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  • Review Article
  • Published:

Inborn errors of metabolism: the flux from Mendelian to complex diseases

Nature Reviews Genetics volume 7, pages 449–459 (2006)Cite this article

Key Points

  • Inborn errors of metabolism (IEM) are a diverse group of diseases that result from perturbations of biochemical pathways.

  • IEM have traditionally been regarded as Mendelian traits; however, it is now increasingly recognized that they represent the best examples of complex gene–environment interactions and, more specifically, gene–nutrient interactions that lead to complex disease. IEM could therefore be a powerful tool for dissecting both monogenic and common multifactorial diseases.

  • The molecular basis of IEM can best be understood by analysing metabolite flux, which is defined as the production or elimination of a quantity of metabolite per mass of organ or organism over a specific time frame (mole/kg/hr).

  • Diagnostic methods that are based on molecular-genetic tools have a limited ability to correlate phenotypes with subtle changes in metabolic fluxes.

  • By contrast, the direct and dynamic measurement of metabolite flux will facilitate the integration of environmental, genetic and biochemical factors with phenotypic information. This integration should lead to new diagnostic and therapeutic approaches that are focused on the manipulation of metabolic pathways.

  • Effective therapy of IEM requires the alteration of metabolite flux. This can be achieved by reducing pathway precursors, restoring adequate biochemical activity or diverting metabolites to alternative pathways.

  • The value of metabolic flux in establishing genotype–phenotype relationships in IEM is illustrated in the review through the discussion of two disorders — Gaucher disease and urea-cycle disorders. These conditions are examples of 'large-molecule' and 'small-molecule' Mendelian diseases, respectively, that also have complex features.

  • The future directions of research in IEM are discussed in relation to the use of metabolic flux to inform genotype–phenotype relationships and the challenges that the field has to overcome (for example, the fact that current, clinically available diagnostic technologies do not assess in vivo metabolite flux).

  • Ultimately, the understanding of complex disease pathogenesis and susceptibility will require our comprehension of the metabolome. To understand the metabolome, we will need to integrate different technologies and data, including genomic, proteomic and physiological fluxes.

Abstract

Inborn errors of metabolism are characterized by dysregulation of the metabolic networks that underlie development and homeostasis, and constitute an important and expanding group of genetic disorders in humans. Diagnostic methods that are based on molecular genetic tools have a limited ability to correlate phenotypes with subtle changes in metabolic fluxes. We argue that the direct and dynamic measurement of metabolite flux will facilitate the integration of environmental, genetic and biochemical factors with phenotypic information. Ultimately, this integration will lead to new diagnostic and therapeutic approaches that are focused on the manipulation of these pathways.

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Figure 1: Inborn errors of metabolism and metabolic networks.
Figure 2: Pathogenetic mechanisms in the inborn errors of metabolism.
Figure 3: Measurement of metabolite flux using isotope tracers.
Figure 4: Urea-cycle disorders, small-molecule diseases.
Figure 5: Metabolic pathway and layers of phenotypic complexity.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics and Howard Hughes Medical Institute, Baylor College of Medicine One Baylor Plaza, Houston, 77030, Texas, USA

    Brendan Lanpher, Nicola Brunetti-Pierri & Brendan Lee

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  1. Brendan Lanpher
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DATABASES

OMIM

Albinism

Alkaptonuria

Cystinuria

Fabry disease

Gaucher disease

MCAD deficiency

OTCD

PD

Pentosuria

Pompe disease

Sickle cell anaemia

FURTHER INFORMATION

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Glossary

Tandem mass spectrometry

Mass spectrometry (MS) is a technique that is used to identify compounds by their mass and charge. Compounds are typically separated, often by chromatography, and then ionized for detection. Tandem MS is a very useful high-throughput technology that uses two mass spectrometers in series: the first separates compounds, and the second identifies them based on their mass and charge.

Rhabdomyolysis

The breakdown of muscle tissue.

Cardiomyopathy

A disease process that alters the structure and function of the heart muscle; it is described as hypertrophic, dilated, or restrictive.

Cell autonomous

Defective enzymes or proteins are said to act in a cell-autonomous fashion if their functions are confined within a cell.

Non-cell-autonomous

Enzymes and metabolites are said to act in a non-cell-autonomous fashion if they are produced in one cell but act in another cell, for example by affecting the transport of substrates between cells.

Genotype–phenotype correlations

Correlations between clinical severity and course with specific genetic variants.

Microarray

An array of DNA fragments of either genomic or cDNA sequences that are deposited on solid support and used to identify copy-number variation and level of gene expression.

Nuclear magnetic resonance spectroscopy

(NMR spectroscopy). An analytical chemistry technique that is used to study molecular structure and dynamics, and explores spectrum differences that are caused by the differential alignment of atomic spins in the presence of a strong magnetic field.

Intermediary metabolites

Compounds that are neither precursors nor endproducts of metabolic pathway. Their accumulation or deprivation in inborn errors of metabolism might have pathologic and diagnostic significance.

Phenylketonuria

(PKU). An autosomal-recessive inborn error of metabolism that leads to the deficiency of the enzyme that converts Phe to Tyr. Phe accumulation leads to mental retardation and other neurological problems. A low-Phe diet is an effective therapy.

Sphingolipidosis

A disorder of the formation or breakdown of sphingolipids, a class of lipid that is derived from sphingosine. The most common disorder of sphingolipid metabolism is Gaucher disease.

Hepatosplenomegaly

An enlargement of the liver and spleen.

Thrombocytopoenia

A decrease in the number of platelets in the blood.

Splenectomy

The surgical removal of the spleen.

Astrogliosis

An abnormal increase in the number of astrocytes, typically owing to neuronal cell death or injury.

Lewy body

An abnormal aggregate that is seen in nerve cells of patients with Parkinson disease or lewy-body dementia.

Hippocampus

An area of the brain within the temporal lobe. It is thought to have a crucial role in the limbic system.

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Lanpher, B., Brunetti-Pierri, N. & Lee, B. Inborn errors of metabolism: the flux from Mendelian to complex diseases. Nat Rev Genet 7, 449–459 (2006). https://doi.org/10.1038/nrg1880

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