Atlas of Inherited Metabolic Diseases

William L Nyhan, Georg F Hoffmann

• Éditeur: CRC Press
• Année: 2020
• ISBN:
  9781138196629
• Édition: 4
• Sujet: Medicine
• Sous-sujet: Medical Theory, Practice & Reference

In a field where even experts may find that years have elapsed since they last encountered a child with a given disorder, it is essential for the clinician to have a comprehensive source of practical and highly illustrated information covering the whole spectrum of metabolic disease to refer to.

The content is divided into sections of related disorders, including disorders of amino acid metabolism, lipid storage disorders, and mitochondrial diseases for ease of reference, with an introductory outline where appropriate summarizing the biochemical features and general management issues. Within the sections, each chapter deals with an individual disease, opening with a useful summary of major phenotypic expression including clear and helpful biochemical pathways, identifying for the reader exactly where the defect occurs.

Throughout the book, plentiful photographs, often showing extremely rare disorders, are an invaluable aid to diagnosis.

Key Features

• Fully updated to incorporate all new developments in the field

• Brand new chapters cover methylmalonic aciduria of ACSF3 deficiency, branched chain keto acid dehydrogenase deficiency, serine deficiencies, purine nucleoside phosphorylase deficiency, antiquitin deficiency, and others

• Excellent and detailed clinical descriptions, with numerous valuable hints and suggestions for management

• Helpful explanatory algorithms and decision trees, and high-quality illustrative material including biochemical pathways and an unrivaled photographic collection, which enhance clinical applicability

The fourth edition of this highly regarded book, authored by two of the foremost authorities in pediatric metabolic medicine, continues to provide incomparable insight into the problems associated with metabolic diseases and remains invaluable to pediatricians, geneticists, and general clinicians worldwide.

Part 1

Organic acidemias

1.Introduction to the organic acidemias

2.Propionic acidemia

3.Methylmalonic acidemia

4.Cobalamin C, D, F, G diseases; methylmalonic aciduria and variably homocystinuria

5.The methylmalonic malonic aciduria of deficiency of AcylCoA synthetase (ACSF3)

6.Multiple carboxylase deficiency/holocarboxylase synthetase deficiency

7.Multiple carboxylase deficiency/biotinidase deficiency

8.Isovaleric acidemia

9.Glutaric aciduria (type I)

10.3-MethylcrotonylCoA carboxylase deficiency/3-methylcrotonylglycinuria

11.D-2-hydroxyglutaric (DL-2hydroxygluturic) aciduria

12.L-2-hydroxyglutaric aciduria

13.4-Hydroxybutyric aciduria

1

Introduction to the organic acidemias

The inborn errors of organic acid metabolism represent a spectrum of disorders, most of them relatively recently recognized. Many of them produce life-threatening illness very early in life. They should be suspected in any patient with metabolic acidosis, and certainly when there is an anion gap (Table 1.1). The variety of metabolic pathways involved is indicated in Figure 1.1.

Figure 1.1 Metabolic interrelations of relevance to the organic acidemias. Many of these disorders are characterized by the accumulation of CoA esters. Many present with lactic acidemia.

Table 1.1 Mnemonic for the differential diagnosis of metabolic acidosis with an elevated anion gap (DIMPLES)
D	Diabetic ketoacidosis
I	Inborn error of metabolism, iron, isoniazid
M	Methanol, metformin
P	Paraldehyde, phenformin
L	Lactic acidemia
E	Ethanol, ethylene glycol
S	Salicylates, solvents, strychnine
The mnemonic has been written as “mudpiles” or “mudpies”, including u for uremia, but, in clinical practice, uremia tends to be recognized as early as the acidosis, making this unnecessary; the latter form leaves out lactic acidemia, an important omission. The current form highlights metabolic causes of acidosis.

The classic presentation of the organic acidemias is in infancy, often in the neonatal period, followed by recurrent episodes of metabolic decompensation, usually precipitated by infection. The infant begins vomiting and becomes anorexic. This may be followed by the rapid deep breathing of acidosis. A ketotic odor may be appreciated. There may be rapid progression through lethargy to coma, or there may be convulsions. Hypothermia may be the only manifestation besides failure to feed and lethargy. Further progression is to apnea and, in the absence of intubation and assisted ventilation, death.

Initial laboratory evaluation involves tests that are readily available in most clinical chemistry laboratories. Most important in early discrimination are the electrolytes and the ammonia. Blood gases are often the first data available in a very sick infant. Acidosis and hyperammonemia are indicative of an organic acidemia. In contrast, a patient with a urea cycle defect has hyperammonemia and alkalosis. It is important not to delay treatment of acidosis in the belief that the problem is a urea cycle defect. Hyperammonemia regardless of cause must be treated. Hypocalcemia may be a nonspecific harbinger of metabolic disease. Elevated levels of lactate in the absence of cardiac disease, shock or hypoxemia are often seen in organic acidemias as well as in the lactic acidemias of mitochondrial disease. The blood count is useful in indicating the presence or absence of infection. More important, neutropenia with or without thrombocytopenia or even with pancytopenia is characteristic of organic acidemia.

In the presence of acidosis suggesting organic aciduria, the assays of choice are organic acid analysis of the urine and acylcarnitine profile of the plasma.

A number of the organic acid disorders are on the catabolic pathways for the branched-chain amino acids, or other amino acids, but the site of the enzymatic defect is sufficiently removed from the step at which the amino group is lost so that the amino acids do not accumulate, and thus these disorders are not detected by methods of amino acid analysis. They remained largely unrecognized until the development of methods of detection, particularly gas chromatography-mass spectrometry (GCMS) [1], that were of sufficient generality not to depend on a single functional group for detection. Quantitative organic analysis is an important aspect of this methodology. Tandem mass spectrometry (MS/MS) [2, 3] (Table 1.2) has added another important method of detection of organic acids as their carnitine esters; this methodology has made these diseases subjects for neonatal screening.

Table 1.2 Acylcar...