Phenylketonuria: Amino Acid Metabolism Disorder
The disease is caused by impaired metabolism of the amino acid phenylalanine. Physical development is usually mildly affected, though microcephaly and delayed dentition may occur. A classic specific finding is a musty or "mousy" odor, caused by sweat gland excretion of phenylalanine metabolites, primarily phenylacetic acid.
The primary treatment is a strict diet severely restricting phenylalanine. If dietary therapy is initiated within the first month of life, central nervous system damage is entirely prevented. After five years of age, brain tissue sensitivity to toxic metabolites decreases, allowing dietary restrictions to be relaxed.
An atypical form exists, caused by a deficiency of the enzyme dihydropteridine reductase. This variant disrupts the combined metabolism of tyrosine and tryptophan, impairing neurotransmitter synthesis. This form cannot be treated with diet alone: severe neurological deficits progress even when blood phenylalanine levels are normalized.
Pregnancy in women with phenylketonuria requires extreme care. High maternal phenylalanine levels have significant teratogenic effects on the fetus. To prevent fetal damage, dietary phenylalanine must be strictly eliminated throughout pregnancy, ideally starting before conception.
Galactosemia: Toxicity of Carbohydrate Metabolites
This autosomal recessive disorder is characterized by impaired galactose metabolism. Clinically, affected infants refuse breast milk and poorly tolerate milk products. Severe forms manifest in the first days of life immediately after feeding, presenting with profuse vomiting, diarrhea, and progressive failure to thrive. Early signs include jaundice and hepatomegaly, with intellectual disability developing by 6–12 months. Terminal stages may lead to portal hypertension.
Subtypes:
- Classic form (severe): Deficiency of the enzyme galactose-1-phosphate uridylyltransferase. Toxic galactose-1-phosphate accumulates in the blood, damaging the liver, kidneys, brain, and erythrocytes.
- Mild form: Deficiency of galactokinase. Galactose itself accumulates, which has significantly lower toxicity. It presents without liver or CNS involvement.
Morphologically, galactosemia affects the liver (initial steatosis progressing to cirrhosis), eyes (rapid cataract formation), and CNS (edema, gliosis, neuronal death, particularly in the inferior olivary nuclei and dentate nuclei of the cerebellum). Without a strict lactose-free diet, it is fatal due to cachexia or E. coli sepsis.
Cystic Fibrosis
Cystic fibrosis is the most common lethal inherited disorder among Caucasians (carrier frequency up to 5%). It is caused by mutations in the CFTR gene (cystic fibrosis transmembrane conductance regulator) located on chromosome 7 (7q31–32). The most common and severe mutation is a phenylalanine deletion at position δF508 (ΔF508).
Normally, this protein regulates chloride, sodium, and water secretion. When mutated, ion transport fails, and mucus gland secretions become abnormally thick and viscous, causing duct obstruction. In sweat glands, NaCl reabsorption is reduced, causing sweat chloride concentrations to increase 3- to 5-fold (the basis for diagnosis).
Clinical and Morphological Manifestations:
- Meconium ileus (5–10%): Viscous meconium causes complete intestinal obstruction in newborns. It may be complicated by perforation and meconium peritonitis (sometimes prenatal, with calcifications and foreign-body giant cells).
- Intestinal/pancreatic insufficiency (5–10%): Pancreatic enzyme deficiency leads to foul-smelling, fatty stools (steatorrhea), abdominal distension, and fat-soluble vitamin deficiencies (A, D, E, K). Liver involvement includes steatosis and focal biliary cirrhosis.
- Bronchopulmonary disease (15–20%): Viscous mucus obstructs airways, rapidly predisposing to infections (Staphylococcus aureus in infants, Pseudomonas aeruginosa in older children). This leads to atelectasis, bronchiectasis, abscesses, and emphysema.
- Mixed form (65–75%): Combined pulmonary and gastrointestinal manifestations.
Pathology of Cystic Fibrosis
Morphological changes in cystic fibrosis are systemic and age-dependent:
- Pancreas: Minimal changes in early infancy. In older patients, the exocrine parenchyma undergoes complete atrophy, becoming firm with multiple cysts, necrosis, and fibrosis. Islets of Langerhans are typically spared (diabetes mellitus occurs in only about 5% of patients).
- Lungs: Macroscopically emphysematous and hyperinflated. Bronchi and bronchioles are diffusely dilated, their lumens plugged with viscid mucopurulent exudate. Squamous metaplasia of the bronchial epithelium may occur.
- Liver: Focal biliary fibrosis and cholangitis. Biliary cirrhosis develops in about 5% of patients.
- Salivary glands: Duct dilation and fibrosis affect mucous glands, whereas serous glands (such as the parotid glands) generally remain spared.