Inborn Errors of Metabolism

Phenylketonuria (PKU) is an autosomal recessive protein metabolism disorder caused by a mutation in the gene for phenylalanine hydroxylase, an enzyme that converts phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine accumulates in the blood, leading to rashes, seizures, growth deficiencies, and severe intellectual disability if left untreated.

A diet limiting phenylalanine intake prevents the accumulation of this amino acid in the blood, thereby avoiding the severe neurological and developmental complications associated with untreated phenylketonuria. Early diagnosis combined with dietary restriction can prevent rashes, seizures, and intellectual disability, though some learning difficulties may still occur.

Classic galactosemia, the most common type of galactosemia, results from a mutation in the GALT gene that codes for galactose-1-phosphate uridyltransferase. This liver enzyme is essential for converting galactose into glucose. Without it, galactose accumulates in the blood, potentially causing life-threatening complications including liver failure and sepsis.

Although initiating a lactose-restricted diet within the first ten days of life prevents immediate life-threatening complications in classic galactosemia, the prior accumulation of galactose can cause lasting damage. Children may still experience developmental delays, speech problems, and motor function abnormalities even with early intervention and dietary management.

Glycogen storage disease occurs when enzymes necessary to convert glycogen back into glucose become dysfunctional. This deficiency leads to excessive glycogen accumulation, particularly in the liver and skeletal muscles, causing these organs to enlarge and impairing their normal function and metabolic capacity.

Both phenylketonuria and classic galactosemia are autosomal recessive inherited disorders, meaning an individual must inherit mutated genes from both parents to develop the condition. These genetic anomalies disrupt specific metabolic processes by affecting enzyme production or function, resulting in the accumulation of metabolic substrates.

Galactosemia has multiple types caused by mutations in different genes: classic galactosemia results from GALT gene mutations, while other forms arise from mutations in the GALE and GALK1 genes. Each type involves deficiency or abnormality of liver enzymes required to convert galactose into glucose, though classic galactosemia is the most common form.