Chapter 7 Disorders of metabolism and homeostasis
INBORN ERRORS OF METABOLISM
Inborn errors of metabolism are single-gene defects resulting in the absence or deficiency of an enzyme or the synthesis of a defective protein. Single-gene defects occur in about 1% of all births, but the diseases caused by them show geographic variations in incidence; this is exemplified by the high incidence of thalassaemias—due to defects in haemoglobin synthesis (Ch. 23)—in Mediterranean regions. These variations reflect the prevalence of specific abnormal genes in different populations.
Inborn errors of metabolism have four possible consequences:
The genetic basis of the inheritance of these disorders is discussed in Chapter 3.
Disorders of carbohydrate metabolism
The commonest disorder of carbohydrate metabolism with an inherited component in its aetiology is diabetes mellitus (see p. 128). Much less common, but with an autosomal recessive pattern of inheritance and often presenting at an early age, are:
Disorders of amino acid metabolism
Several inherited disorders of amino acid metabolism involve defects of enzymes in the phenylalanine/tyrosine pathway (Fig. 7.1).
Phenylketonuria
This autosomal recessive disorder affects approximately 1 in 10000 infants. It is due to a deficiency of phenylalanine hydroxylase, an enzyme responsible for the conversion of phenylalanine to tyrosine (Fig. 7.1).
Alkaptonuria
This rare autosomal recessive deficiency of homogentisic acid oxidase (Fig. 7.1) is a good example of an inborn metabolic error that does not produce serious effects until adult life. The condition is sometimes recognised from the observation that the patient’s urine darkens on standing; the sweat may also be black! Homogentisic acid accumulates in connective tissues, principally cartilage, where the darkening is called ochronosis. This accumulation causes joint damage. The underlying condition cannot be cured; treatment is symptomatic only.
Homocystinuria
Like most inherited disorders of metabolism, homocystinuria is an autosomal recessive disorder. There is a deficiency of cystathionine synthase, an enzyme required for the conversion of homocystine via homocysteine to cystathionine. Homocysteine and methionine, its precursor, accumulate in the blood. Homocystine also accumulates, interfering with the cross-linking of collagen and elastic fibres. The ultimate effect resembles Marfan’s syndrome (see p. 128), but also with mental retardation and fits.
Storage disorders
Inborn metabolic defects result in storage disorders if a deficiency of an enzyme, usually lysosomal, prevents the normal conversion of a macromolecule (e.g. glycogen or gangliosides) into its smaller subunits (e.g. glucose or fatty acids). The macromolecule accumulates within the cells that normally harbour it, swelling their cytoplasm (Fig. 7.2) and causing organ enlargement and deformities. This situation is harmful to the patient because the swelling of cells often impairs their function, or that of their immediate neighbours due to pressure effects, and because of conditions resulting from deficiency of the smaller subunits (e.g. hypoglycaemia in the case of glycogen storage disorders).
Major categories of these autosomal recessive disorders (Table 7.1) are:
Type of disease/examples | Deficiency | Consequences |
---|---|---|
Glycogenoses | Debranching enzyme | |
McCardle’s syndrome | Muscle phosphorylase | |
von Gierke’s disease | Glucose-6-phosphate dehydrogenase | |
Pompe’s disease | Acid maltase | |
Mucopolysaccharidoses | Lysosomal hydrolase | |
Hurler’s syndrome | Alpha-l-iduronidase | |
Hunter’s syndrome | Iduronate sulphate sulphatase | |
Sphingolipidoses | Lysosomal enzyme | |
Gaucher’s disease | Glucocerebrosidase | |
Niemann–Pick disease | Sphingomyelinase | |
Tay–Sachs disease | Hexosaminidase A |
Disorders of cell membrane transport
Inborn metabolic errors can lead to impairment of the specific transport of substances across cell membranes. Examples include:
Channelopathies
Cystic fibrosis
Cystic fibrosis transmembrane conductance regulator (CFTR)
The commonest abnormality (ΔF508) in the CFTR gene is a deletion resulting in a missing phenylalanine molecule. The defective CFTR is unresponsive to cyclic AMP control, so transport of chloride ions and water across epithelial cell membranes becomes impaired (Fig. 7.3).
Diagnosis
The diagnosis can be confirmed by measuring the sodium concentration in the sweat; in affected children it is usually greater than 70 mmol/l. Pregnancies at risk can be screened by prenatal testing of chorionic villus biopsy tissue for the defective CFTR gene.
Porphyrias
The porphyrias, transmitted as autosomal dominant disorders, are due to defective synthesis of haem, an iron–porphyrin complex, the oxygen-carrying moiety of haemoglobin. Haem is synthesised from 5-aminolaevulinic acid. The different types of porphyrin accumulate due to inherited defects in this synthetic pathway (Fig. 7.4).
Clinicopathological features
Accumulation of porphyrins can cause clinical syndromes characterised by:
Acute attacks of porphyria can be precipitated by some drugs, alcohol and hormonal changes (e.g. during the menstrual cycle). The most frequently incriminated drugs include barbiturates, sulphonamides, oral contraceptives and anticonvulsants; these should therefore be avoided.
Disorders of connective tissue metabolism
Osteogenesis imperfecta
Osteogenesis imperfecta is a group of disorders in which there is an inborn error of type I collagen synthesis (Ch. 25). Type I collagen is most abundant in bone, so the principal manifestation is skeletal weakness resulting in deformities and a susceptibility to fractures; the other names for this condition are ‘fragilitas ossium’ and ‘brittle bone disease’. The teeth are also affected and the sclerae of the eyes are abnormally thin, causing them to appear blue. It occurs in dominantly and recessively inherited forms with varying degrees of severity.
Marfan’s syndrome
Marfan’s syndrome is a combination of unusually tall stature, long arm span, dislocation of the lenses of the eyes, aortic and mitral valve incompetence, and weakness of the aortic media predisposing to dissecting aneurysms (Ch. 13). The condition results from a defect in the FBN1 gene encoding for fibrillin, a glycoprotein essential for the formation and integrity of elastic fibres.
ACQUIRED METABOLIC DISORDERS
Diabetes mellitus
Complications of diabetes mellitus
Gout
Gout is a common disorder resulting from high blood uric acid levels. Uric acid is a breakdown product of the body’s purine (nucleic acid) metabolism (Fig. 7.5), but a small proportion comes from the diet. Most uric acid is excreted by the kidneys. In the blood, most uric acid is in the form of monosodium urate. In patients with gout, the monosodium urate concentration may be very high, forming a supersaturated solution, thus risking urate crystal deposition in tissues causing:
Gout occurs more commonly in men than in women, and is rare before puberty. A rare form of gout in children—Lesch–Nyhan syndrome—is due to absence of the enzyme HGPRT (hypoxanthine guanine phosphoribosyl transferase) (Fig. 7.5) and is associated with mental deficiency and a bizarre tendency to self-mutilation.
Clinicopathological features
The clinical features of gout are due to urate crystal deposition in various tissues (Fig. 7.6). In joints, a painful acute arthritis results from phagocytosis of the crystals by neutrophil polymorphs, in turn causing release of lysosomal enzymes along with the indigestible crystals, thus accelerating and perpetuating a cyclical inflammatory reaction. The first metatarsophalangeal joint is typically affected.
Water homeostasis
Water and electrolyte homeostasis is tightly controlled by various hormones, including antidiuretic hormone (ADH), aldosterone and atrial natriuretic peptide, acting upon selective reabsorption in the renal tubules (Ch. 21). The process is influenced by the dietary intake of water and electrolytes (in food or drinking in response to thirst or social purposes) and the adjustments necessary to cope with disease or adverse environmental conditions.
Dehydration
Excessive water loss can be due to:
Dehydration is recognised clinically by a dry mouth, inelastic skin and, in extreme cases, sunken eyes. The blood haematocrit (proportion of the blood volume occupied by cells) will be elevated, causing an increase in whole blood viscosity. This results in a sluggish circulation and consequent impairment of the function of many organs.