[Ontwikkelingsstoornissen bij volwassenen: het nut van de holistische theorie]. / Ontwikkelingsstoornissen bij volwassenen: het nut van de holistische theorie.

During the diagnostic process of developmental disorders in adults, diagnosticians often encounter diagnostic uncertainty. In this article, I describe how the holistic theory can be employed in this context in order to prevent diagnostic reductionism. A fictitious vignette illustrates the method.

Co-Design of a Neurodevelopment Assessment Scale: A Study Protocol.

Neurodevelopmental disorders are a heterogeneous group of conditions with overlapping symptomatology and fluctuating developmental trajectories that transcend current diagnostic categorisation. There is a need for validated screening instruments which dimensionally assess symptomatology from a holistic, transdiagnostic perspective. The primary aim is to co-design a Neurodevelopment Assessment Scale (NAS), a user-friendly transdiagnostic assessment inventory that systematically screens for all signs and symptoms commonly encountered in neurodevelopmental disorders. Our first objective is to undertake development of this tool, utilising co-design principles in partnership with stakeholders, including both those with lived experience of neurodevelopmental disorders and service providers. Our second objective is to evaluate the face validity, as well as the perceived utility, user-friendliness, suitability, and acceptability (i.e., 'social validity'), of the NAS from the perspective of parents/caregivers and adults with neurodevelopmental disorders, clinicians, and service providers. Our third objective is to ascertain the psychometric properties of the NAS, including content validity and convergent validity. The NAS will provide an efficient transdiagnostic tool for evaluating all relevant signs, symptoms, and the dimensional constructs that underpin neurodevelopmental presentations. It is anticipated that this will maximise outcomes by enabling the delivery of personalised care tailored to an individual's unique profile in a holistic and efficient manner.

Validation of the PDMS-2 scale in the Spanish population. Evaluation of physiotherapy intervention and parental involvement in the treatment of children with neurodevelopmental disorders. / Validación de la PDMS-2 en población española. Evaluación de la intervención de fisioterapia y la participación de los padres en el tratamiento de niños con trastornos del neurodesarrollo.

AIM: Cross-culturally adapt the PDMS-2 scale from Spanish-Mexican to Spanish-Spanish and evaluate its validity. To determine the efficacy of physiotherapy treatment (number of physiotherapy sessions and activities proposed by the physiotherapist and performed by the parents) in children with neurodevelopmental disorders between the ages of 0 and 3 years. SUBJECTS AND METHODS: A first prospective descriptive study of validation of the PDMS-2 scale including 74 subjects with neurodevelopmental disorder with aged from 0 and 3 years old. A second randomized clinical trial to evaluate the physiotherapy (Bobath concept) intervention in the experimental group (EG) (n = 37) who received unique 30-minute weekly sessions for 8 weeks against the control group (CG) (n = 37) that did not receive physiotherapy using the PDMS-2 scale for evaluation. RESULTS: An adequate inter-rater reliablity was found (ICC = 0.76). The scale showed also a very good internal consistency (alpha = 0,99). Significant differences between both groups at 8 weeks. EG obtained better scores in the postest after administrating the physiotherapy treatment (p < 0.001) Moderate and significant correlation coefficients were found between the number of physiotherapy sessions and Total Motor Quotient (TMQ) (r = 0.38; p < 0.05) and the home actitvities with TMQ (r = 0.46; p = 0.005). CONCLUSIONS: The Peabody PDMS-2 scale is a valid and reliable instrument to measure gross and fine motor development in children with neurodevelopmental disorder aged from 0 and 3 years old. Physiotherapy is useful for helping children with delayed neurodevelopment improve. The number of physiotherapy sessions and the activities proposed by the physiotherapist and performed at home by the parents show a direct and positive relationship with the results obtained in motor development.

TITLE: Validación de la PDMS-2 en población española. Evaluación de la intervención de fisioterapia y la participación de los padres en el tratamiento de niños con trastornos del neurodesarrollo.Objetivo. Adaptar transculturalmente la escala del desarrollo motor de Peabody, segunda edición (PDMS-2), del español mexicano al español de España y evaluar su validez. Determinar la eficacia del tratamiento fisioterápico (número de sesiones de fisioterapia y actividades propuestas por el fisioterapeuta y realizadas por los padres) en niños con trastornos del neurodesarrollo de 0 a 3 años. Sujetos y métodos. Un primer estudio descriptivo prospectivo de validación de la PDMS-2, que incluyó a 74 sujetos con trastorno del neurodesarrollo con edades comprendidas entre 0 y 3 años. Un segundo ensayo clínico aleatorio para evaluar la intervención de fisioterapia (concepto Bobath) en el grupo experimental (n = 37), que recibió sesiones únicas de 30 minutos semanales durante ocho semanas frente al grupo de control (n = 37), que no recibió fisioterapia y utilizó la PDMS-2 para su evaluación. Resultados. Se encontró una adecuada confiabilidad interagente (coeficiente de correlación intraclase = 0,76). La escala mostró también una muy buena consistencia interna (alfa = 0,99). Hubo diferencias significativas entre ambos grupos a las ocho semanas. El grupo experimental obtuvo mejores puntuaciones en el postest después de administrar el tratamiento de fisioterapia (p menor de 0,001). Se encontraron coeficientes de correlación moderados y significativos entre el número de sesiones de fisioterapia y el cociente motor total (r = 0,38; p menor de 0,05) y las actividades realizadas en casa con el cociente motor total (r = 0,46; p = 0,005). Conclusiones. La PDMS-2 es un instrumento válido y fiable para medir el desarrollo motor grueso y fino en niños con trastorno del neurodesarrollo de 0 a 3 años. La fisioterapia es útil en la mejoría en niños con retraso del neurodesarrollo. El número de sesiones de fisioterapia y las actividades propuestas por el fisioterapeuta y realizadas en casa por los padres muestran una relación directa y positiva con los resultados obtenidos en el desarrollo motor.

Gestational Age, Birth Weight, and Neurocognitive Development in Adolescents in Tanzania.

OBJECTIVES: To investigate the association between gestational age, birthweight, and birthweight adjusted for gestational age, with domains of neurocognitive development and behavioral problems in adolescents in Tanzania. STUDY DESIGN: Data from a long-term follow-up of adolescents aged 11-15 years born to women previously enrolled in a randomized controlled trial of prenatal multiple micronutrient supplementation in Dar es Salaam, Tanzania, were used. A battery of neurodevelopmental tests were administered to measure adolescent general intelligence, executive function, and behavioral problems. The INTERGROWTH-21st newborn anthropometric standards were used to derive birthweight for gestational age z-scores. We assessed the shape of relationships using restricted cubic splines and estimated the associations of gestational age, birthweight, and birthweight for gestational age z-score with adolescent development using multivariable linear regressions. RESULTS: Among adolescents studied (n = 421), higher gestational age (per week), birthweight (per 100 grams), and birthweight for gestational age z-score (per SD) were linearly associated with higher intelligence score (adjusted standardized mean difference, 0.05 SD [95% CI, 0.01-0.09], 0.04 SD [95% CI, 0.02-0.06], and 0.09 SD [95% CI, 0.01-0.17], respectively). Birthweight and birthweight for gestational age z-score, but not gestational age, were also associated with improved executive function. Low birthweight (<2500 g) was associated with lower intelligence and executive function scores. Associations between birthweight and executive function were stronger among adolescents born to women with higher education. CONCLUSIONS: The duration of gestation and birthweight were positively associated with adolescent neurodevelopment in Tanzania. These findings suggest that interventions to improve birth outcomes may also benefit adolescent cognitive function.

What a finding of gene copy number variation can add to the diagnosis of developmental neuropsychiatric disorders.

Among medical disciplines, diagnosis in psychiatry depends highly upon descriptive signs and symptoms, rather than biomarkers. Clear descriptions of specific genetic etiologies have been lacking; genomic technologies, however, are rapidly changing that landscape. Notably, chromosomal microarrays-which detect gene copy number variants (CNVs)-are a recommended standard of care for neurodevelopmental disorders. As a result, an increasing number of patients now receive a clinical diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and an identified genetic etiological variant. However, psychiatric and genetic diagnoses are frequently communicated and managed as two disconnected diagnostic parameters. Here, we advocate for a transition model, allowing the integration of genetic etiological information-starting with diagnostically proven CNVs-within the DSM-5 classification framework.

Additional observation of a de novo pathogenic variant in KCNT2 leading to epileptic encephalopathy with clinical features of frontal lobe epilepsy.

INTRODUCTION: KCNT2 was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy. CASE REPORT: We present an additional observation of a 16-year-old male patient with a novel de novo KCNT2 likely pathogenic variant and review the five previously reported cases of de novo variants in this gene. DISCUSSION: Whole exome sequencing identified the missense variant c.725C > A p.(Thr242Asn), which was confirmed by Sanger sequencing. Our patient has a refractory stereotyped and monomorphic type of hyperkinetic focal motor seizure, similar to what is seen in frontal lobe epilepsy, occurring only during sleep. This type of seizure is not usually seen in epileptic encephalopathies.

Ethical dangers of facial phenotyping through photography in psychiatric genomics studies.

Psychiatric genomics research protocols are increasingly incorporating tools of deep phenotyping to observe and examine phenotypic abnormalities among individuals with neurodevelopmental disorders. In particular, photography and the use of two-dimensional and three-dimensional facial analysis is thought to shed further light on the phenotypic expression of the genes underlying neurodevelopmental disorders, as well as provide potential diagnostic tools for clinicians. In this paper, I argue that the research use of photography to aid facial phenotyping raises deeply fraught issues from an ethical point of view. First, the process of objectification through photographic imagery and facial analysis could potentially worsen the stigmatisation of persons with neurodevelopmental disorders. Second, the use of photography for facial phenotyping has worrying parallels with the historical misuse of photography to advance positive and negative eugenics around race, ethnicity and intellectual disability. The paper recommends ethical caution in the use of photography and facial phenotyping in psychiatric genomics studies exploring neurodevelopmental disorders, outlining certain necessary safeguards, such as a critical awareness of the history of anthropometric photography use among scientists, as well as the exploration of photographic methodologies that could potentially empower individuals with disabilities.

Expanding the Phenotype: Neurodevelopmental Disorder, Mitochondrial, With Abnormal Movements and Lactic Acidosis, With or Without Seizures (NEMMLAS) due to WARS2 Biallelic Variants, Encoding Mitochondrial Tryptophanyl-tRNA Synthase.

BACKGROUND: WARS2 encodes a tryptophanyl tRNA synthetase, which is involved in mitochondrial protein synthesis. Biallelic mutations in WARS2 are rare and have been associated with a spectrum of clinical presentations, including neurodevelopmental disorder with abnormal movements, lactic acidosis with or without seizures (NEMMLAS). CASE PRESENTATION: Here we present the case of an 8-year-old girl with ataxia and parkinsonism with periventricular white matter abnormalities on magnetic resonance imaging (MRI) and global developmental delay. The initial investigations revealed an elevated lactate level. Extensive metabolic testing, including a muscle biopsy, was inconclusive. Cerebrospinal fluid (CSF) neurotransmitter levels were low; however, a trial of levodopa was unremarkable. The chromosomal microarray and initial ataxia gene panel was normal. Zinc supplementation for a heterozygous variant of unknown significance in the CP gene on the ataxia exome panel was not effective in treating her symptoms. Reanalysis of the ataxia exome panel highlighted biallelic mutations in WARS2, which lead to the diagnosis of neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS). This lead to parental genetic testing, redirected therapy, and helped to expand the symptomology of this rare condition. CONCLUSION: Here we emphasize the importance of imminent and repeat expanded genetic testing to ensure early diagnosis and treatment for rare pediatric disorders. The patient is being trialed on a mitochondrial cocktail in an attempt to compensate for defects in mitochondrial protein synthesis associated with this variant. Longitudinal monitoring of disease manifestation will help establish the currently unknown natural history of this condition.

The neurological and psychological phenotype of adult patients with early-treated phenylketonuria: A systematic review.

Newborn screening for phenylketonuria (PKU) and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of PKU, including mental retardation and epilepsy. However, concerns remain that long-term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine-restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early-treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, intelligence quotient (IQ) appears normal but specific deficits in neuropsychological and social functioning were reported in early-treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardized neuropsychological tests. Future research should employ standardized neurological, neuropsychological, and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated PKU-specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life.

Epigenetics, nutrition and mental health. Is there a relationship?

Many aspects of human development and disease are influenced by the interaction between genetic and environmental factors. Understanding how our genes respond to the environment is central to managing health and disease, and is one of the major contemporary challenges in human genetics. Various epigenetic processes affect chromosome structure and accessibility of deoxyribonucleic acid (DNA) to the enzymatic machinery that leads to expression of genes. One important epigenetic mechanism that appears to underlie the interaction between environmental factors, including diet, and our genome, is chemical modification of the DNA. The best understood of these modifications is methylation of cytosine residues in DNA. It is now recognized that the pattern of methylated cytosines throughout our genomes (the 'methylome') can change during development and in response to environmental cues, often with profound effects on gene expression. Many dietary constituents may indirectly influence genomic pathways that methylate DNA, and there is evidence for biochemical links between nutritional quality and mental health. Deficiency of both macro- and micronutrients has been associated with increased behavioural problems, and nutritional supplementation has proven efficacious in treatment of certain neuropsychiatric disorders. In this review we examine evidence from the fields of nutrition, developmental biology, and mental health that supports dietary impacts on epigenetic processes, particularly DNA methylation. We then consider whether such processes could underlie the demonstrated efficacy of dietary supplementation in treatment of mental disorders, and whether targeted manipulation of DNA methylation patterns using controlled dietary supplementation may be of wider clinical value.

Emerging Clinical Benefits of New-Generation Fat Emulsions in Preterm Neonates.

Soybean oil-based intravenous fat emulsions (IVFEs) have been the predominant parenteral nutrition IVFE used in the United States for neonates over the past 45 years. Even though this emulsion has proven useful in supplying infants with energy for growth and essential fatty acids, there have been concerns over its composition in the development of several morbidities, ranging from sepsis to liver disease, bronchopulmonary dysplasia, and impaired neurodevelopment and growth. The exact mechanisms that drive these morbidities in preterm infants are multifactorial, but potential contributors include high ω-6 (n-6) fatty acid composition, low docosahexaenoic acid and antioxidant supplementation, and the presence of potentially harmful nonnutritive components (eg, phytosterols). To address these issues, new-generation IVFEs with various types and amounts of fat have been developed containing greater amounts of the medium-chain fatty acids, long-chain polyunsaturated fatty acid, docosahexaenoic acid, lower concentrations of ω-6 polyunsaturated fatty acids, supplemental vitamin E, and low or negligible amounts of phytosterols. This review examines the clinical outcomes associated with different morbidities of parenteral nutrition in neonates who have received either soybean oil-based or new-generation IVFEs and addresses whether the proposed benefits of new-generation IVFEs have improved outcomes in the neonatal population.

The Use of Cardiac Orienting Responses as an Early and Scalable Biomarker of Alcohol-Related Neurodevelopmental Impairment.

BACKGROUND: Considered the leading cause of developmental disabilities worldwide, fetal alcohol spectrum disorders (FASD) are a global health problem. To take advantage of neural plasticity, early identification of affected infants is critical. The cardiac orienting response (COR) has been shown to be sensitive to the effects of prenatal alcohol exposure and is an inexpensive, easy to administer assessment tool. The purpose of this study was to evaluate the COR effectiveness in assessing individual risk of developmental delay. METHODS: As part of an ongoing longitudinal cohort study in Ukraine, live-born infants of women with some to heavy amounts of alcohol consumption in pregnancy were recruited and compared to infants of women who consumed low or no alcohol. At 6 and 12 months, infants were evaluated with the Bayley Scales of Infant Development-II. CORs were also collected during a habituation/dishabituation learning paradigm. Using a supervised logistic regression classifier, we compared the predictive utility of the COR indices to that of the 6-month Bayley scores for identification of developmental delay based on 12-month Bayley scores. Heart rate collected at each second (Standard COR) was compared to key features (Key COR) extracted from the response. RESULTS: Negative predictive values (NPV) were 85% for Standard COR, 82% for Key COR, and 77% for the Bayley, and positive predictive values (PPV) were 66% for Standard COR, 62% for Key COR, and 43% for the Bayley. CONCLUSIONS: Predictive analysis based on the COR resulted in better NPV and PPV than the 6-month Bayley score. As the resources required to obtain a Bayley score are substantially more than in a COR-based paradigm, the findings are suggestive of its utility as an early scalable screening tool based on the COR. Further work is needed to test its long-term predictive accuracy.

Integrating neurocritical care approaches into neonatology: should all infants be treated equitably?

To improve the neurologic outcomes for infants with brain injury, neonatal providers are increasingly implementing neurocritical care approaches into clinical practice. Term infants with brain injury have been principal beneficiaries of neurologically-integrated care models to date, as evidenced by the widespread adoption of therapeutic hypothermia protocols for hypoxic-ischemic encephalopathy. Innovative therapeutic and diagnostic support for very low birth weight infants with brain injury has lagged behind. Given that concern for significant future neurodevelopmental impairment can lead to decisions to withdraw life supportive care at any gestational age, providing families with accurate prognostic information is essential for all infants. Current variable application of multidisciplinary neurocritical care approaches to infants at different gestational ages may be ethically problematic and reflect distinct perceptions of brain injury for infants born extremely premature.

Neurodevelopmental outcomes of premature infants with severe intraventricular hemorrhage.

OBJECTIVE: Our objective was to determine the neurodevelopmental outcome at 18-24 months' of corrected age (CA) in preterm infants with severe intraventricular hemorrhage (IVH). METHODS: This was a retrospective cohort study of all preterm infants who were <37 weeks' gestation, had Grade 3-4 IVH, were admitted between January 2009 and December 2010 and discharged. The cohort was divided into three groups. Group 1 was defined as infants born with a birth weight (BW) less than 1000 g, group 2 was defined as infants born with a BW between 1000 and 1500 g and group 3 was defined as infants born with a BW between 1501 and 2500 g. Severe IVH was defined as the presence of grade 3-4 IVH on cranial ultrasound. Cranial ultrasound was performed in the first week of life and subsequently at weekly intervals by a radiologist. A comprehensive assessment including hearing, vision, neurological and developmental evaluation with Bayley Scales of Infant Development, Second edition was performed by the experienced researchers at 18-24 months' CA. Neurodevelopmental impairment (NDI) was defined as at the presence of one or more of the following: cerebral palsy; Mental Developmental Index score lower than 70; Psychomotor Developmental Index score lower than 70; bilateral hearing impairment; or bilateral blindness. RESULTS: From January 2009 to December 2010, a total of 138 infants were diagnosed as severe IVH (grade 3-4). Of them, 74 (71.1%) infants (group 1 = 31, group 2 = 29 and group 3 = 14 infants) completed the follow-up visit and evaluated at 18-24 months' CA. Median Apgar score (p < 0.01) and resuscitation at birth (p < 0.01) were significantly different for groups 1-3. The use of catheterization, need for mechanical ventilation, need for phototherapy, retinopathy of premature and bronchopulmonary dysplasia were significantly higher in group 1 compared to groups 2 and 3 (p < 0.001, p < 0.001, p < 0.01, p < 0.01 and p = 0.014, respectively). The duration of hospitalization and mortality rates consistent with the degree of prematurity were significantly higher in group 1 compared to groups 2 and 3 (p = 0.03 and p = 0.01). Among the long-term outcomes, the rates of CP and NDI did not differ between the groups (p = 0.68 and p = 0.068). CONCLUSION: Our results demonstrated that long-term outcomes of preterm infants did not differ between the groups classified according to the BW at two years of age. This has leaded to the conclusion that severe IVH is alone represents a significant risk factor for poor neurodevelopmental outcome in this already high-risk population.