[Recommendation for standardized medical care for children and adolescents with long COVID]. / Einheitliche Basisversorgung von Kindern und Jugendlichen mit Long COVID: Stellungnahme einer multidisziplinären Arbeitsgruppe der DGKJ-Konvent-Gesellschaften (Stand: Februar 2022).

This current consensus paper for long COVID complements the existing AWMF S1 guidelines for long COVID with a detailed overview on the various clinical aspects of long COVID in children and adolescents. Members of 19 different pediatric societies of the DGKJ convent and collaborating societies together provide expert-based recommendations for the clinical management of long COVID based on the currently available but limited academic evidence for long COVID in children and adolescents. It contains screening questions for long COVID and suggestions for a structured, standardized pediatric medical history and diagnostic evaluation for patients with suspected long COVID. A time and resource-saving questionnaire, which takes the clinical complexity of long COVID into account, is offered via the DGKJ and DGPI websites as well as additional questionnaires suggested for an advanced screening of specific neurocognitive and/or psychiatric symptoms including post-exertional malaise (PEM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). According to the individual medical history as well as clinical signs and symptoms a step by step diagnostic procedure and a multidisciplinary therapeutic approach are recommended.

Novel Unbalanced Translocations Affecting the Long Arms of Chromosomes 10 and 22 Cause Complex Syndromes with Very Severe Neurodevelopmental Delay, Speech Impairment, Autistic Behavior, and Epilepsy.

Isolated abnormalities in terminal regions of chromosomes 10q and 22q were formerly described in patients affected by neuropsychological impairment, abnormal facies, and heterogeneous structural abnormalities of the body. Chromosomes 10q and 22q harbor important genes that play a major role in CNS development, like DOCK1 and SHANK3, and in overall body growth, like FGFR2 and HTRA1. By using clinical, neuroradiological, neurophysiological, and genetic assessment, we studied 3 siblings affected by 2 different forms of very severe neuropsychological impairment with structural physical abnormalities, epilepsy, and body overgrowth. The genetic analysis revealed 2 different unbalanced translocations t(10;22)(q26.13;q13.32) of genetic material between the long arms of chromosomes 10 and 22, deriving from a maternal balanced translocation. Consequences of the unbalanced translocation were the simultaneous partial monosomy of 10q26.13 to 10qter and partial trisomy of 22q13.32 to 22qter in 2 patients and the simultaneous trisomy distal q10 and monosomy distal q22 in 1 patient, respectively. To the best of our knowledge, we here describe for the first time a causal association between an unbalanced translocation t(10;22) affecting the long arms of both chromosomes 10 and 22 and a very severe neurodevelopmental delay in 3 siblings.

Exploring two novel cases of suspected ictal epileptic headache, a rare form of paediatric epilepsy.

AIM: Ictal epileptic headache (IEH) is a rare and underestimated epileptic form, characterised by epileptiform discharges and headache attacks without any other ictal sensory-motor manifestations. IEH is difficult to diagnose, because the epileptiform discharges have to be registered during the headache attack and the headache has to disappear after the intravenous administration of an anti-epileptic drug, according to the last diagnostic criteria. This study explored the clinical, neuro-physiological and therapeutic features of IEH in the paediatric population. METHODS: We analysed two novel cases of adolescent female patients with chronic headache and a long history of unsuccessful analgesic oral therapy and without any other ictal sensory-motor events. We also reviewed the entire literature on paediatric IEH. RESULTS: The clinical history and diagnostic process led us to highly suspect IEH in both patients, and the successful therapy with oral anti-epileptic drugs, namely topiramate and ethosuximide, which resolved the chronic headache, enforced our diagnostic hypothesis. Our literature review highlighted the rarity of IEH clinical reports, particularly in the paediatric population, mainly due to the stringent diagnostic criteria. CONCLUSION: Our study sheds further light on IEH in the paediatric population and on the importance of diagnostic electroencephalograms in the clinical management of paediatric patients suffering from chronic headache.

Novel homozygous missense mutation in ALDH7A1 causes neonatal pyridoxine dependent epilepsy.

Pyridoxine dependent epilepsy (PDE) (OMIM#266100) is a neonatal form of epilepsy, caused by dysfunction of the enzyme α-aminoadipic semialdehyde dehydrogenase (ALDH7A1 or Antiquitin). This enzyme converts α-aminoadipic semialdehyde (α-AASA) into α-aminoadipate (AAA), a critical step in the lysine metabolism of the brain. ALDH7A1 dysfunction causes an accumulation of α-AASA and δ1-piperideine-6-carboxylic acid (P6C), which are in equilibrium with each other. P6C binds and inactivates pyridoxal 5'-phosphate (PLP), the active form of pyridoxine. Individuals affected by ALDH7A1 deficiency show pre-natal and post-natal seizures, which respond to oral pyridoxine but not to other pediatric anti-epileptic drugs. We discovered a novel missense mutation (c.566G > A, p.Gly189Glu) in homozygous state residing in the NAD+ binding domain coding region of exon 6 and affecting an highly conserved amino acid residue. The seizures stopped under post-natal pyridoxine therapy, nevertheless a longer follow-up is needed to evaluate the intellectual development of the child, who is additionally treated with oral l-arginine since the 13th month of life. Developmental delay with or without structural cortex abnormalities were reported in several patients. A brain MRI scan revealed hyperintense white matter in the right cerebellum compatible with cerebellar gliosis. Taken together, our studies enlarge the group of missense pathogenic mutations of ALDH7A1 gene and reveal a novel cerebellar finding within the PDE patients cohort.

CANPMR syndrome and chromosome 1p32-p31 deletion syndrome coexist in two related individuals affected by simultaneous haplo-insufficiency of CAMTA1 and NIFA genes.

BACKGROUND: Non-progressive cerebellar ataxia with mental retardation (CANPMR, OMIM 614756) and chromosome 1p32-p31 deletion syndrome (OMIM 613735) are two very rare inherited disorders, which are caused by mono-allelic deficiency (haplo-insufficiency) of calmodulin-binding transcription activator 1 (CAMTA1) and, respectively, nuclear factor 1 A (NFIA) genes. The yet reported patients affected by mono-allelic CAMTA1 dysfunction presented with neonatal hypotonia, delayed and ataxic gait, cerebellar atrophy, psychological delay and speech impairment, while individuals carrying a disrupted NFIA allele suffered from agenesis/hypoplasia of the corpus callosum, ventriculomegaly, developmental delay and urinary tract abnormalities. Both disorders were not seen in one patient together before. RESULTS: In this study two related individuals affected by a complex clinical syndrome, characterized by cognitive, neurological and nephrological features were studied for the underlying genetic disorder(s) by molecular cytogenetics. The two individuals present dysmorphic facies, macrocephaly, generalized ataxia, mild tremor, strabismus, mild mental retardation and kidney hypoplasia. Moreover, neuro-radiological studies showed hypoplasia of corpus callosum. Genetic investigations revealed a paracentric inversion in the short arm of one chromosome 1 with breakpoints within CAMTA1 and NFIA coding sequences. CONCLUSIONS: To the best of our knowledge, this is the first report of two patients harboring the simultaneous mono-allelic disruptions and consequent haplo-insufficiencies of two genes due to an inversion event. Disruption of CAMTA1 and NFIA genes led to neuro-psychological and nephrological dysfunctions, which comprised clinical features of CANPMR syndrome as well as chromosome 1p32-p31 deletion syndrome.