The Central Noradrenergic System in Neurodevelopmental Disorders: Merging Experimental and Clinical Evidence.

The aim of this article is to highlight the potential role of the locus-coeruleus-noradrenergic (LC-NA) system in neurodevelopmental disorders (NdDs). The LC is the main brain noradrenergic nucleus, key in the regulation of arousal, attention, and stress response, and its early maturation and sensitivity to perinatal damage make it an interesting target for translational research. Clinical data shows the involvement of the LC-NA system in several NdDs, suggesting a pathogenetic role in the development of such disorders. In this context, a new neuroimaging tool, LC Magnetic Resonance Imaging (MRI), has been developed to visualize the LC in vivo and assess its integrity, which could be a valuable tool for exploring morphological alterations in NdD in vivo in humans. New animal models may be used to test the contribution of the LC-NA system to the pathogenic pathways of NdD and to evaluate the efficacy of NA-targeting drugs. In this narrative review, we provide an overview of how the LC-NA system may represent a common pathophysiological and pathogenic mechanism in NdD and a reliable target for symptomatic and disease-modifying drugs. Further research is needed to fully understand the interplay between the LC-NA system and NdD.

[Assessment of the importance of neuropediatric diagnostics in the initial clarification of autism]. / Beurteilung des Stellenwertes der neuropädiatrischen Diagnostik im Rahmen der initialen Autismusabklärung.

BACKGROUND: The diagnostics of autism spectrum disorder is complex due to missing biological markers and numerous comorbidities. The aim was to assess the role of neuropediatric diagnostics and to develop a standard operating procedure for a targeted assessment. METHOD: All patients presenting to the neuropediatric outpatient clinic at Saarland University Hospital between April 2014 and December 2017 with ICD code F84 pervasive developmental disorders were included. RESULTS: A total of 82 patients were included (male 78%, female 22%; mean age 5.9 ± 2.9 years, range 2-16 years). The most frequent examination was electroencephalography (EEG) (74/82; 90.2%) with pathological findings in 33.8% (25/74). Based on the history and/or EEG epilepsy was diagnosed in 19.5% (16/82). Magnetic resonance imaging (MRI) was performed in 49/82 (59.8%) patients, 22/49 (44.9%) showed at least 1 cerebral abnormality and definite pathologies could be detected in 63.6% (14/22). A metabolic diagnostic work-up was performed in 44/82 (53.7%) cases and in 5/44 (11.4%) it resulted in a diagnosis or suspicion of a metabolic disease. Genetic testing results were available in 29/82 (35.4%) children and 12/29 (41.4%) showed abnormal results. Delay in motor development was more frequently associated with comorbidities, EEG abnormalities, epilepsy and abnormalities in metabolic and genetic testing. CONCLUSION: Neuropediatric examination in cases of suspected autism should include a detailed history, a thorough neurological examination and an EEG. An MRI, comprehensive metabolic and genetic testing are only recommended if clinically indicated.

Role of Genetics in the Etiology of Autistic Spectrum Disorder: Towards a Hierarchical Diagnostic Strategy.

Progress in epidemiological, molecular and clinical genetics with the development of new techniques has improved knowledge on genetic syndromes associated with autism spectrum disorder (ASD). The objective of this article is to show the diversity of genetic disorders associated with ASD (based on an extensive review of single-gene disorders, copy number variants, and other chromosomal disorders), and consequently to propose a hierarchical diagnostic strategy with a stepwise evaluation, helping general practitioners/pediatricians and child psychiatrists to collaborate with geneticists and neuropediatricians, in order to search for genetic disorders associated with ASD. The first step is a clinical investigation involving: (i) a child psychiatric and psychological evaluation confirming autism diagnosis from different observational sources and assessing autism severity; (ii) a neuropediatric evaluation examining neurological symptoms and developmental milestones; and (iii) a genetic evaluation searching for dysmorphic features and malformations. The second step involves laboratory and if necessary neuroimaging and EEG studies oriented by clinical results based on clinical genetic and neuropediatric examinations. The identification of genetic disorders associated with ASD has practical implications for diagnostic strategies, early detection or prevention of co-morbidity, specific treatment and follow up, and genetic counseling.

[Sleep in chronic neuropediatric diseases]. / Sueño en enfermedades neuropediátricas crónicas.

The prevalence of sleep disorders (SD) is notoriously increased in children with chronic neurological disease, with a negative bidirectional link that aggravates their symptomatology and has a negative impact on the quality of life of the child and their families. Identifying and recognizing this association is key for the child neurologist since the treatment of SD significantly improves daytime symptomatology in neurodevelopmental disorders, epilepsy, primary headaches, cerebral palsy and neuromuscular diseases.

La prevalencia de los trastornos del sueño (TS) se incrementa notoriamente en niños con enfermedad neurológica crónica, con un vínculo bidireccional negativo que agrava su sintomatología y repercute negativamente en la calidad de vida del niño y su familia. Identificar y reconocer dicha asociación es clave para el neuropediatra, ya que el tratamiento del TS mejora significativamente la sintomatología diurna de los trastornos del neurodesarrollo, epilepsia, cefaleas primarias, parálisis cerebral y enfermedades neuromusculares.

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes.

Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span and inconsistent subtle behavior deficits that can be difficult to detect in CLN3 mutant mouse models, thereby limiting their use in preclinical studies. Here, we present a longitudinal characterization of a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, an exon 7-8 deletion (CLN3Δex7/8). Progressive pathology and neuron loss is observed in various regions of the CLN3Δex7/8 miniswine brain and retina. Additionally, mutant miniswine present with retinal degeneration and motor abnormalities, similar to deficits seen in humans diagnosed with the disease. Taken together, the CLN3Δex7/8 miniswine model shows consistent and progressive Batten disease pathology, and behavioral impairment mirroring clinical presentation, demonstrating its value in studying the role of CLN3 and safety/efficacy of novel disease-modifying therapeutics.

Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathy.

Acute necrotizing encephalopathy 1 (ANE1) is a very rare disorder associated with a dominant heterozygous mutation in the RANBP2 (RAN binding protein 2) gene. ANE1 is frequently triggered by a febrile infection and characterized by serious and irreversible neurological damage. Although only a few hundred cases have been reported, mutations in RANBP2 are only partially penetrant and can occur de novo, suggesting that their frequency may be higher in some populations. Genetic diagnosis is a lengthy process, potentially delaying definitive diagnosis. We therefore developed a rapid bedside qPCR-based tool for early diagnosis and screening of ANE1 mutations. Primers were designed to specifically assess RANBP2 and not RGPD (RANBP2 and GCC2 protein domains) and discriminate between wild-type or mutant RANBP2. Nasal epithelial cells were obtained from two individuals with known RANBP2 mutations and two healthy control individuals. RANBP2-specific reverse transcription followed by allele-specific primer qPCR amplification confirmed the specific detection of heterozygously expressed mutant RANBP2 in the ANE1 samples. This study demonstrates that allele-specific qPCR can be used as a rapid and inexpensive diagnostic tool for ANE1 using preexisting equipment at local hospitals. It can also be used to screen non-hospitalized family members and at risk-population to better establish the frequency of non-ANE-associated RANBP2 mutations, as well as possible tissue-dependent expression patterns. Systematic review registration: The protocol was registered in the international prospective register of systematic reviews (PROSPERO- CRD42023443257).

Diagnosis of Aicardi-Goutières Syndrome in Adults: A Case Series.

INTRODUCTION: Aicardi-Goutières syndrome (AGS) is a genetic disease presenting with early-onset encephalopathy, generalized dystonia, spasticity, and cognitive disability. Diagnosis may be difficult in adults, as the clinical course seems static from infancy. METHODS: AGS patients from an adult movement disorders outpatient clinic were retrospectively analyzed. RESULTS: A total of 5 patients and 1 asymptomatic carrier from 3 different families were identified. All had a homozygous c.529G>A,p.A177T mutation in exon 7 of the RNASEH2B gene. Two patients had neonatal-onset AGS, 2 had later onset forms, and 1 was slightly symptomatic. All were diagnosed in adulthood after chilblains, and basal ganglia calcifications were identified on computed tomography scans. DISCUSSION: AGS patients have marked phenotypic variability regarding psychomotor development and morbidity. The present series included 1 asymptomatic carrier and 1 slightly symptomatic patient, both with homozygous RNASEH2B mutations. Chilblains and basal ganglia calcifications identified on computed tomography scan (but not on magnetic resonance imaging) are important clues for late diagnosis.

Historic review: the foundation-period and the first 15 years of the "Gesellschaft fuer Neuropaediatrie" (GNP) between 1950 and 1990.

After the end of Nazi terrorism with many crimes against neuropsychiatric and disabled people, from 1950 on detection and treatment of these diseases in children and adolescents grew continuously: in the 50s and 60s, several German books on neuropediatric topics were published, a journal was founded, and junior pediatricians established many scientific contacts with foreign neuropediatricians. In 1972, the team of the Kehl-Kork Epilepsy Clinic invited neuropediatric colleagues from Germany, Austria, and Switzerland for a first joint workshop. On March 4th, 1975, the Neuropaediatric Society of the German-speaking countries was founded in Heidelberg and its goals, as well as guidelines for membership, were formulated. The first annual meeting took place 1975 in Heidelberg as well. Between 1975 and 1990, the number of members of the GNP continued to increase from 140 to more than 230, despite strict admission criteria. The president was elected for a one-year term and was responsible for organizing the annual meeting, which took place alternately in Germany, Austria or Switzerland. The continuity of the society was ensured by secretary and treasurer as well as several longtime assessors. The meetings covered the entire spectrum of neurological and neuropsychological disorders in children. In addition to the age-dependent clinical investigation, the most important diagnostic methods were electrophysiology, in particular, the EEG and EMG, the new possibilities of cerebral imaging utilizing X-ray computed tomography and ultrasound, and biochemical analyzes for detection of metabolic diseases. Research projects were mostly carried out in university institutions and were only partially multi-center or financed with public funds. International contacts took place on many levels, e.g. through scholarships and personal exchanges with European and US scientific societies and institutions. Unfortunately, the opportunity to exchange ideas with colleagues from the German Democratic Republic (GDR) was limited. Several working groups addressed controversial issues of developmental neurology, epileptology, and alternative therapies. With the establishment of social pediatric centers in Germany from the late 1980s, there was an increasing demand for well-educated and experienced neuropediatricians.

Clínica de crianças com transtornos: quando a preocupação está para além do orgânico / Clinic of children with neuromotor disorders: when the concern is beyond organic / Clínica de niños con trastornos neuromotores: cuando la preocupación está más allá de lo orgánico

Apesar de a constituição do sujeito não residir somente no orgânico, não podemos desconsiderar que limitações no real do corpo podem impor obstáculos no processo de constituição subjetiva. A partir de questionamentos da minha experiência clínica como fisioterapeuta neuropediátrica e do meu percurso acadêmico no curso de especialização em atendimento clínico - ênfase psicanálise, alguns interrogantes sobre a prática clínica com crianças com transtornos neuromotores foram surgindo. Testemunhando uma carência na articulação entre esses saberes, busquei encadear conhecimentos das duas especificidades objetivando propor uma clínica que tome a criança como um sujeito em constituição e não apenas preocupada com o real orgânico da lesão.

Even though the subject's constitution doesn't reside only in the organic, we can't disrespect that limitations in the real of body can impose obstacles in the process of the constitution of the subjectivity. Based on questions of my clinic experience as a neuropediatric physiotherapist and on a specialization course in clinical service with emphasis in psychoanalysis, some questions about clinical practice with children with disabilities came up. Attesting a scarcity on the articulation between these fields of knowledge, my attempt is to articulate knowledge of both specialties in order to propose a clinic that takes the child as a subject in constitution and not only concerned with the organic real of the lesion.

A despecho de la constitución sujetiva no residir solo en lo orgánico, no podemos desconsiderar que las limitaciones en lo real del cuerpo pueden imponer obstáculos en el proceso de constitución del sujeto. A partir de cuestionamientos de mi experiencia clínica como fisioterapeuta neuropediátrica y de mi percurso académico en el curso de especialización en atendimiento clínico - énfasis psicoanálisis, fueron surgiendo algunos interrogantes sobre la práctica clínica de niños con trastornos neuromotores. Percibiendo una carencia en la articulación entre esos saberes, busqué articular conocimientos de las dos especificidades a fin de proponer una clínica que tome al niño como un sujeto en constitución y no solamente preocupada con lo real orgánico de la lesión.