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Inherited Metabolic Disorders


Inherited defects in the make up of enzymes, receptors, transporters and structural proteins can all contribute to the rise of metabolic disorders. These disorders can arise from single mistakes in a gene and if not dealt with quickly, can prove fatal. Because of this, many are tested for at birth or shortly after and such disorders are now commonly known as congenital metabolic diseases or inherited metabolic diseases.

There are around 200 known inborn errors of metabolism where an enzyme defect is responsible for a resulting condition and at least 100 more where a non-enzymic protein is defective.

Phenotypic Analysis

Newborn Testing

Routine phenotypic screening of newborn infants was first introduced in the 1960s and is now standard practice in many countries. In the USA, there are round 30 core disorders tested for at birth (as recommended by the American College of Medical Genetics) with almost as many secondary targets tested for. Of these 60 or so disorders which are routinely checked for, around 90% are errors in metabolism.

It is a standard practice in many countries to check for the disorders phenylketonuria (the lack of working phenylalanine hydroxylase enzymes which prevents breakdown of phenylalanine) and hypothyroidism (the thyroid gland doesn’t produce enough thyroid hormone).

The introduction of Tandem Mass Spectrometry in the 1990s made it possible to easily test for multiple, potential congenital metabolic diseases at once. This meant that phenylketonuria and hypothyroidism could be checked for, along with the other core and secondary target disorders, all from one blood sample.

Considering a Disorder for Mass Screening

Although in most cases, it is beneficial to diagnose a disorder, such as a metabolic disorder, in a mass screening program, there are a few conditions which must first be met. For example if the disease is rare, and treatment cheap, the cost of implementing a mass screening program may be more expensive than treating the disorder as it arises in patients. Such an attitude of course raises ethical questions.

Typically for a condition to be introduced into a mass screening program, it must meet these criteria:

  • Occurs relatively frequently in the population and its effects are severe enough to be a public health concern
  • It should produce a known, detectable range of symptoms
  • The screening test should have high specificity and sensitivity (low false negatives/positives) and should be simple and reliable
  • The disorder should be treatable
  • The cost:benefit ratio should be positive

Screening Practice

Before screening, parents should be aware of the consequences to their child of the possible disorders which may be found during screening. Educational material on living with the disorders should also be available. Parents must also provide consent for testing.

Screening of every newborn should be the reality and is generally the case. Only <1% of infants are not screened, this could be due to early discharge of infant, lack of consent, births out of hospital, etc.

The timing of screening is critical. All tests are performed between 24 hours after normal protein and lactose feeding and 72 hours after birth. Any later than 72 hours and some disorders can become difficult to treat, any earlier than 24 hours after normal feeding and the accumulation of metabolites associated with a disorder will not be present – the disorder will not be found.

The type of blood sample is also important. Placental cord blood cannot be used as again, accumulation of metabolites associated with disorders will not be present. The blood must come from the infant after the 24 hours time period explained above. Typically, a sample is taken from the heel of the infant.

Genotypic Analysis

Whilst phenotypic analysis requires the disorder to be present in order for it to be identified, genotypic analysis (the analysis of DNA) can be conducted even before conception to identify if parents are carriers of a certain disorder and predict the possible phenotypical severity of a disorder. Genotypic analysis can also be used as a safe alternative for some conditions and preformed prenatally or it can be used to confirm the results of a phenotypical analysis.

Direct Analysis

A direct analysis approach towards genotyping for metabolic disorders requires that the gene responsible for the disorder is known. In direct analysis, the gene has also been characterized and the exact mutation responsible for causing the defect is known.

If the mutation is a major one, consisting of large structural rearrangements, then it can be detected by using Southern Blotting, a molecular blotting technique used to identify specific DNA sequences. However, if the mutation is smaller (such as a single base pair substitution, insertion or deletion) PCR-techniques must be used to identify the mutation.

The main restrictions which prevent genotypic analysis from being used in mass newborn screening programs are; genetic heterogeneity – where it may be difficult to determine a positive test result due to a disorder being characterized by number of allele mutations (not just one i.e. pleiotropy) and spontaneous mutations, whereby novel undocumented mutations arise, which are difficult to find using the above techniques.

Indirect Analysis

In contrast to direct analysis, where the gene and its mutation are known, in indirect analysis the gene responsible for the disorder is unknown (or the gene is known, but the mutation unknown due to large amounts of heterogeneity which prevent direct testing). The presence of the mutation is thus inferred by linkage analysis.

Linkage analysis uses the fact that some alleles are inherited together – genetic linkage. For example, certain loci (the location of an allele on a chromosome) are physically close together, this means during meiosis (where genetic variation is introduced in the gametes) these physically close loci remain together i.e. they are genetically linked. Therefore an unknown gene responsible for a metabolic disorder may be genetically linked to another detectable gene – the presence of the mutated gene can be inferred by the detectable gene.

If the gene responsible for the disorder is known (but mutations are too heterogenous for direct analysis) then restriction fragment length polymorphisms (RFLPs) analysis can be used. RFLP analysis is a DNA profiling technique which, by fragmenting DNA, allows (amongst other things) the localization of genes involved in genetic disorders.

Examples of Newborn Metabolic Disorders

(Adapted from Raghuveer,T.S. 2006)



Metabolic error

Key manifestation

Therapy approach

Amino acid metabolism


1:15,000 Phenylalanine hydroxylase (> 98 percent) Mental retardation, acquired microcephaly Diet low in phenylalanine hydroxylase
Biopterin metabolic defects (< 2 percent)
Maple syrup urine disease 1:150,000 (1:1,000 in Mennonites) Branched-chain 3-keto acid dehydrogenase Acute encephalopathy, metabolic acidosis, mental retardation Restriction of dietary branched-chain amino acids

Carbohydrate metabolism


1:40,000 Galactose 1-phosphate uridyltransferase (most common); galactokinase; epimerase Hepatocellular dysfunction, cataracts Lactose-free diet
Glycogen storage disease, type Ia (von Gierke’s disease) 1:100,000 Glucose-6-phosphatase Hypoglycemia, lactic acidosis, ketosis Corn starch and continuous overnight feeds

Fatty acid oxidation

Medium-chain acyl-CoA dehydrogenase deficiency

1:15,000 Medium-chain acyl-CoA dehydrogenase Nonketotic hypoglycemia, acute encephalopathy, coma, sudden infant death Avoid hypoglycemia, avoid fasting

Lactic acidemia

Pyruvate dehydrogenase deficiency

1:200,000 E1 subunit defect most common Hypotonia, psychomotor retardation, failure to thrive, seizures, lactic acidosis Correct acidosis; high-fat, low-carbohydrate diet

Lysosomal storage

Gaucher’s disease

1:60,000; type 1–1:900 in Ashkenazi Jews β-glucocerebrosidase Coarse facial features, hepatosplenomegaly Enzyme therapy, bone marrow transplant
Fabry’s disease 1:80,000 to 1:117,000 α-galactosidase A Acroparesthesias, angiokeratomas hypohidrosis, corneal opacities, renal insufficiency Enzyme replacement therapy
Hurler’s syndrome 1:100,000 α-L-iduronidase Coarse facial features, hepatosplenomegaly Bone marrow transplant

Organic aciduria


1:20,000 Methylmalonyl-CoA mutase, cobalamin metabolism Acute encephalopathy, metabolic acidosis, hyperammonemia Sodium bicarbonate, carnitine, vitamin B12, low-protein diet, liver transplant
Propionic aciduria 1:50,000 Propionyl-CoA carboxylase Metabolic acidosis, hyperammonemia Dialysis, bicarbonate, sodium benzoate, carnitine, low-protein diet, liver transplant


Zellweger syndrome 1:50,000 Peroxisome membrane protein Hypotonia, seizures, liver dysfunction No specific treatment available

Urea cycle

Ornithine transcarbamylase deficiency

1:70,000 Ornithine transcarbamylase Acute encephalopathy Sodium benzoate, arginine, low-protein diet, essential amino acids; dialysis in acute stage


Raghuveer, T.S., Garg, U. & Graf, W.D. 2006, “Inborn errors of metabolism in infancy and early childhood: An update”, American Family Physician, vol. 73, no. 11, pp. 1981-1990.