Mucopolysaccharidosis Type 1 among Children-Neuroradiological Perspective Based on Single Centre Experience and Literature Review.

Mucopolysaccharidosis 1 (MPS 1) is a group of rare lysosomal genetic disorders resulting from the accumulation of undegraded glycosaminoglycans (GAGs) leading to multiorgan damage. Neurological symptoms vary from mild to severe. Neuroimaging-mainly magnetic resonance (MRI)-plays a crucial role in disease diagnosis and monitoring. Early diagnosis is of the utmost importance due to the necessity of an early therapy implementation. New imaging tools like MR spectroscopy (MRS), semiquantitative MRI analysis and applying scoring systems help substantially in MPS 1 surveillance. The presented analysis of neuroimaging manifestations is based on 5 children with MPS 1 and a literature review. The vigilance of the radiologist based on knowledge of neuroradiological patterns is highlighted.

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly.

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

The First Metabolome Analysis in Children with Epilepsy and ALG13-CDG Resulting from c.320A>G Variant.

BACKGROUND: ALG13-CDG belongs to the congenital disorders of glycosylation (CDG), which is an expanding group of multisystemic metabolic disorders caused by the N-linked, O-linked oligosaccharides, shared substrates, glycophosphatidylinositol (GPI) anchors, and dolichols pathways with high genetic heterogeneity. Thus, as far as clinical presentation, laboratory findings, and treatment are concerned, many questions are to be answered. Three individuals presented here may serve as a good example of clinical heterogeneity. This manuscript describes the first metabolomic analysis using NMR in three patients with epileptic encephalopathy due to the recurrent c.320A>G variant in ALG13, characterized to date only in about 60 individuals (mostly female). This is an important preliminary step in the understanding of the pathogenesis of the disease associated with this variant in the rare genetic condition. The disease is assumed to be a disorder of N-glycosylation given that this is the only known function of the ALG13 protein. Despite this, protein electrophoresis, which is abnormal in most conditions due to abnormalities in N-glycosylation, has been normal or only mildly abnormal in the ALG13 patients. METHODS: Nuclear magnetic resonance (NMR) spectroscopy in conjunction with multivariate and univariate modelling were used to analyze the metabolic profile of the blood serum samples acquired from the studied patients. RESULTS: Three metabolites were identified as potential biomarkers: betaine, N-acetyl-glycoprotein, and carnitine. CONCLUSIONS: Since presented data are the first to be collected so far, they need be verified in further studies. Our intention was to turn attention toward possible CDG-ALG13 laboratory markers that would have clinical significance.

Serum very long-chain fatty acids (VLCFA) levels as predictive biomarkers of diseases severity and probability of survival in peroxisomal disorders.

CONCLUSION: VLCFA levels correlate with the severity of the clinical course of ZS, DBP and mild ZSD. The best predictive value for estimating the projected disease severity and survival time is a concentration of C26:0.

NMR-based metabolomics in pediatric drug resistant epilepsy - preliminary results.

Epilepsy in children is the most frequent, heterogeneous and difficult to classify chronic neurologic condition with the etiology found in 35-40% of patients. Our aim is to detect the metabolic differences between the epileptic children and the children with no neurological abnormalities in order to define the metabolic background for therapy monitoring. The studied group included 28 epilepsy patients (median age 12 months) examined with a diagnostic protocol including EEG, videoEEG, 24-hour-EEG, tests for inborn errors of metabolism, chromosomal analysis and molecular study. The reference group consisted of 20 patients (median age 20 months) with no neurological symptoms, no development delay nor chronic diseases. 1H-NMR serum spectra were acquired on 400 MHz spectrometer and analyzed using multivariate and univariate approach with the application of correction for age variation. The epilepsy group was characterized by increased levels of serum N-acetyl-glycoproteins, lactate, creatine, glycine and lipids, whereas the levels of citrate were decreased as compared to the reference group. Choline, lactate, formate and dimethylsulfone were significantly correlated with age. NMR-based metabolomics could provide information on the dynamic metabolic processes in drug-resistant epilepsy yielding not only disease-specific biomarkers but also profound insights into the disease course, treatment effects or drug toxicity.

Comprehensive genomic analysis of patients with disorders of cerebral cortical development.

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes  and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

Mild Zellweger syndrome due to a novel PEX6 mutation: correlation between clinical phenotype and in silico prediction of variant pathogenicity.

Zellweger syndrome (ZS) is a consequence of a peroxisome biogenesis disorder (PBD) caused by the presence of a pathogenic mutation in one of the 13 genes from the PEX family. ZS is a severe multisystem condition characterized by neonatal appearance of symptoms and a shorter life. Here, we report a case of ZS with a mild phenotype, due to a novel PEX6 gene mutation. The patient presented subtle craniofacial dysmorphic features and slightly slower psychomotor development. At the age of 2 years, he was diagnosed with adrenal insufficiency, hypoacusis, and general deterioration. Magnetic resonance imaging showed a symmetrical hyperintense signal in the frontal and parietal white matter. Biochemical tests showed elevated liver transaminases, elevated serum very long chain fatty acids, and phytanic acid. After the death of the child at the age of 6 years, molecular diagnostics were continued in order to provide genetic counseling for his parents. Next generation sequencing (NGS) analysis with the TruSight One™ Sequencing Panel revealed a novel homozygous PEX6 p.Ala94Pro mutation. In silico prediction of variant severity suggested its possible benign effect. To conclude, in the milder phenotypes, adrenal insufficiency, hypoacusis, and leukodystrophy together seem to be pathognomonic for ZS.

Congenital disorder of glycosylphosphatidylinositol (GPI)-anchor biosynthesis--The phenotype of two patients with novel mutations in the PIGN and PGAP2 genes.

BACKGROUND: Glycosylphosphatidylinositol (GPI)-anchor deficiencies are a new subclass of congenital disorders of glycosylation. About 26 genes are involved in the GPI-anchor biosynthesis and remodeling pathway, of which mutations in thirteen have been reported to date as causative of a diverse spectrum of intellectual disabilities. Since the clinical phenotype of these disorders varies and the number of described individuals is limited, we present new patients with inherited GPI-anchor deficiency (IGD) caused by mutations in the PGAP2 and PIGN genes. PATIENTS AND METHODS: The first girl presented with profound psychomotor retardation, low birth parameters, and chest deformities already existing in neonatal period. The disease course was slowly progressive with severe hypotonia, chronic fever, and respiration insufficiency at the age of 6. The second girl showed profound psychomotor retardation, marked hypotonia, and high birth weight (97 centile). Dysmorphy was mild or absent in both girls. Whole exome sequencing revealed novel variants in the genes PGAP2 (c.2T>G and c.221G>A) and PIGN (c.790G>A and c.932T>G). Impaired GPI binding were was subsequently uncovered, although the hyperactivity of alkaline phosphatase (a GPI-anchored protein) occurred only in first case. CONCLUSIONS: Based on our results we can conclude that: 1. GPI-anchor biosynthesis disorders may represent a relatively frequent and overlooked metabolic defect; 2. The utility of GPI binding assessment as a screening test for this group of rare diseases requires further studies.

Four-and-one-half years' experience in monitoring of reproducibility of an MR spectroscopy system--application of in vitro results to interpretation of in vivo data.

The primary purpose of this work was to assess long-term in vitro reproducibility of metabolite levels measured using 1H MRS (proton magnetic resonance spectroscopy). The secondary purpose was to use the in vitro results for interpretation of 1H MRS in vivo spectra acquired from patients diagnosed with Canavan disease. 1H MRS measurements were performed in the period from April 2006 to September 2010. 118 short and 116 long echo spectra were acquired from a stable phantom during this period. Change-point analysis of the in vitro N-acetylaspartate levels was exploited in the computation of fT factor (ratio of the actual to the reference N-acetylaspartate level normalized by the reciprocity principle). This coefficient was utilized in the interpretation of in vivo spectra analyzed using absolute reference technique. The monitored time period was divided into six time intervals based on short echo in vitro data (seven time intervals based on long echo in vitro data) characterized by fT coefficient ranging from 0.97 to 1.09 (based on short echo data) and from 1.0 to 1.11 (based on long echo data). Application of this coefficient to interpretation of in vivo spectra confirmed increased N-acetylaspartate level in Canavan disease. Long-term monitoring of an MRS system reproducibility, allowing for absolute referencing of metabolite levels, facilitates interpretation of metabolic changes in white matter disorders.

Clinical and radiologic features of unilateral and bilateral schizencephaly in polish pediatric patients.

Schizencephaly is a rare and severe congenital brain defect. Its etiology is not unequivocal and its clinical course differs with every case. The aim of the study was to analyze correlations between clinical and radiologic features of schizencephaly in Polish patients. The study group consisted of 25 children. Epileptic seizures were observed in 60% of cases and in 32% epilepsy was drug resistant. Generalized hypotonia was found in 24%, spastic diparesis in 48%, and spastic hemiparesis in 28% of cases. Seizures were more frequent in the bilateral than unilateral schizencephaly subgroup (72% vs 29%, P = .045). There was a correlation between the presence of the bilateral type II schizencephaly and the occurrence of seizures (P = .002, r = 0.578). There is a correlation between the type of schizencephaly and the presence of seizures in Polish pediatric patients. In most of the patients, schizencephaly leads to developmental retardation and epileptic seizures.

The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype-phenotype correlation.

The aim of this study was to assess the natural history of the SCO2 deficiency in relation to the genotype in a cohort of 62 patients with SCO2 mutations (36 this study, 26 previous reports). A novel, milder phenotype (disease onset delayed until one year after birth, nonspecific encephalomyopathy, and 2-4 year survival period) associated with compound heterozygosity of the common p.E140K and a novel p.M177T mutations extends the range of symptoms of the SCO2 deficiency. The prevalence of SCO2 deficiency in Poland is relatively high. A search for SCO2 mutations in patients with histology resembling SMA appears to efficiently improve the detection rate.

Apolipoprotein E genotype and LRP1 polymorphisms in patients with different clinical types of metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is a severe, neurodegenerative, metabolic disease which is caused by deficient activity of arylsulfatase A (ARSA). Sulfatides and other substrates of ARSA are stored in central and peripheral nervous systems, and in some other organs. Accumulated sulfatides are especially toxic to oligodendrocytes and Schwann cells leading to progressive demyelination. The kind of apolipoprotein E (apoE) isoform is of essential significance for the modulation of sulfatide quantity in the brain as apoE4 contains more sulfatides than apoE3. Taking into consideration the fact that apoE4 leads to the loss of sulfatides in CSF of Alzheimer's disease patients, we examined if apoE isoforms display any impact on clinical outcome in patients with different forms of MLD in whom sulfatides accumulate. The significant association of age at the onset of MLD symptoms with APOE ε2/ε3/ε4 and LRP1 c.766C>T polymorphisms was shown in multivariate stepwise regression analysis, in which other factors known to affect age at onset of the disease, i.e. clinical type of MLD, family connection of the patient and sex were also analyzed. As expected, the clinical type of MLD explained about 80% of the variance of the dependent variable. The impact of both polymorphisms on age of onset of the disease was considerably lower: 2.0% in the case of APOE polymorphism and 1.0% in the case of LRP1 polymorphism. Thus, the clinical outcome in MLD patients is related principally to the genotype of the ARSA gene, while the polymorphisms in the APOE and LRP1 genes are only slightly modifying factors.

[Joubert syndrome and related disorders].

The cerebellum plays a role not only in motor control but also in motor learning and cognition. Joubert syndrome is a rare heterogeneous inherited genetic disorder characterized by ataxia, hypotonia, developmental delay, and at least one of the following features: neonatal respiratory disturbances or abnormal eye movement. The estimated frequency of Joubert syndrome in the United States is around 1 : 100 000. The term Joubert syndrome and related disorders (JSRD) has been recently coined to describe all disorders presenting with molar tooth sign on brain neuroimaging. Joubert syndrome is believed to be a representative of a new group of disorders named ciliopathies. The identification of seven causal genes (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67/MKS3, ARL13B, CC2D2A) has led to substantial progress in the understanding of the genetic basis of Joubert syndrome. The authors focus on clinical presentation of JSRD, differential diagnosis and molecular background.

Hyperammonemia in children: on the crossroad of different disorders.

BACKGROUND: Symptoms of hyperammonemia occur in patients irrespective of the kind of metabolic diseases. Age, metabolic and nutritional status, and decompensation factors such as infections influence clinical manifestations. Prolonged, untreated hyperammonemia leads to brain injury and intellectual disability. Treatment is directed at lowering plasma ammonia. Brain ammonium concentrations are 1.5 to 3.0 times higher than that in blood. REVIEW SUMMARY: The authors discuss the pathophysiology of the symptoms and consequences of hyperammonemia in children, focusing on the metabolic disorders leading to an increased level of ammonia. CONCLUSIONS: Ammonia toxicity has been investigated for a long time. According to the main hypotheses, the neurological alterations are connected to alterations in glutamatergic neurotransmission.

Isolated rhomboencephalosynapsis - a rare cerebellar anomaly.

BACKGROUND: Rhomboencephalosynapsis (RES, RS) is a unique entity usually recognized in infancy based on neuroimaging. Cerebellar fusion and absence of cerebellar vermis is often associated with supratentorial findings. Since now there are about 50 cases described worldwide, with approximately 36 patients diagnosed by MRI. The authors present the first in Poland case of this uncommon malformation and review the literature. CASE REPORT: The authors describe a 28-month-old-girl with microcephaly and proper psychomotor development. The family history was unrelevant. Based on MRI the congenital malformation of posterior fossa-rhombencephalosynapsis was confirmed CONCLUSIONS: Presented patient is a typical example of MRI usefulness especially in patients with RES. RES symptoms are mild and that is why the diagnosis is usually made only in adulthood.

Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing.

Congenital disorders of glycosylation type I (CDG-I) form a growing group of recessive neurometabolic diseases. Identification of disease genes is compromised by the enormous heterogeneity in clinical symptoms and the large number of potential genes involved. Until now, gene identification included the sequential application of biochemical methods in blood samples and fibroblasts. In genetically unsolved cases, homozygosity mapping has been applied in consanguineous families. Altogether, this time-consuming diagnostic strategy led to the identification of defects in 17 different CDG-I genes. Here, we applied whole-exome sequencing (WES) in combination with the knowledge of the protein N-glycosylation pathway for gene identification in our remaining group of six unsolved CDG-I patients from unrelated non-consanguineous families. Exome variants were prioritized based on a list of 76 potential CDG-I candidate genes, leading to the rapid identification of one known and two novel CDG-I gene defects. These included the first X-linked CDG-I due to a de novo mutation in ALG13, and compound heterozygous mutations in DPAGT1, together the first two steps in dolichol-PP-glycan assembly, and mutations in PGM1 in two cases, involved in nucleotide sugar biosynthesis. The pathogenicity of the mutations was confirmed by showing the deficient activity of the corresponding enzymes in patient fibroblasts. Combined with these results, the gene defect has been identified in 98% of our CDG-I patients. Our results implicate the potential of WES to unravel disease genes in the CDG-I in newly diagnosed singleton families.

Feeding problems in children with neurological disorders.

INTRODUCTION: The aim of this study was to evaluate the prevalence of selected risk factors of weight deficiency in children with chronic metabolic diseases. MATERIAL AND METHODS: The study group involved 160 children, from 2 months to 15 years (mean age 3.14 years), with diseases of the nervous system and body weight deficiency. According to the type of neurological disease the following groups of patients were separated: static encephalopathies, progressive encephalopathies, disorders of mental development of undetermined etiology, genetically determined diseases. As the exponent of malnutrition, z-score of weight-for-age standards was used. An inclusion criterion for the study group was z-score of weight-for-age < - 2SD. The analysed risk factors of body weight deficiency were: mode of feeding children, neurological disorders, oral motor dysfunction, diseases of other organs, gastrointestinal motility disorders (oral cavity, esophagus, intestines) and type of nutritional therapy. RESULTS: The most advanced malnutrition was in children with progressive encephalopathies and genetically determined diseases. Seizures and muscular hypotonia were most common neurological disorders. Oral motor dysfunctions were observed in 40% of patients. CONCLUSIONS: Malnutrition in children with neurological disorders is associated mainly with neurological deficits. In this group of children monitoring of somatic development and early nutritional intervention are necessary.

[Opsoclonus-myoclonus syndrome in a 2 year old boy with prenatally diagnosed retroperitoneal tumour]. / Zespol opsoklonie-mioklonie (the opsoclonus-myoclonus syndrome- OMS) u 2-letniego chlopca z rozpozpoznanym prenatalnie guzem przestrzeni zaotrzewnowej

Opsoclonus-myoclonus syndrome, also named Myoclonic Encephalopathy of Infants, Opsoclonus- Myoclonus Ataxia, Dancing Eyes - Dancing Feet Syndrome, Dancing Eyes Syndrome, Kinsbourne syndrome, is a rare, paraneoplastic or possibly post-viral chronic neurological disorder. The age of presentation ranges from 6 months to 3 years. In 50% of affected children the syndrome is associated with an underlying occult or clinically apparent neuroblastoma. In most patients the tumour is localized, small and well differentiated, with no NMYC gene copy number amplification. The syndrome may also occur after tumour resection or at relapse. The opsoclonus-myoclonus syndrome can occur in children without neuroblastoma, in such idiopathiccases, the onset of neurological symptoms is related to infection. It is assumed, that in idiopathic cases the syndrome could have developed in the course of neuroblastoma which had undergone a complete spontaneous regression. The most characteristic clinical features of opsoclonus-myoclonus syndrome are: opsoclonus, myoclonus, ataxia, irritability, mutism and sleep disturbances. The disease course is usually long-term with episodes of remission and relapses. Approximately 80% of children with opsoclonus-myoclonus syndrome suffer from mild to severe neurological handicaps, mainly cognitive impairment. The authors present a 2-year old boy with opsoclonus-myoclonus syndrome preceded by involution of prenatally documented retroperitoneal area tumour.

Clinical and neuropathological picture of ethylmalonic aciduria - diagnostic dilemma.

Increased ethylmalonic acid (EMA) in urine is a non-specific finding, and is observed in a number of inborn errors of metabolism, as well as in individuals who carry one of two common polymorphisms identified in the SCAD coding region. The authors present an 8-month-old girl with a suspicion of neuroinfection, although the clinical presentation led to diagnosis of ethylmalonic aciduria. From the neuropathological point of view the most remarkable changes were observed in the brain cortex, which was diffusely damaged practically in all regions of the brain. Of note, the most severe destruction was observed in the deepest regions of the sulci. The cortex of the affected regions showed no normal stratification and its structure was almost totally replaced by a form of "granulation tissue" with a markedly increased number of capillaries. To the authors' knowledge this is the first clinical report of ethylmalonic aciduria with brain autopsy findings.