Metabolic Diseases — The Dana Guide


by Edwin H. Kolodny

March, 2007

sections include: a spectrum of symptomsmechanisms and causal factorsdiagnosis and treatment 

The word metabolism refers to how our bodies process the food we ingest to make the many chemicals we need to live. Our brains are uniquely sensitive to disturbances in this body chemistry. The brain needs amino acids to make and then break down neurotransmitters, and many specialized structural and catalytic proteins. Because of the brain’s specialized role in generating electrical impulses, it requires a flow of such ions as sodium, potassium, and calcium. It also needs lipids to form the myelin sheaths that insulate axons connecting cortical nerve cells with other parts of the nervous system.

Any disturbance in the brain’s chemical environment can lead to a metabolic disorder. Such a disease can take many forms. The lack of an enzyme or vitamin necessary for a specific chemical reaction in the body can cause a deficiency of an essential metabolic product (called a metabolite). That lack may impair brain development (as with cholesterol in Smith-Lemli-Opitz syndrome), cause seizures (as with copper in kinky hair disease), or have other harmful effects. Slowed chemical reactions can also cause the buildup of a compound that would otherwise be metabolized. The stored material may become toxic, as with lactic acid in the case of a mitochondrial disease, which in turn can lead to loss of nerve cells and breakdown of brain white matter. Some metabolic disorders produce mental retardation, cerebral palsy and seizures.

Metabolic dysfunction can also be the result of an external factor, such as a toxin or a nutritional deficiency. It can be the effect of disease in the liver, endocrine glands, or other organs. The fetal brain may be harmed by the mother’s alcohol abuse, thyroid deficiency, or phenylketonuria. This section is primarily concerned, however, with metabolic disorders that arise from a child’s genes.

A Spectrum of Symptoms

The symptoms of a genetic metabolic disorder can appear at any age, even in adulthood. Sometimes a child’s brain can be seen to have developed abnormally even before it is born, as in Zellweger’s syndrome, Smith-Lemli-Opitz syndrome, and other disorders. 

Symptoms of neurometabolic disease apparent just after a baby is born include seizures and lack of normal consciousness, muscle tone, movements, reflex activity, vision, breathing, sucking and swallowing. Some newborns with diseases known as lysosomal storage diseases exhibit generalized accumulation of fluid, a condition called nonimmune fetal hydrops. Unusually shaped facial features and limbs may suggest a chromosomal defect but can also arise from a metabolic disease.

Doctors begin to suspect a metabolic problem if a young infant fails to progress developmentally, exhibits severely weak muscle tone, is too easily startled, lies or sits abnormally, or suffers recurrent episodes of respiratory distress, vomiting, or lethargy. An abnormal odor of the body or urine, eye defects, a persistently small head, and seizures may also prompt investigation.

Toward the end of a baby’s first year, metabolic brain disease can cause more delays in development or even regression from skills the child has learned. Older infants may also show difficulty walking, twitching and seizures, skeletal abnormalities, and enlargement of the liver or spleen. In some cases, parents may see abnormalities of their child’s skin and hair. Often a child with a metabolic disorder responds poorly to going without food or having a fever because his or her metabolism is so fragile. The metabolic problem may thus be most apparent when a child is sick.

Toddlers, too, may have developed normally but then encounter problems. Again, these might appear as developmental delays or the loss of previously acquired skills. Children’s walking may become unsteady (ataxia), and their muscle tone increased (spasticity) or decreased (hypotonia). Other possible symptoms include visual problems, poor coordination, a disturbance in speech, and jerking muscles. If a child develops an unusually large or small head while showing signs of developmental delay or regression, doctors should investigate.

Generally, the later the onset of metabolic brain disease, the slower it progresses. However, an unrelated illness or other stress can bring about an acute health crisis with acidosis, coma and seizures. This is often how the disorder glutaric aciduria appears.

Mechanisms and Causal Factors

Metabolic disorders have long been known to run in families. Archibald Garrod first proposed the concept of an inborn error in 1909, and that path of inquiry led to the idea “one gene, one enzyme.” Each gene in our bodies determines the expression of a single protein, many of which (but not all) are enzymes. If a defect or mutation in one gene disrupts the structure and function of its corresponding protein enzyme, that leads to a particular metabolic disease. (Many of the neurodegenerative diseases that begin in later life involve similar defects in nonenzymatic, structural proteins.)

Two people can have mutations of the same gene without suffering the same health problems because each variant of the gene can produce a different clinical picture. One child might be obviously and severely ill at birth and die soon afterward, while another might be only mildly affected by symptoms appearing later in life.

We now know of more than a thousand gene defects, of which at least 30 percent affect brain function. Since there are probably more than 30,000 genes in the human genome, we are likely to discover many more inborn errors of metabolism. The frequency of inherited metabolic diseases varies widely, from greater than 1 in 3,000 children for common disorders to less than 1 per million for rare conditions. The table above lists the major classes of inborn errors causing neurological disease, and some examples of each, but it obviously cannot list the hundreds of genetic brain disorders we know about.

The vast majority of inborn errors of metabolism are inherited in an autosomal recessive manner. This means that both parents carry an abnormal DNA sequence for the same gene on one of a pair of nonsex chromosomes. Since each parent also carries one chromosome with the normal gene sequence, he or she produces half of the normal protein—which is usually enough to remain healthy. However, if both parents pass on the abnormal gene sequence to their child, he or she will be unable to make any of the normal protein and will have the disease. Thus, each child of such parents has a 25 percent chance of being affected.

Because most metabolic conditions are inherited as recessive traits, their prevalence is higher in families in which relatives intermarry. Particular ethnic groups may have developed a genetic predilection for certain diseases, as is the case with Tay-Sachs disease and type 1 Gaucher’s disease among Jews of Eastern European ancestry. In these circumstances, it is hypothesized that a single ancestor passed along a mutation that remains within a relatively small population that is geographically or culturally isolated and thus more likely to intermarry. Alternatively, the mutant gene may confer some specific environmental advantage on its carriers that helps them have more offspring, even if those children are at greater risk for disease. For example, sickle-cell patients may be resistant to malaria, which would explain the sickle-cell trait’s continuing presence in a population.

In the case of diseases carried on the X chromosome, males are more severely affected because they have only one copy. Females who have one X chromosome with the gene defect and one without may or may not develop symptoms. Normally only one of a female’s two corresponding genes on her X chromosomes is expressed as a protein, so chance helps determine the severity of her disease. Examples of X-linked conditions with mild symptoms in women include adrenoleukodystrophy (a peroxisomal disease) and Fabry disease (a lysosomal disorder).

People also inherit diseases of mitochondrial DNA (mtDNA) from their mothers. MtDNA encodes a number of proteins involved in the production of energy by mitochondria, which are the powerplants of the cell. Mitochondria are also very important during development and after brain injury because proteins released from mitochondria can trigger programmed cell death. An individual’s total complement of mtDNA normally comes from the egg from which he or she grew, and that egg came from the mother alone. Disorders of mtDNA may affect both males and females, but only women will pass on the genetic defect. MELAS (which stands for mitochondrial encephalopathy, lactic acidosis, and stroke) is inherited in this way. 

Diagnosis and Treatment

If a child shows the symptoms of a metabolic disorder, physicians must often perform many tests to confirm the cause. They may examine urine for metabolites. Blood studies might include a complete blood count and measurement of cholesterol, electrolytes, ammonia, uric acid, lactic acid, pyruvic acid, acylcarnitines, and blood gases. Doctors can sample cerebrospinal fluid for its content of glucose, protein, lactic and pyruvic acids, amino acids, and neurotransmitter metabolites.

A magnetic resonance imaging (MRI) scan is especially helpful in looking for a congenital malformation in the brain, cortical atrophy (shrinking), or leukodystrophy. Doctors may also take a specimen of skin, using electron microscopy to rule out a storage disease and culturing cells for tests of the body’s enzymes and DNA.

In the metabolic brain disease, an electroencephalograph (EEG) shows slower-than-normal background electrical activity. Seizures often produce a particular wave pattern. Evoked-potential studies can show whether certain pathways in the brain are impaired because of lost myelin or axons. Doctors perform electromyogram (EMG) and nerve conduction studies to assess whether peripheral nerves and muscle are involved.

Once physicians identify the biochemical abnormality of a child’s nervous system, they can design appropriate therapy. To reduce the amount of a toxic metabolite, they might prescribe a restricted diet or add a substance that joins with the offending material to neutralize it and facilitate its elimination. Another approach is to block the reaction producing that toxic product.

When a child’s system is not generating an essential metabolite in healthy quantity, large amounts of the right vitamins can often activate the dysfunctional enzymes enough to overcome the defect. Enzyme-replacement therapy has been used successfully in Gaucher’s disease and is now being tried in several other lysosomal storage diseases. For several of the inherited leukodystrophies, a bone marrow transplant before the symptoms have progressed far usually minimizes the damage; however, this approach has not proven effective in diseases involving nerve cell storage.

When metabolic disorders produce mental retardation, cerebral palsy, or seizures, doctors must treat those conditions along with the underlying problem. Therapies include anticonvulsants for seizures and muscle relaxants for spasticity. Supports and braces can help children sit and move more easily. Physical, occupational, and speech therapy can help them learn particular tasks. Some children may require tube feeding because they have difficulty swallowing. Others need basic help to maintain adequate nutrition, prevent contractures, and avoid infection. Quality of life is far better for people who can both understand and express themselves through language, so therapists often focus on helping children learn to communicate, if necessary through a picture board, computer, or sign language.

Unfortunately, no definitive therapy is yet available for the vast majority of people with inherited neurometabolic diseases. Indicators of a particularly severe prognosis are a small head that is not growing, blindness, absence of speech, and the inability to sit, stand, and walk. Intractable seizures and severe hypotonia or hypertonia are also unfavorable prognostic signs.

Researchers are developing animal models of more and more human diseases, making it possible to develop new therapeutic strategies, especially using bone marrow transplants. Recombinant DNA technology is facilitating the large-scale production of proteins that we may be able to use in enzyme-replacement therapy. Gene therapy is also a theoretical possibility for metabolic disorders; it has restored enzyme activity and improved symptoms in several animal studies of the storage diseases.

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