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Aim: To compare the predictive values of the General Movements Assessment (GMA) and the Standardized Infant NeuroDevelopmental Assessment (SINDA) neurological scale for atypical neurodevelopmental outcome in 3-month-old at-risk infants., Method: A total of 109 infants (gestational age 30 weeks; range: 24-41; 52 males) attending a non-academic outpatient clinic were assessed with the GMA and the SINDA at 3 (2-4) months corrected age. The GMA pays attention to the complexity of general movements and presence of fidgety movements. Atypical neurodevelopmental outcome at 24 months corrected age (and older) implied cerebral palsy (CP) or a Bayley Mental Development Index or Bayley Psychomotor Development Index lower than 70., Results: At 24 months corrected (and older) age, 16 children had an atypical outcome, including 14 children with CP. Regarding markedly reduced general movement complexity in combination with absent or sporadic fidgety movements, the GMA predicted an atypical outcome with specificity, positive, and negative predictive values greater than 0.900, and sensitivity of 0.687 (95% confidence interval [CI] = 0.460-0.915). SINDA predicted an atypical outcome with sensitivity, specificity, and negative predictive value greater than 0.900 and a positive predictive value of 0.652 (95% CI = 0.457-0.847). Regarding absent fidgety movements only or markedly reduced general movement complexity, the GMA predicted the outcome less well than both general movement criteria., Interpretation: The SINDA and GMA both predict neurodevelopmental outcome well, but SINDA is easier to learn than the GMA; being a non-video-based assessment, it allows caregiver feedback during the consultation whereas the GMA usually does not., (© 2024 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Aim: To assess the reliability and predictive validity of the developmental and socio-emotional scales of the Standardized Infant NeuroDevelopmental Assessment (SINDA)., Method: To assess reliability, two sets of three assessors forming eight assessor-pairs independently rated the developmental and socio-emotional scales of 60 infants. To evaluate predictive validity, 223 infants (gestational age 30wks [range 23-41wks]; 117 males, 106 females) attending a non-academic outpatient clinic were assessed by different assessors with SINDA's neurological, developmental, and socio-emotional scales. Atypical neurodevelopmental outcome at a corrected age of 24 months or older implied a Bayley Mental or Psychomotor Developmental Index score of less than 70 or neurological disorder (including cerebral palsy). Behavioural and emotional disorders were classified according to the International Classification of Diseases, 10th Revision. Predictive values were calculated from SINDA (2-12mo corrected age, median 7mo) and typical versus atypical outcome, and for intellectual disability only (Mental Developmental Index <70)., Results: Assessors highly agreed on the developmental and socio-emotional assessments (developmental scores: Spearman's rank correlation coefficient ρ=0.972; single socio-emotional behaviour items: Cohen's κ=0.783-0.896). At 24 months or older, 65 children had atypical outcome. Atypical neurological scores predicted atypical outcome (sensitivity 83%, specificity 96%); atypical developmental scores predicted intellectual disability (sensitivity 77%, specificity 92%). Atypical emotionality and atypical self-regulation were associated with behavioural and emotional disorders., Interpretation: SINDA's three scales are reliable, and have a satisfactory predictive validity for atypical developmental outcome at 24 months or older in a non-academic outpatient setting. SINDA's developmental scale has promising predictive validity for intellectual disability. SINDA's socio-emotional scale is a tool for caregiver counselling., What This Paper Adds: Standardized Infant NeuroDevelopmental Assessment (SINDA)'s developmental and socio-emotional scales have excellent interrater reliability. Replication of the satisfactory validity of SINDA's neurological scale for atypical outcome., (© 2019 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Aim: To assess reliability and predictive validity of the neurological scale of the Standardized Infant NeuroDevelopmental Assessment (SINDA), a recently developed assessment for infants aged 6 weeks to 12 months., Method: To assess reliability, three assessors independently rated video-recorded neurological assessments of 24 infants twice. Item difficulty and discrimination were determined. To evaluate predictive validity, 181 infants (median gestational age 30wks [range 22-41wks]; 92 males, 89 females) attending a non-academic outpatient clinic were assessed with SINDA's neurological scale (28 dichotomized items). Atypical neurodevelopmental outcome at 24 months or older corrected age implied a Bayley Mental Developmental Index or Psychomotor Developmental Index lower than 70 or a diagnosis of cerebral palsy (CP). Predictive values were calculated from SINDA (2-12mo corrected age, median 3mo) and typical versus atypical outcome., Results: Intraclass correlation coefficients of intrarater and interrater agreement of the neurological score varied between 0.923 and 0.965. Item difficulty and discrimination were satisfactory. At 24 months or older, 56 children (31%) had an atypical outcome (29 had CP). Atypical neurological scores (below 25th centile, ≤21) predicted atypical outcome and CP with sensitivities of 89% and 100%, and specificities of 94% and 81% respectively., Interpretation: SINDA's neurological scale is reliable and in a non-academic outpatient setting has a satisfactory predictive validity for atypical developmental outcome, including CP, at 24 months or older., What This Paper Adds: The Standardized Infant NeuroDevelopmental Assessment's neurological scale has a good to excellent reliability. The scale has promising predictive validity for cerebral palsy. The scale has promising predictive validity for other types of atypical developmental outcome., (© 2018 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date., Methods: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data., Results: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein., Conclusions: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups.

The so-called molar tooth sign is the radiologic hallmark of JSRD. Joubert syndrome is a rare, most often autosomal-recessive disorder with a characteristic malformation of the midhindbrain. We describe 3 patients with JSRD and the additional MR finding of tissue resembling heterotopia in the interpeduncular fossa, which in one patient was combined with a more extensive intramesencephalic heterotopia. Interpeduncular heterotopia has not been reported previously, either in the context of JSRD or as a separate entity. This new imaging feature enlarges the spectrum of brain stem abnormalities in JSRD. In view of the underlying ciliopathy, it seems likely that the interpeduncular heterotopia results from misdirected migration.

The aim of this study was to evaluate if a diagnostic work-up should be recommended for 2-year-old children with developmental language delay (LD), or if the widely chosen 'wait and see' strategy is adequate. Children with LD were identified in paediatric practices during routine developmental check-ups using a German parent-report screening questionnaire (adapted from the MacArthur Communicative Development Inventories). A standardized German instrument and the Netherlands version of Bayley Scales of Infant Development (2nd ed.) were used to assess language ability and nonverbal cognitive development respectively in 100 children with LD (65 males, 35 females; mean age 24.7 mo [SD 0.9]) and a control group of 53 children with normal language development (33 males, 20 females; mean age 24.6 mo [SD 0.8]). Neurological and audiometric testing were also performed. Sixty-one per cent of the LD group had specific expressive LD and 17% specific receptive-expressive LD. In 22%, LD was associated with other neurodevelopmental problems, 6% showed significant deficits in nonverbal cognitive abilities, and in 12%, nonverbal cognitive abilities were borderline. Four per cent fulfilled the criteria of childhood autism. LD at 2 years proved to represent a sensitive marker for different developmental problems. Adequate early intervention requires a clear distinction between specific expressive or receptive-expressive LD and LD associated with other neurodevelopmental problems. Though catch-up development is to be expected in a substantial proportion of 'late talkers', our data demonstrate that a general 'wait and see' approach is not justified in young children with LD. A proposal for a rational diagnostic work-up is presented.

Classical phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase, resulting in an accumulation of its upstream metabolite phenylalanine in brain tissue and cerebrospinal fluid of PKU patients. PKU is neuropathologically characterized by reduced dendritic arborization, loss of synapses, and neurodegeneration. We investigated whether increased concentrations of phenylalanine cause reduced synaptic density and alter dendritic branching. We treated primary cortical neurons differentiated for 21 d in vitro with 5 mM phenylalanine in the presence of all essential amino acids. Immunocytochemical analysis of 12 and 21 d in vitro primary neurons revealed no changes of dendritic morphology or neuronal viability but a significant difference in synaptic density, suggesting that elevated concentrations of extracellular phenylalanine cause an impairment of synaptogenesis. Although impairment of cerebral energy metabolism has been identified as an important pathophysiological principal in many diseases, respiratory chain function has not been extensively studied in PKU before. We investigated whether phenylalanine inhibits respiratory chain complexes I-V. In vitro analysis revealed no inhibitory effect of phenylalanine on complexes I-V, but an inhibition of pyruvate kinase, a key enzyme of glycolysis, catalyzing the formation of pyruvate. Pyruvate kinase is part of the enzyme assay to investigate enzyme activity of mitochondrial complex V and it remains to be elucidated whether this finding is relevant in vivo. In conclusion, elevated concentrations of phenylalanine might be involved in mechanisms underlying impaired synaptogenesis in PKU, supporting the common therapeutic strategy to reduce phenylalanine concentrations in the brain to prevent neurodegeneration.

Background and Purpose: Our purpose was to specify the most severely affected brain structures in early treated phenylketonuria regarding volume loss and establish possible correlations between volume loss and plasma levels of phenylalanine (Phe)., Methods: In 31 patients with early treated phenylketonuria and in 27 healthy volunteers, we acquired volumetric MR imaging data. Serum Phe concentrations at different times were measured as well. Semiautomatic volumetric postprocessing of the cerebellum, cerebrum (supratentorial brain tissue), hippocampus, intracranial volume, lateral ventricles, nucleus caudatus, nucleus lentiformis, pons, and thalamus, as well as the two-dimensional extension of the corpus callosum, was performed using the software BRAINS2. For each separate brain structure, the relative differences between the normal and the phenylketonuria group (delta(rel)) were calculated., Results: The cerebrum, corpus callosum, hippocampus, intracranial volume, and pons were significantly smaller in patients with phenylketonuria than in healthy patients. The volume of the lateral ventricles was significantly larger in patients with phenylketonuria than in healthy ones. The most severely affected structures were the pons (delta(rel) = 16%), hippocampus (delta(rel) = 14.5%), cerebrum (delta(rel) = 13%), and corpus callosum (delta(rel) = 10%). No significant differences were found for the basal ganglia, cerebellum, and thalamus. There were no significant correlations found between the volume of any of the different brain structures and the metabolic parameters., Conclusion: The most severely affected brain structures in early-treated patients with phenylketonuria regarding volume loss are the cerebrum, corpus callosum, hippocampus, and pons.

Both severe impairments of brain development in untreated infants and acute reversible neurotoxic effects on brain function are clinical features of phenylketonuria (PKU). For determining whether impairments of cerebral energy metabolism play a role in the pathophysiology of PKU, quantitative in vivo 31P magnetic resonance spectroscopy (MRS) was performed in a supratentorial voxel of 11 adult PKU patients and controls. Peak areas of inorganic phosphate; phosphocreatine; alpha-, beta-, and gamma-ATP; NAD; phosphomonoesters; phosphodiesters; and a broad phospholipid signal were converted to millimolar concentrations. Mg2+, pH, ADP, the phosphorylation potential, and the relative velocity of oxidative metabolism V/Vmax were derived. Clinical evaluation included mutation analysis, neurologic investigation, intelligence testing, magnetic resonance imaging, and concurrent plasma and brain phenylalanine (Phe), the last by 1H-MRS. Phe loading was performed in five patients with an oral dose of 100 mg/kg body wt L-Phe monitored by spectral EEG analysis. Under steady-state conditions, 31P-MRS revealed normal values for ATP, phosphocreatine, NAD, phosphomonoesters, phosphodiesters, Mg2+, and pH in PKU. ADP (+11%) and the phosphorylation potential (+22%) were increased. Peak areas of inorganic phosphate (-22%) and phospholipid (-8%) were decreased. ADP correlated with concurrent plasma (r = 0.65) and brain (r = 0.55) Phe. During the Phe load, blood Phe levels increased steeply. EEG revealed slowing of background activity. The phosphorylation potential decreased, whereas ADP and V/Vmax increased. In vivo 31P-MRS demonstrated subtle abnormalities of cerebral energy metabolism in PKU in steady-state conditions that were accentuated by a Phe load, indicating a link between Phe neurotoxicity and imbalances of cerebral energy metabolism.

We investigated a male, aged 4 years 11 months, who fulfilled the criteria of Asperger syndrome). In addition to the typical pattern of autistic symptoms, psychological testing revealed prosopagnosia in tasks for face recognition and matching. Prosopagnosia was also present when he tried to identify the faces of his parents and himself in photographs whenever these were presented with photographs of other persons. Although impairment in reciprocal social interaction in individuals with Asperger syndrome is closely correlated to their impaired perceptional abilities in non-verbal communication, especially facial expression, overt prosopagnosia seems to be a rare neuropsychological symptom in persons with autistic disorders.

Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased. This hypothesis was tested by measuring brain Phe in patients with PKU by quantitative 1H magnetic resonance spectroscopy during an oral Phe challenge with and without additional supplementation with all other LNAAs. Baseline plasma Phe was approximately 1,000 micromol/l and brain Phe was approximately 250 micromol/l in both series. Without LNAA supplementation, brain Phe increased to approximately 400 micromol/l after the oral Phe load. Electroencephalogram (EEG) spectral analysis revealed acutely disturbed brain activity. With concurrent LNAA supplementation, Phe influx was completely blocked and there was no slowing of EEG activity. These results are relevant for further characterization of the LNAA carrier and of the pathophysiology underlying brain dysfunction in PKU and for treatment of patients with PKU, as brain function might be improved by continued LNAA supplementation.

Cerebral concentrations of phenylalanine (PHE) were measured by means of quantitative in vivo 1H MR spectroscopy in 8 adult patients treated early for phenylketonuria type I. A 1.5-Tesla routine magnetic resonance scanner, localization sequence with short echo time (20 ms), and a fully automated data processing scheme were used. Baseline plasma PHE concentrations were 1.04 (0.70-1.39) mmol/L PHE with concurrent brain PHE concentrations of 0.27 (0.13-0.41) mmol/kg of wet weight resulting in a plasma/brain ratio of 4.12. Plasma and brain concentrations correlated significantly (Kendall tau b = 0.91, p < 0.01). During an oral load with a single dose of 100 mg L-PHE per kg of body weight in four patients, plasma levels steeply increased. Concurrent brain PHE increase was less steep, was significantly delayed, and still continued up to 20 h postload. Despite the proven rise in plasma and brain concentrations of PHE, neuropsychologic examinations revealed no impairment of attentional and fine motor abilities from preload up to 20 h postload.