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Bassen Kornzweig syndrome [keywords]
- Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. [JOURNAL ARTICLE]
- J Inherit Metab Dis 2013 Nov 28.
Abetalipoproteinemia (ABL; OMIM 200100) and homozygous hypobetalipoproteinemia (HHBL; OMIM 107730) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein (apo) B-containing lipoprotein particles due to mutations either in both alleles of the MTP (alias MTTP) gene encoding microsomal triglyceride transfer protein (MTP) or both alleles of the APOB gene itself in the case of ABL and HHBL, respectively. Clinical diagnosis is based on signs and symptoms, acanthocytosis on blood smear, and virtually absent apo B-containing lipoproteins, including chylomicrons, very low density lipoprotein and low density lipoprotein. Obligate heterozygote parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance, while heterozygous parents of HHBL patients typically have half normal levels of apo B-containing lipoproteins consistent with autosomal co-dominant inheritance. Definitive diagnosis involves sequencing the MTP and APOB genes, for which >30 and >60 mutations have been described for ABL and HHBL, respectively. Follow-up includes monitoring for ophthalmologic, neurologic, hematologic, and hepatic complications, as well as compliance with treatment. Investigations include lipid profile, serum transaminases, markers for lipid-soluble vitamins, and periodic instrumental assessment of ocular and neurological function. Mainstays of treatment include adherence to a low-fat diet, and supplementation with essential fatty acids and high oral doses of fat soluble vitamins. Prognosis is variable, but early diagnosis and strict adherence to treatment can recover normal neurological function and halt disease progression.
- Knee pain: an unanticipated finding related to a rare genetic disorder--abetalipoproteinemia. [Journal Article]
- J Am Assoc Nurse Pract 2013 Jun; 25(6):297-301.
The purpose of this case study is to raise awareness about an uncommon cause of knee pain.Review of literature was done using PubMed, CINAHL, and Medline. There was no limitation placed on the publication year. Only articles written in English were included.Knee pain is a common diagnosis that many healthcare providers see on a daily basis in their practice. Musculoskeletal injury or trauma is most commonly identified as the cause of this symptom. However, there are rare instances in which an unexpected finding in a client's history and physical exam lead us to an unexpected cause, such as abetalipoproteinemia. Abetalipoproteinemia is a rare autosomal recessive disorder in which an affected individual does not absorb lipids or the lipid-soluble vitamins A, D, E, and K. Multiple body systems are impacted by this fat malabsorption and resultant vitamin deficiencies. Without corrective supplementation, clinical manifestations which are directly related to the vitamin deficiencies will appear as presented in this case study-knee pain.This case study emphasizes the need for nurse practitioners to seek out opportunities to further our knowledge which will enhance our clinical expertise as well as the quality of the health care we provide to our clients.
- Clinical features and molecular genetics of two Tunisian families with abetalipoproteinemia. [Journal Article]
- J Clin Neurosci 2014 Feb; 21(2):311-5.
Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T>A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9+2T>G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins.
- [Therapeutic developments in chronic ataxias]. [English Abstract, Journal Article]
- Medicina (B Aires) 2013.:49-54.
Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich's ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.
- A case of McLeod phenotype of neuroacanthocytosis brain MR features and literature review. [Case Reports, Journal Article, Review]
- Neuroradiol J 2013 Feb; 26(1):21-6.
Huntington's disease and neuroacanthocytosis may present similar clinical and MRI features. It is important to differentiate these findings since treatment and prognosis vary vastly between them. The aim of this article is to familiarize radiologists with the differentiating features of Huntington's disease and various diseases comprising neuroacanthocytosis. A 40-year-old Indian man with extrapyramidal symptoms was referred for MRI. The clinical diagnosis was Huntington's disease, but there were a few atypical clinical features such as a history of biting the tongue, tics, marked hyporeflexia and lower limb muscle wasting. MR showed atrophy of the caudate nucleus and putamen with iron deposition in the basal ganglia, which can be seen in Huntington's disease and in neuroacanthocytosis. An increased blood acanthocyte level was subsequently confirmed. Further work-up revealed increased serum creatine phosphokinase levels, normal serum lipoprotein levels and depressed K cell antigen activity on serological studies, confirming the diagnosis of McLeod syndrome. McLeod syndrome is one of the distinct phenotypes of neuroacanthocytosis. Neuroacanthocytosis is a group of disorders with increased serum acanthocyte counts and neurological involvement. Various causes of neuroacanthocytosis are discussed. It is important to consider the possibility of neuroacanthocytosis when features typical of Huntington's disease are encountered on imaging.
- Diagnosis and management of familial dyslipoproteinemias. [Journal Article, Research Support, Non-U.S. Gov't, Review]
- Curr Cardiol Rep 2013 Jun; 15(6):371.
The three major pathways of lipoprotein metabolism provide a superb paradigm to delineate systematically the familial dyslipoproteinemias. Such understanding leads to improved diagnosis and treatment of patients. In the exogenous (intestinal) pathway, defects in LPL, apoC-II, APOA-V, and GPIHBP1 disrupt the catabolism of chylomicrons and hepatic uptake of their remnants, producing very high TG. In the endogenous (hepatic) pathway, six disorders affect the activity of the LDLR and markedly increase LDL. These include FH, FDB, ARH, PCSK9 gain-of-function mutations, sitosterolemia and loss of 7 alpha hydroxylase. Hepatic overproduction of VLDL occurs in FCHL, hyperapoB, LDL subclass pattern B, FDH and syndrome X, often due to insulin resistance and resulting in high TG, elevated small LDL particles and low HDL-C. Defects in APOB-100 and loss-of-function mutations in PCSK9 are associated with low LDL-C, decreased CVD and longevity. An absence of MTP leads to marked reduction in chylomicrons and VLDL, causing abetalipoproteinemia. In the reverse cholesterol pathway, deletions or nonsense mutations in apoA-I or ABCA1 transporter disrupt the formation of the nascent HDL particle. Mutations in LCAT disrupt esterification of cholesterol in nascent HDL by LCAT and apoA-1, and formation of spherical HDL. Mutations in either CETP or SR-B1 and familial high HDL lead to increased large HDL particles, the effect of which on CVD is not resolved. The major goal is to prevent or ameliorate the major complications of many familial dyslipoproteinemias, namely, premature CVD or pancreatitis. Dietary and drug treatment specific for each inherited disorder is reviewed.
- Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E. [Journal Article]
- Handb Clin Neurol 2013.:1799-810.
The catalytic properties of many enzymes depend on the participation of vitamins as obligatory cofactors. Vitamin B12 (cobalamin) and folic acid (folate) deficiencies in infants and children classically present with megaloblastic anemia and are often accompanied by neurological signs. A number of rare inborn errors of cobalamin and folate absorption, transport, cellular uptake, and intracellular metabolism have been delineated and identification of disease-causing mutations has improved our ability to diagnose and treat many of these conditions. Two inherited defects in biotin metabolism are known, holocarboxylase synthetase and biotinidase deficiency. Both lead to multiple carboxylase deficiency manifesting with metabolic acidosis, neurological abnormalities, and skin rash. Thiamine-responsive megaloblastic anemia is characterized by megaloblastic anemia, non-type I diabetes, and sensorineural deafness that responds to pharmacological doses of thiamine (vitamin B1). Individuals affected with inherited vitamin E deficiencies including ataxia with isolated vitamin E deficiency and abetalipoproteinemia present with a spinocerebellar syndrome similar to patients with Friedreich's ataxia. If started early, treatment of these defects by oral or parenteral administration of the relevant vitamin often results in correction of the metabolic defect and reversal of the signs of disease, stressing the importance of early and correct diagnosis in these treatable conditions.
- Molecular characterization of Tunisian families with abetalipoproteinemia and identification of a novel mutation in MTTP gene. [JOURNAL ARTICLE]
- Diagn Pathol 2013 Apr 4; 8(1):54.
BACKGROUND:Abetalipoproteinemia (ABL; OMIM 200100) is a rare monogenic disorder of lipid metabolism characterized by reduced plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and almost complete absence of apolipoprotein B (apoB). ABL results from genetic deficiency in microsomal triglyceride transfer protein (MTP; OMIM 157147). In the present study we investigated two unrelated Tunisian patients, born from consanguineous marriages, with severe deficiency of plasma low-density lipoprotein (LDL) and apo B.
METHODS:Intestinal biopsies were performed and The MTTP gene was amplified by Polymerase chain reaction then directly sequenced in patients presenting chronic diarrhea and retarded growth.
RESULTS:First proband was homozygous for a novel nucleotide deletion (c. 2611delC) involving the exon 18 of MTTP gene predicted to cause a non functional protein of 898 amino acids (p.H871I fsX29). Second proband was homozygous for a nonsense mutation in exon 8 (c.923 G > A) predicted to cause a truncated protein of 307 amino acids (p.W308X), previously reported in ABL patients.
CONCLUSIONS:We discovered a novel mutation in MTTP gene and we confirmed the diagnosis of abetalipoproteinemia in new Tunisian families. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8134027928652779.
- Inhibitory effects of in vivo oxidized high-density lipoproteins on platelet aggregation: evidence from patients with abetalipoproteinemia. [Journal Article, Research Support, Non-U.S. Gov't]
- FASEB J 2013 Jul; 27(7):2855-61.
There is evidence that high-density lipoproteins (HDLs) may regulate platelet function, but disparate results exist regarding the effects of oxidized HDLs on platelets. The objective of our study was to determine the role of in vivo oxidized HDLs on platelet aggregation. Platelet aggregation and redox status were investigated in 5 patients with abetalipoproteinemia (ABLP) or homozygous hypobetalipoproteinemia, two rare metabolic diseases characterized by the absence of apolipoprotein B-containing lipoproteins, compared to 5 control subjects. Platelets isolated from plasma of patients with ABLP aggregated 4 to 10 times more than control platelets, depending on the agonist. By contrast, no differences in the extent of platelet aggregation were observed between ABLP platelet-rich plasma (PRP) and control PRP, suggesting the presence of a protective factor in ABLP plasma. ABLP HDLs inhibited agonist-induced platelet aggregation by binding to SR-BI, while control HDLs had no effect. On the other hand, lipoprotein-deficient plasma from patients with ABLP did not inhibit platelet aggregation. Severe oxidative stress was evidenced in patients with ABLP. Compared to control HDLs, ABLP HDLs showed a 40% decrease of α-tocopherol and an 11-fold increased malondialdehyde concentration. These results demonstrate that in vivo oxidized HDLs do not lose their antiaggregatory properties despite oxidation.
- Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- J Lipid Res 2013 Jun; 54(6):1541-9.
Mutations in microsomal triglyceride transfer protein (MTP) cause abetalipoproteinemia (ABL), characterized by the absence of plasma apoB-containing lipoproteins. In this study, we characterized the effects of various MTP missense mutations found in ABL patients with respect to their expression, subcellular location, and interaction with protein disulfide isomerase (PDI). In addition, we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion. All the mutants colocalized with calnexin and interacted with PDI. We found that R540H and N780Y, known to be deficient in triglyceride transfer activity, also lacked phospholipid transfer activity. Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion. In contrast, D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion. These studies point out that ABL is associated with the absence of both triglyceride and phospholipid transfer activities in MTP.