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Journal of Clinical Laboratory Analysis Mar 2021Our aims were to describe the first Mexican patient with abetalipoproteinemia and to perform a comparative analysis of biochemical, clinical, and genetic characteristics...
A novel p.Gly417Valfs*12 mutation in the MTTP gene causing abetalipoproteinemia: Presentation of the first patient in Mexico and analysis of the previously reported cases.
BACKGROUND
Our aims were to describe the first Mexican patient with abetalipoproteinemia and to perform a comparative analysis of biochemical, clinical, and genetic characteristics of 100 cases reported in the literature.
METHODS
We performed biochemical and molecular screenings in a Mexican girl with extremely low lipid levels and in her family. Further, we integrated and evaluated the characteristics of the cases with abetalipoproteinemia described in the literature.
RESULTS
Our patient is a six-year-old girl who presented vomiting, chronic diarrhea, failure to thrive, malabsorption, acanthocytosis, anemia, transaminases elevation, and extremely low lipid levels. MTTP gene sequencing revealed homozygosity for a novel mutation p.Gly417Valfs*12 (G deletion c.1250). With the analysis of the reported cases, 60 clinical features (14 classical and 46 non-classical) were observed, being the most common acanthocytosis (57.5%), malabsorption (43.7%), and diarrhea (42.5%); 48.8% of the patients presented only classic clinical features, while the remaining 51.2% developed secondary effects due to a fat-soluble vitamin deficiency. An odds ratio analysis disclosed that patients diagnosed after 10 years of age have an increased risk for presenting clinical complications (OR = 18.0; 95% CI 6.0-54.1, p < 0.0001). A great diversity of mutations in MTTP has been observed (n = 76, being the most common p.G865X and p.N139_E140) and some of them with possible residual activity.
CONCLUSION
The first Mexican patient with abetalipoproteinemia presents a novel MTTP mutation p.Gly417Valfs*12. Three factors that could modulate the phenotype in abetalipoproteinemia were identified: age at diagnosis, treatment, and the causal mutation.
Topics: Abetalipoproteinemia; Adolescent; Adult; Carrier Proteins; Child; Female; Humans; Male; Mexico; Middle Aged; Mutation; Pedigree
PubMed: 33258201
DOI: 10.1002/jcla.23672 -
Arteriosclerosis, Thrombosis, and... Sep 2020Dyslipidemias include both rare single gene disorders and common conditions that have a complex underlying basis. In London, ON, there is fortuitous close physical...
Dyslipidemias include both rare single gene disorders and common conditions that have a complex underlying basis. In London, ON, there is fortuitous close physical proximity between the Lipid Genetics Clinic and the London Regional Genomics Centre. For >30 years, we have applied DNA sequencing of clinical samples to help answer scientific questions. More than 2000 patients referred with dyslipidemias have participated in an ongoing translational research program. In 2013, we transitioned to next-generation sequencing; our targeted panel is designed to concurrently assess both monogenic and polygenic contributions to dyslipidemias. Patient DNA is screened for rare variants underlying 25 mendelian dyslipidemias, including familial hypercholesterolemia, hepatic lipase deficiency, abetalipoproteinemia, and familial chylomicronemia syndrome. Furthermore, polygenic scores for LDL (low-density lipoprotein) and HDL (high-density lipoprotein) cholesterol, and triglycerides are calculated for each patient. We thus simultaneously document both rare and common genetic variants, allowing for a broad view of genetic predisposition for both individual patients and cohorts. For instance, among patients referred with severe hypertriglyceridemia, defined as ≥10 mmol/L (≥885 mg/dL), <1% have a mendelian disorder (ie, autosomal recessive familial chylomicronemia syndrome), ≈15% have heterozygous rare variants (a >3-fold increase over normolipidemic individuals), and ≈35% have an extreme polygenic score (a >3-fold increase over normolipidemic individuals). Other dyslipidemias show a different mix of genetic determinants. Genetic results are discussed with patients and can support clinical decision-making. Integrating DNA testing into clinical care allows for a bidirectional flow of information, which facilitates scientific discoveries and clinical translation.
Topics: Biomarkers; DNA Copy Number Variations; Dyslipidemias; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; High-Throughput Nucleotide Sequencing; History, 20th Century; History, 21st Century; Humans; Lipids; Multifactorial Inheritance; Phenotype; Prognosis; Risk Assessment; Risk Factors
PubMed: 32762461
DOI: 10.1161/ATVBAHA.120.313065 -
Advances in Experimental Medicine and... 2020Rare diseases are gathering increasing attention in last few years, not only for its effects on innovation scientific research, but also for its propounding influence on... (Review)
Review
Rare diseases are gathering increasing attention in last few years, not only for its effects on innovation scientific research, but also for its propounding influence on common diseases. One of the most famous milestones made by Michael Brown and Joseph Goldstein in metabolism field is the discovery of the defective gene in familial hypercholesterolemia, a rare human genetic disease manifested with extreme high level of serum cholesterol (Goldstein JL, Brown MS, Proc Natl Acad Sci USA 70:2804-2808, 1973; Brown MS, Dana SE, Goldstein JL, J Biol Chem 249:789-796, 1974). Follow-up work including decoding the gene function, mapping-related pathways, and screening therapeutic targets are all based on the primary finding (Goldstein JL, Brown MS Arterioscler Thromb Vasc Biol 29:431-438, 2009). A series of succession win the two brilliant scientists the 1985 Nobel Prize, and bring about statins widely used for lipid management and decreasing cardiovascular disease risks. Translating the clinical extreme phenotypes into laboratory bench work has turned out to be the first important step in the paradigm conducting translational and precise medical research. Here we review the main categories of rare disorders related with lipoprotein metabolism, aiming to strengthen the notion that human rare inheritable genetic diseases would be the window to know ourselves better, to treat someone more efficiently, and to lead a healthy life longer. Few rare diseases related with lipoprotein metabolism were clustered into six sections based on changes in lipid profile, namely, hyper- or hypocholesterolemia, hypo- or hyperalphalipoproteinemia, abetalipoproteinemia, hypobetalipoproteinemia, and sphingolipid metabolism diseases. Each section consists of a brief introduction, followed by a summary of well-known disease-causing genes in one table, and supplemented with one or two diseases as example for detailed description. Here we aimed to raise more attention on rare lipoprotein metabolism diseases, calling for more work from basic research and clinical trials.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Lipid Metabolism, Inborn Errors; Lipoproteins; Rare Diseases
PubMed: 32705600
DOI: 10.1007/978-981-15-6082-8_11 -
Advances in Experimental Medicine and... 2020Microsomal triglyceride transfer protein (MTP) was first identified as an endoplasmic reticulum (ER) resident protein that helps in the transfer of neutral lipids to... (Review)
Review
Microsomal triglyceride transfer protein (MTP) was first identified as an endoplasmic reticulum (ER) resident protein that helps in the transfer of neutral lipids to nascent apolipoprotein B (apoB). Its critical role in the assembly and secretion of apoB-containing lipoproteins was identified in abetalipoproteinemia patients who have mutations in MTP and completely lack apoB-containing lipoproteins in the circulation. It has been established now that MTP not only is involved in the transfer of neutral lipids but also plays a role in cholesterol ester and cluster of differentiation 1d (CD1d) biosynthesis. Besides neutral lipids, MTP may also help in the transfer of sphingolipids such as ceramides and sphingomyelin to the apoB-containing lipoproteins. MTP is a multifunctional protein, and its deregulation during pathophysiological conditions gives rise to different metabolic conditions. This book chapter discusses the physiological role and regulation of MTP to maintain the homeostasis of lipids and lipoproteins. It also reviews the regulation of MTP during certain pathophysiological conditions and provides a brief overview of therapeutic interventions that can be possibly used to target its activity or expression to alleviate some of these metabolic diseases.
Topics: Abetalipoproteinemia; Apolipoproteins B; Carrier Proteins; Humans; Lipid Metabolism; Metabolic Diseases
PubMed: 32705593
DOI: 10.1007/978-981-15-6082-8_4 -
Annals of Indian Academy of Neurology 2020Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary...
Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements. Movement disorders in children are frequently caused by metabolic disorders, both inherited and acquired. Many of these respond to vitamin supplementation. Examples include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects. Recognition of these disorders by pediatricians and neurologists is imperative as they are easily treated by vitamin supplementation. In this review, we discuss vitamin-responsive movement disorders in children.
PubMed: 32606520
DOI: 10.4103/aian.AIAN_678_19 -
Journal of Clinical Immunology Jul 2020X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on...
BACKGROUND
X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype.
METHODS
We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types.
RESULTS
The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well.
CONCLUSION
This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.
Topics: Abetalipoproteinemia; Adolescent; Adult; Child; Child, Preschool; Female; Follow-Up Studies; France; Granulomatous Disease, Chronic; Humans; Infant; Isoantibodies; Male; NADPH Oxidase 2; Neuroacanthocytosis; Retrospective Studies; Survival Analysis; Young Adult
PubMed: 32562208
DOI: 10.1007/s10875-020-00791-w -
Journal of Pediatric Hematology/oncology Apr 2021We report a probable case of abetalipoproteinemia in an infant who presented with unusual symptoms of late-onset vitamin K deficiency. Abetalipoproteinemia is a rare...
We report a probable case of abetalipoproteinemia in an infant who presented with unusual symptoms of late-onset vitamin K deficiency. Abetalipoproteinemia is a rare autosomal recessive disease caused by mutation of the microsomal triglyceride transfer protein gene, resulting in the absence of microsomal triglyceride transfer protein function in the small bowel. It is characterized by the absence of plasma apolipoprotein B-containing lipoproteins, fat malabsorption, hypocholesterolemia, retinitis pigmentosa, progressive neuropathy, myopathy, and acanthocytosis. A biopsy of the small intestine characteristically shows marked lipid accumulation in the villi of enterocytes. Large supplements of fat-soluble vitamins A, D, E, and K have been shown to limit neurologic and ocular manifestations. Dietary fat intake is limited to medium-chain triglycerides.
Topics: Abetalipoproteinemia; Duodenum; Enterocytes; Female; Humans; Infant; Infant, Newborn; Vitamin K Deficiency
PubMed: 32433446
DOI: 10.1097/MPH.0000000000001831 -
Gastroenterology Nov 2020
Topics: Abetalipoproteinemia; Biopsy; Child, Preschool; Duodenum; Endoscopy, Digestive System; Humans; Intestinal Mucosa; Male; Steatorrhea
PubMed: 32311359
DOI: 10.1053/j.gastro.2020.03.079 -
Journal of Clinical Research in... Jun 2020
Topics: Abetalipoproteinemia; Genes; Humans; Hypothyroidism; Mutation; Thymine Nucleotides
PubMed: 32157853
DOI: 10.4274/jcrpe.galenos.2020.2020.0015 -
Current Opinion in Lipidology Apr 2020Several mutations in the apolipoprotein (apo) B, proprotein convertase subtilisin kexin 9 (PCSK9) and microsomal triglyceride transfer protein genes result in low or... (Review)
Review
PURPOSE OF REVIEW
Several mutations in the apolipoprotein (apo) B, proprotein convertase subtilisin kexin 9 (PCSK9) and microsomal triglyceride transfer protein genes result in low or absent levels of apoB and LDL cholesterol (LDL-C) in plasma which cause familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL). Mutations in the angiopoietin-like protein 3 ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). Clinical manifestations range from none-to-severe, debilitating and life-threatening disorders. This review summarizes recent genetic, metabolic and clinical findings and management strategies.
RECENT FINDINGS
Fatty liver, cirrhosis and hepatocellular carcinoma have been reported in FHBL and ABL probably due to decreased triglyceride export from the liver. Loss of function mutations in PCSK-9 and ANGPTL3 cause FHBL but not hepatic steatosis. In 12 case-control studies with 57 973 individuals, an apoB truncation was associated with a 72% reduction in coronary heart disease (odds ratio, 0.28; 95% confidence interval, 0.12-0.64; P = 0.002). PCSK9 inhibitors lowered risk of cardiovascular events in large, randomized trials without apparent adverse sequelae.
SUMMARY
Mutations causing low LDL-C and apoB have provided insight into lipid metabolism, disease associations and the basis for drug development to lower LDL-C in disorders causing high levels of cholesterol. Early diagnosis and treatment is necessary to prevent adverse sequelae from FHBL and ABL.
Topics: Abetalipoproteinemia; Animals; Cardiovascular Diseases; Humans; Hypobetalipoproteinemias; Lipid Metabolism; Liver; Liver Diseases
PubMed: 32039990
DOI: 10.1097/MOL.0000000000000663