Inborn errors of metabolism or inherited metabolic diseases comprise a large class of genetic diseases involving disorders of metabolism. In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Their overall incidence is around 1 out of 1000-1400 births. Specific diagnosis is usually difficult due to the presence of non-specific signs and symptoms and the need for sophisticated diagnostic tests. However, adequate neonatal screenings for these disorders coupled with a prompt treatment are certainly very rewarding, improving and extending life in most of these inherited conditions.

Isovaleric Acidaemia (IVA)

IVA occurs when an enzyme, called “isovaleryl-CoA dehydrogenase”, is either missing or not working properly. The job of this enzyme is to help break down a substance called “isovaleryl-CoA”. This substance is the result of leucine (aminoacid) break-down. When a child with IVA ingests food containing leucine, a metabolite called isovaleric acid builds up in the blood and causes problems. Leucine is found in all foods containing protein. If left untreated, many babies die during their first metabolic crisis. In those who survive, repeated episodes of this metabolic crisis can cause brain damage, leading to life-long learning dissability or even mental retardation. In the chronic or intermittent form of this disease, symptoms often start around one year of age. Some children, though, do not have symptoms until later in childhood.

Episodes of metabolic crisis can be trigger by concomitant illnesses, infection, or by eating large amounts of protein. When a child is sick, body protein is broken down for energy. In a child with IVA, protein this can cause high levels of isovaleric acid and results in a metabolic crisis.

Cystic Fibrosis

Cystic fibrosis (CF) is an inherited condition that causes problems with lung function, and also, often, with the GI tract.  CF causes thick, sticky mucus and fluids to build up in certain organs in the body, especially the lungs and pancreas. When glands and organs in the body become blocked, their normal functions slow down or stop working well.  This results in chronic health problems. 

In people with CF, the thickened mucus that lines the lungs and bronchioles can lead to repeated lung infections.  In people who do not have CF, thin slippery mucus normally lines the nose and the tubes leading to the lungs.  This mucus has the job of picking up bacteria, viruses and dirt from the air we breathe and moving them up and out of the lungs.  The thick, sticky mucus found in people with CF can no longer do this job well.  CF also reduces the immune cells’ ability to fight infections.  People with CF develop chronic coughing and recurrent lung infections. 

In addition to lung problems, many children with CF also have pancreatic insufficiency. The pancreas is an organ behind the stomach.  One of its jobs is to make special digestive enzymes that break down the food we eat into nutrients small enough to get into the blood.  If the pancreas is blocked, the enzymes cannot get to the small intestine to do their job.  Without digestive enzymes, food in the small intestine cannot be broken down properly and nutrients cannot be absorbed.  This often leads to poor growth and poor weight gain.  It can also cause sluggishness and anemia. Because fat is not absorbed well, it ends up in the stools and causes them to be bulky, lighter in color and have a stronger odor.


Affecting 1 in 15,000 people worldwide, phenylketonuria (PKU) most commonly occurs when any two of the known approximately 700 loss of function mutations in the gene for PAH (phenylalanine hydroxylase) the hepatic enzyme are inherited by a patient. Without phenylalanine hydroxylase to convert phenylalanine into tyrosine, phenylalanine and its alternative metabolites accumulate to neurotoxic levels in the blood. One of these metabolites, phenylketone, is excreted in the urine giving the condition its name. Untreated PKU results in severe neurological damage including tremors, seizures, and mental retardation. Treated patients may have minor secondary conditions accompanying PKU including mood disorders, minor cognitive defects, early onset osteopenia, and markers of systemic inflammation. Additionally, pregnant women with PKU must maintain very low blood phenylalanine levels (120–360μM) to prevent cardiac and neurological birth defects in their infants (maternal PKU). 

Restriction of dietary phenylalanine is the only effective treatment for all PKU patients. Phenylalanine, an essential amino acid, cannot be removed from the diet and no natural proteins are phenylalanine free.

Tyrosinemia 1

Tyrosinaemia types I, II and III are rare metabolic disorders caused by enzyme deficiencies involving the breakdown of the amino acid tyrosine. Tyrosinaemia type I is the most severe, and if untreated can lead to progressive liver failure, renal tubular dysfunction and risk of hepatocellular carcinoma (tumor of the liver). Clinical symptoms of Tyrosinaemia type II are skin and eye abnormalities, while neurological abnormalities have been reported in type III. Successful treatment is possible with dietary tyrosine and phenylalanine restrictions in all three conditions. Orfadin (nitisinone) is very effective preventing the accumulation of toxic substances, improving the natural history of the patients with Type I tyrosinemia.

Maple syrup urine disease (MSUD)

Maple Syrup Urine Disease is an inherited metabolic disorder caused by a deficiency in the body’s ability to properly metabolize the branched-chain amino acids (BCAA) leucine, isoleucine and valine. The disease name originates from the sweet or maple syrup smell of the urine. Delay in starting treatment may result in severe, sometimes fatal, neurological decline. Early diagnosis, combined with long term metabolic control is essential in minimizing neurological impairment and poor intellectual development. Leucine is considered to be the most toxic of the BCAA's and it is present in food in greater concentration than isoleucine or valine. The goal of dietary therapy is to achieve normal plasma concentrations of branched-chain amino acids, especially leucine.

This is accomplished by restricting intake of branched-chain amino acids using commercially available formulas and medical food. Sufficient quantities of these amino acids are provided to support normal growth and intellectual development. Dietary restriction is maintained throughout life. Valine supplements are often needed.

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Methylmalonic Acidemia (MMA)/Propionic Acidemia (PA)

MMA and PA are inherited disorders in which the body is unable to process certain proteins, including methionine, threonine, isoleucine, and valine properly, as well as certain fatty acids from foods. Symptoms such as fatigue, drowsiness vomiting and dehydration typically appear in early infancy. If left untreated, long – term consequences of MMA and PA can result in mental retardation. Dietary management involves a food plan that is low in protein and limited in the amino acids methionine, threonine, isoleucine, and valine.

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Homocystinuria (HCU)

Homocystinuria is an inherited metabolism disorder of the amino acid methionine, resulting in elevated plasma concentration of both methionine and homocysteine. Symptoms of HCU include, but are not limited to displacement of the lens of the eye, nearsightedness, and the formation of blood clots in the arteries and veins. Treatment approaches aimed at lowering total homocysteine may include drug or dietary interventions, or a combination of both. Dietary treatment involves lifetime compliance of a methionine restricted, cystine enriched diet in those individuals who are non responsive or only partially responsive to pyridoxine (vitamin B6) therapy. The administration of Betaine reduces homocystein levels and FDA has approved its use for the treatment of HCU.

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Cystinosis is a genetic disorder characterized by an accumulation of cystine in different organs and tissues, leading to potentially severe organ dysfunction, typically involving the kidney. Therapy of cystinosis consists of both amelioration of symptoms, the administration of cysteamine, and renal transplantation for those who progress to end-stage renal disease.

Urea cycle disorders

The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body. Deficiency of any of the enzymes in the pathway causes a specific urea cycle disorder (UCD). There are six different UCDs, most of them result in accumulation of ammonium with life-threatening consequences. Prompt recognition and treatment of high ammonium levels are needed to improve outcome. The treatment of urea cycle disorders consists of dietary management to limit ammonia production in conjunction with medications and/or supplements which provide alternative pathways for the removal of ammonia from the bloodstream. Treatment may include supplementation with special amino acid formulas developed specifically for urea cycle disorders, which can be prescribed to provide approximately 50% of the daily dietary protein allowance. Some patients may require individual branched chain amino acid supplementation.

Sodium phenylbutyrate (Buphenyl) is the primary medication being used to treat urea cycle disorders, that creates an alternate pathway to excrete nitrogen precursors.

Orotic Aciduria

Hereditary orotic aciduria is a condition that occurs when the body cannot make a compound called UMP synthetase, which is an important enzyme that produces the chemicals that make up DNA. The main symptoms of this disease are megaloblastic anemia, as well as delays in physical and intellectual development. Orotic aciduria is caused by inherited changes (mutations) in the UMPS gene. Treatment consists of taking supplements of a compound called uridine.