Makindo Medical Notes

Early diagnosis of Phenylketonuria (PKU) and avoidance of phenylalanine can prevent sequelae.

About

• PKU is a treatable autosomal recessive disease, routinely screened for after birth.
• Occurs in approximately 1 in 10,000 to 20,000 live births.
• High phenylalanine levels cause symptoms if untreated.
• Symptomatic disease is rare in regions with screening programs and early dietary intervention.

Genetics

• Caused by loss of function in the PAH gene, which encodes phenylalanine hydroxylase.
• Without PAH, phenylalanine builds up in the body.

Aetiology

• Deficient phenylalanine hydroxylase (located on Chromosome 12).
• Deficiency of the cofactor tetrahydrobiopterin, due to mutations on Chromosomes 10 and 4.
• Milder forms exist, known as Hyperphenylalaninaemia or Non-PKU Hyperphenylalaninaemia.

Clinical Presentation

• Mental developmental delays, hypopigmentation, and seizures.
• In older untreated children, hyperactivity, purposeless movements, rhythmic rocking, and athetosis are common.
• Characteristic seborrheic or eczematoid rash, usually mild and resolves with age.
• Children have a distinctive musty or mousy body odour due to phenylacetic acid.
• No consistent findings on neurological examination, but infants often present with hypertonia and hyperactive reflexes.
• 25% of children experience seizures, and over 50% show abnormal EEG findings.
• Other findings in untreated cases include microcephaly, prominent maxilla, widely spaced teeth, enamel hypoplasia, and growth retardation.

Investigations

• Elevated blood and urine phenylalanine levels, with normal plasma tyrosine and cofactor (tetrahydrobiopterin) levels.
• Guthrie Test: Performed on the second or third day of life to detect elevated phenylalanine from a heel prick.
• EEG: Abnormal in about 50% of cases, indicating neurological involvement.
• Can be diagnosed prenatally via chorionic villus sampling (CVS).
• Cerebral white matter changes are seen in older patients and may reflect late diagnosis or dietary non-adherence.

Management

• Strict phenylalanine restriction with dietary support to balance growth requirements while minimizing intake.
• For cofactor deficiencies, a diet low in phenylalanine with added neurotransmitter precursors is necessary.
• Diet must be rigorously controlled in pregnant PKU patients to avoid fetal complications.
• Some cognitive impairment may persist despite dietary management, ranging from detectable on tests to more significant impairment.