1 What is an enzymopathy and how does it result in clinical symptoms?

An enzymopathy is a genetic disease in which a deficiency in activity of an enzyme leads to a block in a metabolic pathway. The altered (usually reduced) enzymatic activity can be due to reduced cellular expression of the enzyme or to expression of a dysfunctional enzyme. The pathologic manifestations of the enzyme deficiency are a result of the accumulation of substrate (or its derivatives) prior to the blockage, a lack of the product(s), or a combination of both (Fig. 11-1).

Figure 11-1 Mechanisms by which an enzymopathy produces clinical symptoms. ↑ = increased, ↓ = decreased.

(From Brown TA, Brown D: USMLE Step 1 Secrets. Philadelphia, Hanley & Belfus, 2004.)

2 What is the typical pattern of inheritance observed in enzymopathies?

Almost all enzymes are produced in excess of minimal requirements. So although heterozygous carriers of an enzyme deficiency typically have only 50% of normal enzyme activity levels, usually they are phenotypically normal. Thus, almost all enzymopathies have an autosomal recessive pattern of inheritance, in which a phenotypic abnormality manifests only when there is nearly no enzyme activity. This generalization is extremely useful for the boards.

3 Explain why the pathologic consequences of X-linked enzymopathies are manifested almost exclusively in males

Again, enzyme deficiencies generally require a near-total loss of enzyme activity to result in phenotypic abnormalities. As males have only a single X chromosome, inheritance of a single defective copy of an X-linked gene from the mother will result in the pathologic consequences of the enzyme deficiency/abnormality. Because females have two X chromosomes, they will generally exhibit the disease only if they are homozygous for the mutated alleles, which is far less likely. (For example, if the odds of a male inheriting a single defective gene is 1/p, the odds of a female inheriting two defective copies will be approximately 1/p².)

Important examples of X-linked recessive enzymopathies include hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), glucose-6-phosphate dehydrogenase deficiency, and Lesch-Nyhan syndrome (LNS) (hypoxanthine-guanine phosphoribosyltransferase [HGPRT] deficiency).

4 What is the process of lyonization and how may it cause the manifestation of X-linked diseases in females?

Because females have two X chromosomes, they would have twice the level of expression of genes located on the X chromosome were it not for the random inactivation of one X chromosome that occurs in each somatic cell early in embryogenesis. This process is called lyonization (named after the scientist Lyon, who was the first to propose it). One of the manifestations of lyonization is the Barr body, a condensed, often drumstick-shaped body of DNA seen at the periphery of the nuclei of the cells of females, which corresponds to the inactivated X chromosome. Another nonpathologic manifestation of lyonization is the coloration pattern of calico cats.

Owing to the normally random nature of the X chromosome inactivation, some females may happen to have a mutated X-linked allele on the active X chromosome of a large number of cells and, as a result, may exhibit some pathologic features. These rare individuals are termed “mosaics” or “manifesting heterozygotes.” For example, some female carriers of hemophilia A will have some degree of anemia if a large enough proportion of their bone marrow cells inactivate the X chromosome carrying the normal factor VIII allele.

5 Why do some diseases show an autosomal dominant pattern of inheritance? Why do the genetic diseases of connective tissue usually fall within this category?

In autosomal dominant diseases, the disease manifests even though there is a normal copy of the gene remaining that produces 50% of the normal amount of gene product. Dominance of a defective gene can be attributed to one of the following reasons: more than 50% of normal gene product is needed for a nondiseased physiologic state; the defective protein adversely affects the normal gene product (a dominant negative effect); or the defective protein has acquired a novel, detrimental property.

Most diseases caused by mutations in nonenzymatic structural proteins (e.g., collagen, fibrillin) or in membrane receptors (e.g., low-density lipoprotein [LDL] receptor) are inherited in an autosomal dominant manner. This again is a useful generalization for the boards.

6 What is the general relationship between the function of a protein and its pattern of inheritance?

Table 11-1 shows these relationships.

Table 11-1 Proteins in Enzyme Deficiency

7 What are the following molecular biology diagnostic methods used for? Explain briefly how they work

This technique involves detecting the presence of a specific DNA sequence within a mixture of DNA by using a sequence-specific strand of complementary DNA or messenger RNA (a “probe”) that is able to hybridize to the targeted DNA. The specific steps include separating the mixture of DNA fragments by gel electrophoresis, denaturing the DNA (i.e., altering the DNA solution so that the double-stranded DNA separates into single strands), transferring (i.e., blotting) the DNA onto a membrane, and mixing the blotted DNA mixture with radioactively labeled probes to allow for hybridization. In the laboratory, it is often used to detect the presence of large unique DNA sequences (such as a gene mutation) within a patient’s genome.

Northern blotting is very similar to Southern blotting, except that a specific sequence of RNA (rather than DNA) is detected using a nucleic acid probe. This technique is commonly used to measure expression of a gene in a patient, as determined by its production of messenger RNA (mRNA).

PCR allows for detection of a specific DNA sequence (such as a mutant allele) by making billions of copies of that allele from as little as a single DNA molecule. This test is performed by using two primers, which are complementary to the DNA regions at the ends of the sequence of interest that is to be amplified. The target DNA is amplified via multiple rounds of DNA denaturation, primer hybridization (or annealing), and extension catalyzed by a temperature-insensitive DNA polymerase.

This test is similar to Southern or Northern blotting, but rather than detecting a nucleic acid, it measures the level of a specific protein. First, the protein mixture is coated by a negatively charged detergent molecule that denatures the proteins (i.e., unfolds it into linear peptides) such that the proteins can be separated according to size using gel electrophoresis. Next, the proteins are blotted onto a membrane to which an antibody against the protein of interest (the primary antibody) is added. If the protein is present, the primary specific antibody will bind to the membrane and this binding, in turn, will be detected using a secondary antibody that is both directed against the first antibody and labeled in an assayable fashion. (For example, the primary antibody may be a specific sheep antibody, but the secondary antibody is an antisheep antibody linked to an enzyme that produces a colored product upon exposure to the reagents.) Western blots are used clinically to measure the degree of protein expression of a gene. This is important because diseases can be caused by translational problems, in which transcription of the gene into mRNA occurs normally but the translation of this mRNA is defective.

1 What is the most likely diagnosis in this baby and how is it inherited?

The most likely diagnosis is phenylketonuria (PKU), which, as with most enzymopathies, is inherited in an autosomal recessive manner.

2 What is the major defect and underlying pathophysiology of this disorder?

PKU is caused by the defective conversion of phenylalanine to tyrosine resulting from mutations in the phenylalanine hydroxylase (PAH) gene (classic PKU). The PAH enzyme deficiency leads to both an accumulation of phenylalanine (substrate) and its derivatives phenylpyruvic acid and other phenylketones, as well as a decrease in the levels of tyrosine (product) and its derivatives (such as dopa and melanin). A rarer form of PKU involves a defect in the synthesis of tetrahydrobiopterin (BH₄), which serves as a cofactor for PAH. This cofactor is also required for the synthesis of L-dopa from tyrosine. L-Dopa is then converted to dopamine, which can be used to synthesize the catecholamines norepinephrine and epinephrine. In order to distinguish between the genetic causes of PKU, one can examine levels of dopamine and prolactin. Recall that dopamine is a negative inhibitor of prolactin release. Because classic PKU does not affect dopamine synthesis, prolactin levels should be relatively normal. BH₄ deficiency, on the other hand, will reduce dopamine synthesis and thus prolactin levels will be elevated in these patients.

The pathology is primarily a result of substrate (phenylalanine) accumulation, which causes severe neuronal damage, mental retardation, growth retardation, and motor dysfunction. The lack of neurotransmitter compounds derived from tyrosine (particularly the catecholamines dopamine, norepinephrine, and epinephrine) may also contribute to damage of the central nervous system (CNS). Other manifestations include a predisposition to eczema, a “musty” odor (caused by phenylketone excretion into sweat), and fair skin coloring (due to tyrosine deficiency, which normally serves as a precursor to melanin) (Fig. 11-2).

Figure 11-2 Pathologic mechanisms of phenylketonuria.

(From Brown TA, Brown D: USMLE Step 1 Secrets. Philadelphia, Hanley & Belfus, 2004.)

3 How is phenylketonuria treated?

Patients with PKU need to follow a strict diet that restricts phenylalanine intake and is supplemented with tyrosine. If started within the first month of life, this diet is very effective in preventing mental retardation. Because phenylalanine is found in breast milk, most babies suffering from PKU must be placed on special phenylalanine-restricted formulas. Phenylalanine is also found in high concentrations in artificial sweeteners such as aspartame.

4 Given the fact that phenylketonuria is a relatively rare condition (prevalence rates range from 1 in 2600 to 1 in 200,000 live births), why does it make sense to screen all neonates for this condition?

The screening test (Guthrie test) is inexpensive (as it simply involves measuring plasma phenylalanine levels), and PKU is easily prevented by dietary modifications. Furthermore, early screening detects the disease before irreparable damage (particularly to the CNS) has occurred (i.e., early intervention affects outcome).

5 If the parents have a female child with this disease, why is it crucial to advise the child about the risks to her baby if she becomes pregnant when she is older?

As patients generally tolerate more dietary phenylalanine with age, most women with PKU abandon the diet therapy by their early teens, well before they reach childbearing age. This termination of dietary therapy generally has limited ill effects on the women themselves at this age but will cause irreparable harm to a developing fetus should they become pregnant. Specifically, high levels of phenylalanine can diffuse across the placenta, causing brain damage in the developing fetus. So, although these babies will (virtually always) be heterozygous for the PAH mutation and are thus born without PKU, they can exhibit severe mental retardation, a condition termed maternal PKU.

6 Why is screening for congenital hypothyroidism (cretinism), congenital adrenal hyperplasia, and galactosemia also routinely performed in newborns?

These diseases are similarly screened for because they are additional preventable causes of mental retardation or death. In general, screening is performed on diseases for which treatment is available, for which a rapid and low-cost laboratory test is available, and that are frequent and serious enough to justify the screening cost.

1 If the parents decide to have another child, what is the probability of that child having cystic fibrosis?

Because CF is an autosomal recessive disease, the chance of the second child having CF remains at 25%. Each parent is a heterozygous carrier of the mutant allele such that each parent has a 50% chance of passing it on to their offspring, and the chance of the child receiving both mutant alleles is 0.5 × 0.5 = 0.25, or 25%.

Note: Each birth is a completely independent event, such that the outcomes of prior pregnancies do not affect the odds of disease transmission in subsequent pregnancies.

2 If the parents want to have another child, what kind of genetic screening methods are available for them to consider?

A few genetic screening methods are available:

The first method involves preimplantation diagnosis using in vitro fertilization (IVF). The zygotes resulting from IVF are allowed to develop into an 8-cell or 16-cell blastomere, from which a single cell is removed. The DNA is isolated from this single cell and PCR is then used to screen for a mutation in the cystic fibrosis transmembrane regulator (CFTR) gene locus. Only the unaffected embryos (wild type or carrier status) are implanted.

Other genetic screening methods involve prenatal diagnosis using either amniocentesis (the withdrawal of 20-30 mL of amniotic fluid at 15-17 weeks of gestation) or chorionic villus sampling (the aspiration of several milligrams of villus tissues at 10-11 weeks of gestation).

3 Despite having mutations in the same gene, why do patients with cystic fibrosis exhibit significant variability in disease severity?

First, different patients may have different mutations of the same gene, with certain mutations causing less severe phenotypes. For example, mutations of the chloride channel gene that have a smaller detrimental effect on its function result in milder clinical manifestations. There are over a thousand mutations of CFTR that have been identified in patients with CF. This phenomenon of different mutations of the same allele resulting in differing disease manifestations is known as allelic heterogeneity. Interestingly, many patients with CF (>33%) are compound heterozygotes, with a different locus mutated on each copy of their CFTR genes.

Second, even in patients with identical mutations, there is often some degree of clinical heterogeneity. This may be due to other genetic differences or to environmental variables that influence disease expression.

Note: Many genetic diseases have allelic heterogeneity, leading to significant heterogeneity in clinical manifestations.

4 Assuming a cystic fibrosis prevalence rate of 1 in 2500, what is the carrier frequency for this disease?

Here, the Hardy-Weinberg law can be used to describe the genotypic distribution of an abnormal allele (p + q = 1) and the phenotypic distribution of the disorder:

These equations are easy to remember if one realizes that the phenotype equation is simply the square of the genotype equation:

Assuming a CF prevalence of 1 in 2500, q² = 1/2500 such that q = 0.02. Because p + q = 1, p is 0.98. Therefore, the carrier frequency for CF is 2pq = 2 (0.98) (0.2) = 0.039, or approximately 4% of the population. Thus, in this example, 1 in every 25 is a carrier. This is roughly the carrier frequency in whites, whereas the mutation and the disease are less common in nonwhites.

The Hardy-Weinberg law can be applied to alleles and populations that are in “genetic equilibrium” (i.e., populations in which the allele frequency is not undergoing rapid change). For the purposes of the USMLE, usually such equilibrium can be assumed.

1 What two diagnoses are top considerations in the differential diagnosis at this point?

Progressive neurodegeneration and macular cherry-red spots in a child should automatically make you think of Tay-Sachs disease (TSD) and Niemann-Pick disease (NPD). Both are autosomal recessive lysosomal storage diseases and, more specifically, sphingolipidoses. TSD is caused by a deficiency of hexosaminidase A, and NPD is caused by a deficiency in sphingomyelinase. The prevalence of both these diseases is higher in Ashkenazi Jews.

Note: Many of the lysosomal storage diseases have multiple subtypes based on the underlying biochemical and molecular characteristics. The syndromes described here correspond to the most common subtype (i.e., type 1 or type A) of each disorder.

2 Now what is the most likely diagnosis?

This feature is associated with TSD but not NPD. On the other hand, “foamy histiocytes” (macrophages filled with sphingomyelin) are found the tissues of patients with NPD.

Note: The exaggerated startle reaction reported in the initial vignette was particularly suggestive of TSD. The startle reaction is caused by hyperacusis and, as it does not occur in NPD, can be a major clue to the early diagnosis of TSD.

3 What is the pathogenesis of Tay-Sachs disease?

Hexosaminidase A is a lysosomal enzyme that cleaves a cerebral ganglioside (G_M2, a sphingolipid). Mutations make this enzyme less effective, leading to massive accumulation of G_M2 and its byproducts within the lysosomes of neurons. These lysosomes become enormously enlarged such that they begin to interfere with normal cell function and ultimately cause neuronal death. Neuronal death that overlies the fovea centralis of the retina is responsible for the cherry-red spot seen on funduscopic examination. More specifically, ganglion cells in the retina fill with lipid, which imparts an opaque gray color to the retina. Because the optic disk does not contain ganglion cells, it remains red on a gray background, giving the look of a cherry-red spot. This is a common buzzword used by USMLE test makers.

The pathogenesis of other sphingolipidoses such as NPD or Gaucher disease is similarly due to accumulation of substrates of lysosomal enzymes. The differing disease manifestations of these sphingolipidoses depend upon the organs in which the sphingolipids accumulate and the underlying organ sensitivities. For example, visceral sphingolipid accumulation and hepatosplenomegaly are prominent in NPD but not in TSD. TSD, in contrast, is characterized by relatively isolated central nervous system (CNS) sensitivity to G_M2 accumulation.

4 Which is the most common sphingolipidosis?

Gaucher disease is not only the most common sphingolipidosis but also the most common lysosomal storage disease. The disease is caused by deficiency of glucocerebrosidase and is characterized by the presence of glucocerebroside-laden Gaucher cells, macrophages with characteristic “crumpled-tissue paper” appearance and nuclei displaced by lipid. It also more common among Ashkenazi Jews.

Unlike TSD and NPD, Gaucher disease usually spares neuronal tissue. Glucocerebroside instead accumulates in the reticuloendothelial system, namely, the spleen and liver (causing hepatosplenomegaly), bone (causing bone pain and fractures), and bone marrow (causing pancytopenia, with particularly prominent thrombocytopenia).

Note: Despite the characteristic histologic or cytologic findings of many storage diseases, virtually all of these disorders are today diagnosed using testing for the underlying specific genetic defects.

5 What are the mucopolysaccharidoses?

Mucopolysaccharidoses are a different type of lysosomal storage disease in which the substrates that accumulate in the lysosomes are extracellular matrix molecules called glycosaminoglycans (which were previously known as mucopolysaccharides). Like the sphingolipidoses, these diseases are caused by hereditary deficiency of lysosomal enzymes. The two main examples of this type of disease, Hurler syndrome and the similar but less severe Hunter syndrome, are both caused by accumulation of the glycosaminoglycans heparan sulfate and dermatan sulfate (Table 11-2).

Table 11-2 Mucopolysaccharidoses: Hurler Syndrome and Hunter Syndrome

To keep these two disorders straight, think of the hunter being male (X-linked) with aggressive behavior and great vision (no corneal clouding). The only other commonly tested lysosomal storage disease that is X-linked recessive is Fabry disease (α-galactosidase A deficiency). Look for peripheral neuropathy and cardiovascular/renal involvement in a patient presenting with Fabry disease on the USMLE Step 1.

6 Quick review: Cover the three columns on the right side of Table 11-3 and attempt to describe the enzyme deficiency, accumulated substrate, inheritance pattern, pathophysiology, and any high-yield associations for the listed lysosomal storage disorders

1 What is the most likely diagnosis?

Lesch-Nyhan syndrome (LNS), a rare X-linked recessive disease, is caused by a defective HPRT (hypoxanthine phosphoribosyltransferase) enzyme. The HPRT enzyme is present in most cell types and is involved in the salvage pathway of purine metabolism. The most striking and characteristic neurologic symptom of this disease is self-mutilation.

Recall that the purine bases are adenine and guanine and the respective nucleosides are adenosine and guanosine. A nitrogenous base linked to a sugar ribose or deoxyribose is referred to as a nucleoside, whereas a phosphorylated nucleoside is referred to as a nucleotide.

The mnemonics “PURe As Gold” and “CUT the PY” can be used to remember that Adenine and Guanine are Purine bases, whereas Cytosine, Uracil, and Thymine are PYrimidines. Likewise, although addition of sugar to a base produces a nucleoside, nucleotides are nucleosides that are “tied” to a phosphate.

2 What is the normal function of the purine “salvage” pathway?

The purine salvage pathway functions to “salvage” purine metabolites such as hypoxanthine and guanine, preventing them from being unnecessarily degraded and then renally excreted as uric acid. (Hypoxanthine is another purine that is an intermediate in the synthesis or degradation of adenosine monophosphate [AMP] or guanosine monophosphate [GMP]; Fig. 11-3). As shown in Figure 11-3, the salvage pathway recycles these metabolites to replenish the purine bases guanine and adenine by the action of the HGPRT enzyme. Normally, the de novo pathway (smaller dark arrows) provides only about 10% of the daily purine requirement, whereas the salvage pathway (large curved arrows) provides the remaining 90%. The amount of net degradation to uric acid (open arrows) is always balanced with the amount of purines synthesized via the de novo pathway. It follows that the loss of the salvage pathway would result in a dramatic increase in de novo purine synthesis and a similarly dramatic increase in uric acid generation.

Figure 11-3 The purine salvage pathway. See additional discussion in text. AMP, adenosine monophosphate; GMP, guanosine monophosphate; HPRT, hypoxanthine phosphoribosyltransferase; IMP, inosine monophosphate; PRPP, 5′-phosphoribosyl-1-pyrophosphate; XO, xanthine oxidase.

(From Brown TA, Brown D: USMLE Step 1 Secrets. Philadelphia, Hanley & Belfus, 2004.)

3 How do defects in the purine salvage pathway cause hyperuricemia?

In LNS, HGPRT activity is less than 1% of normal. Owing to the absence of HGPRT, the ability to reutilize hypoxanthine and guanine to make the purine nucleotides inosine monophosphate (IMP) and GMP is lost, so these intermediates are degraded to uric acid. As explained already in the preceding question, the purine requirements in this case must be met by increased de novo synthesis. Additionally, because of the reduced levels of IMP and GMP, the feedback inhibition normally exerted by IMP and GMP upon the de novo pathway is lost (broken arrows in Fig. 11-3), even further promoting the activity of the de novo synthesis pathway. Because purine synthesis via the de novo pathway must be balanced by purine degradation into to uric acid, the dramatic increase in de novo synthesis results in severe hyperuricemia.

In other words, both excessive activation of the de novo pathway and insufficient HGPRT salvage of purine metabolites contribute to the hyperuricemia in LNS.

4 What was the orange “sand” in his diapers observed by his parents?

The sand represents uric acid crystals. Uric acid has limited solubility such that in conditions of extreme hyperuricemia, it will precipitate from urine, forming visible orange “sand.” It can also precipitate from the plasma and accumulate in the joints, causing gouty arthritis. Interestingly, most patients with LNS do not develop gout, presumably because of the patients’ short life span (of about 20 years). However, patients with only a partial deficiency of HPRT (with 1-20% of normal activity) have a normal life span but are susceptible to developing severe tophaceous gout.

5 Why do boys with Lesch-Nyhan syndrome typically present with renal dysfunction?

Patients with LNS develop kidney disease primarily from repeated uric acid kidney stones and urinary tract obstruction. In addition to nephrolithiasis, chronic hyperuricemia (from any cause) can result in renal insufficiency caused by urate deposition in the renal parenchyma, a process referred to as urate nephropathy.

Note: In contrast with the renal and joint disease, the cause of the neurologic symptoms in LNS is not well-established.

6 How might this patient be managed pharmacologically?

Allopurinol is useful in the treatment of hyperuricemia of any cause. It works by preventing uric acid production by inhibiting the enzyme xanthine oxidase (XO) (see Fig. 11-3). The xanthine and hypoxanthine that accumulate instead are more soluble and readily excreted than uric acid.

Other, more common uses of allopurinol include the treatment or (more commonly) the prevention of urate nephropathy, uric acid stones, gouty arthritis, and tumor lysis syndrome (which is caused by treatment of acute leukemias or disseminated lymphomas).

1 What is the diagnosis?

Type 1 glycogen storage disease (or von Gierke disease), an autosomal recessive disorder, is caused by deficiency of the enzyme G6Pase.

2 What type of enzymatic deficiency is present in all types of glycogen storage diseases?

These disorders are caused by a defect in either an enzyme required for glycogen synthesis or an enzyme required for glycogen catabolism (i.e., glycogenolysis) called glucose-6-phosphatase (G6Pase). Glycogen storage diseases principally affect either the liver or skeletal muscle, which are the main sites where glycogen is stored. When they affect the liver, they can lead to hepatomegaly and can predispose to hypoglycemia and its attendant complications (e.g., seizures and, with repeated episodes of hypoglycemia, neurologic impairment). When they affect the skeletal muscles, they can cause muscle pain and exercise intolerance, but they do not result in hypoglycemic episodes, as skeletal muscle plays no role in maintaining plasma glucose. Recall that skeletal muscle lacks G6Pase, so it cannot deliver glucose to the bloodstream, as glucose-6-phosphate (G6P) is unable to cross the plasma membrane (see question 10).

3 How is glycogen normally synthesized and degraded in the liver?

Upon entry into a liver cell, glucose is prevented from diffusing out by phosphorylation to G6P, a reaction catalyzed by the enzyme glucokinase (this function is served by hexokinase in nonhepatic tissues). G6P is then converted into glucose-1-phosphate by phosphoglucomutase and then uridine diphosphoglucose (UDP-glucose) prior to attachment to glycogen by the enzyme glycogen synthetase.

Glycogen degradation is primarily dependent on the activity of the enzyme glycogen phosphorylase (Fig. 11-4).

Figure 11-4 Glycogen synthesis and degradation. 1, Glycogen synthetase; 2, brancher enzyme; 3, debrancher enzyme; 4, phosphoglucomutase; 5, glucose-6-phosphatase.

(From Kliegman RM, Marcdante KJ, Jenson HB, Behrman RE: Nelson Essentials of Pediatrics, 5th ed. Philadelphia, WB Saunders, 2006.)

4 What is the function of glucose-6-phosphatase?

This hepatic enzyme cleaves phosphate off glucose, which then enables glucose to diffuse out of the cell. This reaction is important in the maintenance of blood glucose because the final product of both glycogenolysis and gluconeogenesis is G6P.

5 Why is hepatomegaly seen on examination?

The deficiency of G6Pase causes G6P to accumulate, which stimulates glycogen synthesis, which in turn enlarges the liver.

6 What is the explanation for his severe fasting hypoglycemia and lactic acidosis?

During short-term fasting, liver glycogenolysis is the major pathway that maintains blood glucose. When G6Pase is deficient, glycogenolysis is not effective at releasing glucose into the bloodstream, leading to hypoglycemia. In addition, the release of glucose made by gluconeogenesis during fasting is also impaired because this process is also dependent upon the enzyme G6Pase. This further contributes to hypoglycemia. Excessive accumulation of G6P greatly promotes glycolysis, resulting in high levels of pyruvate production. The pyruvate is then converted into lactate when the mitochondrial uptake of pyruvate is saturated, resulting in lactic acidosis (see Fig. 11-4).

For your own review, recall that the production of lactic acid from pyruvate does not cause any additional increase in production of adenosine triphosphate (ATP). The function of this pathway is to simply regenerate the electron carrier NAD⁺ from NADH.