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Protein-dependent inborn errors of metabolism 

Protein-dependent inborn errors of metabolism

Protein-dependent inborn errors of metabolism

Georg F. Hoffmann

and Stefan Kölker


July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.


3-methylglutaconic acidurias—expanded discussion to reflect the increasing number of underlying defects that are recognized, with use of new nomenclature specifying syndrome and affected gene.

D-2-Hydroxyglutaric aciduria type 2—revised description of clinical presentation.

Combined D-2-and L-2-Hydroxyglutaric aciduria—description of this newly recognized condition.

Updated on 27 Feb 2014. The previous version of this content can be found here.
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date: 30 March 2017

Protein-dependent inborn errors of metabolism are caused by inherited enzyme defects of catabolic pathways or intracellular transport of amino acids. Most result in an accumulation of metabolites upstream of the defective enzyme (amino acids and/or ammonia), causing intoxication.

Protein-dependent metabolic diseases usually have a low prevalence except for some high-risk communities with high consanguinity rates. However, the cumulative prevalence of these disorders is considerable (i.e. at least >1:2000 newborns) and represents an important challenge for all public health systems.

Types of protein-dependent inborn errors of metabolism

Amino acid disorders—enzyme deficiencies in the proximal part of amino acid catabolism result in accumulation of precursor amino acids which are detectable by ninhydrin (a chemical used to detect ammonia or primary and secondary amines) and thus are called amino acid disorders. Phenylketonuria (PKU) is the most frequent such condition in white people.

Organic acid disorders—distal enzyme defects of amino acid degradation result in pathological accumulation of organic acids but not the precursor amino acid. These disorders became detectable after the introduction of gas chromatography–mass spectrometry (GC/MS) and are called organic acid disorders.

Urea cycle defects—breakdown of amino acids results in the release of ammonia that is detoxified by the urea cycle, which is composed of five catalytic enzymes, a cofactor producer, and at least two transport proteins. The biochemical hallmark of urea cycle defects is hyperammonaemia.

Understanding of the protein-dependent inborn errors is based on the observation that some pathological metabolites impair key intracellular functions, such as energy metabolism, and thus when elevated may become toxic. These metabolites are excreted by urine or following conjugation to l-carnitine or l-glycine. However, in some diseases, such as disorders of tetrahydrobiopterin (BH4) metabolism, clinical symptoms result from inadequate production of essential metabolites, such as the monoaminergic neurotransmitters.

Clinical presentation

Children with inherited disorders of amino acid, organic acid, or the urea cycle are usually born at term after an uneventful pregnancy and are initially asymptomatic. The onset of the first symptoms is varied, ranging from neonatal metabolic decompensation to onset of symptoms during adulthood. Irreversible organ damage and/or early death often follow if the diagnosis is delayed or missed. Metabolic decompensations in childhood are triggered by excess intake of protein and—most importantly—secondary to breakdown of body protein during episodes that induce catabolism.

Family history—if carefully taken, this may reveal important clues to the diagnosis of protein-dependent inborn metabolic errors. Most disorders are inherited as autosomal recessive traits, which may be suspected if the parents are consanguineous or the family has a confined ethnic or geographic background. Carriers for particular disorders and affected children may be more frequent in certain communities (e.g. Amish), ethnic groups (e.g. Ashkenazi Jews, Arabic tribes), or countries that have seen little immigration over many centuries (e.g. Finland). Specialist investigations are often started only after a second affected child is born into a family: older siblings may be found to suffer from a similar disorder as the index patient or have died from an acute unexplained disease.

Disease spectrum—this is broad, but follows a distinct pattern in specific disorders, for instance: (1) Untreated patients with classical PKU and cerebral organic acid disorders characteristically present with neurological symptoms. (2) Acute life-threatening decompensation is common in classical organic acid and urea cycle defects and maple syrup urine disorder; the young infant vomits or refuses to feed and then deteriorates rapidly. (3) Asymptomatic protein-dependent inborn metabolic errors are rare, but there are a few known enzyme defects, such as histidinaemia, which do not produce disease.

Investigation and management

Every infant presenting with symptoms of unexplained metabolic crisis, intoxication, or encephalopathy requires urgent evaluation of metabolic parameters, including analyses of arterial blood gases, serum glucose and lactate, plasma ammonia and amino acids, acylcarnitine profiling in dried blood spots, and organic acid analysis in urine.

Acute emergency therapy—basic principles are to (1) suppress muscle and liver protein catabolism and ensure a glucose supply above the basal metabolic demand; (2) treat the precipitating illness; (3) reduce increased production of toxic metabolites by reduction or omission of natural protein; (4) enhance detoxifying mechanisms and urinary excretion of pathological metabolites; (5) aggressively treat dehydration and acidosis; (6) prevent secondary carnitine depletion; (7) provide alternative routes of ammonia disposal in hyperammonaemia.

Long-term treatment—this aims principally to mitigate the metabolic consequences of enzyme deficiencies by compensating for them, including: (1) reduction of toxic metabolites by dietary restriction of precursor amino acids, prevention of catabolism, stimulation of residual enzyme activity and detoxification strategies; and (2) substitution with depleted substrates, such as biotin, cobalamin, or l-dopa. However, efficacy is often low in patients in whom diagnosis is made after the onset of symptoms, hence newborn screening programmes have been introduced in many countries, the criteria for implementation of which include: (1) reliable presymptomatic disease detection, (2) treatability of the disease, and (3) starting of treatment in presymptomatic children.

Successful treatment of affected individuals is often difficult to achieve. Careful supervision in metabolic centres involving an experienced multidisciplinary team is invaluable for the best outcome. Treatment is time- and cost-intensive, often lifelong, and mostly performed at home, hence regular training and support of patients and their families is essential to prevent irreversible complications. All patients should carry an emergency card that gives details of their condition and relevant contact numbers. Parent and patient organizations can offer useful support.

Detailed description of individual disorders is to be found in the text of this chapter, and further information on diagnosis, genetic testing, treatment and follow-up is available from several online databases (see ‘Further reading’).

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