Ewa Jamroz

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.

AGENESIS OF CORPUS CALLOSUM: CLINICAL DESCRIPTION AND ETIOLOGY

In 135 children (aged 3 months to 15 years) with structural defects of the central nervous system found on magnetic resonance imaging, agenesis of the corpus callosum was evident in 7. The etiology of agenesis of the corpus callosum has been established in four children: partial trisomy of chromosome 13, partial duplication of the long arm of chromosome 10, Aicardis syndrome, and intracranial bleeding during the fetal period as a result of injury. Agenesis of the corpus callosum coexisted with a Dandy-Walker malformation in one other patient, which suggests a genetic etiology. In spite of these variable etiologies, dysmorphic features were identified in all seven patients, as was psychomotor retardation. Epileptic seizures had occurred in six patients, and all manifested abnormalities on neurologic examination. (J Child Neurol 2000;15:401-405).

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.

Angelman syndrome revisited.

Objectives:Angelman syndrome (AS) is characterized by severe mental retardation, epilepsy, absent speech, dysmorphic facial features, and a characteristic behavioral phenotype. It is caused by deficiency of gene expression from maternally derived chromosome 15q11-q13. Study Design:The authors present the clinical picture of 9 children (median age, 4.9 years; range, 1 to 10 years) with confirmed Angelman syndrome. The patients complied with the international consensus criteria for AS and were consecutively investigated for psychomotor development, epilepsy, and electroencephalogram (EEG) profiles. Results:The median age at diagnosis was 3.9 years. The motor milestones were delayed. Median developmental quotient level was 26. All patients but 1 experienced predominantly polymorphic seizures. In 4 cases, the epilepsy was refractory to treatment. The EEG of all patients displayed an abnormal sleep pattern and generalized abnormalities, with a maximum over the posterior areas. Conclusions:Milder or less typical phenotypes of AS may remain undiagnosed, leading to an overall underdiagnosis of the disease. The EEG shows no clear relation to genotype, clinical picture, or to the presence and severity of epilepsy. AS should be considered in the differential diagnosis of children with severe cryptogenic epilepsy and a characteristic configuration of clinical features.

Topical Review : Friedreich's Ataxia

Friedreichs ataxia is one of the most frequent hereditary ataxias of childhood. The disease is inherited in an autosomal recessive mode. The current state of knowledge concerning genetics, pathophysiology, pathology, clinical course, differential diagnosis, genotype-phenotype correlation, and therapy is presented. (J Child Neurol 2002;17:315-319).

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.

A novel PANK2 gene mutation: clinical and molecular characteristics of patients short communication.

Pantothenate kinase—associated neurodegeneration (PKAN) is a progressive neurodegenerative disorder with autosomal recessive inheritance. The major symptoms of PKAN include the onset before the age of 20 years, progressive pyramidal and extrapyramidal signs, retinitis pigmentosa, optic atrophy, dementia, and iron depositions in the globus pallidus. The authors present 3 patients with proven molecular diagnosis of PKAN, in whom 2 novel mutations of PANK2 gene have been identified.

Isolated rhomboencephalosynapsis - a rare cerebellar anomaly.

Summary 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.

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