25. METABOLIC DISORDERS OF AMINO ACIDS

Introduction

Amino acids are the fundamental building blocks of proteins. Out of the twenty amino acids, nine are essential — meaning they cannot be produced by the human body and must be obtained through diet. Apart from forming proteins, amino acids also help in the synthesis of vital molecules like hormones, neurotransmitters, pigments, and oxygen-carrying compounds.

Sometimes, due to inherited genetic defects, the body fails to process or break down amino acids properly. These are called hereditary metabolic disorders. Such conditions occur when faulty genes are passed from parents to their children.

Disorders of amino acid metabolism usually affect the body’s ability to either break down amino acids or transport them into cells. Common examples include:

Phenylketonuria (PKU)
Tyrosinemia
Homocystinuria
Non-ketotic hyperglycinemia
Maple syrup urine disease (MSUD)

These disorders are typically autosomal recessive, meaning both parents must carry the defective gene. Diagnosis is often made by analyzing amino acid levels in body fluids.

1) Phenylketonuria (PKU)

Phenylketonuria occurs due to decreased activity of the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine into tyrosine — a precursor for important hormones and pigments like melanin.

When this enzyme is defective, phenylalanine accumulates in the blood while tyrosine levels decrease. This buildup leads to symptoms such as:

Developmental delay and learning disabilities
Small head size
Behavioral issues and seizures
Lighter hair, skin, and eyes due to reduced melanin

Treatment: A special low-protein diet and formulas low in phenylalanine can help maintain normal intelligence if started early. However, in rare cases where the defect involves biopterin (a PAH cofactor), the response to diet therapy may be poor.

2) Tyrosinemia

Tyrosinemia Type I (classic or hepatorenal type) occurs due to deficiency of the enzyme fumarylacetoacetate hydrolase (FAH) — the last step in tyrosine breakdown.

Symptoms include:

Severe liver disease and poor weight gain
Kidney problems and nerve involvement
High risk (about 40%) of liver cancer by age 5 if untreated

Treatment: A drug called nitisinone (NTBC) blocks the production of toxic tyrosine metabolites and improves symptoms. However, liver cancer can still occur, and liver transplantation may be required in severe cases.

There is also a mild, temporary neonatal form of tyrosinemia that improves with protein restriction and vitamin C supplementation.

3) Homocystinuria

Homocystinuria results from a defect in the enzyme cystathionine β-synthase, which is involved in methionine metabolism. The defect causes a buildup of homocysteine in the blood and urine.

Common features include:

Flushed cheeks and tall, thin body structure
Lens dislocation in the eyes
Vascular (blood vessel) problems and osteoporosis
Intellectual disability or psychiatric issues

Treatment: About half of patients respond well to vitamin B6 (pyridoxine). Folic acid, betaine, aspirin, and a diet low in methionine and protein can also help manage the condition.

4) Non-Ketotic Hyperglycinemia (NKH)

Non-ketotic hyperglycinemia is a rare inherited disorder caused by a defect in the enzyme system that breaks down glycine. This results in a dangerous buildup of glycine in body tissues and fluids.

Symptoms usually appear in infants and include:

Seizures
Low muscle tone
Breath-holding and frequent hiccups
Severe developmental delay

Because glycine acts as a neurotransmitter, its excess in the brain causes neurological symptoms. There is no cure, but medications such as dextromethorphan (blocks glycine action), a low-protein diet, and sodium benzoate (a glycine scavenger) can help relieve symptoms.

5) Maple Syrup Urine Disease (MSUD)

Maple syrup urine disease is a disorder of branched-chain amino acid metabolism, involving leucine, isoleucine, and valine. Due to defective enzyme activity, these amino acids and their byproducts accumulate in body fluids, giving the urine a sweet “maple syrup” odor.

It is more common among certain populations, like the Mennonites of Pennsylvania. Symptoms usually begin in infancy and include:

Lethargy and poor feeding
Seizures and coma (in severe cases)
Progressive neurological deterioration

Treatment: Restrict dietary protein and provide special formulas low in branched-chain amino acids. Early diagnosis and treatment can allow normal brain development, though intellectual impairment may still occur in some cases. Mild forms can be managed with vitamin B1 (thiamine) and protein restriction.