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Lipids in Health and Disease Mar 2018Abetalipoproteinemia and homozygous hypobetalipoproteinemia are classical Mendelian autosomal recessive and co-dominant conditions, respectively, which are...
BACKGROUND
Abetalipoproteinemia and homozygous hypobetalipoproteinemia are classical Mendelian autosomal recessive and co-dominant conditions, respectively, which are phenotypically similar and are usually caused by bi-allelic mutations in MTTP and APOB genes, respectively. Instances of more complex patterns of genomic variants resulting in this distinct phenotype have not been reported.
METHODS
A 43 year-old male had a longstanding severe deficiency of apolipoprotein (apo) B-containing lipoproteins and circulating fat soluble vitamins consistent with either abetalipoproteinemia or homozygous familial hypobetalipoproteinemia (FHBL). He also had acanthocytosis, a long term history of fat malabsorption, and mild retinopathy, but was free from coagulopathy, myopathy and neuropathy. He had taken high dose oral fat soluble vitamins since childhood.
RESULTS
Targeted next generation DNA sequencing revealed several rare heterozygous missense variants in both MTTP and APOB genes known or predicted to be deleterious, in addition to a novel heterozygous missense variant in SAR1B, which encodes the gene causing chylomicron retention disease. Evaluation of first degree relatives with mild FHBL clarified the segregation of variants.
CONCLUSIONS
The proband's characteristic phenotype likely resulted from an oligogenic interaction involving multiple rare variants in MTTP and APOB, and related genes, each of which individually was associated with a milder or minimal clinical and biochemical phenotype.
Topics: Adult; Apolipoprotein B-100; Carrier Proteins; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Homozygote; Humans; Hypobetalipoproteinemias; Male; Monomeric GTP-Binding Proteins; Mutation, Missense
PubMed: 29540175
DOI: 10.1186/s12944-018-0680-1 -
Tremor and Other Hyperkinetic Movements... 2017Huntington's Disease-like 2 (HDL2) is classified as a neuroacanthocytosis; however, this remains unverified. We aim to determine if acanthocytes are present in HDL2 and... (Comparative Study)
Comparative Study
BACKGROUND
Huntington's Disease-like 2 (HDL2) is classified as a neuroacanthocytosis; however, this remains unverified. We aim to determine if acanthocytes are present in HDL2 and whether acanthocytes can differentiate HDL2 from Huntington's disease (HD).
METHODS
We prospectively compared 13 HD and 12 HDL2 cases against 21 unaffected controls in Johannesburg. Blood smears were prepared using international standards and reviewed by at least two blinded reviewers. An acanthocytosis rate of greater than 1.2% in the dry smear or greater than 3.7% in the wet smear was designated a priori as the threshold for clinical significance based on previously established standards. Flow cytometry was performed on all but four of the cases. Red cell membrane protein analysis was performed on all participants.
RESULTS
There were 12 HDL2, 13 HD, and 21 controls enrolled. None of the HD or HDL2 participants had defined acanthocytosis or other morphological abnormalities. None of the HD or HDL2 cases had evidence of an abnormal band 3.
DISCUSSION
Acanthocytosis was not identified in either HDL2 or HD in our patient population. Our results, based on the first prospective study of acanthocytes in HDL2 or HD, suggest that screening for acanthocytes will not help establish the diagnosis of HD or HDL2, nor differentiate between the two disorders and raises the question if HDL2 should be placed within the neuroacanthocytosis syndromes.
Topics: Abetalipoproteinemia; Acanthocytes; Adult; Aged; Blood Cell Count; Chorea; Cognition Disorders; Dementia; Flow Cytometry; Heredodegenerative Disorders, Nervous System; Humans; Huntington Disease; Middle Aged; Prospective Studies; Young Adult
PubMed: 29226019
DOI: 10.7916/D81J9PDX -
Journal of Ayub Medical College,... 2017Non-infectious causes of chronic diarrhoea are important and easily missed. The study was done with the objectives to identify different causes of chronic non-infectious... (Observational Study)
Observational Study
BACKGROUND
Non-infectious causes of chronic diarrhoea are important and easily missed. The study was done with the objectives to identify different causes of chronic non-infectious diarrhoea in infants less than 6 months of age.
METHODS
All patients less than 6 months of age presenting for the first time to a Paediatric Gastroenterology tertiary care centre with a history of chronic diarrhoea and negative stool cultures were enrolled over a period of 8 months. Demographical profile and various factors under observation were recorded in this observational study. Collected data was analysed using SPSS version 20. Chi square test was applied as a test of significance for any qualitative variable, p value (p<0.05) was taken as significant.
RESULTS
Among 72 enrolled patients, female to male ratio was1.05:1. Age at onset of symptoms was between 15 days to 6 months. Aetiology found was Cow's milk protein allergy (CMPA) in 58 (80.6%), Primary intestinal lymphangiectasia (PIL) 6 (8.3%), Cystic fibrosis (CF) 3 (4.2%), Immunodeficiency (SCID) 2 (2.8%), 1 (1.4%) for each Abetalipoproteinemia (ABL), Glucose galactose malabsorption (GGM) and Congenital chloride diarrhoea (CCD).
CONCLUSIONS
Among noninfectious causes of chronic diarrhoea in early infancy, cow's milk protein allergy is most common followed by Primary intestinal lymphangiectasia and Cystic fibrosis.
Topics: Chronic Disease; Cystic Fibrosis; Diarrhea; Female; Humans; Infant; Infant, Newborn; Lymphangiectasis, Intestinal; Lymphedema; Male; Milk Hypersensitivity
PubMed: 28712180
DOI: No ID Found -
Cell Reports May 2017Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to...
Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids. MTTP iPSC-derived cardiomyocytes failed to secrete apoB, accumulated intracellular lipids, and displayed increased cell death, suggesting intrinsic defects in lipid metabolism due to loss of MTTP function. Importantly, these phenotypes were reversed after the correction of the MTTP mutation by CRISPR/Cas9 gene editing. Together, these data reveal clear cellular defects in iPSC-derived hepatocytes and cardiomyocytes lacking MTTP activity, including a cardiomyocyte-specific regulated stress response to elevated lipids.
Topics: Abetalipoproteinemia; Apolipoproteins B; Carrier Proteins; Gene Editing; Hepatocytes; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Phenotype; Stress, Physiological
PubMed: 28514664
DOI: 10.1016/j.celrep.2017.04.064 -
Journal of Internal Medicine Jun 2017Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and... (Review)
Review
Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.
Topics: Bone and Bones; Brain; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus, Type 2; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Immune System Phenomena; Lipoproteins, LDL; Mutation; Neoplasms; Proprotein Convertase 9; Risk Factors
PubMed: 28295777
DOI: 10.1111/joim.12614 -
Neurologia May 2019Autosomal recessive spinocerebellar ataxia refers to a large group of diseases affecting the cerebellum and/or its connections, although they may also involve other... (Review)
Review
INTRODUCTION
Autosomal recessive spinocerebellar ataxia refers to a large group of diseases affecting the cerebellum and/or its connections, although they may also involve other regions of the nervous system. These diseases are accompanied by a wide range of systemic manifestations (cardiopathies, endocrinopathies, skeletal deformities, and skin abnormalities).
DEVELOPMENT
This study reviews current knowledge of the most common forms of autosomal recessive spinocerebellar ataxia in order to provide tips that may facilitate diagnosis.
CONCLUSIONS
A thorough assessment of clinical phenotype (pure cerebellar or cerebellar-plus syndrome, with or without systemic manifestations), laboratory tests (vitamin E, acanthocytosis, albumin, cholesterol, phytanic acid, lactic acid, creatine kinase, cholestanol, coenzyme Q10, alpha-fetoprotein, copper, ceruloplasmin, chitotriosidase), nerve conduction studies (presence and type of neuropathy), and an magnetic resonance imaging study (presence of cerebellar atrophy, presence and location of signal alterations) may help establish a suspected diagnosis, which should be confirmed by detecting the underlying genetic mutation. A positive genetic test result is necessary to determine prognosis and provide adequate genetic counselling, and will also permit appropriate treatment of some entities (abetalipoproteinaemia, ataxia with vitamin E deficiency, Refsum disease, cerebrotendinous xanthomatosis, Niemann-Pick disease type C, Wilson disease). Without a genetic diagnosis, conducting basic research and therapeutic trials will not be possible.
Topics: Brain; Cerebellar Ataxia; Cerebellum; Genes, Recessive; Humans; Magnetic Resonance Imaging; Mutation; Phenotype; Spinocerebellar Ataxias
PubMed: 27460185
DOI: 10.1016/j.nrl.2016.06.006 -
Atherosclerosis Jul 2016Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by decreased plasma levels of LDL-cholesterol and apolipoprotein B (ApoB). Currently,...
BACKGROUND AND AIMS
Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by decreased plasma levels of LDL-cholesterol and apolipoprotein B (ApoB). Currently, genetic diagnosis in FHBL relies largely on Sanger sequencing to identify APOB and PCSK9 gene mutations and on western blotting to detect truncated ApoB species.
METHODS
Here, we applied targeted enrichment and next-generation sequencing (NGS) on a panel of three FHBL genes and two abetalipoproteinemia genes (APOB, PCSK9, ANGPTL3, MTTP and SAR1B).
RESULTS
In this study, we identified five likely pathogenic heterozygous rare variants. These include four novel nonsense mutations in APOB (p.Gln845*, p.Gln2571*, p.Cys2933* and p.Ser3718*) and a rare variant in PCSK9 (Minor Allele Frequency <0.1%). The affected family members tested were shown to be carriers, suggesting co-segregation with low LDL-C.
CONCLUSIONS
Our study further demonstrates that NGS is a reliable and practical approach for the molecular screening of FHBL-causative genes that may provide a mean for deciphering the genetic basis in FHBL.
Topics: Abetalipoproteinemia; Adolescent; Adult; Aged; Aged, 80 and over; Apolipoprotein B-100; Cholesterol, LDL; Codon, Nonsense; Gene Library; Genetic Variation; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Hypobetalipoproteinemias; Middle Aged; Mutation; Pedigree; Phenotype; Proprotein Convertase 9; Reproducibility of Results; Sequence Analysis, DNA; Young Adult
PubMed: 27179706
DOI: 10.1016/j.atherosclerosis.2016.04.010 -
Journal of Clinical and Diagnostic... Dec 2015Diarrhoea is a common clinical problem for treating clinicians in developing countries. Mostly, it is attributed to malnutrition and infection. We, as clinicians, tend...
Diarrhoea is a common clinical problem for treating clinicians in developing countries. Mostly, it is attributed to malnutrition and infection. We, as clinicians, tend to miss some of cases who have inherited enteropathies because of lack of suspicion and non availability of diagnostic facilities. Here, we report a case of homozygous hypobetalipoproteinaemia in a nine-month-old female patient presenting with chronic diarrhoea and failure to thrive. Simple parental screening of lipid parameters led to correct diagnosis and early intervention in present case.
PubMed: 26816882
DOI: 10.7860/JCDR/2015/14166.6919 -
Disease Models & Mechanisms Jan 2016Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life... (Review)
Review
Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD(ENT)) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD(ENT). Here, we review recent progress in understanding the cellular mechanisms of CDD(ENT). We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD(ENT) and expediting the discovery of novel therapeutic strategies.
Topics: Abetalipoproteinemia; Animals; Chylomicrons; Diarrhea; Diarrhea, Infantile; Enterocytes; Facies; Fetal Growth Retardation; Hair Diseases; Heterozygote; Humans; Hypobetalipoproteinemias; Lipids; Mice; Mice, Knockout; Microvilli; Models, Animal; Mutation; Protein Transport; Registries; Stem Cells
PubMed: 26747865
DOI: 10.1242/dmm.022269