Pyruvate dehydrogenase complex deficiency (PDHA) is a genetic disorder that results in a malfunctioning of the Krebs, or tricarboxylic acid (TCA), cycle. It is sex-linked and appears to be a dominant trait.
Description
PDHA is one of the most common of the genetic disorders that cause abnormalities of mitochondrial metabolism. The mitochondria are the organelles inside cells that are reponsible for energy production and respiration at the cellular level. One of the most important processes in the mitochondria is the TCA cycle (also known as the Krebs cycle). The TCA cycle produces the majority of the ATP (chemical energy) necessary for maintenance (homeostasis) of the cell. The production of this ATP is accomplished by chemically converting molecules of the chemical pyruvate into carbon dioxide, water, and ATP. After a blood sugar (glucose) molecule has been broken down into two pyruvate molecules, one of two things will occur: if energy is required by the cell, the molecules will be further broken down into ATP, carbon dioxide, and water; or, if energy is not needed by the cell, the pyruvate molecules will be put back together to
reform a glucose molecule. These transformations of pyruvate are accomplished primarily by two enzymes: pyruvate carboxylase, an enzyme that converts pyruvate molecules into oxaloacetate molecules in preparation to reform glucose molecules; and pyruvate dehydrogenase (PDH), an enzyme that begins the breakdown of the pyruvate into the eventual products of carbon dioxide, water, and ATP. To break down the pyruvate, PDH gets some help from two other enzymes: dihydrolipoyl transacetylase and dihydrolipoyl dehydrogenase. These three enzymes and the five coenzymes (CoA, NAD+, FAD+, lipoic adic, and TPP) that assist these enzymes are collectively known as the pyruvate dehydrogenase complex (PDH complex).
Individuals affected with PDHA have deficiencies in one or more of the three enzymes within the PDH complex. Most have a deficiency of the PDH enzyme itself. Tissues that require the greatest amounts of oxygen (highly aerobic tissues), such as those of the brain and the rest of the central nervous system, are most sensitive to deficiencies in the PDH complex.
People with PDHA have either a complete inability or a severely limited ability to produce PDH. Since these individuals cannot produce the amounts of PDH required to break down pyruvate, the cells cannot produce enough energy, in the form of ATP, to maintain themselves. This causes a progressive degeneration of the tissues, with the most profound effects observed in the brain and central nervous system.
PDH is an enzyme. An enzyme is a chemical that facilitates (catalyzes) the chemical reaction of another chemical or of other chemicals; it is neither a reactant nor a product in the chemical reaction that it facilitates (catalyzes). As a result, enzymes are not used up in chemical reactions; they are recycled. One molecule of an enzyme may be used to facilitate (catalyze) the same chemical reaction over and over again several hundreds of thousands of times. All the enzymes necessary for catalyzing the various reactions of human life are produced within the body by genes. Genetic enzyme deficiency disorders, such as PDHA, result from only one cause: the affected individual cannot produce enough of the necessary enzyme because the gene designed to make the enzyme is faulty. Enzymes are not used up in chemical reactions, but they do eventually wear out, or accidentally get expelled. Also, as an individual grows, they may require greater quantities of an enzyme. Therefore, most enzyme deficiency disorders will have a time component to them. Individuals with no ability to produce a particular enzyme may show effects of this deficiency at birth or shortly thereafter. Individuals with only a partial ability to produce a particular enzyme may not show the effects of this deficiency until their need for the enzyme, because of growth or maturation, has outpaced their ability to produce it.
The level of ability of the pyruvate dehydrogenase complex deficiency affected individual to produce PDH, or his or her ability to sustain existing levels of PDH, are the sole determinants of the severity of the observed symptoms in that individual and the age of onset of these symptoms.
PDHA is the most common cause of non-exerciserelated build-up of lactic acid in the tissues (primary lactic acidosis). When a tissue requires more energy than it can gain from aerobic processing (TCA cycle), it begins to break down carbohydrates, via an anaerobic process, in order to gain the necessary energy. Lactic acid is the by-product of carbohydrate metabolism. The build-up of lactic acid in the muscle tissues and red blood cells is normal during strenuous exercise. However, the accumulation of lactic acid in other tissues without exercise or without oxygen deprivation is symptomatic of an underlying problem in the normal aerobic process (TCA cycle).
Genetic profile
The gene responsible for PDHA has been mapped to Xp22.2-p22.1. This gene is now termed the PDHA1 gene. At least 50 different mutations of this gene resulting in varying symptoms of PDHA have been identified. Because the gene for PDHA is on the X chromosome, it is called a sex-linked disease. PDHA shows a dominant inheritance pattern: therefore, females with only one affected X chromosome also exhibit symptoms of the disease.
Demographics
Almost equal numbers of males and females have been identified as being affected with PDHA. Even though PDHA is known to be transmitted as a sex-linked dominant trait on the X chromosome, it is not necessarily lethal in affected males (who possess only a single X chromosome), because the symptoms of PHDA are quite different depending on the precise mutation responsible for the symptoms in each individual. The genetic mutations are linked to the sex of the affected individual. Affected liveborn males tend to have minor (missense/nonsense type) mutations, while affected females tend to have more major (insertion/deletion type) mutations. The almost unobserved insertion/deletion mutations in males with PDHA suggests that these mutations are fatal to males with only a single X chromosome (homozygous males). Females with two X chromosomes, only one of which contains an insertion/deletion type mutation (heterozygous females) and males with an extra X
chromosome (XXY males) with this type of mutation on only one chromosome (heterozygous males) are affected with non-lethal forms of PDHA.
A fixed sequence difference between African and non-African samples of the PDHA1 gene has been identified. That is, those of African descent carry a different version of the PDHA1 gene than those of non-African descent. It has been established that these differences in the subpopulations arose more than 200,000 years ago, which predates the earliest known modern human fossils. This genetic evidence is interesting in that it suggests that the modern human emerged from already genetically divided subpopulations.
Signs and symptoms
PDHA affects primarily the brain and central nervous system. In individuals with extreme deficiencies of PDH, the brain may fail to reach normal size during fetal development leading to a small brain and skull (microcephaly). Abnormal development of the cerebrum, cerebellum, and brainstem are the most common brain dysfunctions associated with PDHA. The normal hollow cavities (ventricles) within the brain are usually much larger than normal (dilated) in individuals affected with PDHA. The connection between the left and right hemispheres of the brain (corpus callosum) is generally under-developed or completely absent as well.
A condition in which the normal insulating layer (myelin) that surrounds the neurons is either absent or insufficent (leukodystrophy) is observed in many individuals affected with PDHA. Some PDHA affected individuals also have periods of brain malfunctioning in which the neurons within the cerebellum temporarily lose the ability to act in a coordinated fashion (cerebellar ataxia). These attacks of cerebellar ataxia generally last from a few days to a few weeks and reoccur every three to six months thoughout life with decreasing severity after puberty. Lactic acid accumulation in the brain may also lead to breathing (respiratory) and kidney (renal) problems.
Some individuals affected with PDHA experience increased muscle tone in both legs (spastic diplegia) or in all four limbs (spastic tetraplegia) similar to that seen in the classic case of cerebral palsy. Seizures occur in almost all individuals with PDHA. A seizure is the result of sudden abnormal electrical activity in the brain. This electrical activity can result in a wide variety of clinical symptoms including muscle twitches; tongue biting; fixed, staring eyes; a loss of bladder control resulting in involuntary urination; total body shaking (convulsions); and/or loss of consciousness.
Unusual, or dysmorphic, facial features are sometimes associated with PDHA. These include a broad or upturned nose; low-set ears; downward-slanted eyes, drooping eyelids; and a staring or squinting appearance. Other physical symptoms of PDHA include short fingers and arms, urogenital malformations, low muscle tone (hypotonia), and feeding difficulties. Mental impairment is present in some cases. Delayed physical and motor development can also occur.
Diagnosis
Improper brain development in individuals with PDHA is observable in the womb via ultrasound or MRI after birth, although brain malformations may result from any number of other factors. Babies born with PDHA may exhibit low birth weight, a weak suck, failure to thrive, lack of muscle tone, and unusual appearance of the head, face, and limbs. Convulsions, developmental delay, and eye problems may develop a few months after birth. A diagnosis of PDHA is generally confirmed with a blood test for severe lactic acidosis, an observance of deficient PDH activity in sampled or cultured fibroblasts, or by an observance of elevated amounts of lactate and pyruvate in the cerebrospinal fluid drawn in a spinal tap.
Treatment and management
Treatment of PDHA is on a case-by-case basis depending on the observed symptoms. These treatments may include early and continuing intervention programs for developmental delays and mental retardation, anti-convulsants to control seizures, muscle relaxants to control spasticity, and/or surgery to release the permanent muscle, tendon, and ligament tightening (contracture) at the joints that is characteristic of longer term spasticity.
A high fat diet including beer as an alternative source of the chemical acetyl-CoA that is not produced in high enough supply because of the deficiency of PDH enzyme is often recommended for those individuals affected with PDHA. Dietary supplements of thiamine, liproic acid and L-carnitine have also proven beneficial in some cases.
Prognosis
The prognosis for PDHA affected individuals varies widely with the severity of the symptoms. Until gene or enzyme replacement therapy becomes available, the most seriously affected individuals are not likely to receive relief from their symptoms and many will die at early ages. For those less seriously affected, several treatments are available to improve quality of life. Many less severely affected individuals live normal lifespans with their abilities and quality of life only limited by the degree of mental impairment and muscle spasticity that is present.
PERIODICALS
Harris, E. and J. Hey "X chromosome evidence for ancient human histories." Proceedings of the National Academy of Sciences of the United States of America (March 1999): 3320-4.
Hesterlee, S. "Mitochondrial disease in prespecitve: Symptoms, diagnosis and hope for the future."Quest (October 1999).
Lissens, W. et al. "Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency." Human Mutations (2000): 209-19.
