Phenylketonuria: amino acid metabolism disorder
The disease is associated with impaired metabolism of the amino acid phenylalanine. Physical development in such children is mildly affected, although some microcephaly and delayed tooth eruption may be observed. A characteristic specific sign is the «musty odor», which occurs due to the excretion of phenylalanine metabolites by sweat glands, primarily phenylacetic acid.
The main method of management is a strict diet with a sharp restriction of phenylalanine. If dietary therapy is initiated in the first month of life, central nervous system damage is completely prevented. After the age of five, the sensitivity of brain tissue to toxic metabolites decreases, allowing the discontinuation of strict dietary restrictions.
An atypical form is also distinguished, associated with a deficiency of the enzyme dihydropteridine reductase. In this variant, the combined metabolism of tyrosine and tryptophan is disrupted, leading to impaired neurotransmitter synthesis. This form cannot be treated with diet alone: severe neurological disorders progress even with normal blood phenylalanine levels.
Special attention is required for the management of pregnancy in women with phenylketonuria. High blood phenylalanine levels have a pronounced teratogenic effect on the fetus. To prevent fetal damage, complete elimination of phenylalanine from the diet is necessary throughout pregnancy, and ideally, even at the planning stage.
Galactosemia: carbohydrate metabolite toxicity
This autosomal recessive disease is characterized by impaired galactose metabolism. Clinically, infants refuse the breast early and tolerate milk poorly. Severe forms manifest in the very first days of life immediately after feeding, presenting with profuse vomiting, diarrhea, and progressive failure to thrive. Early signs include jaundice and hepatomegaly, while mental retardation develops by 6–12 months. In terminal stages, portal hypertension develops.
Forms of the disease:
- Common form (severe): deficiency of the enzyme galactose-1-phosphate uridyltransferase. Toxic galactose-1-phosphate accumulates in the blood, damaging the liver, kidneys, brain, and erythrocytes.
- Rare form (mild): galactokinase deficiency. Galactose itself accumulates, possessing significantly lower toxicity. It proceeds without liver and CNS involvement.
Morphologically, galactosemia affects the liver (initially steatosis progressing to cirrhosis), eyes (rapid cataract formation), and CNS (edema, gliosis, neuronal loss, particularly in the region of the inferior olives and cerebellar dentate nuclei). Without a strict dairy-free diet, fatal outcome ensues from cachexia or colibacillary sepsis.
Cystic fibrosis
Cystic fibrosis is the most frequent lethal hereditary disease among Caucasians (carrier frequency up to 5%). The cause is a mutation in the gene on chromosome 7 (7q31–32) encoding the protein cystic fibrosis transmembrane conductance regulator (CFTR). The most severe form is associated with the loss of phenylalanine at position δF508.
Normally, this protein ensures the secretion of chlorides, sodium, and water. With a mutation, transport is impaired, and the secretion of mucous glands becomes abnormally thick and viscous, causing duct obstruction. In sweat glands, NaCl reabsorption is reduced, causing sweat chloride concentration to increase 3–5 fold (the diagnostic basis).
Clinical and morphological forms:
- Meconium ileus (5–10%): accumulation of thick meconium causes complete intestinal obstruction in newborns. May be complicated by perforation and meconium peritonitis (sometimes intrauterine, with calcified deposits and giant cells).
- Intestinal form (5–10%): pancreatic enzyme deficiency leads to foul-smelling stools with abundant fat, abdominal distension, and vitamins A, D, K deficiency. Steatosis and cholestatic hepatitis develop in the liver.
- Bronchopulmonary form (15–20%): viscous mucus blocks the airways. Infection joins rapidly (Staphylococcus aureus in infants, Pseudomonas aeruginosa in older children). Atelectasis, bronchiectasis, abscesses, and emphysema develop.
- Mixed form (65–75%): combined pulmonary and intestinal involvement.
Pathological anatomy of cystic fibrosis
Morphological changes in cystic fibrosis are systemic in nature and depend on the patient's age:
- Pancreas: in early childhood, changes are minimal. In older patients, the exocrine portion completely atrophies, the gland becomes firm, with multiple cysts, foci of necrosis, and fibrosis. Only the islets of Langerhans are preserved (diabetes mellitus occurs in only 5% of patients).
- Lungs: macroscopically emphysematously inflated. Bronchi and bronchioles are diffusely dilated, their lumens plugged with viscous mucopurulent exudate. Squamous cell metaplasia of the epithelium is possible.
- Liver: focal fibrosis, cholangitis. Biliary cirrhosis develops in 5% of patients.
- Salivary glands: duct dilation and fibrosis are characteristic of mucous glands. Parotid glands (serous type) usually remain intact.
Briefly: answers to topical questions
What are the clinical manifestations and pathogenesis of the atypical form of phenylketonuria?
The atypical form of phenylketonuria is caused by dihydropteridine reductase deficiency. The pathogenesis of the disease consists of a combined impairment of tyrosine and tryptophan metabolism, leading to disrupted neurotransmitter synthesis. Clinical manifestations include neurological disorders that develop even when maintaining a normal phenylalanine level through diet; the disease is not curable by dietary therapy alone.
What is the mechanism of the CFTR gene mutation in cystic fibrosis?
The mechanism of the most common CFTR gene mutation (at position δF508) consists of the loss of the amino acid phenylalanine. As a result of this mutation, the cystic fibrosis transmembrane conductance regulator is absent from the cell surface. This leads to the inability of mucus-secreting epithelial cells to secrete water and chlorides. Due to the chloride transport defect, sodium chloride reabsorption in sweat glands is reduced, and the secretion of mucous glands becomes abnormally thick and viscous, obstructing the ducts.
What is the pathogenesis of meconium ileus in newborns?
The pathogenesis of meconium ileus in newborns consists of the excessive accumulation of thick, viscous meconium, leading to complete intestinal obstruction in the first days of life. Due to filling with thick, dark green meconium, sharp dilation of the small intestine loops occurs (primarily in the proximal sections of the ileum), while the large intestine remains collapsed. At the microscopic level, villi are compressed by meconium, mucous gland lumens are filled with thick secretion, and epithelial cells become flattened and atrophic.
To remember pneumonia pathogens in cystic fibrosis: «Infants fear Staphylococcus, while older children fear Pseudomonas aeruginosa» (Staphylococcus aureus in early age, Pseudomonas aeruginosa in older children).
Class and exam questions
What is the primary diagnostic method for cystic fibrosis?
The clinical basis of diagnosis is the sweat test—detection of a 3–5 fold increase in sweat chloride concentration in the patient.
Why do liver and CNS damage develop in galactosemia?
In the classical form, due to a galactose-1-phosphate uridyltransferase defect, toxic galactose-1-phosphate accumulates in the blood, exerting a damaging effect on tissues.
What is the danger of pregnancy for women with phenylketonuria?
High levels of phenylalanine in the maternal blood possess a teratogenic effect and cause severe damage to the developing fetus.
What else to study on this topic
- Morphology of respiratory distress syndrome in newborns
- Pathogenesis and morphology of bronchopulmonary dysplasia
- Hemolytic disease of the newborn: causes and morphogenesis
- Ascending and hematogenous intrauterine infection
- Chromosomal diseases and microcytogenetic syndromes
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