Justyna Paprocka

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.

Difficulties in differentiation of Parry–Romberg syndrome, unilateral facial sclerodermia, and Rasmussen syndrome

IntroductionParry–Romberg syndrome (progressive facial hemiatrophy) is a unilateral, slowly progressive atrophy affecting the skin, subcutaneous tissues, muscles, and bones. The relationship between Parry–Romberg syndrome and connective tissue disorders, especially scleroderma en coup de sabre, is still unclear. The neurological symptoms, including epilepsy, migraine, and brain lesion, on neuroimaging may be similar. Rasmussen encephalitis (RE) is connected with chronic inflammation and damage of one hemisphere. Clinically, it is manifested by epileptic partial seizures and unilateral neurological symptoms.Case ReportThe authors present the case of a 10-year-old girl with features suggestive of RE, with refractory partial motor dextrolateral seizures followed by development of hemiparesis and with progressive intellectual deterioration. At the age of 2 years, some changes on the left part of the face typical of Parry–Romberg syndrome or a linear form of scleroderma were noticed.DiscussionThe authors discussed the difficulties in differential diagnosis in that patient. The presented girl constitute the case from the borderline zone of the aforementioned disorders.

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 ‘H 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. PACS numbers: 87.19.lf, 87.61.Tg, 87.64.K‐, 87.64.kj

Melatonin in Epilepsy: A New Mathematical Model of Diurnal Secretion

Purpose. The main objective of the study was to create a mathematical model that describes the melatonin circadian secretion and, then the functionality of the model was tested by a comparison of the melatonin secretions in children with and without epilepsy. Material and Methods. The patients were divided into the epilepsy group (EG, n = 52) and the comparison group (CG, n = 30). The melatonin level was assessed by a radioimmunoassay method. The diurnal melatonin secretion was described using a nonlinear least squares method. Spearmans rank correlation coefficient was chosen to estimate the dependence of the acquired data. The model reproduces blood concentration profiles and its parameters were statistically analyzed using the Mann-Whitney-Wilcoxon test and logistic regression. Results. The correlation analysis performed for the EG and CG groups showed moderate correlations between age and the melatonin secretion model parameters. Patients with epilepsy are characterized by an increased phase shift of melatonin release.

Bridging the gap between metabolic profile determination and visualization in neurometabolic disorders: a multivariate analysis of proton magnetic resonance in vivo spectra

The purpose of this work was to check the degree of overlap between rare inborn errors of metabolism and other neurological disorders using principal component analysis of proton magnetic resonance spectroscopy (1H MRS) in vivo data. We examined 60 patients (median age of 22 months). Fourteen of them were diagnosed with neurometabolic disorders (three cases of metachromatic leukodystrophy, two cases of Canavan disease, two cases of megalencephalic leukoencephalopathy with subcortical cysts, three cases of mitochondrial cytopathy, one case of nonketotic hyperglycinemia, one case of globoid leukodystrophy, one case of congenital disorders of glycosylation, and one case of ethylmalonic encephalopathy). The remaining 46 patients were diagnosed with epilepsy, cerebral palsy, and developmental delay. Results obtained from principal component analysis of complete unresolved 1H MRS in vivo spectra were interpreted parallelly with LCModel‐derived metabolite levels. The main attention was paid to the following metabolites: N‐acetylaspartate, glutamate + glutamine, creatine, choline, myo‐inositol signal with an uncertain contribution of glycine, and glucose. 1H MRS in vivo coupled with multivariate analysis is an efficient tool in visualization of metabolic abnormalities in several inborn errors of metabolism (metachromatic leukodystrophy, globoid leukodystrophy, megalencephalic leukoencephalopathy with subcortical cysts, and Canavan disease). Copyright

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.

CDG type Ia and congenital cytomegalovirus infection: two coexisting conditions.

Congenital disorders of glycosylation are a heterogeneous group of disorders with multisystemic involvement. The most common form is phosphomannomutase deficiency or congenital disorders of glycosylation type Ia with an autosomal recessive inheritance and incidence estimated at 1/20000— 1/50000 live born. Congenital disorders of glycosylation Ia can manifest as severe multisystemic disease of infancy or milder disorder with only neurological problems including ataxia, hypotonia, and psychomotor retardation. The brain pathological findings in congenital disorders of glycosylation type Ia patients corroborate with cerebellar dysfunction. Usually the most affected part is the anterior lobe of the vermis. Microscopic analysis demonstrates the prominent Purkinje cell loss and subtotal loss of the external and internal granule cell layers. The authors present clinical and pathological picture of a 4-month-old girl with congenital disorders of glycosylation type Ia, additionally complicated by congenital cytomegalovirus infection. The diagnosis was confirmed by low phosphomannomutase activity in patients fibroblasts and mutations on both alleles of phosphomannomutase 2 gene.

Melatonin in Tuberous Sclerosis Complex Analysis Using Modern Mathematical Modeling Methods

Purpose. The aim of the study was to assess melatonin secretion pattern in children with TSC and to compare it with the secretion patterns in children with and without epilepsy. Material and Methods. Melatonin secretion was measured every three hours using the RIA method in four children with recognized TSC. The parameters of the melatonin secretion models were interpreted and compared with those obtained for the patients with epilepsy (n = 76) and the children from the control, nonepileptic group (n = 36). To describe the diurnal melatonin secretion, mathematical model was constructed and nonlinear least squares method with the Levenberg-Marquardt optimization algorithm was applied to approximate its parameters. The dim light melatonin onset (DLMO) parameters were also estimated from the model. Results and Conclusions. Statistically significant differences were found between the TSC melatonin secretion profiles and the nonepileptic control group. The profiles for the epileptic and TSC groups were found to be similar. For the TSC group, though a small one, the variations in the MLT release amplitudes seem to be independent of the total number of seizures; however, the MLT release shift appears to depend on the number of seizures.

Do children with Adams-Oliver syndrome require endocrine follow-up? New information on the phenotype and management

Kalina MA, Kalina‐Faska B, Paprocka J, Jamroz E, Pyrkosz A, Marszał E, Małecka‐Tendera E. Do children with Adams‐Oliver syndrome require endocrine follow‐up? New information on the phenotype and management.

The Prenatal and Perinatal Risk Variables of the Sensory Processing Disorder

Sensory Processing Disorder has a negative effect on a child’s functioning. The etiology and pathomechanics of sensory processing disorder has not yet been fully identified. The prenatal and perinatal variables have been described as the significant causes. The purpose of this work was to determine the most common and presently occurring prenatal and perinatal problems that may serve as the predictors of SPD. The studied group consisted of 89 children with identified sensory processing disorder and no other neurological disorders. The control group consisted of 88 children within the same age group which were healthy and did not suffer from the sensory processing disorder. The retrospective data from the prenatal and perinatal periods were collected through a questionnaire, prepared specifically for the purpose of this project. Besides that, the complex assessment of the children consisted of a pediatrics neurologic and physiotherapy/SI diagnosis examination. The age appropriate checklist, prepared by the American Occupational Therapy Association, has also been used. In the case of children between the ages of 7 months to 3 years old, Georgia A. De Gangi’s Infant-Toddler Symptom Checklist was applied. Furthermore, during the examination, the therapist applied the Clinical Observation Checklist as well as the South Carolina Sensory Integration Tests trials for the children above 4 years old. It has been demonstrated that there is a predilection towards the type of sex in sensory processing disorder, and it occurs three times more frequently among boys than among girls, in the studied group. Among all analyzed variables, six of them occurred statistically significantly more frequently in the group with the sensory processing disorder. Considering the frequency of occurrence, those variables included the following: a low birthweight, a low Apgar score at 1 min, infections and cervical insufficiency, and, less frequently occurring, placental abruption. The multivariable analysis demonstrates that the concurrence of two out of six risk variables with the highest prediction results in 80% probability of the emergence of sensory processing disorder, and the concurrence of 3 variables results in 90% of that probability. Our research study results indicate that the children with the prenatal and perinatal history should be under a specialized multidisciplinary supervision at least until they start school. In case of the concurrence of two and more variables, such supervision should be mandatory.