Introduction
Inherited metabolic disorders are genetic conditions that result from defects in specific enzymes involved in metabolism. Two classic examples are Alkaptonuria and Phenylketonuria (PKU). These disorders are autosomal recessive, meaning a child must inherit defective genes from both parents to be affected. Early diagnosis and management are critical to prevent complications.
a) Alkaptonuria
Cause:
- Alkaptonuria is caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD).
- This enzyme is essential for breaking down the amino acids tyrosine and phenylalanine.
- The gene responsible is located on chromosome 3.
- Deficiency leads to accumulation of homogentisic acid (HGA) in tissues and urine.
Symptoms:
- Dark urine: One of the first noticeable signs, especially when exposed to air.
- Ochronosis: Bluish-black pigmentation in connective tissues such as ears and eyes.
- Joint and spine problems: Arthritis and back pain due to deposition of HGA in cartilage.
- Heart problems: In severe cases, heart valves and blood vessels can calcify.
Diagnosis:
- Urine analysis shows darkening upon standing.
- Gas chromatography or tandem mass spectrometry can detect HGA levels.
Treatment:
- There is no complete cure, but symptoms can be managed.
- Low-protein diet to reduce phenylalanine and tyrosine intake.
- Vitamin C may slow down ochronosis.
- New drug nitisinone is being studied to block HGA formation.
b) Phenylketonuria (PKU)
Cause:
- PKU is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH).
- This enzyme converts phenylalanine to tyrosine.
- The defective PAH gene is located on chromosome 12.
- As a result, phenylalanine accumulates and becomes toxic to the brain.
Symptoms:
- Intellectual disability: If untreated, it leads to severe cognitive impairment.
- Seizures and tremors
- Musty odor: Due to excess phenylalanine in body fluids.
- Skin problems: Eczema and light skin due to decreased melanin production.
- Delayed development: Motor skills and speech may be affected.
Diagnosis:
- Newborn screening using heel-prick blood test (Guthrie test).
- Genetic testing for PAH mutations.
Treatment:
- Lifelong low-phenylalanine diet (avoid meat, dairy, nuts, aspartame).
- Special medical formulas for infants and children.
- Use of sapropterin (Kuvan), a synthetic form of BH4 cofactor, in responsive patients.
Conclusion
Both Alkaptonuria and Phenylketonuria are inherited metabolic disorders that can lead to severe complications if not diagnosed early. While they have no definitive cure, early intervention with dietary management and medication can significantly improve quality of life and prevent serious health issues. Genetic counseling is also recommended for families with a history of such disorders.