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Inborn Metabolic Diseases Diagnosis And Treatment Pdf

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A more recent article on inborn errors of metabolism is available. GRAF, M. Recent innovations in medical technology have changed newborn screening programs in the United States.

Pediatric Neurometabolic Disorders View all 6 Articles. Inherited metabolic diseases or inborn errors of metabolism frequently manifest with both hyperkinetic dystonia, chorea, myoclonus, ataxia, tremor, etc. The diagnosis of these diseases is in many cases difficult, because the same movement disorder can be caused by several diseases. Through a literature review, two hundred and thirty one inborn errors of metabolism presenting with movement disorders have been identified.

A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting With Movements Disorders

CONTEXT: Inborn errors of metabolism cause hereditary metabolic diseases HMD and classically they result from the lack of activity of one or more specific enzymes or defects in the transportation of proteins. Clinical cases are presented with the peculiar symptoms of various diseases. This review includes inheritance patterns and clinical and laboratory findings of the more common IEM diseases within a clinical classification that give a general idea about these disorders.

A summary of treatment types for metabolic inherited diseases is given. They are also to be found in neurological, pediatric, obstetrics, surgical and psychiatric clinics seeking diagnoses, prognoses and therapeutic or supportive treatment. Key words: Inborn errors of metabolism. Metabolic inherited disease. In the doctor Archibald E. Garrod described alkaptonuria, a disease he classified as a lifelong congenital chemical alteration.

Later on, in , he described other diseases: albinism, cystinuria, porphyria and pentosuria, which he named "Inborn Errors of Metabolism". Garrod's conclusions were completely correct in relation to the genetic basis of metabolic disorders and the gene-enzyme concept.

According to Scriver, in the foreword of "Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases", 2 the importance of Garrod's observation that inborn errors of metabolism IEM are manifestations of biochemical individuality was never recognized during his lifetime, nor has it been in our days, because many doctors still think of IEM as situations of extreme rarity that will never be seen in the typical medical practice.

IEM produces manifestations in every organ, from the fetus to geriatric life and they are omnipresent in appearance, not respecting the doctor's qualifications as a generalist or specialist. Inborn errors of metabolism cause hereditary metabolic diseases HMD and classically they result from the lack of activity of one or more specific enzymes or defects in the transportation of proteins. The consequences can usually be the accumulation of substances present in small amounts, the deficiency of critical intermediary products, the deficiency of specific final products or furthermore the noxious excess of products of alternative metabolic pathways.

The molecular basis of biochemical disorders in HMD are genetic mutations in enzymatic loci that affect activator proteins or co-factors for enzymes, protein transportation, carrier systems or recognition markers.

More than three hundred human diseases are known today that are caused by inborn errors of metabolism and this number is constantly growing because of new identification techniques for the various biochemical phenotypes.

However, the detection of HMD incidence has not been increasing in parallel, probably because its diagnosis is being underestimated. Faulty diagnosis of IEM is related to a series of factors: 1 they are individually considered rare and therefore many physicians do not consider IEM until most frequent conditions have been ruled out, 2 blood and urine samples for investigation of metabolic errors need to be collected at the right time in relation to the course of the disease, and 3 many metabolic diseases only produce intermittent abnormalities.

IEM are not rare diseases when we observe their cumulative incidence, 7 which is about one in every live births. Nevertheless, the prevalence of each disease has many variables, especially relating to race. Examples of frequency for specific diseases include: 1 in for familial hypercholesterolemia; 8 1 in 12, for phenylketonuria; 4,9 1 in 15, for organic acidurias; 10 1 in 60, for glycogen storage diseases; 4 1 in 45, for galactosemia; 8 1 in , to homocystinuria 8 and 1 in , for maple syrup urine disease.

In Brazil the incidence of some specific IEM disorders have been found to be: 1 in 11, to 1 in 15, for phenylketonuria; 12,13 1 in 43, for maple syrup urine disease; 12 and 1 in , for biotin deficiency. The majority of HMD are inherited autosomal recessive traits, i. Table 1 shows a summary of the authors' classification.

Diseases that only affect a functional or anatomical system or an organ, such as the endocrine system, immune system, coagulation factors or lipoproteins. The symptoms are uniform and the correct diagnosis is usually easy, because the basis of the biochemical defect incorporates the given consequence, for example, the tendency to bleed seen in cases of coagulation defects. Diseases in which the biochemical basis affects one metabolic pathway common to a great number of cells or organs, such as in storage diseases due to lysosomal disorders, or is restricted to one organ with humoral and systemic consequences, such as hyperammonemia in defects of the urea cycle or hypoglycemia in hepatic glycogenesis.

Diseases in this category have great clinical diversity. The central nervous system CNS is frequently attacked and in the evolution of the disease many secondary abnormalities can appear, making the diagnosis more difficult. This category includes many errors in intermediary metabolism carbohydrate defects; amino acid or organic acid metabolism with primary or secondary disturbances of vitamin or metal homeostasis; purine and peroxisome disorders , diseases of intracellular transport endoplasmic reticulum and Golgi apparatus defects and lysosomal disorders.

These diseases can be divided into three groups from a physiopathological perspective, greatly assisting in diagnostic reasoning. Disturbances in the synthesis or catabolism of complex molecules.

The symptoms are permanent, progressive, independent of incidental events and are not related to alimentary ingestion. Lysosomal Disorders. Also called storage diseases. These lead to the progressive accumulation of undigested substrates, usually polymers, that cannot usually be hydrolyzed.

The polymers accumulate in lysosomes, where they can be seen using optical or electron microscopy. The affected tissues are those in which the substance is usually catabolized in great quantities: circulating lymphocytes, fibroblasts, liver, spleen, conjunctiva, bone marrow and intestinal mucosa.

The clinical manifestations in this group are generally hepatomegaly or hepatosplenomegaly; dysmorphic features coarse facial features that are present at birth GM1 gangliosidosis or develop in the first years of life mucopolysaccharidosis ; ophthalmological, bone, joint and central nervous system CNS involvement.

Table 2 4 lists lysosomal disorders. Peroxisomal Biogenesis Disorders. Involving many anabolic functions. These include the biosynthesis of plasmalogen, which is a major myelin component, cholesterol and bile acids. Generalized peroxisomal b-oxidation deficiency results in a variety of disturbances that are still not well understood, partly because there is an overlap in function between the peroxisomes and other organelles such as the mitochondria and the endoplasmic reticulum.

These multiple and complex biochemical abnormalities result in specific defects of neuronal migration with malformations and severe neurologic dysfunction, hypotonia, mental retardation and developmental regression.

In contrast to lysosomal disorders, there is no intracellular accumulation of undigested polymers. A useful marker for their diagnosis is the accumulation of very long chain fatty acids in plasma, such as X-linked adrenoleukodystrophy "Lorenzo's oil disease". Table 2 4 lists the diseases in this group. Defects In Intracellular Transport.

Involving defects in intracellular transport and protein processing. This group includes a1-antitrypsin deficiency and carbohydrate-deficient glycoprotein syndrome.

Inborn errors of intermediary metabolism leading to acute and recurrent intoxication metabolic acidosis, vomiting, lethargy, dehydration, thromboembolic complications or chronic and progressive intoxication developmental delay or ectopia lentis from the accumulation of toxic compounds proximal to the metabolic block. In this group are the aminoacidopathies, organic acidurias, urea cycle defects and sugar intolerance.

The main characteristics of this group are the existence of periods free from symptoms and the relationship with alimentary ingestion. The clinical expression is late-starting, intermittent or related to the introduction of the noxious substratum. Table 3 4 lists the diseases in this group. Energy deficiency diseases. The symptoms are at least partially caused by deficiency in energy production or utilization resulting from defects in intermediary metabolism in the liver, myocardium, muscles or brain.

This group includes glycogenosis, glyconeogenesis defects, congenital lactic acidemias, fatty acid oxidation defects and mitochondrial diseases. The diseases of this group present overlapping clinical manifestations that may result in the accumulation of toxic components or deficiency in energy production.

The common symptoms include hypoglycemia, hyperlacticemia, severe generalized hypotonia, myopathy, cardiomyopathy, growth retardation, cardiac failure, circulatory collapse and sudden infant death syndrome.

Congenital malformations indicating abnormal processes in fetal energy pathways are also in this group, as observed in pyruvate dehydrogenase complex deficiency. Table 4 4 lists the diseases in this group. The clinical findings for patients with HMD presenting life-threatening acute metabolic crises are nonspecific and include poor feeding, vomiting, dehydration, lethargy, hypotonia and seizures.

This picture is similar to that of septicemia, which may also be present, since IEM predisposes to infectious conditions. When a child with undiagnosed HMD dies, this fact is attributed in general only to the sepsis, resulting in an error of diagnosis. The autopsy findings in such cases are frequently nonspecific, not allowing for the diagnosis of a HMD. There are some symptoms that are unusual in HMD, like the case of inspiratory stridor in an month-old boy 16 that became progressively worse over a period of 4 weeks, needing assisted ventilation.

Ethylmalonic-adipic aciduria was diagnosed, a mild variant of multiple acyl-CoA dehydrogenation. The child greatly improved with riboflavin supplementation. The authors suggest research into organic aciduria in the presence of unexplained laryngeal stridor. Among the clinical findings of HMD there are descriptions of dysmorphic features present at birth, 18 generally when fetal energy is affected, 2,5 or developed during the first years of life as in lysosomal diseases.

Clinical experience of HMD has shown that when we have difficult or peculiar cases that cannot be explained by known disease physiopathologies, we should think of IEM as an etiology, because there is probably a very large variety of symptoms beyond those that have been described.

When we talk about the clinical picture of HMD, it is always in a general way, because within one disorder there is individual variation in symptoms and severity.

Table 5 3,6 lists clues suggesting an IEM and Table 6 lists frequent signs and symptoms in neonates and infants. The clinical manifestations of IEM are not limited to childhood and adolescence: they can also appear in adult life.

Pregnant mothers with phenylketonuria face problems in that they need rigorous diet control so as not to affect the fetus. However, these levels are sufficiently elevated during pregnancy to provoke microcephaly or mental retardation in the fetus, and so these women also are going to need diet control.

Therapeutic progress in glycogen storage disease, especially after uncooked cornstarch therapy, 34 has decreased the need for hepatic transplantation and consequently the numbers of individuals that survive until adult life have been increasing. In addition to cases of individuals detected in the neonatal or childhood periods such that they can reach adult life, as described above, there is HMD that is only diagnosed in adult life. This may occur because of one of the following reasons:.

Mild clinical manifestations in childhood and adolescence. Examples: propionic acidemia in a boy that had vomiting in childhood for days, improved with fasting at home without medical attendance and in adult life presented chorea and progressive dementia; 37 patients with hereditary fructose intolerance who developed an aversion to sweet food, then spending the whole life without symptoms until fructose-containing solutions were used during a surgery, when the patient had a severe metabolic crisis; hyperammonemia episodes, even fatal, especially in women receiving protein overload or under stress, as in childbirth, because they are carriers of the ornithine transcarbamylase OTC mutation, a urea cycle defect of X-linked inheritance; hyperammonemia coma in two young siblings with lysinuric protein intolerance, both having been underweight with intermittent gastrointestinal symptoms.

Diseases with clinical manifestation at the onset of adulthood. Table 7 lists the more common signs and symptoms of adult-onsetting IEM. These methods are not very widely available, especially in our country.

Such tests are however only suitable when there is a strong and more specific suspicion of IEM diagnosis. In fact, what is more important than the exact tests for the HMD diagnosis is the clinical judgement capable of leading towards a probably safe diagnosis via identifying the group that the disease belongs to. A lot of information can be gained from the history, physical examination, and more commonly available laboratory tests, allowing the treatment to be started as soon as possible, when such therapeutic treatment exists.

The initial laboratory evaluation suggested in the HMD literature varies in relation to the number and type of tests and it is generally accomplished in a progressive way, according to the results that are to be obtained, as indicated below.

Urine tests for IEM are not done very much in major diagnosis centers, although they are still of great importance for small laboratories and in countries where higher technical sophistication is not available. Some tests are not specific, but a positive test can direct the investigator towards one or more specific tests.

Looking at and smelling urine samples should be routine practice for good metabolism laboratories and Table 9 lists some peculiar urine odors. The investigation of organic acids in urine chromatography, mass spectrometry 91 and plasma amino acid analysis 92 are requested in accordance with clinical and laboratory indications.

The blood tests ,10,18,86 include complete blood count, blood gases, blood electrolytes Na, K, Cl, P, Ca , lactate, glucose, ammonia, liver function testing, cholesterol, triglycerides, pyruvate, urea, creatinine and uric acid. Magnetic resonance imaging of the CNS is generally superior to computed tomography in HMD, allowing evaluation of the demyelination that is frequent in these diseases.

Electroencephalography, electroretinography, electromyography, cerebrospinal fluid analysis and evoked potential are indicated in specific cases. The study of cells and tissues obtained via biopsy has been particularly useful in the characterization of many IEM: in the storage diseases, establishing the nature of the accumulated material; in diseases producing alterations in the organelles such as mitochondria or peroxisomes, performing morphologic studies; and in diseases with tissue markers suggestive of metabolic diseases.

Advances in inborn errors of metabolism

CONTEXT: Inborn errors of metabolism cause hereditary metabolic diseases HMD and classically they result from the lack of activity of one or more specific enzymes or defects in the transportation of proteins. Clinical cases are presented with the peculiar symptoms of various diseases. This review includes inheritance patterns and clinical and laboratory findings of the more common IEM diseases within a clinical classification that give a general idea about these disorders. A summary of treatment types for metabolic inherited diseases is given. They are also to be found in neurological, pediatric, obstetrics, surgical and psychiatric clinics seeking diagnoses, prognoses and therapeutic or supportive treatment. Key words: Inborn errors of metabolism.


Essential resource in the interdisciplinary field of inborn metabolic diseases Included format: EPUB, PDF; ebooks can be used on all reading devices.


Ebook: Metabolic Diseases

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Inborn errors of metabolism are rare diseases caused by defects of single genes, which code for enzymes that facilitate the conversion of substrates into metabolites.

It seems that you're in Germany. We have a dedicated site for Germany. Editors: Fernandes , J. Since the publication of the first edition sixteen years ago, Inborn Metabolic Diseases — Diagnosis and Treatment has become a classic textbook, indispensable for those involved in the care of children and adults with inborn errors of metabolism, including pediatricians, biochemists, die- th cians, neurologists, internists, geneticists, psychologists, nurses, and social workers. This new 4 edition has been extensively revised.

Inherited Metabolic Disorders

The Spanish Association of Pediatrics has as one of its main objectives the dissemination of rigorous and updated scientific information on the different areas of pediatrics. Annals of Pediatrics is the Body of Scientific Expression of the Association and is the vehicle through which members communicate. The Impact Factor measures the average number of citations received in a particular year by papers published in the journal during the two receding years. CiteScore measures average citations received per document published. Read more.

Some conditions can damage cell development and brain function. Inherited metabolic disorders are also known as hereditary metabolic disorders and inborn errors of metabolism. Metabolism refers to chemical processes that occur in the body. Your body needs these processes to sustain life. Inherited metabolic disorders occur when abnormal chemical reactions interfere with these processes. Some inherited metabolic disorders can be detected before birth, or at birth during a routine physical exam.


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