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Nutritional Deficiencies
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Deepa Bhupali, Fernando D. Testai
Treat the underlying cause of vitamin E deficiency. Equivalence is calculated as 1 mg of vitamin E = 1.47 IU “natural source” vitamin E = 2.2 IU synthetic vitamin E. Replacement dose varies, mainly according to the cause of the deficiency: Abetalipoproteinemia: 100–200 IU/kg/day.Chronic cholestasis: 15–25 IU/kg/day.Cystic fibrosis: 5–10 IU/kg/day.Short bowel syndrome: 200–3600 IU/day.Isolated vitamin E deficiency: 800–3600 IU/day.
Atherosclerosis
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
The smooth endoplasmic reticulum and Golgi apparatus play important roles in the formation of apoB.318 Abetalipoproteinemia is a rare autosomal recessive disease characterized by fat malabsorption, acanthocytosis, and retinitis pigmentosa. Hepatocytes from patients with this disease contain large fat droplets and are deficient in smooth endoplasmic reticulum membranes with very low number of Golgi vacuoles.519 In these patients, apoB is completely absent, and consequently, chylomicrons, VLDL, and LDL are not synthetized properly. In contrast, apoB levels in the serum have shown a correlation with the extent of coronary occlusion.650 The metabolism of apoB in large triglyceride rich VLDL particles shows differences between normal and hypertriglyceridemic subjects.478,479
Hemolytic Anemia Associated with Red Cell Membrane Defects
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Abetalipoproteinemia is a rare, autosomal recessive condition caused by mutations in the microsomal triglyceride transfer protein, resulting in a failure to produce lipoproteins containing apolipoprotein β. Clinically, patients have a progressive neurologic disease, retinitis pigmentosa, and absent β lipoproteins in the blood. From 50% to 90% of the erythrocytes are acanthocytes due to abnormal membrane lipids. Hemolysis is typically mild.
Evinacumab: a new option in the treatment of homozygous familial hypercholesterolemia
Published in Expert Opinion on Biological Therapy, 2022
Angela Pirillo, Alberico L. Catapano
Abetalipoproteinemia is a rare autosomal recessive disorder characterized by the lack of plasma apoB-containing lipoproteins and is caused by mutations in the gene encoding the microsomal triglyceride transfer protein (MTP); MTP plays a crucial role in the assembly of apoB-containing lipoproteins in both the liver (VLDL) and intestine (chylomicrons) [23]. Lomitapide inhibits the activity of MTP and lowers LDL-C levels by approximately 45% in an LDLR-independent way (Table 1) [24,25]. Based on its mechanism of action, lomitapide is approved for the treatment of adult HoFH as an adjunct to a low-fat diet and other lipid-lowering drugs with or without lipoprotein apheresis. Patients must comply with a low-fat diet to reduce gastrointestinal adverse events, which represent the major cause of drug discontinuation. A phase 3 trial and its open-label extension study have reported elevations in the hepatic fat content in patients treated with lomitapide, although no overt liver disease has been observed [25,26]. A modeling analysis has suggested that a lifelong lomitapide therapy started early in life (18 years of age) would increase life expectancy by 11.2 years and delay the time to the first MACE by 5.7 years in HoFH [27]. Gastrointestinal side effects and hepatic fat accumulation may limit the tolerability of this drug. The ongoing LOWER registry will evaluate the long-term safety and efficacy of lomitapide in real-life clinical practice [28].
Perspectives on the pharmacological management of dystonia
Published in Expert Opinion on Pharmacotherapy, 2021
Marina Svetel, Aleksandra Tomić, Nikola Kresojević, Nataša Dragašević, Vladimir Kostić
A thoughtful diagnostic and clinical evaluation are the first steps in therapeutic strategy because, rarely, for some subtypes of dystonia (mostly combined or complex) causal treatments are available, or it is possible to find a treatable cause (Wilson’s disease, structural brain lesions, metabolic abnormalities). Dopa-responsive dystonia (DRD) is among rare treatable syndromes in which the underlying mechanisms have been explained [7]. In some genetically proved cases, removal of a toxic substances (Wilson disease, Neumann Pick type C, manganese transporter deficiencies etc.), avoidance of specific triggers (GLUT 1 deficiency, rapid/onset dystonia parkinsonism, etc.) or dietary restriction (abetalipoproteinemia, etc.) can prevent or reduce symptoms, and sometimes even completely or partially reverse them [8].
Preclinical discovery and development of evolocumab for the treatment of hypercholesterolemia
Published in Expert Opinion on Drug Discovery, 2020
Etienne Khoury, Diane Brisson, Daniel Gaudet
Importantly, the cardiovascular health condition in individuals naturally carrying these identified PCSK9 loss-of-function mutations was excellent. A study by Cariou B. et al. described a case of two women and a man without significant health issues showing hypobetalipoproteinemia and diminished levels of LDL-C as low as 0.4 mmol/L (15.5 mg/dL) with a complete lack of PCSK9 expression [45]. Another case of a compound heterozygous 32-year-old African American with no circulating PCSK9 was also shown to have LDL-C levels reaching 0.36 mmol/L (14 mg/dL) and reported no significant impact on his overall health status [46]. Such LDL-C levels are also encountered in other cases, as, for example, the ones with naturally occurring loss-of-function carriers in Apo B (i.e. hypobetalipoproteinemia) or microsomal triglyceride transfer protein (MTTP) (i.e. abetalipoproteinemia). The association between PCSK9 loss-of-function mutations, low levels of LDL-C and reduced incidence of CVD became well established and PCSK9 inhibition was then considered to be the next breakthrough target for CVD risk management [47].