The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

OBJECTIVE: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. METHODS: We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. RESULTS: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. INTERPRETATION: Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

Effects of Levetiracetam and Sulthiame on EEG in benign epilepsy with centrotemporal spikes: A randomized controlled trial.

PURPOSE: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG. METHODS: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated. RESULTS: Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures. CONCLUSION: Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures.

Novel DCC variants in congenital mirror movements and evaluation of disease-associated missense variants.

Congenital mirror movements (CMM) are involuntary movements of one side of the body that mirror intentional movements of the other side. Heterozygous missense, frameshift and nonsense variants and small intragenic deletions in DCC cause CMM, isolated agenesis of the corpus callosum (ACC) or both. We report here the clinical phenotype and natural history of ten individuals with CMM carrying five different monoallelic DCC variants, including the missense variant p.(Trp273Arg), two duplications, one deletion and one deletion-insertion; all are novel and absent from databases. We re-evaluated the 15 known disease-associated DCC missense variants by determining minor allele frequency (MAF) and pathogenicity using four in silico tools combining previous pathogenicity scores and the ACMG/AMP standards and guidelines and classified them in three groups. Group I contains three DCC missense variants that are rather unlikely to be associated with a higher risk to CMM and/or ACC. The five variants in group II may represent susceptibility factors to altered midline crossing in the central nervous system. Group III includes seven variants absent in publically available databases and representing possible pathogenic alleles, with four predicted to have a severe impact on protein function. Based on this data and the variable expressivity and incomplete penetrance present in heterozygous carriers of a DCC variant, classification and clinical interpretation of missense variants is challenging in the absence of evidence of pathogenicity originated from functional studies. Evaluation of missense variants by MAF and a weighted combination of several computational algorithms is recommended.

FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.

PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.

Confirmation of mutations in PROSC as a novel cause of vitamin B 6 -dependent epilepsy.

Vitamin-B6-dependent epilepsies are a heterogenous group of treatable disorders due to mutations in several genes (ALDH7A1, PNPO, ALPL or ALDH4A1). In neonatal seizures, defects in ALDH7A1 and PNPO explain a major fraction of cases. Very recently biallelic mutations in PROSC were shown to be a novel cause in five families. We identified four further unrelated patients harbouring a total of six different mutations, including four novel disease mutations. Vitamin B6 plasma profiles on pyridoxine did not enable the differentiation of patients with PROSC mutations. All four patients were normocephalic and had normal cranial imaging. Pyridoxine monotherapy allowed complete seizure control in one, while two patients had occasional febrile or afebrile seizures and one needed additional valproate therapy for photosensitive seizures. Two patients underwent a controlled pyridoxine withdrawal with signs of encephalopathy within a couple of days. Three had favourable outcome with normal intellectual properties at age 12.5, 15.5 and 30 years, respectively, while one child had marked developmental delay at age 27 months. The clinical and electroencephalographic phenotype in patients with PROSC mutations was indistinguishable from ALDH7A1 and PNPO deficiency. We therefore confirm PROSC as a novel gene for vitamin-B6-dependent epilepsy and delineate a non-specific plasma vitamin B6 profile under pyridoxine treatment.

Outcome of patients with classical infantile pompe disease receiving enzyme replacement therapy in Germany.

PURPOSE: Enzyme replacement therapy (ERT) has been shown to improve outcome in classical infantile Pompe disease. The purpose of this study was to assess mortality, morbidity, and shortcomings of ERT in a larger cohort of patients treated outside clinical trials. To accomplish this, we retrospectively analyzed the data of all 23 subjects with classical infantile Pompe disease having started ERT in Germany between January 2003 and December 2010. RESULTS: Ten patients (43%) deceased and four others (17%) became ventilator dependent. Seven infants (30.5%) made no motor progress at all, while seven (30.5%) achieved free sitting, and nine (39%) gained free walking. Besides all the seven patients (100%) attaining no improvement of motor functions, four out of the seven (57%) achieving to sit without support, and three out of the nine (33%) being able to walk independently, secondarily deteriorated, and died or became ventilator dependent. Sustained reduction of systolic function despite reversal of cardiac hypertrophy (n = 3), gastroesophageal reflux (n = 5), swallowing difficulties or failure to thrive (n = 11), recurrent pneumonias (n = 14), port system complications (n = 4), anesthesia-related incidents (n = 2), severe allergic reactions (n = 6), hearing loss (n = 3), and orthopedic deformities (n = 4) were problems frequently encountered. CONCLUSION: Although this study has important shortcomings due to its retrospective nature and because important variables potentially influencing outcome were not available for a substantial amount of patients, these data suggest that classical infantile Pompe disease still remains a life-threatening condition associated with high morbidity and often dismal prognosis. Currently, a relevant number of patients do not benefit definitely from ERT.

A novel ATP1A3 mutation with unique clinical presentation.

Mutations in the ATP1A3 gene are associated with rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) as well as RDP/AHC intermediate presentations. Phenotypic diversity is being recognized. In order to identify ATP1A3-related phenotypes not meeting the classical criteria for RDP or AHC we lowered the threshold for mutation analysis in clinical presentations resembling AHC or RDP. A novel heterozygous ATP1A3 missense mutation c.2600G>A (p.Gly867Asp, G867D) was detected in a 15-year-old girl. Her clinical phenotype is partially consistent with an intermediate presentation between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism and comprises additional yet unreported features. With onset at 4½ years of age recurrent paroxysmal flaccid hemiplegia alternating in laterality was triggered by watching television or playing computer games. Occlusion of both eyes reliably stopped the plegic attacks with the patient remaining awake. Our observation further widens the phenotypic spectrum associated with ATP1A3 mutations.

The expanding clinical and genetic spectrum of ATP1A3-related disorders.

OBJECTIVE: We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation. METHODS: We identified 16 new patients with alternating hemiplegia of childhood (AHC) and 3 new patients with rapid-onset dystonia-parkinsonism (RDP) and included these as well as the clinical and molecular findings of all previously reported 164 patients with mutation-positive AHC and RDP in our analyses. RESULTS: Major clinical characteristics shared in common by AHC and RDP comprise a strikingly asymmetric, predominantly dystonic movement disorder with rostrocaudal gradient of involvement and physical, emotional, or chemical stressors as triggers. The clinical courses include an early-onset polyphasic for AHC, a later-onset mono- or biphasic for RDP, as well as intermediate forms. Meta-analysis of the 8 novel and 38 published ATP1A3 mutations shows that the ones affecting transmembrane and functional domains tend to be associated with AHC as the more severe phenotype. The majority of mutations are located in exons 8, 14, 17, and 18. CONCLUSION: AHC and RDP constitute clinical prototypes in a continuous phenotypic spectrum of ATP1A3-related disorders. Intermediate phenotypes combining criteria of both conditions are increasingly recognized. Efficient stepwise mutation analysis of the ATP1A3 gene may prioritize those exons where current state of knowledge indicates mutational clusters.

Is the Children's Depression Inventory Short version a valid screening tool in pediatric care? A comparison to its full-length version.

OBJECTIVE: This is the first study to validate and to compare the Children's Depression Inventory (CDI) and its short version (CDI:S) as screening tools for medically ill children. METHODS: A sample of 406 pediatric hospital patients, aged 9 to 12 years (56.2% male, 77.1% inpatients), completed the German CDI. Criterion validity of the 26-item CDI and the 10-item CDI:S was calculated by receiver operating characteristic (ROC) curves. DSM-IV diagnoses of depression based on the structured diagnostic interview for mental disorders in children and adolescents (Kinder-DIPS) served as the reference standard. Areas under the ROC curves as well as sensitivities and specificities for the optimal cutoffs were compared for both versions. RESULTS: Diagnoses of major or minor depression were established for 7.4% of the children. Areas under the curve for the 26-item CDI (87.7%) and the 10-item CDI:S (88.2%) were comparable. For the CDI, the cutoff≥12 yielded the best balance between sensitivity (83.3%) and specificity (82.7%). At the optimal cutoff≥3, the CDI:S resulted in a high sensitivity of 93.3% and a specificity of 70.7%. Thus, the CDI:S proved to be as sensitive as the CDI, but was less specific than the full-length version. CONCLUSION: Both the CDI and the CDI:S are valid screening instruments for depression in medically ill children. The sensitive and brief CDI:S is a promising tool in time-pressed settings such as pediatric care, but has to be followed by a thorough diagnostic assessment to rule out false positive cases.

Children's Depression Screener (ChilD-S): development and validation of a depression screening instrument for children in pediatric care.

The aim of the present study was to develop and validate the Children's Depression Screener (ChilD-S) for use in pediatric care. In two pediatric samples, children aged 9-12 (N(I) = 200; N(II) = 246) completed an explorative item pool (subsample I) and a revised item pool (subsample II). Diagnostic accuracy of each of the 22 items from the revised pool was evaluated in order to select the best items for the brief instrument ChilD-S. Areas under the curve (AUCs) of the revised item pool and the ChilD-S were compared. A diagnostic interview, the Kinder-DIPS, served as gold standard. For the purpose of screening for depressive disorders in children, the eight-item ChilD-S (AUC = 0.97) performed just as well as the revised 22-item pool (AUC = 0.94). For the ChilD-S the optimal cut-off point of ≥11 yielded a sensitivity of 0.91 and a specificity of 0.89. The ChilD-S shows high potential for depression screening of children in pediatric care.

Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients.

To describe the clinical and neurophysiological spectrum and prognosis in a large cohort of biochemically and genetically proven late onset Pompe patients. Thirty-eight diagnosed with late onset Pompe disease at our neuromuscular department during 1985 and 2006 are described in detail. The mean delay from onset of symptoms or first medical consultation until diagnosis was 10.4 and 7.1 years, respectively. A different diagnosis was suggested in 11 of 38 patients. Ten patients underwent repeated muscle biopsies before diagnosis of Pompe disease was established. Limb girdle weakness was the most frequent presenting sign. Six patients complained of myalgia. Wolf-Parkinson-White syndrome was found in 3 of 38 patients. Respiratory failure preceded the onset of overt limb muscle weakness in three patients. The course of the patients was progressive in all, but there was a wide variety of progression, which did not correlate with the age of disease onset. In 71% of the patients, neurophysiological investigations revealed a myopathic EMG pattern, half of the patients had spontaneous activity including complex repetitive discharges. A normal EMG was found in 9% of the patients. Nerve conduction studies were normal in all. Pompe disease should be taken into consideration in patients with unexplained limb girdle muscular weakness with respiratory failure. Cardiac manifestations may not be restricted to infantile Pompe disease.

eIF2B-related disorders: antenatal onset and involvement of multiple organs.

Leukoencephalopathy with vanishing white matter, also called "childhood ataxia with central nervous system hypomyelination," is the first human disease related to mutations in any of the five genes encoding subunits of eukaryotic initiation factor eIF2B or any translation factor at all. eIF2B is essential in all cells of the body for protein synthesis and the regulation of this protein synthesis under different stress conditions. It is surprising that mutations in the eIF2B genes have been reported to lead to abnormalities of the white matter of the brain only, although it has been shown recently that ovarian failure may accompany the leukoencephalopathy. Another surprising observation is that the onset of the disease varies from early childhood to adulthood, with the exception of Cree leukoencephalopathy, a disease related to a particular mutation in one of the eIF2B genes, which invariably has its onset within the first year of life. We analyzed the eIF2B genes of nine patients with an antenatal- or early-infantile-onset encephalopathy and an early demise and found mutations in eight of the patients. In addition to signs of a serious encephalopathy, we found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Until now, no evidence had been found for a genotype-phenotype correlation, but the consistently severe phenotype in affected siblings among our patients and in Cree encephalopathy patients suggests an influence of the genotype on the phenotype.