Inborn Error Of Metabolism

Download 0.84 Mb.
Date conversion28.06.2018
Size0.84 Mb.
  1   2   3   4   5
Inborn Error Of Metabolism
Many childhood conditions are caused by single gene mutations that encode specific proteins. These mutations can result in the alteration of primary protein structure or the amount of protein synthesized. The function of a protein, whether it is an enzyme, receptor, transport vehicle, membrane, or structural element, may be relatively or seriously compromised. These hereditary biochemical disorders are also termed inborn errors of metabolism or inherited metabolic

So inborn error of metabolism are a large group of hereditary biochemical diseases in which specific gene mutation cause abnormal or missing proteins that lead to alter function

Although individually rare, inborn errors of metabolism are an important cause of pediatric morbidity and mortality.

Single gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, or fats.

Most are due to a defect in an enzyme or transport protein, which results in a block in a metabolic pathway.

Effects are due to toxic accumulations of substrates before the block and by a deficiency of products beyond the block, or a combination of these metabolic deviations.

Common Characteristics of Genetic Disorders of Metabolism
Although the manifestations of genetic metabolic disorders are quite variable, the following features are shared among most of these conditions:



The affected infant is normal at birth and becomes symptomatic later on in life. This differentiates these infants from those who appear sick at birth due to birth trauma, intrauterine insults, chromosomal abnormalities or other genetic diseases.



The nature of the mutation that causes the dysfunction of the gene usually varies from family to family. This results in variation in severity of the phenotype in different families.



Mutations causing severe malfunction of the gene or its product result in clinical manifestations shortly after birth. In general, the earlier the appearance of clinical symptoms the more severe is the disease.



The majority of conditions are inherited as autosomal recessive traits. Therefore, a history of consanguinity in the parents or of an unexplained death in the neonatal period may raise the question of an inherited metabolic disease in the sick infant.



Most of the genetic metabolic conditions can be controlled successfully by some form of therapy, and a few can be potentially cured by the use of bone marrow or liver transplants. These patients can have a normal life if diagnosed and treated early, before irreversible damage to organs, especially to the brain, occurs. This underlines the importance of early diagnosis, which can be achieved through screening of all newborn infants.

An inborn error of metabolism may be suspected before birth from a positive family history or previous unexplained deaths in the family.

After birth, inborn errors of metabolism usually, but not invariably, present in one of five ways:

  • As a result of newborn screening, e.g. phenylketonuria (PKU), or family screening, e.g. familial hypercholesterolaemia

  • After a short period of apparent normality, with a severe neonatal illness with poor feeding, vomiting, encephalopathy, acidosis, coma and death, e.g. organic acid or urea cycle disorders

  • As an infant or older child with an illness similar to that described above but with hypoglycaemia as a prominent feature or as an ALTE (acute life-threatening episode) or near-miss 'cot death',

  • In older children it should be considered in any child with one or more of the following manifestations:

a. unexplained mental retardation, developmental delay, motor deficits or convulsions.

b. unusual odor particularly during an acute illness

c. intermittent episodes of unexplained vomiting, acidosis, mental retardation or coma.

d. hepatomegaly.

e. renal stones.

  • In a subacute way, after a period of normal development, with regression, organomegaly and coarse facies, or As a dysmorphic syndrome.

Mass Screening of Newborn Infants

Common characteristics of genetic metabolic conditions make a strong argument for screening all newborn infants for the presence of these conditions. During the past half-century, methods have been developed to screen all infants inexpensively with accurate and fast-yielding results. Tandem mass spectrometry (MS/MS) is the latest technical advance in the field. These tests are done on a spot of blood from a heel-prick collected onto a filter paper and mailed to a central laboratory for assay


The majority of patients with genetic disorders of metabolism respond to one or all of the following treatments:



Special diets play an important role in the treatment of affected children. Dietary changes should be tailored to the pathophysiology of the condition and vary greatly among disorders.



Peritoneal dialysis or hemodialysis for expeditious removal of accumulated noxious compounds. This is a very effective modality for treatment of the acute phase of the condition.



Administration of the deficient metabolite.



Administration of the deficient enzyme.



Administration of the cofactor or coenzyme to maximize the residual enzyme activity.



Activation of alternate pathways to reduce the noxious compounds accumulated because of the genetic mutation.



Bone marrow transplantation.



Liver transplantation.

The last two modalities have the potential to cure the metabolic abnormalities. Replacement of the mutant gene with a normal one (gene therapy) is still in the experimental phase.

Treatment of genetic disorders of metabolism is complex and requires medical and technical expertise. The therapeutic regimen often needs to be tailored to the individual patient because of large phenotypic variations in the severity of the disease, even within a single family. Providing education and support for the family is the key to successful long range therapy. Effective treatment is best achieved by a team of specialists (physician specialist, nutritionist, geneticist, neurologist, and psychologist) in a major medical center.
Defects in Metabolism of Amino Acids


This occurs in 1 in 10 000-15 000 live births in the UK. It is either due to a deficiency of the enzyme phenylalanine hydroxylase (classical PKU) or in the synthesis or recycling of the biopterin cofactor for this enzyme.


This is due to cystathionine synthetase deficiency. Presentation is with developmental delay and eventually subluxation of the ocular lens (ectopia lentis). There is progressive learning difficulty, psychiatric disorders and convulsions. Skeletal manifestations resemble Marfan syndrome. The complexion is usually fair with brittle hair. Thromboembolic episodes may occur at any age. Almost half respond to large doses of the coenzyme pyridoxine. Those who do not respond are treated with a low-methionine diet supplemented with cysteine and with the addition of the re-methylating agent betaine.

Defects in Metabolism of Carbohydrates


This rare, recessively inherited disorder results from deficiency of the enzyme galactose-1-phosphate uridyltransferase, which is essential for galactose metabolism. When lactose-containing milk feeds such as breast or infant formula are introduced, affected infants feed poorly, vomit and develop jaundice, hypoglycemia and hepatomegaly and hepatic failure there is increase risk of sepsis by E.coli. Chronic liver disease, cataracts and developmental delay are inevitable if the condition is untreated. Even if treated early, there are usually moderate learning difficulties (adult IQ 60-80).


- positive reducing substance in urine (galactose)

- elevated level of galactose in the blood (during neonatal screening)

- enzyme assay in blood sample

Management is with a lactose- and galactose-free diet for life.

  1   2   3   4   5

The database is protected by copyright © 2016
send message

    Main page