scholarly journals Pharmacological complementation remedies an inborn error of lipid metabolism

2019 ◽  
Author(s):  
Meredith D. Hartley ◽  
Mitra D. Shokat ◽  
Margaret J. DeBell ◽  
Tania Banerji ◽  
Lisa L. Kirkemo ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Inborn Error ◽  
Axonal Degeneration ◽  
Parent Drug ◽  
Neurological Deficits ◽  
Long Chain Fatty Acids ◽  
The Central Nervous System ◽  
Cns Penetration ◽  
Long Chain ◽  
Slow Turnover

SummaryX-linked adrenoleukodystrophy (X-ALD) is a rare, genetic disease in which increased very long chain fatty acids (VLCFAs) in the central nervous system (CNS) cause demyelination and axonal degeneration, leading to severe neurological deficits. Sobetirome, a potent thyroid hormone agonist, has been shown to lower VLCFA levels in the periphery and CNS. In this study, two pharmacological strategies for enhancing the effects of thyromimetics were tested in Abcd1 KO mice, a murine model that has the same inborn error in metabolism as X-ALD patients. First, a sobetirome prodrug (Sob-AM2) with increased CNS penetration lowered CNS VLCFAs more potently than sobetirome, and was better tolerated with lower peripheral exposure, but was unable to unable to break the efficacy threshold of CNS VLCFA lowering in Abcd1 KO mice. Second, co-administration of thyroid hormone with sobetirome enhanced VLCFA lowering in the periphery compared to sobetirome alone but did not produce greater lowering in the CNS. These data suggest that the extent of CNS VLCFA lowering in Abcd1 KO mice is limited by a mechanistic threshold related to slow turnover kinetics, potentially related to the lack of frank X-ALD disease in this model. However, Sob-AM2 has improved potency at correcting the lipid abnormality associated with X-ALD in the CNS with better tolerance than the parent drug sobetirome.

X-linked Adrenoleukodystrophy

2016 ◽  
Author(s):  
Björn M. van Geel ◽  
Marc Engelen ◽  
Stephan Kemp
Keyword(s):  
Axonal Degeneration ◽  
Age Of Onset ◽  
Diagnostic Testing ◽  
Neurological Deficits ◽  
Long Chain Fatty Acids ◽  
Adrenocortical Insufficiency ◽  
Beta Oxidation ◽  
Prenatal Diagnostic ◽  
Prenatal Diagnostic Testing ◽  
Female Carriers

X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disorder. Hallmarks are increased levels of plasma very long-chain fatty acids (VLCFA), mutations in the ABCD1 gene, impaired function of ALD-protein and, consequently, decreased import of VLCFA-CoA esters in peroxisomes and VLCFA beta-oxidation. Cerebral demyelination and axonal degeneration of the spinal cord are the main causes of neurological deficits. Endocrine dysfunction, particularly adrenocortical insufficiency, is very frequent. Based upon the age of onset of symptoms and the organs most severely affected, several phenotypes can be distinguished. Adrenomyeloneuropathy (AMN) and childhood cerebral adrenoleukodystrophy (CCALD) are the most frequent variants. At least 80% of female carriers will eventually develop neurological symptoms similar to men with AMN. The thin and scanty scalp hair in affected men may facilitate diagnosis of X-ALD. Identification of patients is of utmost importance, as adrenocortical insufficiency can be treated, rapidly progressive cerebral demyelination can be halted, and prenatal diagnostic testing is available. Furthermore, symptomatic therapies and multidisciplinary support may help patients coping with this disease.

scholarly journals Clinical Manifest X-Linked Recessive Adrenoleukodystrophy in a Female

2013 ◽  
Vol 2013 ◽  
pp. 1-3 ◽  
Author(s):  
Gyda Hlin Skuladottir Jack ◽  
Karolina Malm-Willadsen ◽  
Anja Frederiksen ◽  
Dorte Glintborg ◽  
Marianne Andersen
Keyword(s):  
Adrenal Glands ◽  
Present Report ◽  
Lower Limbs ◽  
Long Chain Fatty Acids ◽  
Intracellular Accumulation ◽  
Biochemical Tests ◽  
The Central Nervous System ◽  
Climbing Stairs ◽  
Long Chain ◽  
Tendon Reflexes

Adrenoleukodystrophy (ALD) is a rare X-linked inherited leukodystrophy with a reduced capacity for degradation of very long chain fatty acids (VLCFAs). The intracellular accumulation of VLCFA leads to demyelination in the central nervous system (CNS) and cell destruction in the adrenal glands. ALD primarily affects males; however, females may develop milder symptoms that may be difficult to recognize. The present report describes a 35-year-old female who experienced a feeling of heaviness in the upper and lower limbs, pain in both knees, and difficulty climbing stairs, running, and jumping. Clinical examination revealed decreased sensitivity in the feet, particularly to touch. Deep tendon reflexes in the lower limbs were brisk, and Babinski's sign was present bilaterally. Multiple sclerosis (MS) was excluded, and all clinical and biochemical tests were normal. After two years of progressing symptoms, the patient was reevaluated and plasma levels of VLCFA were found to be elevated. Seven years prior to this finding, the patient had been found to be heterozygous for the missense mutation c.1679C>T, p.Pro560Leu on theABCD1gene (ATP-Binding Cassette subfamily D1). In conclusion, the patient's symptoms could be attributed to ALD. The present case underlines the importance of reevaluating family history in women presenting with vague neurological symptoms.

scholarly journals X-linked adrenoleukodystrophy: clinical and laboratory findings in 15 Brazilian patients

2000 ◽  
Vol 23 (2) ◽  
pp. 261-264 ◽  
Author(s):  
Carmen R. Vargas ◽  
Daniella de M. Coelho ◽  
Alethéa G. Barschak ◽  
Carolina F.M. de Souza ◽  
Ana C.S. Puga ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Early Identification ◽  
Signs And Symptoms ◽  
Long Chain Fatty Acids ◽  
Adrenocortical Insufficiency ◽  
Limb Weakness ◽  
Laboratory Findings ◽  
Physician Awareness ◽  
The Central Nervous System ◽  
Long Chain

Adrenoleukodystrophy (X-ALD) is an X-linked recessively inherited peroxisomal disorder, phenotypically heterogeneous, characterized by progressive white-matter demyelination of the central nervous system and adrenocortical insufficiency. We investigated 15 male X-ALD patients varying in age from 7 to 39, diagnosed among 108 suspected patients referred for investigation. Plasma levels of very long chain fatty acids (VLCFA) were measured at our laboratory using gas chromatography (GC). Eleven cases of childhood X-ALD and four cases of adrenomyeloneuropathy (AMN) were diagnosed. Adrenal leukodystrophy insufficiency and limb weakness were the most frequent symptoms, appearing in 12, 8 and 6 of the patients, respectively. Physician awareness of X-ALD seems inadequate to judge by age at diagnosis and lengthy interval between the start of symptoms and diagnosis. This is the first published series of Brazilian patients with X-ALD. We determined signs and symptoms relevant for diagnosis, as early identification seems important for treatment outcome. In addition, diagnosis identifies carriers, who could benefit from genetic counselling and prenatal diagnosis.

scholarly journals Action of long-chain fatty acids in vitro on Ca2+-stimulatable, Mg2+-dependent ATPase activity in human red cell membranes

1987 ◽  
Vol 248 (2) ◽  
pp. 511-516 ◽  
Author(s):  
F B Davis ◽  
P J Davis ◽  
S D Blas ◽  
M Schoenl
Keyword(s):  
Fatty Acids ◽  
Enzyme Activity ◽  
Oleic Acid ◽  
Thyroid Hormone ◽  
Atpase Activity ◽  
Red Cell ◽  
Long Chain Fatty Acids ◽  
Long Chain ◽  
Chain Fatty Acids

Human red cell membrane Ca2+-stimulatable, Mg2+-dependent adenosine triphosphatase (Ca2+-ATPase) activity and its response to thyroid hormone have been studied following exposure of membranes in vitro to specific long-chain fatty acids. Basal enzyme activity (no added thyroid hormone) was significantly decreased by additions of 10(-9)-10(-4) M-stearic (18:0) and oleic (18:1 cis-9) acids. Methyl oleate and elaidic (18:1 trans-9), palmitic (16:0) and lauric (12:0) acids at 10(-6) and 10(-4) M were not inhibitory, nor were arachidonic (20:4) and linolenic (18:3) acids. Myristic acid (14:0) was inhibitory only at 10(-4) M. Thus, chain length of 18 carbon atoms and anionic charge were the principal determinants of inhibitory activity. Introduction of a cis-9 double bond (oleic acid) did not alter the inhibitory activity of the 18-carbon moiety (stearic acid), but the trans-9 elaidic acid did not cause enzyme inhibition. While the predominant effect of fatty acids on erythrocyte Ca2+-ATPase in situ is inhibition of basal activity, elaidic, linoleic (18:2) and palmitoleic (16:1) acids at 10(-6) and 10(-4) M stimulated the enzyme. Methyl elaidate was not stimulatory. These structure-activity relationships differ from those described for fatty acids and purified red cell Ca2+-ATPase reconstituted in liposomes. Thyroid hormone stimulation of Ca2+-ATPase was significantly decreased by stearic and oleic acids (10(-9)-10(-4) M), but also by elaidic, linoleic, palmitoleic and myristic acids. Arachidonic, palmitic and lauric acids were ineffective, as were the methyl esters of oleic and elaidic acids. Thus, inhibition of the iodothyronine effect on Ca2+-ATPase by fatty acids has similar, but not identical, structure-activity relationships to those for basal enzyme activity. To examine mechanisms for these fatty acid effects, we studied the action of oleic and stearic acids on responsiveness of the enzyme to purified calmodulin, the Ca2+-binding activator protein for Ca2+-ATPase. Oleic and stearic acids (10(-9)-10(-4) M) progressively inhibited, but did not abolish, enzyme stimulation by calmodulin (10(-9) M). Double-reciprocal analysis of the effect of oleic acid on calmodulin stimulation indicated noncompetitive inhibition. Addition of calmodulin to membranes in the presence of equimolar oleic acid restored basal enzyme activity. Oleic acid also reduced 125I-calmodulin binding to membranes, but had no effect on the binding of [125I]T4 by ghosts. The mechanism of the decrease by long chain fatty acids of Ca2+-ATPase activity in situ in human red cell ghosts thus is calmodulin-dependent and involves reduction in membrane binding of calmodulin.

scholarly journals The conditional nature of the dietary need for polyunsaturates: a proposal to reclassify ‘essential fatty acids’ as ‘conditionally-indispensable’ or ‘conditionally-dispensable’ fatty acids

2000 ◽  
Vol 84 (6) ◽  
pp. 803-812 ◽  
Author(s):  
Stephen C. Cunnane
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
De Novo ◽  
Essential Fatty Acids ◽  
Essential Amino Acids ◽  
Long Chain Fatty Acids ◽  
Healthy Individuals ◽  
The Brain ◽  
Long Chain ◽  
Slow Turnover

The term essential fatty acid no longer clearly identifies the fatty acids it was originally used to describe. It would be more informative if the concept of essentiality shifted away from the symptoms arising from the lack of de novo synthesis of linoleate or α-linolenate and towards the adequacy of the capacity for synthesis and conservation of both the parent and the derived long-chain polyunsaturates. For instance, despite the existence of the pathway for synthesis of docosahexaenoate from α-linolenate, the former would be more correctly classified as ‘conditionally indispensable’ because the capacity of the pathway appears insufficient during early development, although it may be sufficient later in life in healthy individuals. Similarly, despite the inability to synthesize linoleate de novo, abundant linoleate stores and its relatively slow turnover in healthy adults probably makes linoleate ‘conditionally dispensable’ for long periods. There are two other anomalies with the terms essential and non-essential fatty acids: (1) under several different experimental circumstances, the C-skeleton of essential fatty acids is avidly used in the synthesis of non-essential fatty acids; (2) to function normally, the brain is required to endogenously synthesize several non-essential fatty acids. As with essential amino acids, which have been reclassified as indispensable or conditionally indispensable, such a change in terminology should lead to an improved understanding of the function and metabolism of polyunsaturates in particular, and long-chain fatty acids in general.

The biochemistry of copper deficiency - II. Synthetic processes

1956 ◽  
Vol 145 (919) ◽  
pp. 195-205 ◽  
Keyword(s):  
Fatty Acids ◽  
Central Nervous System ◽  
Nervous System ◽  
Nucleic Acid ◽  
Copper Deficiency ◽  
Long Chain Fatty Acids ◽  
Phospholipid Synthesis ◽  
The Central Nervous System ◽  
Long Chain ◽  
Chain Fatty Acids

The biochemistry of copper deficiency is studied in order to gain some understanding of the metabolic disturbances which lead to demyelination of the central nervous system in disease. In the preceding paper we reported our investigation of the enzyme systems, blood chemistry and amino-acid excretion in copper-deficient rats, and in this paper extend the study to investigate the syntheses of phospholipid, long-chain fatty acids, ribose nucleic acid, protein and protohaem. Phospholipid synthesis is found to be depressed considerably in copper deficiency. This is due to a failure in the process of condensation of acyl CoA with α-glycerophosphate to form phosphatidic acids. The reasons are discussed. The syntheses of long-chain fatty acids and ribose nucleic acid are normal, whilst the synthesis of protein is inconstantly affected by copper deficiency. Protohaem synthesis is depressed by a degree which exactly parallels the anaemia. The conclusion is drawn that the anaemia is due to a decrease in haematopoiesis rather than an increased destruction of red cells. The possible interrelationships of the disturbances of phospholipid synthesis and cytochrome oxidase activity and the relevance of each to demyelination of the central nervous system are discussed.

Postprandial Activation of Coagulant Factor VII by Long-chain Dietary Fatty Acids

1996 ◽  
Vol 76 (03) ◽  
pp. 369-371 ◽  
Author(s):  
T A B Sanders ◽  
G J Miller ◽  
Tamara de Grassi ◽  
Najat Yahia
Keyword(s):  
Fatty Acids ◽  
Dietary Fatty Acids ◽  
Factor Vii ◽  
Fat Intake ◽  
Long Chain Fatty Acids ◽  
Postprandial Lipaemia ◽  
Increased Risk ◽  
Coagulant Activity ◽  
Long Chain Triglycerides ◽  
Long Chain

SummaryFactor VII coagulant activity (FVIIc) is associated with an increased risk of fatal ischaemic heart disease (IHD). Several reports have suggested that dietary fat intake or hypertriglyceridaemia are associated with elevated levels of FVII. This study demonstrates that an intake of long-chain fatty acids sufficient to induce postprandial lipaemia in healthy subjects leads to a substantial elevation in both FVIIc and the concentration of FVII circulating in the activated form. Such an increase in FVIIc could not be induced by medium-chain triglycerides. These results suggest that the consumption of a sufficient amount of long-chain triglycerides to induce postprandial lipaemia induces the activation of FVII.

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