data of 38 patients with FH deficiency uterine leiomyoma were screened and analyzed. The expressions of FH, S-(2-succino)-cysteine (2SC), desmin, p16, p53, CD10 and cell proliferation associated nuclear antigen (Ki-67) proteins were detected by immunohistochemistry, and their clinicopathological features were analyzed retrospectively. Results: (1) Clinical features: the median age of the patients was (42.5±7.4) years old. Twenty-one cases (55%) of them were myomas found in physical examination, and the median maximum diameter of the tumor was 6.0 cm (range: 5.0-7.5 cm); myomectomy was performed in 23 cases (61%), total hysterectomy with or without bilateral appendages in 15 cases (39%); laparoscopic surgery in 27 cases (71%), open surgery in 11 cases (29%); none of the patients had renal cell carcinoma. (2) Histological features: atypical nuclear cells were distributed locally or diffusely, eosinophilic nucleoli and intranuclear inclusion bodies could be seen, glass like globules could be seen in the cytoplasm, nuclear division was 0-4/10 high power field (HPF), and antler like blood vessels and pulmonary edema-like changes could be seen in the stroma. Among 38 patients with FH deficiency uterine leiomyoma, FH was negative in 37 cases (97%), and positive in 1 case (3%); 2SC, desmin, p16, p53, CD10 and Ki-67 showed focal positive expression in 38 cases (100%), including 35 cases (92%) with Ki-67 index<10% and 3 cases (8%) with Ki-67 index ≥10%. (3) Follow-up: 4 cases (11%) recurred, and there was no death. There were significant differences in age, family history, distribution of atypical nuclei and mitosis number between recurrent group and non-recurrent group (all P<0.05). Conclusions: FH deficiency uterine leiomyoma is a rare tumor, which needs pathological examination,immunohistochemical examination and clinical history. Patients younger than 43 years old, with family history, histologically atypical diffuse nuclear distribution and mitotic number ≥3/10 HPF should be alert to the risk of recurrence.

Psychomotor semiology in depression: a standardized clinical psychomotor approach.

BACKGROUND: Although psychomotor symptoms are associated with the clinical symptomatology of depression, they are rarely assessed and standardized clinical evaluation tools are lacking. Psychomotor retardation is sometimes assessed through direct patient observations by clinicians or through a clinical observation grid, in the absence of a standardized psychomotor assessment. In this pilot study, we evaluated the feasibility of standardized psychomotor examination of patients with major depressive disorder (MDD) and detailed a psychomotor semiology in these patients. METHODS: We used a standardized psychomotor assessment to examine 25 patients with MDD and 25 age- and sex-matched healthy controls (HC) and compared their psychomotor profiles. Using standardized tests, we assessed muscle tone and posture, gross motor skills, perceptual-motor skills, and body image/organization. Clinical assessments of depressive symptoms (levels of psychomotor retardation, anxiety, and self-esteem) comprised this detailed psychomotor examination. RESULTS: All participants were examined using the standardized psychomotor assessment. The main results of the psychomotor examination highlighted low body image of MDD participants (p < 0.001). Significant differences between groups were found in passive muscle tone, posture, emotional control, jumping, manual dexterity, walking, and praxis. Among these psychomotor variables, body image, passivity, jumping and rhythm scores predicted an MDD diagnosis. CONCLUSIONS: Beyond the psychomotor retardation known to be present in MDD patients, this examination revealed an entire psychomotor symptomatology characterized by elevated muscle tone, poor body image associated with poor self-esteem, slowness in global motor skills and manual praxis, and poor rhythmic adaptation. In light of these results, we encourage clinicians to consider using a standardized tool to conduct detailed psychomotor examination of patients with depressive disorders. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04031937 , 24/07/2019.

Reward-based reinforcement learning is altered among individuals with a history of major depressive disorder and psychomotor retardation symptoms.

Reward-based reinforcement learning impairments are common in major depressive disorder, but it is unclear which aspects of reward-based reinforcement learning are disrupted in remitted major depression (rMDD). Given that the neurobiological substrates that implement reward-based RL are also strongly implicated in psychomotor retardation (PmR), the present study sought to test whether reward-based reinforcement learning is altered in rMDD individuals with a history of PmR. Three groups of individuals (1) rMDD with past PmR (PmR+, N = 34), (2) rMDD without past PmR (PmR-, N = 44), and (3) healthy controls (N = 90) completed a reward-based reinforcement learning task. Computational modeling was applied to test for group differences in model-derived parameters - specifically, learning rates and reward sensitivity. Compared to controls, rMDD PmR + exhibited lower learning rates, but not reduced reward sensitivity. By contrast, rMDD PmR- did not significantly differ from controls on either of the model-derived parameters. Follow-up analyses indicated that the results were not due to current psychopathology symptoms. Results indicate that a history of PmR predicts altered reward-based reinforcement learning in rMDD. Abnormal reward-related reinforcement learning may reflect a scar of past depressive episodes that contained psychomotor symptoms, or a trait-like deficit that preceded these episodes.

Compound heterozygous variants of the NARS2 gene in siblings with developmental delay, epilepsy, and neonatal diabetes syndrome.

Neonatal diabetes mellitus (NDM) with developmental delay and epilepsy is classified as developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. The majority of DEND syndrome are due to severely damaging variants of K-ATP channels, and few mitochondria-related genes have been reported. We report here two Japanese siblings who were clinically diagnosed with DEND syndrome in whom NARS2 compound heterozygous variants were detected. Patient 1 was a 3-year-old girl and presented with diabetes ketoacidosis at 3 months old. Patient 2 was a 1-year-old boy who presented with severe hyperglycemia and started insulin therapy at 3 days old. After the first episodes, they both presented with severe developmental delay, hearing loss and treatment-resistant epilepsy accompanied by progressive brain atrophy. Whole-exome sequencing revealed compound heterozygous NARS2 p.R159C and p.L217V variants, and the GATA4 p.P407Q variant in both patients. They were treated by mitochondrial supportive therapy of vitamin B1, L-carnitine, and coenzyme Q10. Patient 2 was withdrawn from insulin therapy at 6 months old. This is the first report of NDM in which variants of the NARS2 gene coding mitochondrial protein were detected. Genetic analysis including mitochondrial genes should be considered in patients with neonatal onset diabetes associated with neurogenic symptoms.

Asociación entre neuroimagen y secuelas neurológicas en pacientes con infección congénita por citomegalovirus / Association between neuroimaging findings and neurological sequelae in patients with congenital cytomegalovirus infection

Introducción: La infección congénita por citomegalovirus (CMV) supone una importante causa de discapacidad. Existen escasas evidencias acerca del valor pronóstico de las lesiones presentes en los estudios de neuroimagen. Objetivo: Analizar la gravedad de las lesiones en la resonancia magnética (RM) y la ecografía transfontanelar, y su relación con déficits neurológicos a largo plazo. Pacientes y métodos: Se realizó un estudio observacional analítico retrospectivo de 36 pacientes con infección congénita por CMV. Se revisaron los estudios de neuroimagen y se clasificaron según la escala de Noyola et al. modificada. Se relacionaron los hallazgos de neuroimagen con la afectación neurológica en su última visita en la consulta de neuropediatría. Resultados: Un total de 36 pacientes fueron estudiados, habiéndose realizado ecografía transfontanelar en 30 y RM cerebral en 29. La ecografía transfontanelar estuvo alterada en 20/30 pacientes, de los cuales, 11 tuvieron alteración en la RM (p = 0,04) y 10 afectación neurológica (p = 0,008). Tuvo una sensibilidad del 83,3%, IC 90%: 58-100 y una especificidad del 44,4%, IC 90%: 18,7-70,2 para la predicción de secuelas neurológicas. La RM estuvo alterada en 20/29 pacientes. Dieciséis de ellos tuvieron afectación neurológica (p < 0,001), teniendo una sensibilidad del 94%, IC 95%: 80-100 y una especificidad del 66,6%, IC 95%: 36-97,5 para la predicción de secuelas neurológicas. Una escala de Noyola et al. ≥ 2 se asoció a retraso psicomotor (p < 0,001). Conclusión: Nuestro trabajo valida los estudios previos en los que se encuentra correlación estadísticamente significativa entre la extensión de las lesiones en neuroimagen y la gravedad de los déficits neurológicos. (AU)

Background: Congenital cytomegalovirus (CMV) infection is an important cause of disability. There is little evidence on the prognostic value of lesions identified in neuroimaging studies. Aim: The study aimed to assess the severity of lesions detected with brain MRI and transfontanellar ultrasound and their relationship with long-term neurological deficits. Patients and methods: We performed a retrospective, analytical, observational study of 36 patients with congenital CMV infection. Neuroimaging studies were reviewed and classified according to the modified Noyola’ scale. Imaging findings were compared with neurological alterations in the patients’ most recent follow-up evaluation at the paediatric neurology department. Results: Thirty-six patients were studied (transfontanellar ultrasound: 30; brain MRI: 29). Twenty of 30 patients showed ultrasound abnormalities; of these, 11 showed alterations on brain MR images (P=.04) and 10 had neurological impairment (P=.008). Transfontanellar ultrasound had a sensitivity of 83.3%, 90% CI: 58-100 and a specificity of 44.4%, 90% CI: 18.7-70.2 for predicting neurological sequelae. Brain MRI displayed abnormalities in 20 of 29 patients, of whom 16 had neurological impairment (P<.001). MRI had a sensitivity of 94%, 95% CI: 80-100 and a specificity of 66.6%, 95% CI: 36-97.5 for predicting neurological sequelae. Modified Noyola’ scale values >2 were correlated with psychomotor retardation (P<.001). Conclusions: Our findings validate previous studies reporting a statistical significant correlation between the extension of neuroimaging lesions and severity of neurological deficits. (AU)

AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease.

AGC1/Aralar/Slc25a12 is the mitochondrial carrier of aspartate-glutamate, the regulatory component of the NADH malate-aspartate shuttle (MAS) that transfers cytosolic redox power to neuronal mitochondria. The deficiency in AGC1/Aralar leads to the human rare disease named "early infantile epileptic encephalopathy 39" (EIEE 39, OMIM # 612949) characterized by epilepsy, hypotonia, arrested psychomotor neurodevelopment, hypo myelination and a drastic drop in brain aspartate (Asp) and N-acetylaspartate (NAA). Current evidence suggest that neurons are the main brain cell type expressing Aralar. However, paradoxically, glial functions such as myelin and Glutamine (Gln) synthesis are markedly impaired in AGC1 deficiency. Herein, we discuss the role of the AGC1/Aralar-MAS pathway in neuronal functions such as Asp and NAA synthesis, lactate use, respiration on glucose, glutamate (Glu) oxidation and other neurometabolic aspects. The possible mechanism triggering the pathophysiological findings in AGC1 deficiency, such as epilepsy and postnatal hypomyelination observed in humans and mice, are also included. Many of these mechanisms arise from findings in the aralar-KO mice model that extensively recapitulate the human disease including the astroglial failure to synthesize Gln and the dopamine (DA) mishandling in the nigrostriatal system. Epilepsy and DA mishandling are a direct consequence of the metabolic defect in neurons due to AGC1/Aralar deficiency. However, the deficits in myelin and Gln synthesis may be a consequence of neuronal affectation or a direct effect of AGC1/Aralar deficiency in glial cells. Further research is needed to clarify this question and delineate the transcellular metabolic fluxes that control brain functions. Finally, we discuss therapeutic approaches successfully used in AGC1-deficient patients and mice.