Inherited disorders of intermediary metabolism – a group-based approach

Urea cycle disorders and inherited hyperammonaemias

Free ammonium derived mostly from amino acid breakdown is a highly neurotoxic metabolite and requires rapid and effective removal. This is achieved by producing water-soluble urea from carbamoyl phosphate (from ammonium and bicarbonate) and the amino group of aspartate in the four-enzyme urea cycle. Depending on the functional severity, disorders that primarily affect ammonium detoxification present with acute or chronic-fluctuating brain dysfunction. In the newborn period, severely affected children after a brief symptom-free interval develop a rapidly progressive encephalopathy with lethargy, hyperventilation, seizures, and coma. Manifestation patterns later in life include acute/episodic or chronic neurologic symptoms. Essential for diagnosis is the determination of blood ammonium in the acute situation (Figure 2). Plasma amino acid analysis usually shows elevated glutamine concentrations and may reveal specific alterations of other amino acids. Treatment includes controlled protein intake, maintenance of an anabolic state, removal of ammonium if necessary by haemodiafiltration, and amino group removal with specific drugs [3]. The most frequent and important urea cycle disorder is ornithine transcarbamylase (OTC) deficiency, which is inherited as an X-linked trait and not only causes mostly severe neonatal hyperammonaemia in boys but may trigger acute lethal metabolic decompensation in previously healthy heterozygous females at any age.

Figure 2

Urea cycle disorders.

Organic acidurias

The group of organic acidurias comprises inherited disorders in the metabolism of CoA-activated carboxylic acids mostly derived from deamination of amino acids [4], [5]. The enzymes involved are usually localized in the mitochondria, and the biochemical disturbance often interferes with energy metabolism. As stated in the name, specific organic acidurias are recognized by urinary organic acid analysis but they also generate specific acylcarnitine patterns (Figure 3). Most of the classical organic acidurias – such as propionic, methylmalonic, and isovaleric aciduria – are caused by enzyme deficiencies in branched-chain amino acid (valine, leucine, and isoleucine) breakdown, and typically manifest as acute or intermittent encephalopathy sometimes associated with other organ damage (e. g. heart, kidney). Basic metabolic tests often show metabolic acidosis with elevated concentrations of ketones, lactate, and ammonium; hypoglycaemia may occur. No systemic metabolic derangement is usually found in the cerebral organic acidurias (e. g. glutaric aciduria) which may show specific neurological symptoms and neuroradiological alterations. Some genetically and biochemically defined organic acidurias can remain asymptomatic throughout life.

Figure 3

Classical organic acidurias.

Aminoacidopathies

Figure 4

Aminoacidopathies.

Breakdown of the 20 proteinogenic amino acids requires a large number of specific enzymes. The initial steps are mostly localized in the cytosol. Deficiencies of these enzymes cause clinical manifestations usually depending on the specific toxicity of the accumulating metabolites. Diagnosis is based on the analysis of plasma amino acids (Figure 4); urinary amino acid analysis is not relevant for the majority of conditions.

1. Most disorders of branched-chain amino acid metabolism are classified as organic acidurias; the main exception is maple syrup urine disease, which causes neonatal or late-onset encephalopathy.

2. The disorders of phenylalanine and tyrosine metabolism include phenylketonuria (PKU, untreated progressive intellectual disability), alkaptonuria (generation of dark pigments, osteoarthritis), and three types of tyrosinaemia. Accumulating metabolites in tyrosinaemia type 1 are highly toxic; their production is prevented by pharmaceutical blockage of an upstream enzyme with the drug nitisinone (NTBC).

3. Disorders of the metabolism of sulphur-containing amino acids (methionine, homocysteine, cysteine) and hydrogen sulphide cause predominately neurological symptoms. S-adenosylmethionin is the most important methyl group donor in cellular metabolism, and its replenishment requires remethylation of homocysteine to methionine linked to the folate cycle. Classical homocystinuria causes a Marfan-like disease.

4. Disorders of serine metabolism are multi-system disorders, in severe cases with prenatal onset (Neu–Laxova syndrome). Non-ketotic hyperglycinaemia caused by the mitochondrial glycine cleavage system is an important epileptic encephalopathy.

5. Disorders affecting the other amino acids (ornithine, proline, and hydroxyproline; lysine, hydroxylysine, and tryptophan; glutamate/glutamine and aspartate/asparagine; and histidine) are mostly rare and cause a wide range of neurological and non-neurological manifestations. Some conditions (such as histidinaemia) remain asymptomatic. Alanine – the amino acid corresponding to pyruvate – is often elevated in mitochondrial disorders.

6. The disorders of amino acid transport include cystinuria, a renal reabsorption deficiency of lysine, arginine, ornithine, and cysteine, responsible for 6–8 % of renal stones in childhood.

Disorders of galactose and fructose metabolism

There are two main nutritive disaccharides: lactose (milk sugar, galactose-glucose disaccharide) and sucrose (table sugar, glucose-fructose disaccharide). Utilization of galactose (Gal) and fructose (Fru) involves phosphorylation at the carbon-1 position; the respective metabolites Gal-1-P and Fru-1-P are toxic particularly for the liver and kidneys. Correspondingly, deficiencies of the enzymes required for Gal-1-P and Fru-1-P processing cause progressive liver and renal dysfunction starting with the intake of the respective disaccharide [8]. Classical galactosaemia becomes manifest with milk feeds after birth and is also an important cause of cataracts; it is detected by analyses of galactose metabolites (Figure 5) and enzyme studies in newborn screening programs. Hereditary fructose intolerance becomes manifest after weaning or upon addition of sucrose/fructose to the diet; there is no specific biochemical analysis, and the diagnosis is made by mutation analysis. Both conditions are treated by removal of the respective carbohydrate from the diet.

Figure 5

Disorders of galactose and fructose metabolism.

Disorders of glycogen metabolism (glycogen storage diseases [GSDs], glycogenoses)

Glycogen, the main storage form of glucose in humans, is particularly abundant in the liver – where it is used for glucose homeostasis – and the muscle – where it is used for the provision of energy during exercise [9], [10]. Enzymes required for glycogen synthesis or release may be ubiquitous or may have two (liver- or muscle-specific) isoforms. Correspondingly, diseases in this group have three prototypic clinical presentations:

1. Liver glycogenoses typically present with hypoglycaemia at the onset of fasting (e. g. 3–4 hours after meals), hepatomegaly and other storage features, growth retardation, and variable other features. The most frequent disease is GSD type 1 (von Gierke). Laboratory analyses in the acute phase show marked lipaemia and elevated triglycerides caused by massive lipolysis, elevated lactate and uric acid, and ketonuria (Figure 6). Treatment is based on frequent meals, slowly resorbed carbohydrates, and continuous nasogastric tube feeding overnight.

2. Muscle glycogenoses frequently cause exercise intolerance, muscle cramps, and myoglobinuria; treatment is mostly symptomatic. GSD type 2 (Pompe) is characterized by severe muscle weakness and cardiomyopathy, which can be treated with enzyme replacement therapy.

3. Mixed/generalized glycogenoses show both liver and muscle manifestations including cardiomyopathy.

Figure 6

Glycogen storage disease type 1.

Other disorders of carbohydrate metabolism

Group-specific clinical presentations based on the function in intermediary metabolism can also be defined for the other disorders of carbohydrate metabolism:

1. Disorders of gluconeogenesis show recurrent hypoglycaemia, elevated lactate, and ketosis. Fructose-1,6-bisphosphatase deficiency, which is close to Glc-6-P in gluconeogenesis, also has marked hepatomegaly and may resemble GSD type 1. Progressive neurodegeneration and severe lactic acidosis are features of enzyme deficiencies closer to the Krebs cycle, such as in pyruvate carboxylase deficiency.

2. Disorders of glycolysis can cause haemolytic anaemia combined with variable neurologic, muscle, and retinal manifestations.

3. The disorders of pentose metabolism include glucose-6-phosphate dehydrogenase deficiency, an X-chromosomal disease with recurrent haemolysis triggered by specific foods (favism), drugs, and other factors, prevalent in malaria regions.

4. Disorders of carbohydrate transmembrane transport and absorption cause a variety of renal, gastrointestinal, neurological, or multi-system manifestations, based on the deficient transport functions.