Rose-Mary Boustany - Academia.edu (original) (raw)
Papers by Rose-Mary Boustany
HAL (Le Centre pour la Communication Scientifique Directe), Mar 23, 2017
We describe four new mutations in the JI-galactosidase gene. These are the first mutations causin... more We describe four new mutations in the JI-galactosidase gene. These are the first mutations causing infantile and juvenile GM1-gangliosidosis to be described in American patients. Cell lines from two patients with juvenile and from six patients with infantile GM1-gangliosidosis were analyzed. Northern blot analysis showed the acid P-galactosidase message to be of normal size and quantity in two juvenile and four infantile cases and of normal size but reduced quantity in two infantile cases. The mutations are distinct from the Japanese mutations. All are point mutations leading to amino acid substitutions: Lyss-77 .Arg, Arg590>-His, and Glu632-'-Gly. The fourth mutation, Arg208-*Cys, accounts for 10 of 16 possible alleles. Two infantile cases from Puerto Rico of Spanish ancestry are homozygous for this mutation, suggesting that this allele may have come to South America and North America via Puerto Rico. That these mutations cause clinical disease was confirmed by marked reduction in catalytic activity of the mutant proteins in the Cos-1 cell expression system.
PLOS ONE, 2021
PurposeThe aim of our study was to determine the prevalence of amblyopia risk factors in children... more PurposeThe aim of our study was to determine the prevalence of amblyopia risk factors in children visiting the American University of Beirut Medical Center (AUBMC) using automated vision screening.MethodsThis was a hospital-based screening of 1102 children aged between 2 and 6 years. Vision screening was performed using PlusoptiX S12 over 2 years (2018–2020). The need for referral to a pediatric ophthalmologist was based on the amblyopia risk factors set forth by the American Association for Pediatric Ophthalmology and Strabismus. Referred patients underwent a comprehensive eye examination.ResultsA total of 1102 children were screened, 63 were referred for amblyopia risk factors (5.7%); 37/63 (59%) underwent comprehensive eye examination and 73% were prescribed glasses. Of the non-referred group of children, 6.35% had astigmatism, 6.25% were hyperopic and 3.27% were myopic. The refractive errors observed among the examined patients were distributed as follows: 41% astigmatism, 51% h...
Nature Reviews Neurology, 2013
Since the discovery of the lysosome in 1955, advances have been made in understanding the key rol... more Since the discovery of the lysosome in 1955, advances have been made in understanding the key roles and functions of this organelle. The concept of lysosomal storage diseases (LSDs)--disorders characterized by aberrant, excessive storage of cellular material in lysosomes--developed following the discovery of α-glucosidase deficiency as the cause of Pompe disease in 1963. Great strides have since been made in understanding the pathobiology of LSDs and the neuronal ceroid lipofuscinoses (NCLs). The NCLs are neurodegenerative disorders that display symptoms of cognitive and motor decline, seizures, blindness, early death, and accumulation of lipofuscin in various cell types, and also show some similarities to 'classic' LSDs. Defective lysosomal storage can occur in many cell types, but the CNS and PNS are particularly vulnerable to LSDs and NCLs, being affected in two-thirds of these disorders. Most LSDs are inherited in an autosomal recessive manner, with the exception of X-linked Hunter disease, Fabry disease and Danon disease, and a variant type of adult NCL (Kuf disease). This Review provides a summary of known LSDs, and the pathways affected in these disorders. Existing therapies and barriers to development of novel and improved treatments for LSDs and NCLs are also discussed.
Neurology, 2000
Autosomal dominant hereditary spastic paraplegia is genetically heterogeneous, with at least five... more Autosomal dominant hereditary spastic paraplegia is genetically heterogeneous, with at least five loci identified by linkage analysis. Recently, mutations in spastin were identified in SPG4, the most common locus for dominant hereditary spastic paraplegia that was previously mapped to chromosome 2p22. We identified five novel mutations in the spastin gene in five families with SPG4 mutations from North America and Tunisia and showed the absence of correlation between the predicted mutant spastin protein and age at onset of symptoms.
Journal of Inherited Metabolic Disease, 1993
Human Molecular Genetics, 2002
Juvenile Batten disease (JNCL) is an autosomal recessive disease that results from mutations in t... more Juvenile Batten disease (JNCL) is an autosomal recessive disease that results from mutations in the CLN3 gene. The wild-type CLN3 gene coding sequence has 15 exons, and the translated protein consists of 438 amino acids. The most commonly observed mutation is a 1.02 kb deletion in the genomic DNA. This deletion results in a truncated protein due to the loss of amino acids 154-438, and the introduction of 28 novel amino acids at the c-terminus. We demonstrate that, compared to normal controls, CLN3-deficient immortalization of lymphoblasts homozygous for this deletion grow at a slower rate, and show increased sensitivity to etoposide-induced apoptosis, supporting the notion that CLN3 may negatively regulate apoptosis. Using immortalized JNCL lymphoblast cell lines as a model system, we assess the effects of specific CLN3 mutations on cell growth rates and protection from etoposide-induced apoptosis. Protection from etoposideinduced apoptosis occurs and the cell growth rate is restored following transfection of JNCL lymphoblasts with mutant CLN3 cDNA that includes exons 11 or 13. We show that deletion of the glycosylation sites 71NQSH74 and 310NTSL313, and also mutations within the highly conserved amino acid stretches 184WSSGTGGAGLLG195, 291VYFAE295 and 330VFASRSSL337, result in slowed growth and susceptibility to apoptosis.
Biochemistry & Pharmacology: Open Access, 2021
Ophthalmic Genetics, 2020
Background: Congenital fibrosis of the extraocular muscles (CFEOM) is characterized by ptosis and... more Background: Congenital fibrosis of the extraocular muscles (CFEOM) is characterized by ptosis and nonprogressive restrictive ophthalmoplegia. CFEOM1 is a stereotypical phenotype with isolated bilateral ptosis, bilateral ophthalmoplegia, absent upgaze, and globe infraduction. CFEOM3 is a more variable phenotype that can include unilateral disease, absent ptosis, residual upgaze, and/or orthotropia. Most cases of CFEOM1 result from recurrent heterozygous KIF21A missense mutations and less commonly from recurrent heterozygous TUBB3 missense mutations. While most cases of CFEOM3 result from recurrent heterozygous TUBB3 missense mutations, several pedigrees harbored pathogenic variants in KIF21A. Here, we asked if Lebanese pedigrees with CFEOM3 harbor pathogenic variants in TUBB3 or KIF21A. Materials and Methods: Families affected with congenital cranial dysinnervation disorders were prospectively recruited from the American University of Beirut pediatric ophthalmology clinic and included two probands with CFEOM. KIF21A hotspot exons and TUBB3 coding sequence were sequenced. Available family members were sequenced for co-segregation analysis. Results: Both families were found to have CFEOM3 and to harbor pathogenic variants in KIF21A(OMIM 608283). A simplex proband with CFEOM3 from a consanguineous Iraqi family harbored a de novo heterozygous KIF21A c.2860 C > T variant (p.R954W); this variant accounts for the majority of reported KIF21A mutations but is typically implicated in CFEOM1. A Lebanese father with CFEOM3 and his son with CFEOM1 segregated a heterozygous KIF21A c.2830 G > C variant (p.E944Q), previously reported in an individual with CFEOM1. Conclusions: These results support prior reports of KIF21A mutations as a rare cause of CFEOM3. These families are Middle Eastern or Chinese, supporting a genetic modifier in these populations.
Journal of Global Oncology, 2019
PURPOSE Breast cancer is the most prevalent female cancer and has a higher incidence in young Leb... more PURPOSE Breast cancer is the most prevalent female cancer and has a higher incidence in young Lebanese patients as compared with the West. Interestingly, this particularity of breast cancer in the Lebanese population was not found to be associated with higher BRCA1/2 gene mutations. Hence, our research focuses on investigating molecular mechanisms and associated epigenetic signatures that underlie breast cancer in young patients. We are specifically interested in microRNA (miRNA), small noncoding RNAs that act as master players at all stages of breast cancer development and that are increasingly recognized as potential diagnostic and prognostic biomarkers. We have previously shown that differential expression of certain miRNAs in Lebanese breast cancer tissues could be different than what is reported in the West. METHODS We recently assessed the miRNA microarray profile expression in Lebanese breast cancer tissues, performed a comparative miRNA profile analysis with matched American...
Annals of Neurology, 2019
ObjectiveCLN3 disease is the commonest of the neuronal ceroid lipofuscinoses, a group of pediatri... more ObjectiveCLN3 disease is the commonest of the neuronal ceroid lipofuscinoses, a group of pediatric neurodegenerative disorders. Functions of the CLN3 protein include antiapoptotic properties and facilitating anterograde transport of galactosylceramide from Golgi to lipid rafts. This study confirms the beneficial effects of long‐term exogenous galactosylceramide supplementation on longevity, neurobehavioral parameters, neuronal cell counts, astrogliosis, and diminution in brain and serum ceramide levels in Cln3 Δex7/8 knock‐in mice. Additionally, the impact of galactosylceramide on ceramide synthesis enzymes is documented.MethodsA group of 72 mice received galactosylceramide or vehicle for 40 weeks. The effect of galactosylceramide supplementation on Cln3 Δex7/8 mice was determined by performing behavioral tests, measuring ceramide in brains and serum, and assessing impact on longevity, subunit C storage, astrogliosis, and neuronal cell counts.ResultsGalactosylceramide resulted in en...
Revue neurologique, 1989
Neuronal ceroid lipofuscinosis is a common cause of neurodegenerative disease in children. The di... more Neuronal ceroid lipofuscinosis is a common cause of neurodegenerative disease in children. The disease is characterized by visual failure, seizures and dementia. The presence of cortical atrophy by computerized axial tomography and distinctive ultrastructural findings by skin biopsy, together with a suggestive clinical course and neurophysiologic abnormalities, lead to a diagnosis. Presently four subtypes and rare atypical forms are recognized: the infantile, late infantile, juvenile and adult or Kufs variants and atypical early juvenile and protracted juvenile types. The inheritance pattern is autosomal recessive in all subtypes with some of the adult cases representing autosomal dominant inheritance. The biochemical characterization of this disorder is just beginning. There is some evidence to implicate overglycosylation of proteins as playing a role in pathogenesis. Further biochemical description coupled with linkage analysis techniques using DNA probes are needed to develop a b...
American Journal of Medical Genetics, 1988
Neuronal ceroid-lipofuscinosis is the most common class of neurodegenerative disease in children.... more Neuronal ceroid-lipofuscinosis is the most common class of neurodegenerative disease in children. After decades of study, the biochemical basis for this group of diseases continues to elude scientists. One obstacle has been the difficulty in establishing specific criteria for diagnosis. This paper reviews case material from 65 patients
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006
The CLN6 vLINCL is caused by molecular defects in CLN6 gene coding for an ER resident transmembra... more The CLN6 vLINCL is caused by molecular defects in CLN6 gene coding for an ER resident transmembrane protein whose function is unknown. In the present study gene expression profiling of CLN6-deficient fibroblasts using cDNA microarray was undertaken in order to provide novel insights into the molecular mechanisms underlying this neurodegenerative fatal disease. Data were validated by qRT-PCR. Statistically significant alterations of expression were observed for 12 transcripts. The two most overexpressed genes, versican and tissue factor pathway inhibitor 2, are related to extracellular matrix (ECM), predicting changes in ECM-related proteins in CLN6-deficient cells. Transcript profiling also suggested alterations in signal transduction pathways, apoptosis and the immune/inflammatory response. Up-regulated genes related to steroidogenesis or signalling, and the relationship between cholesterol dynamics and glycosphingolipid sorting, led to investigation of free cholesterol and gangliosides in CLN6-deficient fibroblasts. Cholesterol accumulation in lysosomes suggests a homeostasis block as a result of CLN6p deficiency. The cholesterol imbalance may affect structure/function of caveolae and lipid rafts, disrupting signalling transduction pathways and sorting cell mechanisms. Alterations in protein/lipid intracellular trafficking would affect the composition and function of endocytic compartments, including lysosomes. Dysfunctional endosomal/lysosomal vesicles may act as one of the triggers for apoptosis and cell death, and for a secondary protective inflammatory response. In conclusion, the data reported provide novel clues into molecular pathophysiological mechanisms of CLN6-deficiency, and may also help in developing disease biomarkers and therapies for this and other neurodegenerative diseases.
Journal of autism and developmental disorders, 2018
This case-control study explores the association between pregnancy/birth complications and other ... more This case-control study explores the association between pregnancy/birth complications and other factors with Autism Spectrum Disorder (ASD) in Lebanese subjects aged 2-18 years. Researchers interviewed 136 ASD cases from the American University of Beirut Medical Center Special Kids Clinic, and 178 controls selected by systematic digit dialing in the Greater-Beirut area. Male gender (Adjusted Odds Ratio [95% CI]: 3.9 [2.2-7.0]); postpartum feeding difficulties (2.5 [1.2-5.4]); maternal infections/complications during pregnancy (2.9 [1.5-5.5], 2.1 [1.1-3.9]); consanguinity (2.5 [1.0-6.0]); family history of psychiatric disorders (2.2 [1.1-4.4]) were risk factors for ASD. Being born first/second (0.52 [0.28-0.95]) and maternal psychological support during pregnancy (0.49 [0.27-0.89]) were negatively associated with ASD. Identifying ASD correlates is crucial for instigating timely screening and subsequent early intervention.
The American Journal of Human Genetics
ABSTRACT
HAL (Le Centre pour la Communication Scientifique Directe), Mar 23, 2017
We describe four new mutations in the JI-galactosidase gene. These are the first mutations causin... more We describe four new mutations in the JI-galactosidase gene. These are the first mutations causing infantile and juvenile GM1-gangliosidosis to be described in American patients. Cell lines from two patients with juvenile and from six patients with infantile GM1-gangliosidosis were analyzed. Northern blot analysis showed the acid P-galactosidase message to be of normal size and quantity in two juvenile and four infantile cases and of normal size but reduced quantity in two infantile cases. The mutations are distinct from the Japanese mutations. All are point mutations leading to amino acid substitutions: Lyss-77 .Arg, Arg590>-His, and Glu632-'-Gly. The fourth mutation, Arg208-*Cys, accounts for 10 of 16 possible alleles. Two infantile cases from Puerto Rico of Spanish ancestry are homozygous for this mutation, suggesting that this allele may have come to South America and North America via Puerto Rico. That these mutations cause clinical disease was confirmed by marked reduction in catalytic activity of the mutant proteins in the Cos-1 cell expression system.
PLOS ONE, 2021
PurposeThe aim of our study was to determine the prevalence of amblyopia risk factors in children... more PurposeThe aim of our study was to determine the prevalence of amblyopia risk factors in children visiting the American University of Beirut Medical Center (AUBMC) using automated vision screening.MethodsThis was a hospital-based screening of 1102 children aged between 2 and 6 years. Vision screening was performed using PlusoptiX S12 over 2 years (2018–2020). The need for referral to a pediatric ophthalmologist was based on the amblyopia risk factors set forth by the American Association for Pediatric Ophthalmology and Strabismus. Referred patients underwent a comprehensive eye examination.ResultsA total of 1102 children were screened, 63 were referred for amblyopia risk factors (5.7%); 37/63 (59%) underwent comprehensive eye examination and 73% were prescribed glasses. Of the non-referred group of children, 6.35% had astigmatism, 6.25% were hyperopic and 3.27% were myopic. The refractive errors observed among the examined patients were distributed as follows: 41% astigmatism, 51% h...
Nature Reviews Neurology, 2013
Since the discovery of the lysosome in 1955, advances have been made in understanding the key rol... more Since the discovery of the lysosome in 1955, advances have been made in understanding the key roles and functions of this organelle. The concept of lysosomal storage diseases (LSDs)--disorders characterized by aberrant, excessive storage of cellular material in lysosomes--developed following the discovery of α-glucosidase deficiency as the cause of Pompe disease in 1963. Great strides have since been made in understanding the pathobiology of LSDs and the neuronal ceroid lipofuscinoses (NCLs). The NCLs are neurodegenerative disorders that display symptoms of cognitive and motor decline, seizures, blindness, early death, and accumulation of lipofuscin in various cell types, and also show some similarities to 'classic' LSDs. Defective lysosomal storage can occur in many cell types, but the CNS and PNS are particularly vulnerable to LSDs and NCLs, being affected in two-thirds of these disorders. Most LSDs are inherited in an autosomal recessive manner, with the exception of X-linked Hunter disease, Fabry disease and Danon disease, and a variant type of adult NCL (Kuf disease). This Review provides a summary of known LSDs, and the pathways affected in these disorders. Existing therapies and barriers to development of novel and improved treatments for LSDs and NCLs are also discussed.
Neurology, 2000
Autosomal dominant hereditary spastic paraplegia is genetically heterogeneous, with at least five... more Autosomal dominant hereditary spastic paraplegia is genetically heterogeneous, with at least five loci identified by linkage analysis. Recently, mutations in spastin were identified in SPG4, the most common locus for dominant hereditary spastic paraplegia that was previously mapped to chromosome 2p22. We identified five novel mutations in the spastin gene in five families with SPG4 mutations from North America and Tunisia and showed the absence of correlation between the predicted mutant spastin protein and age at onset of symptoms.
Journal of Inherited Metabolic Disease, 1993
Human Molecular Genetics, 2002
Juvenile Batten disease (JNCL) is an autosomal recessive disease that results from mutations in t... more Juvenile Batten disease (JNCL) is an autosomal recessive disease that results from mutations in the CLN3 gene. The wild-type CLN3 gene coding sequence has 15 exons, and the translated protein consists of 438 amino acids. The most commonly observed mutation is a 1.02 kb deletion in the genomic DNA. This deletion results in a truncated protein due to the loss of amino acids 154-438, and the introduction of 28 novel amino acids at the c-terminus. We demonstrate that, compared to normal controls, CLN3-deficient immortalization of lymphoblasts homozygous for this deletion grow at a slower rate, and show increased sensitivity to etoposide-induced apoptosis, supporting the notion that CLN3 may negatively regulate apoptosis. Using immortalized JNCL lymphoblast cell lines as a model system, we assess the effects of specific CLN3 mutations on cell growth rates and protection from etoposide-induced apoptosis. Protection from etoposideinduced apoptosis occurs and the cell growth rate is restored following transfection of JNCL lymphoblasts with mutant CLN3 cDNA that includes exons 11 or 13. We show that deletion of the glycosylation sites 71NQSH74 and 310NTSL313, and also mutations within the highly conserved amino acid stretches 184WSSGTGGAGLLG195, 291VYFAE295 and 330VFASRSSL337, result in slowed growth and susceptibility to apoptosis.
Biochemistry & Pharmacology: Open Access, 2021
Ophthalmic Genetics, 2020
Background: Congenital fibrosis of the extraocular muscles (CFEOM) is characterized by ptosis and... more Background: Congenital fibrosis of the extraocular muscles (CFEOM) is characterized by ptosis and nonprogressive restrictive ophthalmoplegia. CFEOM1 is a stereotypical phenotype with isolated bilateral ptosis, bilateral ophthalmoplegia, absent upgaze, and globe infraduction. CFEOM3 is a more variable phenotype that can include unilateral disease, absent ptosis, residual upgaze, and/or orthotropia. Most cases of CFEOM1 result from recurrent heterozygous KIF21A missense mutations and less commonly from recurrent heterozygous TUBB3 missense mutations. While most cases of CFEOM3 result from recurrent heterozygous TUBB3 missense mutations, several pedigrees harbored pathogenic variants in KIF21A. Here, we asked if Lebanese pedigrees with CFEOM3 harbor pathogenic variants in TUBB3 or KIF21A. Materials and Methods: Families affected with congenital cranial dysinnervation disorders were prospectively recruited from the American University of Beirut pediatric ophthalmology clinic and included two probands with CFEOM. KIF21A hotspot exons and TUBB3 coding sequence were sequenced. Available family members were sequenced for co-segregation analysis. Results: Both families were found to have CFEOM3 and to harbor pathogenic variants in KIF21A(OMIM 608283). A simplex proband with CFEOM3 from a consanguineous Iraqi family harbored a de novo heterozygous KIF21A c.2860 C > T variant (p.R954W); this variant accounts for the majority of reported KIF21A mutations but is typically implicated in CFEOM1. A Lebanese father with CFEOM3 and his son with CFEOM1 segregated a heterozygous KIF21A c.2830 G > C variant (p.E944Q), previously reported in an individual with CFEOM1. Conclusions: These results support prior reports of KIF21A mutations as a rare cause of CFEOM3. These families are Middle Eastern or Chinese, supporting a genetic modifier in these populations.
Journal of Global Oncology, 2019
PURPOSE Breast cancer is the most prevalent female cancer and has a higher incidence in young Leb... more PURPOSE Breast cancer is the most prevalent female cancer and has a higher incidence in young Lebanese patients as compared with the West. Interestingly, this particularity of breast cancer in the Lebanese population was not found to be associated with higher BRCA1/2 gene mutations. Hence, our research focuses on investigating molecular mechanisms and associated epigenetic signatures that underlie breast cancer in young patients. We are specifically interested in microRNA (miRNA), small noncoding RNAs that act as master players at all stages of breast cancer development and that are increasingly recognized as potential diagnostic and prognostic biomarkers. We have previously shown that differential expression of certain miRNAs in Lebanese breast cancer tissues could be different than what is reported in the West. METHODS We recently assessed the miRNA microarray profile expression in Lebanese breast cancer tissues, performed a comparative miRNA profile analysis with matched American...
Annals of Neurology, 2019
ObjectiveCLN3 disease is the commonest of the neuronal ceroid lipofuscinoses, a group of pediatri... more ObjectiveCLN3 disease is the commonest of the neuronal ceroid lipofuscinoses, a group of pediatric neurodegenerative disorders. Functions of the CLN3 protein include antiapoptotic properties and facilitating anterograde transport of galactosylceramide from Golgi to lipid rafts. This study confirms the beneficial effects of long‐term exogenous galactosylceramide supplementation on longevity, neurobehavioral parameters, neuronal cell counts, astrogliosis, and diminution in brain and serum ceramide levels in Cln3 Δex7/8 knock‐in mice. Additionally, the impact of galactosylceramide on ceramide synthesis enzymes is documented.MethodsA group of 72 mice received galactosylceramide or vehicle for 40 weeks. The effect of galactosylceramide supplementation on Cln3 Δex7/8 mice was determined by performing behavioral tests, measuring ceramide in brains and serum, and assessing impact on longevity, subunit C storage, astrogliosis, and neuronal cell counts.ResultsGalactosylceramide resulted in en...
Revue neurologique, 1989
Neuronal ceroid lipofuscinosis is a common cause of neurodegenerative disease in children. The di... more Neuronal ceroid lipofuscinosis is a common cause of neurodegenerative disease in children. The disease is characterized by visual failure, seizures and dementia. The presence of cortical atrophy by computerized axial tomography and distinctive ultrastructural findings by skin biopsy, together with a suggestive clinical course and neurophysiologic abnormalities, lead to a diagnosis. Presently four subtypes and rare atypical forms are recognized: the infantile, late infantile, juvenile and adult or Kufs variants and atypical early juvenile and protracted juvenile types. The inheritance pattern is autosomal recessive in all subtypes with some of the adult cases representing autosomal dominant inheritance. The biochemical characterization of this disorder is just beginning. There is some evidence to implicate overglycosylation of proteins as playing a role in pathogenesis. Further biochemical description coupled with linkage analysis techniques using DNA probes are needed to develop a b...
American Journal of Medical Genetics, 1988
Neuronal ceroid-lipofuscinosis is the most common class of neurodegenerative disease in children.... more Neuronal ceroid-lipofuscinosis is the most common class of neurodegenerative disease in children. After decades of study, the biochemical basis for this group of diseases continues to elude scientists. One obstacle has been the difficulty in establishing specific criteria for diagnosis. This paper reviews case material from 65 patients
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006
The CLN6 vLINCL is caused by molecular defects in CLN6 gene coding for an ER resident transmembra... more The CLN6 vLINCL is caused by molecular defects in CLN6 gene coding for an ER resident transmembrane protein whose function is unknown. In the present study gene expression profiling of CLN6-deficient fibroblasts using cDNA microarray was undertaken in order to provide novel insights into the molecular mechanisms underlying this neurodegenerative fatal disease. Data were validated by qRT-PCR. Statistically significant alterations of expression were observed for 12 transcripts. The two most overexpressed genes, versican and tissue factor pathway inhibitor 2, are related to extracellular matrix (ECM), predicting changes in ECM-related proteins in CLN6-deficient cells. Transcript profiling also suggested alterations in signal transduction pathways, apoptosis and the immune/inflammatory response. Up-regulated genes related to steroidogenesis or signalling, and the relationship between cholesterol dynamics and glycosphingolipid sorting, led to investigation of free cholesterol and gangliosides in CLN6-deficient fibroblasts. Cholesterol accumulation in lysosomes suggests a homeostasis block as a result of CLN6p deficiency. The cholesterol imbalance may affect structure/function of caveolae and lipid rafts, disrupting signalling transduction pathways and sorting cell mechanisms. Alterations in protein/lipid intracellular trafficking would affect the composition and function of endocytic compartments, including lysosomes. Dysfunctional endosomal/lysosomal vesicles may act as one of the triggers for apoptosis and cell death, and for a secondary protective inflammatory response. In conclusion, the data reported provide novel clues into molecular pathophysiological mechanisms of CLN6-deficiency, and may also help in developing disease biomarkers and therapies for this and other neurodegenerative diseases.
Journal of autism and developmental disorders, 2018
This case-control study explores the association between pregnancy/birth complications and other ... more This case-control study explores the association between pregnancy/birth complications and other factors with Autism Spectrum Disorder (ASD) in Lebanese subjects aged 2-18 years. Researchers interviewed 136 ASD cases from the American University of Beirut Medical Center Special Kids Clinic, and 178 controls selected by systematic digit dialing in the Greater-Beirut area. Male gender (Adjusted Odds Ratio [95% CI]: 3.9 [2.2-7.0]); postpartum feeding difficulties (2.5 [1.2-5.4]); maternal infections/complications during pregnancy (2.9 [1.5-5.5], 2.1 [1.1-3.9]); consanguinity (2.5 [1.0-6.0]); family history of psychiatric disorders (2.2 [1.1-4.4]) were risk factors for ASD. Being born first/second (0.52 [0.28-0.95]) and maternal psychological support during pregnancy (0.49 [0.27-0.89]) were negatively associated with ASD. Identifying ASD correlates is crucial for instigating timely screening and subsequent early intervention.
The American Journal of Human Genetics
ABSTRACT