Petah Tikva, Israel
Petah Tikva, Israel

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Behar D.M.,Raphael Recanati Genetics Institute | Behar D.M.,Molecular Medicine Laboratory | Basel-Vanagaite L.,Raphael Recanati Genetics Institute | Basel-Vanagaite L.,Felsenstein Medical Research Center | And 16 more authors.
Journal of Lipid Research | Year: 2014

Congenital pancreatic lipase (PNLIP) deficiency is a rare monoenzymatic form of exocrine pancreatic failure characterized by decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health. While considered to be an autosomal recessive state affecting a few dozens of individuals world-wide and involving the PNLIP gene, no causative mutations for this phenotype were so far reported. Here, we report the identification of the homozygote missense mutation, Thr221Met [c.662C>T], in two brothers from a consanguineous family of Arab ancestry. The observed genotypes among the family members were concordant with an autosomal recessive mode of inheritance but moreover a clear segregation between the genotype state and the serum PNLIP activity was evident. Based on biophysical computational tools, we suggest the mutation disrupts the protein's stability and impairs its normal function. Although the role of PNLIP is well established, our observations provide genetic evidence that PNLIP mutations are causative for this phenotype. -Behar, D. M., L. Basel-Vanagaite, F. Glaser, M. Kaplan, S. Tzur, N. Magal, T. Eidlitz-Markus, Y. Haimi-Cohen, G. Sarig, C. Bormans, M. Shohat, and A. Zeharia. Identification of a novel mutation in the PNLIP gene in two brothers with congenital pancreatic lipase deficiency. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc..


Amir J.,Tel Aviv University | Schwarz M.,Tel Aviv University | Levy I.,Tel Aviv University | Levy I.,Pediatric Infectious Disease Unit | And 4 more authors.
Archives of Disease in Childhood | Year: 2011

Background: In previous studies, lenticulostriated vasculopathy (LSV) was detected in 0.4-5.8% of neonates who had undergone brain ultrasound studies during the neonatal period. Most infants were referred from neonatal intensive cAre units. Various clinical conditions were associated with LSV including intrauterine infections. Objective: To investigate whether LSV as a single abnormal finding in neonates with congenital cytomegalovirus (CMV) infection is a sign of central nervous system (CNS) involvement. Methods: Ultrasonographic and clinical data of all infants with congenital CMV infection, followed in our hospital, were collected. All infants with symptomatic congenital CMV infection and CNS involvement were treated with ganciclovir for 6 weeks, followed by valganciclovir until the age of 1 year. Infants with asymptomatic as well as symptomatic infections were followed up with brainstem evoked response and behavioural studies every 4 months until 4 years of age. Results: 92 infants diagnosed with congenital CMV infection were included in the study. In 50 (54.3%) infants, LSV was detected on initial brain ultrasound. Among these patients, 21 (42%) infants had other ultrasonographic findings consistent with congenital CMV infection; 11 (22%) had other symptoms of CNS involvement and in 18 (36%) cases the only abnormal finding was LSV. In 9 of the 18 infants with LSV as the only finding on initial examination, antiviral therapy was not started. Hearing deterioration developed in all nine infants between ages 4 and 34 months. Subsequent to these cases, the authors modified their therapy protocol and began treating congenital CMV infants with only LSV. 9 infants were treated and all maintained normal hearing after 8-27 months of follow-up (p<0.01). Conclusions: LSV is a common finding in infants with symptomatic congenital CMV infection and is a sign of CNS involvement. Moreover, LSV is a possible marker of high risk for sensorineural hearing loss in infants with congenital CMV infection.


Koehler K.,TU Dresden | Malik M.,Jena University Hospital | Mahmood S.,University of Health Sciences, Lahore | Giesselmann S.,Jena University Hospital | And 32 more authors.
American Journal of Human Genetics | Year: 2013

In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism. © 2013 The American Society of Human Genetics. All rights reserved.


Bilavsky E.,Tel Aviv University | Schwarz M.,Tel Aviv University | Schwarz M.,Schneider Childrens Medical Center | Pardo J.,Tel Aviv University | And 8 more authors.
Acta Paediatrica, International Journal of Paediatrics | Year: 2015

Aim This study investigated the relationship between lenticulostriated vasculopathy (LSV) and hearing loss in 141 infants with congenital cytomegalovirus (cCMV) infection. Methods We included all infants with cCMV infection who were followed in our clinic for more than a year with only LSV signs of brain involvement on initial brain ultrasound. Group one comprised 13 infants with no hearing impairment at birth who were not treated with gan/valganciclovir during 2006-2009. Group two was 51 infants with LSV and no hearing impairment who had been treated since mid-2009. Group three was 25 infants born with LSV and hearing loss, who had been treated from birth. Group four was 52 control infants born during the same period with asymptomatic cCMV. Hearing tests were performed during the neonatal period and every four to six months until four years of age. Results Hearing deterioration was more extensive in group one (85%) than in group two (0%, p < 0.001) and the asymptomatic group (10%, p < 0.001) and occurred more often in group four (10%) than in group two (0%, p = 0.008). Conclusion Lenticulostriated vasculopathy was common in infants with cCMV infection and may serve as a sign of central nervous system involvement and further hearing deterioration. Antiviral treatment may be prudent in such infants. ©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd.


Bilavsky E.,Schneider Childrens Medical Center | Bilavsky E.,Tel Aviv University | Schwarz M.,Tel Aviv University | Schwarz M.,Schneider Childrens Medical Center | And 10 more authors.
Acta paediatrica (Oslo, Norway : 1992) | Year: 2015

AIM: This study investigated the relationship between lenticulostriated vasculopathy (LSV) and hearing loss in 141 infants with congenital cytomegalovirus (cCMV) infection.METHODS: We included all infants with cCMV infection who were followed in our clinic for more than a year with only LSV signs of brain involvement on initial brain ultrasound. Group one comprised 13 infants with no hearing impairment at birth who were not treated with gan/valganciclovir during 2006-2009. Group two was 51 infants with LSV and no hearing impairment who had been treated since mid-2009. Group three was 25 infants born with LSV and hearing loss, who had been treated from birth. Group four was 52 control infants born during the same period with asymptomatic cCMV. Hearing tests were performed during the neonatal period and every four to six months until four years of age.RESULTS: Hearing deterioration was more extensive in group one (85%) than in group two (0%, p < 0.001) and the asymptomatic group (10%, p < 0.001) and occurred more often in group four (10%) than in group two (0%, p = 0.008).CONCLUSION: Lenticulostriated vasculopathy was common in infants with cCMV infection and may serve as a sign of central nervous system involvement and further hearing deterioration. Antiviral treatment may be prudent in such infants. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.


Waisbourd-Zinman O.,Day Hospitalization Unit
Harefuah | Year: 2010

Nontuberculous mycobacterial infections in immunocompetent children usually presents as chronic lymphadenitis involving the neck and face. Mycobacterium avium complex is the most common pathogen, although recent series found Mycobacterium haemophilum, to be a major cause of chronic lymphadenitis in otherwise healthy children. The authors describe a 9-month-old baby who presented with a 4-month history of preauricular lymphadenitis. Mycobacterial culture yielded Mycobacterium haemophilum. A no-intervention approach was chosen. At the 6-month follow-up, the swelling had ameliorated and the skin showed a small scar with near-normal overlying skin color. A literature review of the clinical manifestations and diagnosis of Mycobacterium haemophilum lymphadenitis and of the different management options for nontuberculous mycobacterial lymphadenitis in otherwise healthy children is presented.


Haimi Cohen Y.,Day Hospitalization Unit | Haimi Cohen Y.,Tel Aviv University | Shalva N.,Edmond and Lily Safra Childrens Hospital | Shalva N.,Tel Aviv University | And 14 more authors.
Molecular Genetics and Metabolism | Year: 2012

McArdle disease is caused by a myophosphorylase deficiency consequent to defects in the PYGM gene. A minority of the over-133 known mutations are associated with ethnicity, occurring mainly in patients from western Europe, the United States, and Japan. We identified a novel mutation, c.632delG, in three unrelated families of Jewish descent originating from the Caucasus region. This possibly ethnicity-associated mutation can significantly facilitate the diagnosis in Jews of the Caucasus and contribute to genetic consultations. © 2012 Elsevier Inc.


PubMed | Day Hospitalization Unit
Type: Case Reports | Journal: Harefuah | Year: 2011

Nontuberculous mycobacterial infections in immunocompetent children usually presents as chronic lymphadenitis involving the neck and face. Mycobacterium avium complex is the most common pathogen, although recent series found Mycobacterium haemophilum, to be a major cause of chronic lymphadenitis in otherwise healthy children. The authors describe a 9-month-old baby who presented with a 4-month history of preauricular lymphadenitis. Mycobacterial culture yielded Mycobacterium haemophilum. A no-intervention approach was chosen. At the 6-month follow-up, the swelling had ameliorated and the skin showed a small scar with near-normal overlying skin color. A literature review of the clinical manifestations and diagnosis of Mycobacterium haemophilum lymphadenitis and of the different management options for nontuberculous mycobacterial lymphadenitis in otherwise healthy children is presented.


PubMed | Day Hospitalization Unit
Type: Journal Article | Journal: Molecular genetics and metabolism | Year: 2012

McArdle disease is caused by a myophosphorylase deficiency consequent to defects in the PYGM gene. A minority of the over-133 known mutations are associated with ethnicity, occurring mainly in patients from western Europe, the United States, and Japan. We identified a novel mutation, c.632delG, in three unrelated families of Jewish descent originating from the Caucasus region. This possibly ethnicity-associated mutation can significantly facilitate the diagnosis in Jews of the Caucasus and contribute to genetic consultations.


PubMed | Day Hospitalization Unit
Type: | Journal: JIMD reports | Year: 2013

Hyperargininemia is a rare autosomal recessive disorder of the last step of the urea cycle characterized by a deficiency in liver arginase1. Clinically, it differs from other urea cycle defects by a progressive paraparesis of the lower limbs (spasticity and contractures) with hyperreflexia, neurodevelopmental delay and regression in early childhood. Growth is affected as well. Hyperammonemia is episodic, if present at all. The disease is caused by mutations in the ARG1 gene; there are approximately 20 different known ARG1 mutations with considerable genetic heterogeneity. We describe two Arab siblings with a late diagnosis of hyperargininemia and present the genetic findings in their family. As ARG1 sequencing was unrevealing despite suggestive clinical and laboratory findings, molecular cDNA analysis was performed. The ARG1 expression pattern identified a 125-bp out-of-frame insertion between exons 3 and 4, leading to the addition of 41 amino acids and a premature termination codon TGA at the sixth codon downstream. The insertion originated at intron 3 and was attributable to a novel c.305 + 1323 t > c intronic base change that enabled an enhancement phenomenon. This is the first reported exon-splicing-enhancer mutation in patients with hyperargininemia. The clinical course and genetic findings emphasize the possibility that hyperargininemia causes neurological deterioration in children and the importance of analyzing the expression pattern of the candidate gene when sequencing at the DNA level is unrevealing.

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