Aceruloplasminemia E-Book

Durga Kumawat

• Herausgeber: via tolino media
• Kategorie: Fachliteratur
• Sprache: Englisch

Veröffentlichungsjahr: 2023

Beschreibung

"Aceruloplasminemia: Understanding the Rare Genetic Disorder" is an informative and insightful book that delves into the complex world of a rare genetic disorder that affects iron metabolism and can lead to neurodegeneration. This comprehensive guide provides an in-depth understanding of the clinical manifestations, biochemical features, genetic variants, and advanced imaging techniques used for diagnosis. The book also explores the mechanisms of iron-induced neurotoxicity and the role of ceruloplasmin in iron metabolism. This book is an invaluable resource for researchers, clinicians, and patients alike, providing a thorough understanding of the disease and its impact on the global population. With its concise yet comprehensive coverage of the subject matter, this book is sure to be a must-read for anyone seeking to deepen their knowledge of this rare genetic disorder.

Leseprobe

Inhaltsverzeichnis

Introduction to Aceruloplasminemia

History of Aceruloplasminemia

Understanding Iron Metabolism

Symptoms and Diagnosis of Aceruloplasminemia

Genetic Causes of Aceruloplasminemia

Epidemiology of Aceruloplasminemia

Pathophysiology of Aceruloplasminemia

Differentiating Aceruloplasminemia from other Disorders

Iron Overload in Aceruloplasminemia

Iron Chelation Therapy for Aceruloplasminemia

Neurological Consequences of Aceruloplasminemia

Ophthalmological Consequences of Aceruloplasminemia

Psychiatric Symptoms in Aceruloplasminemia

Impact on Quality of Life in Aceruloplasminemia Patients

Comorbidities in Aceruloplasminemia

Management of Aceruloplasminemia

Nutritional Management in Aceruloplasminemia

Cardiopulmonary Complications in Aceruloplasminemia

Non-Transferrin-Bound Iron in Aceruloplasminemia

Advances in Aceruloplasminemia Research

Clinical Trials and Emerging Therapies for Aceruloplasminemia

Patient Advocacy and Support for Aceruloplasminemia

Coping with Aceruloplasminemia: Tips for Patients and Caregivers

Familial Aceruloplasminemia and Genetic Counseling

Case Studies in Aceruloplasminemia

Acute Complications of Aceruloplasminemia

Long-Term Management of Aceruloplasminemia

Palliative Care for Aceruloplasminemia Patients

Clinical Manifestations of Aceruloplasminemia

Cognitive Impairment in Aceruloplasminemia

A Comprehensive Guide to Iron Homeostasis

The Role of Ceruloplasmin in Iron Metabolism

Biochemical Features of Aceruloplasminemia

Imaging Techniques in Aceruloplasminemia Diagnosis

Histopathological Features of Aceruloplasminemia

Association of Aceruloplasminemia with Neurodegenerative Disorders

Differential Diagnosis of Aceruloplasminemia

Functional Consequences of Aceruloplasminemia

Iron Metabolism and Neurodegeneration

Mechanisms of Iron-Induced Neurotoxicity

Animal Models of Aceruloplasminemia

Iron-Induced Oxidative Stress in Aceruloplasminemia

Iron-Mediated Neuroinflammation in Aceruloplasminemia

Genetics and Epigenetics of Aceruloplasminemia

Genetic Variants Associated with Aceruloplasminemia

Genetic Testing for Aceruloplasminemia

Gene Therapy for Aceruloplasminemia

Advances in Iron Chelation Therapy

Global Burden of Aceruloplasminemia

Impressum

Aceruloplasminemia

Understanding the Rare Genetic Disorder

Durga Kumawat

© 2023 Durga Kumawat. All rights reserved.

Imprint: Independently Published.

Email: [email protected]

Disclaimer:

The author assume no liability for damage of any kind that arises directly or indirectly from the use of the information provided in this book.

Introduction to Aceruloplasminemia

Aceruloplasminemia is a rare, autosomal recessive genetic disorder characterized by abnormal accumulation of iron in various organs and tissues, particularly the brain and liver, due to the absence or reduced activity of ceruloplasmin, a copper-containing protein that plays a crucial role in iron metabolism and transport. Aceruloplasminemia was first described in 1987 by Miyajima and colleagues in a Japanese patient with neurological and ophthalmological symptoms and high serum iron levels despite normal transferrin saturation and ferritin levels. Since then, over 200 cases of aceruloplasminemia have been reported worldwide, with the majority being of Japanese, Chinese, or European descent.

Genetics

Aceruloplasminemia is caused by mutations in the CP gene on chromosome 3, which encodes ceruloplasmin. The CP gene consists of 21 exons and spans approximately 80 kilobases. To date, more than 50 pathogenic mutations have been identified in the CP gene, including missense, nonsense, frameshift, and splice site mutations, as well as large deletions and insertions. Most mutations result in truncated or nonfunctional ceruloplasmin or interfere with its secretion or stability, leading to low or undetectable serum ceruloplasmin levels and decreased ferroxidase activity. Some mutations may also affect the copper-binding or iron-binding sites of ceruloplasmin, impairing its ability to mobilize and detoxify iron.

Inheritance

Aceruloplasminemia is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated CP gene (one from each parent) to develop the condition. Individuals with only one copy of the mutated CP gene are carriers and usually do not have any symptoms. When two carriers have children, there is a 25% chance that each child will inherit two mutated copies of the gene and develop aceruloplasminemia, a 50% chance that each child will inherit one mutated copy and be a carrier, and a 25% chance that each child will inherit two normal copies of the gene and not be affected.

Clinical Features

Aceruloplasminemia is a multisystem disorder that can manifest with a wide range of clinical features and severity, depending on the age of onset, the rate and extent of iron deposition, and the organs and tissues affected. The most common and prominent symptoms of aceruloplasminemia are related to iron overload in the brain and liver, which can lead to neurodegeneration, diabetes mellitus, and retinal degeneration.

Neurological Symptoms

Neurological symptoms usually develop in early adulthood, but can also occur in childhood or later in life. The most common neurological features of aceruloplasminemia are movement disorders, such as dystonia, parkinsonism, chorea, and ataxia, which can be disabling and progressive. These movement disorders are thought to be due to iron deposition in the basal ganglia and cerebellum, respectively, and are often resistant to conventional treatment. Other neurological symptoms include cognitive impairment, mood disturbances, psychiatric disorders, and neuropathy. Cognitive impairment can range from mild cognitive decline to dementia, with deficits in attention, memory, executive function, and visuospatial skills. Psychiatric disorders can include depression, anxiety, psychosis, and suicidal ideation. Neuropathy can present as sensory or motor deficits, or both, and can affect the peripheral nerves, spinal cord, or optic nerves.

History of Aceruloplasminemia

Aceruloplasminemia is a relatively recent discovery in the field of medicine. The condition was first identified in 1987 by a team of researchers led by Dr. Kiyoshi Miyajima at the University of Tokyo, who described a Japanese patient with neurological and ophthalmological symptoms and high serum iron levels despite normal transferrin saturation and ferritin levels. The patient was found to have undetectable serum ceruloplasmin levels and decreased ferroxidase activity, which led to the diagnosis of aceruloplasminemia.

Over the next few years, several more cases of aceruloplasminemia were reported in Japan, which led to the characterization of the clinical and genetic features of the condition. In 1995, the CP gene was identified as the causative gene for aceruloplasminemia, and mutations in the gene were found to result in low or absent ceruloplasmin levels and iron accumulation in various organs and tissues.

Since then, aceruloplasminemia has been reported in other countries, including China, Europe, and the United States. The majority of cases, however, still occur in Japan, where the prevalence is estimated to be 1 in 2 million individuals. The high incidence of aceruloplasminemia in Japan is thought to be due to a founder effect, where a common mutation arose in the Japanese population and was subsequently passed down through generations.

The discovery of aceruloplasminemia has had a significant impact on our understanding of iron metabolism and transport in the body. Ceruloplasmin was previously known to be involved in the oxidation and transport of iron, but its exact role was not well understood. The identification of mutations in the CP gene and the subsequent characterization of aceruloplasminemia have shown that ceruloplasmin plays a crucial role in regulating iron homeostasis and preventing iron overload.

The diagnosis and management of aceruloplasminemia have also improved over the years. Early diagnosis and treatment can help prevent or delay the onset of neurological and ophthalmological symptoms and improve the quality of life for affected individuals. Treatment options include phlebotomy, which involves the removal of blood to reduce iron levels, and iron chelation therapy, which involves the use of drugs that bind to excess iron and facilitate its excretion from the body.

In addition, research on aceruloplasminemia has led to a better understanding of other conditions that involve abnormal iron metabolism and transport, such as hemochromatosis and neurodegenerative disorders like Alzheimer's and Parkinson's diseases. The identification of common pathways and mechanisms involved in these conditions may lead to the development of new treatments and therapies that can benefit a wider range of patients.

In conclusion, the discovery of aceruloplasminemia has had a significant impact on the field of medicine, particularly in the areas of iron metabolism and neurodegenerative disorders. The continued study of this condition and its underlying mechanisms may lead to new insights and treatments that can improve the lives of affected individuals and advance our understanding of human health and disease.

Understanding Iron Metabolism

Iron is an essential nutrient for many processes in the body, including oxygen transport, energy production, and DNA synthesis. However, excess iron can be toxic and lead to tissue damage, inflammation, and oxidative stress. Therefore, the regulation of iron metabolism is critical for maintaining a balance between the need for iron and the potential harm from excess iron.

Iron is primarily absorbed from the diet in the duodenum of the small intestine. The absorption of dietary iron is tightly regulated by the body to prevent excess accumulation. Iron is absorbed in the ferrous (Fe2+) form, which is facilitated by the presence of a protein called divalent metal transporter 1 (DMT1). Once inside the enterocyte, iron can be stored as ferritin or transported across the basolateral membrane into the bloodstream by ferroportin.

Iron in the bloodstream is bound to the transport protein transferrin, which delivers iron to tissues throughout the body. Iron uptake by cells is regulated by the expression of transferrin receptor 1 (TfR1), which binds to transferrin and mediates iron entry through receptor-mediated endocytosis. Once inside the cell, iron can be used for various metabolic processes or stored in ferritin.

Iron metabolism is regulated by several proteins and pathways, including hepcidin, ferroportin, transferrin, and ceruloplasmin. Hepcidin is a peptide hormone produced by the liver in response to high iron levels and inflammation. Hepcidin binds to ferroportin, the only known iron exporter in the body, leading to its internalization and degradation. This reduces iron export from cells and promotes iron retention in storage sites, thereby limiting iron availability to pathogens and other tissues.

Ceruloplasmin is a multi-copper oxidase that plays a critical role in iron homeostasis. Ceruloplasmin catalyzes the oxidation of ferrous iron to ferric iron, which is required for efficient iron uptake by transferrin. Ceruloplasmin also has ferroxidase activity, which is essential for iron export from cells and the regulation of iron metabolism. Individuals with aceruloplasminemia, who lack ceruloplasmin, accumulate iron in various organs and tissues, leading to tissue damage and neurological symptoms.

Iron metabolism is also regulated by other proteins, such as heme oxygenase 1 (HO-1), which degrades heme and releases iron and carbon monoxide, and ferritin, which stores iron and prevents its toxicity. Dysregulation of iron metabolism can lead to a variety of disorders, including iron-deficiency anemia, hemochromatosis, and neurodegenerative diseases like Alzheimer's and Parkinson's.

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