Inborn errors of metabolism (IEMs) due to enzyme or transporter deficiencies are taken as an example for OD. Accumulation of substrates proximal to the deficient enzyme during catabolic episodes leads to autointoxication with acute onset of symptoms. IEMs due to transporter deficiency usually have a more stable, chronic course.
Therapeutic options are substrate reduction by diet or drugs, vitamin/cofactor supplementation, enzyme replacement, enzyme augmentation and transplantation of organs or cells.
Phenylketonuria (PKU) is the prototype of an IEM which can be successfully treated by diet. The outcome of hepatorenal tyrosinaemia type 1 was revolutionarized by substrate reduction using nitisinone (NTBC) which was discovered by chance. Lysosomal storage diseases are examples where enzyme replacement therapy is successful. Enzyme augmentation can be achieved in some IEM-patients with a mild phenotype (residual enzyme activity) by chaperones which stabilize the enzyme. Organ transplantation is an option in those patients who cannot be managed by drugs and/or diet. Bone marrow transplantation is successful in some patients where CNS-involvement occurs. The CNS cannot be reached by enzyme replacement therapy (blood–brain barrier).
While safety and efficacy of drugs for OD have been demonstrated pre-marketing, post-marketing surveys are often necessary to include more patients.
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