Inherited Metabolic Diseases

Research, Epidemiology and Statistics, Research, Epidemiology and Statistics

Steve Hannigan, Steve Field

• Publisher: CRC Press
• Year: 2018
• Print ISBN:
  9781846190995
• eBook ISBN:
  9781315347271
• Topic: Medicine
• Subtopic: Diseases & Allergies

Inherited Metabolic Diseases are common enough for health, social service and education professionals to encounter them periodically, but rare enough for them to be poorly understood. They severely affect up to 1 in 10,000 people, and lead to a wide range of special needs in care and education. This guide provides specialist information on metabolic diseases for the non-specialist. In a concise, accessible and family-friendly format, each entry lists the names by which a condition is known, and explains the genetic causes of the disease, the physical effects, the patient's symptoms, and available treatments. Key diseases from all ten major groups of metabolic disorders are described, and all entries have been reviewed by Specialist Advisers. The work has been coordinated by the charity Climb, Children Living with Inherited Metabolic Diseases. This uniquely comprehensive source of information is a vital reference for hospital doctors including paediatricians, general practitioners, nurses and other health professionals, social service and education staff and managers, and the families and carers of children with the conditions.

Introduction

About Climb

Children Living with Inherited Metabolic Diseases (Climb) is a registered charity in the UK, and as an organisation we see many books whose subject is one of the many metabolic diseases. We currently support over 700 of these diseases, and the majority of our information is presented in a family-friendly format which, I am sorry to say, cannot be said about a lot of the information that is available in published form or on the Internet.

The charity was started in 1981 and changed its name to Climb in 1999. In 2004 we launched the National Information Centre for Metabolic Diseases as part of the Climb group. Since the launch of the National Information Centre our support base has grown considerably, and in 2005-06 we provided information and support to over 23,000 families and professionals worldwide, and supported individuals and organisations in over 80 different countries.

This is the first of several books designed as a guide for anyone affected by or working with metabolic diseases. Through this medium we are trying to help people to understand, in a family-friendly way, what the particular disease involves. We have divided the 700 diseases that we support into 10 main groups, which are as follows:

• amino acid and urea cycle disorders
• organic acid and fatty acid oxidation disorders
• mitochondrial and peroxisomal disorders
• lysosomal, sterol and lipid disorders
• carbohydrate and glycosylation disorders
• purine, pyrimidine and porphyria disorders
• hormone disorders
• musculoskeletal and connective tissue disorders
• blood and immune system disorders
• associated disorders.

In this, the irst volume, we have covered 100 diseases, ranging from those that affect approximately 1 in 10,000 people to diseases that are very rare and affect around 1 in 100,000.

We update our information on a regular basis, and we work with a large group of Specialist Advisers around the world to ensure that the information is correct and up to date.

The idea for the books came from our Executive Director, Steve Hannigan, and the trustees and staf have been very supportive in the production of the information contained in this book. Our Information Research Officer, Helen Watts, deserves a special mention, as her dedication, tact and diplomacy as the liaison for our Specialist Advisers have been pivotal in the gathering of information for publication.

Metabolic diseases

Each of the diferent metabolic diseases is inherited through one of four routes. These are summarised below.

Autosomal dominant Inheritance

This method of inheritance occurs when a single copy of the diseased gene will dominate the other normal gene. Therefore if a defective gene is inherited from either parent, the child will be afected with the disorder. This means that for each pregnancy if either of the parents has a defective gene, there is a 50% chance of a child being afected by the disease.

Autosomal recessive inheritance

This occurs when a child inherits a gene for the disease from both parents. The risk that the ofspring of a couple who are both carriers of the disease will be afected is 25%. There is a 50% chance that their child will be a carrier, and there is a 25% chance that the child will not carry the abnormal gene.

MtDNA inheritance

Disorders inherited in this way are caused by a defect in the mitochondrial DNA (mtDNA). This can be inherited from the maternal line, as the mtDNA is only passed down from mothers to their children. During fertilisation the instructions in the mtDNA from the father are lost, so all the instructions in the mtDNA come from the mother. This means that girls will always pass on a defect in their mtDNA and boys will never pass on a defect in their mtDNA to their children.

X-linked inheritance

This occurs when diseases are coded on the X chromosomes of genes. Females have two X chromosomes, and any disease trait on one of the X chromosomes is usually masked by the other normal X chromosome. Males have one X and one Y chromosome, so because there is only one X chromosome, 50% of male children may inherit the disease.

Chapter 1

Amino acid disorders and urea cycle disorders

Amino acid disorders

Amino acid disorders can be caused by problems with transport of the amino acids into the cells or by impairment of the breakdown of amino acids. Amino acids are the building blocks of proteins. Some amino acids can be synthesised by the body, while others must be obtained through protein from the diet. The latter are known as the essential amino acids. A deficiency in one of the enzymes needed to break down amino acids means that the body is unable to use them for growth and repair. Newborn babies are routinely screened for several metabolic disorders. Of these screening tests, the most commonly known is the heel prick test, which is used to diagnose phenylketonuria (PKU).

Urea cycle disorders

The urea cycle disorders (UCDs) are a group of genetic disorders that are caused by a deficiency of one of six enzymes in the urea cycle, which is responsible for the removal of ammonia. These six enzymes are:

• arginase
• argininosuccinate lyase
• argininosuccinate synthetase
• carbamyl phosphate synthetase
• N-acetylglutamate synthetase
• ornithine transcarbamylase.

When protein is digested by the body, it is broken down into small molecules known as amino acids. These are transported via the bloodstream to the cells. They may be used to build bodily protein or to produce glucose and energy. Most of us eat more protein than we need to, and the excess amino acids are converted to ammonia, which is a toxic substance. In the liver the ammonia is converted into a harmless substance known as urea, which is excreted in the urine. In UCDs, the functioning of one of the six enzymes is impaired and ammonia is not removed from the bloodstream. This leads to a build-up of ammonia with high blood concentrations (hyper-ammonaemia), causing the symptoms of these disorders.

Argininosuccinic aciduria

Other names for this condition

• Argininosuccinase deficiency
• Argininosuccinate lyase deficiency
• Argininosuccinic acidaemia
• ASA
• ASL

This disorder is one of a group of conditions, known as the urea cycle disorders, in which the body’s ability to manage dietary protein is impaired. In argininosuccinic aciduria there is a deficiency or absence of the enzyme argininosuccinate lyase (ASL), which is an important part of the urea cycle. This leads to an accumulation of the amino acid argininosuccinic acid (hence the name), and may lead to a build-up of ammonia (and its related product glutamine) in the body, giving rise to the symptoms of the disorder.

The pattern of inheritance of this disorder is autosomal recessive. It is thought to occur in about 1 in 70,000 of the population.

Like many inherited metabolic diseases, argininosuccinic aciduria may manifest itself at different ages and in different ways. This probably depends on whether the enzyme is completely or partially absent. In the severe form of ASA, babies show complete absence of the ASL enzyme and exhibit symptoms soon after birth. There is usually a symptom-free period of 24-48 hours with normal feeding, before the baby becomes lethargic, with poor feeding, vomiting, irritability and liver enlargement (hepatomegaly). These symptoms are similar to, and often mistaken for, those of infection. As the ammonia level rises, breathing problems (apnoea), seizures and coma may ensue, with swelling of the brain (cerebral oedema). If left untreated, this severe form is life-threatening. Even with appropriate treatment, the baby may suffer signiicant neurological impairment or may not survive.

Partial deiciency of the ASL enzyme leads to a less severe form of ASA in which symptoms may not develop until infancy or childhood. Typically they may appear at the time of weaning or change from formula to cows’ milk. Infection or high protein intake may also precipitate symptoms. These may include recurrent acute episodes of vomiting, lethargy, sleepiness, agitation, seizures and coma, or a more gradual failure to gain weight and delay in neurological development. Children with ASL may develop movement disorders (ataxia) and an aversion to higher-protein foods. Characteristically the hair is brittle and remains short.

Even in the milder forms of ASL, high levels of ammonia during acute episodes may afect the brain and lead to long-term neurological impairment.

In the acute situation with very high ammonia levels (severe hyperammonaemic episodes), it is important to reduce the ammonia levels as quickly as possible. Intravenous drugs (arginine, sodium benzoate and phenylbutyrate) help to boost the effectiveness of the urea cycle and enable the excretion of ammonia in the urine by using diferent metabolic pathways. Protein intake is temporarily stopped and intravenous glucose is given to provide energy and to reduce the breakdown of bodily protein (catabolism). Haemodialysis (blood filtering by machine) may be necessary to remove ammonia directly from the bloodstream.

The a...

Table of contents

• Cover
• Title Page
• Copyright Page
• Contents
• A note from the Executive Director of Climb
• Specialist Advisers
• Introduction