Case report: Cerebrotendinous xanthomatosis treatment follow-up

Xanthomatosis is a genetic disease inherited in an autosomal recessive manner. The specific phenotypic features are associated with patient’s genetic profile. The result of the mutation is disorder of cholesterol synthesis and the accumulation of its precursors in tissues. The characteristic symptoms are progressive cerebellar ataxia, cataract, diarrhea, and the deposition of cholesterol in the tendons. Our objective is to follow-up information to treatment efficacy of 22-year-old patient diagnosed with cerebrotendinous xanthomatosis through 1.5 year observation. In 2012, an 11-year-old patient with a long history of deformed feet and frequent yellowing of the skin, was admitted to the Department of Neurology due to seizures. In 2013, the patient began to suffer from diarrhea, and its frequency was correlated with the concentration of bilirubin in the blood. In the same year cataract was diagnosed. Gradually, the patient starts to complain about progressive difficulties in moving. In 2019, genetic tests confirmed the diagnosis of cerebrotendinous xanthomatosis. Since July 2021, the patient has been treated with chenodeoxycholic acid. The deterioration of patient’s mobility has been significantly inhibited, consequently his quality of life has improved. The presented case report underscores the efficacy of CDCA supplementation in halting the progression of CTX, resulting in marked improvements in the patient’s quality of life

Wewnątrzrodzinna zmienność fenotypu i rozwoju intelektualnego w zespole Pfeiffera wywołana mutacją p.P252R w genie FGFR1

Pfeiffer Syndrome (OMIM#101600) is a genetic disorder which belongs to cranio-facial dysostosis group inherited in an autosomal dominant pattern with variation of feature expression. It affects about 1 in 100,000 live-births. Typical features include: premature fusion of certain bones of the skull (craniosynostosis), maxillary hypoplasia and digital abnormalities of the hands and feet. Basing on the phenotype three clinical subtypes of Pfeiffer Syndrome can be distinguished: types 1, 2 and 3. This condition can be caused by heterozygous mutations in either fibroblast growth factor receptor gene type 1 or 2 (FGFR1 or FGFR2). FGFR1 mutations often result in less severe craniofacial involvement, no craniosynostosis, abnormalities of the limbs and most individuals have normal intelligence. The authors describe the family of three members (a son, a father and a daughter) variably affected by phenotype and intellectual development with Pfeiffer Syndrome type 1 caused by p.P252R mutation in FGFR1 gene. We showed that in investigating mental retardation the medical examination of the whole family and genetic counseling are important.Zespół Pfeiffera (OMIM#101600) jest rzadkim zespołem uwarunkowanym genetycznie zaliczanym do dysostoz czaszkowo- -twarzowych, który dziedziczy się w sposób autosomalnie dominujący ze zmienną ekspresją cech klinicznych. Występuje z częstością około 1:100 000 wśród żywo urodzonych dzieci. Typowe objawy zespołu obejmują: przedwczesne zarastanie szwów czaszkowych (kraniosynostoza), hipoplazja szczęki oraz wady dłoni i stop. Objawy zespołu Pfeiffera wywołują heterozygotyczne mutacje w genach czynnika wzrostu fibroblastów typu 1 lub 2 (fibroblast growth factor receptor gene type 1 or 2 – FGFR1 lub FGFR2). Mutacje występujące w genie FGFR1 skutkują mniej nasilonymi objawami fenotypowymi twarzoczaszki, wadami kończyn i najczęściej prawidłowym rozwojem intelektualnym. W niniejszej pracy autorzy przedstawiają trzy przypadki z jednej rodzinny (syn, ojciec i córka) prezentujące dużą zmienność objawów fenotypowych i intelektualnych w przebiegu zespołu Pfeiffera typu 1 wywołanego mutacją p.P252R w genie FGFR1. Autorzy zwracają uwagą na celowość wykonywania badań rodzinnych w kontekście diagnostyki niepełnosprawności intelektualnej i poradnictwa genetycznego

The spectrum of PLP1 gene mutations in patients with the classical form of the Pelizaeus-Merzbacher disease.

Uterine and umbilical blood flow measurements are reviewed in terms of studies carried out in uncomplicated human pregnancies. The review includes the perspective of how those estimates of flow fit with current knowledge of human fetal O2 consumption and uterine O2 and glucose consumption. From the consideration of both the O2 data and the flow measurements, we conclude that the best estimates for mean umbilical blood flow at term range between 120 and 145 ml•min-1•(kg fetus)-1. The uterine flow estimate from physiologic data would equate to ~270 ml•min-1•(kg fetus)-1. This estimate, based upon estimates of uterine O2 and glucose consumption, is much higher than some estimates made by imaging techniques. The reasons for this discrepancy are not yet established. However, given the enormous variability in uterine flow measurements made with imaging techniques, it is clear that more research into improvement in these non-invasive approaches is still required and all current estimates of uterine flow must be regarded as rather crude trials

Współwystępowanie choroby Parkinsona i pierwotnie postępującej postaci stwardnienia rozsianego

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Expanding the phenotype associated with missense mutations of the ARX gene.

The Aristaless-related homeobox gene (ARX, OMIM# 300382)located in chromosome Xp21.3 belongs to a family of homeobox genes that encode transcription factors playing a crucial role during early embryogenesis. In the brain, ARX is involved in cerebral development and patterning. Mutations in ARX have been shown to cause different forms of intellectual disability, which are classified as a malformation and a nonmalformation group of phenotypes. The latter involves mainly expansions of the trinucleotide repeats coding the second and first polyalanine tracts (polyA). Only few missense mutations in ARX have been reported in nonmalformed patients to date [Shoubridge et al., 2010; Sartori et al., 2011]. Here, we report on a large family with recurrence of intellectual disability and dystonia due to a novel missense mutation in ARX. There were nine affected males over two generations and there was an X-linked pattern of inheritance (Fig. 1). Patient cognitive and social skills were assessed by means of the Wechsler Intelligence Scale for Children (WISC-R) and Edgar Doll’s Vineland Social Maturity Scale (VSMS

Immune dysregulation in patients with chromosome 18q deletions : searching for putative loci for autoimmunity and immunodeficiency

INTRODUCTION: Autoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions. MATERIAL AND METHODS: Medical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG(1-4) serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR—a free web resource for gene prioritization. RESULTS: 18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min–max: 4.0–33.5). Autoimmune disorders were present in 14/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG(1-4)) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls. CONCLUSIONS: Patients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21

Comparative Genomic Hybridization to Microarrays in Fetuses with High-Risk Prenatal Indications: Polish Experience with 7400 Pregnancies

The aim of this study was to determine the suitability of the comparative genomic hybridization to microarray (aCGH) technique for prenatal diagnosis, but also to assess the frequency of chromosomal aberrations that may lead to fetal malformations but are not included in the diagnostic report. We present the results of the aCGH in a cohort of 7400 prenatal cases, indicated for invasive testing due to ultrasound abnormalities, high-risk for serum screening, thickened nuchal translucency, family history of genetic abnormalities or congenital abnormalities, and advanced maternal age (AMA). The overall chromosomal aberration detection rate was 27.2% (2010/7400), including 71.2% (1431/2010) of numerical aberrations and 28.8% (579/2010) of structural aberrations. Additionally, the detection rate of clinically significant copy number variants (CNVs) was 6.8% (505/7400) and 0.7% (57/7400) for variants of unknown clinical significance. The detection rate of clinically significant submicroscopic CNVs was 7.9% (334/4204) for fetuses with structural anomalies, 5.4% (18/336) in AMA, 3.1% (22/713) in the group of abnormal serum screening and 6.1% (131/2147) in other indications. Using the aCGH method, it was possible to assess the frequency of pathogenic chromosomal aberrations, of likely pathogenic and of uncertain clinical significance, in the groups of cases with different indications for an invasive test

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