Inherited Diseases of Intermediary Metabolism: Molecular Basis


Inherited abnormalities in the complex pathways of carbohydrate, amino and organic acids and lipids lead to the inborn errors of metabolism. A variety of genetic aberrations lead to single or multiple protein/enzyme defects at the translational, postā€translational and organelle targeting levels that lead to the disease biochemistry and clinical manifestations.

Keywords: intermediary metabolism; genetics; lysosome; gene therapy

Figure 1.

Autosomal and X‐linked recessive inheritance. Squares and circles represent males and females, respectively. The open symbols represent normal individuals. For autosomal recessive inheritance, completely black symbols represent affected individuals who are homozygotes, i.e. they have two copies of the disease allele (a). Half‐filled symbols represent heterozygote carriers, i.e. they have one copy of the disease allele (a), one copy of the normal allele (A), and have a normal phenotype. For X‐linked inheritance, circles with black dots are heterozygote carriers and filled squares are affected males with one disease allele on their single X‐chromosome, i.e. hemizygous. XN and XM represent the normal (N) and mutated (M) allele, respectively, on the X‐chromosome. Y is the Y‐chromosome.

Figure 2.

A metabolic pathway. A, B, E, F represent intermediate metabolites in the normal (a) and disease‐involved (b) pathways. The size of the letters indicates the relative amount of each intermediate that is present in the steady state.

Figure 3.

(a) Idealized retrovirus (RNA virus) used for gene therapy. LTR, GAG, POL and ENV represent the long terminal repeats, the glycoprotein coat protein, reverse transcriptase and envelope protein, respectively, that are present in the infective or wild‐type virus. (b) The GAG, POL and ENV are removed from a potential therapeutic virus and replaced by the gene of interest. The Ψ sequence is needed to produce viral particles that contain all the elements for infection, i.e. it is a packaging signal.



Gravel RA, Clarke JT, Kaback MM et al. (1995) The GM2 gangliosidoses. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 7th edn, pp. 2839–2882. New York: McGraw‐Hill.

Kay RM and Woo SLC (1994) Gene therapy for metabolic disorders. Trends in Genetics 10: 253–257.

Scriver CR, Beaudet AL, Sly WS and Valle D (eds) (1995) The Metabolic and Molecular Bases of Inherited Disease, 7th edn. New York: McGraw‐Hill.

Smith S (1994) The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. FASEB Journal 8: 1248–1259.

Vogel JM and Motulsky A (1996) Human Genetics. Berlin: Springer.

Further Reading

Rottier RJ, Hahn CN, Mann LW, del Pilar Martin M, Smeyne RJ, Suzuki K, d’Azzo A (1998) Lack of PPCA expression only partially coincides with lysosomal storage in galactosialidosis mice: indirect evidence for spatial requirement of the catalytic rather than the protective function of PPCA. Human Molecular Genetics 7: 1787–1794.

Desnick RJ and Grabowski GA (1981) Advances in the treatment of inherited metabolic diseases. Advances in Human Genetics 11: 281–369.

Garrod AE (1996) The incidence of alkaptonuria: a study in chemical individuality. Molecular Medicine 2: 274–282.

Scriver CR and Waters PJ (1999) Monogenic traits are not simple: lessons from phenylketonuria. Trends in Genetics 15: 267–272.

von Figura K, Schmidt B, Selmer T and Dierks T (1998) A novel protein modification generating an aldehyde group in sulfatases: its role in catalysis and disease. Bioessays 20: 505–510.

Childs B (1995) A logic of disease. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw‐Hill.

Leinekugel P, Michel S, Conzelmann E and Sandhoff K (1992) Quantitative correlation between the residual activity of beta‐hexosaminidase A and arylsulfatase A and the severity of the resulting lysosomal storage disease. Human Genetics 88: 513–523.

Scriver CR and Childs B (1995) Garrod's The Inborn Factors in Disease. Oxford: Oxford University Press.

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Grabowski, Gregory A(Apr 2001) Inherited Diseases of Intermediary Metabolism: Molecular Basis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0001403]