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MEDICAL BIOCHEMISTRY. Enzyme Kinetics Enzymes are protein catalysts that, like all catalysts, speed up the rate of a chemical reaction without being used up in the process.
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Enzyme Kinetics • Enzymes are protein catalysts that, like all catalysts, speed up the rate of a chemical reaction without being used up in the process. • They achieve their effect by temporarily binding to the substrate and, in doing so, lowering the activation energy needed to convert it to a product. • The rate at which an enzyme works is influenced by several factors, e.g., • the concentration of substrate molecules (the more of them available, the quicker the enzyme molecules collide and bind with them). The concentration of substrate is designated [S] and is expressed in units of molarity. • the temperature. As the temperature rises, molecular motion — and hence collisions between enzyme and substrate — speed up. But as enzymes are proteins, there is an upper limit beyond which the enzyme becomes denatured and ineffective. • the presence of inhibitors. • competitive inhibitors are molecules that bind to the same site as the substrate — preventing the substrate from binding as they do so — but are not changed by the enzyme. • noncompetitive inhibitors are molecules that bind to some other site on the enzyme reducing its catalytic power. • pH. The conformation of a protein is influenced by pH and as enzyme activity is crucially dependent on its conformation, its activity is likewise affected.
The study of the rate at which an enzyme works is called enzyme kinetics. Let us examine enzyme kinetics as a function of the concentration of substrate available to the enzyme. • We set up a series of tubes containing graded concentrations of substrate, [S]. • At time zero, we add a fixed amount of the enzyme preparation. • Over the next few minutes, we measure the concentration of product formed. If the product absorbs light, we can easily do this in a spectrophotometer. • Early in the run, when the amount of substrate is in substantial excess to the amount of enzyme, the rate we observe is the initial velocity of Vi.
Plotting Vi as a function of [S], we find that • At low values of [S], the initial velocity,Vi, rises almost linearly with increasing [S]. • But as [S] increases, the gains in Vi level off (forming a rectangular hyperbola). • The asymptote represents the maximum velocity of the reaction, designated Vmax • The substrate concentration that produces a Vi that is one-half of Vmax is designated the Michaelis-Menten constant, Km (named after the scientists who developed the study of enzyme kinetics). • Km is (roughly) an inverse measure of the affinity or strength of binding between the enzyme and its substrate. The lower the Km, the greater the affinity (so the lower the concentration of substrate needed to achieve a given rate).
Plotting the reciprocals of the same data points yields a "double-reciprocal" or Lineweaver-Burk plot. This provides a more precise way to determine Vmax and Km. • Vmax is determined by the point where the line crosses the 1/Vi = 0 axis (so the [S] is infinite). • Note that the magnitude represented by the data points in this plot decrease from lower left to upper right. • Km equals Vmax times the slope of line. This is easily determined from the intercept on the X axis.
The Effects of Enzyme Inhibitors • Enzymes can be inhibited • competitively, when the substrate and inhibitor compete for binding to the same active site or • noncompetitively, when the inhibitor binds somewhere else on the enzyme molecule reducing its efficiency. • The distinction can be determined by plotting enzyme activity with and without the inhibitor present. • Competitive Inhibition • In the presence of a competitive inhibitor, it takes a higher substrate concentration to achieve the same velocities that were reached in its absence. So while Vmax can still be reached if sufficient substrate is available, one-half Vmax requires a higher [S] than before and thus Km is larger.
Noncompetitive Inhibition • With noncompetitive inhibition, enzyme molecules that have been bound by the inhibitor are taken out of the game so • enzyme rate (velocity) is reduced for all values of [S], including • Vmax and one-half Vmax but • Km remains unchanged because the active site of those enzyme molecules that have not been inhibited is unchanged. • This Lineweaver-Burk plot displays these results.
Amino acids Each amino acid contains an "amine" group (NH3) and a "carboxy" group (COOH) (shown in black in the diagram).The amino acids vary in their side chains (indicated inblue in the diagram).The eight amino acids in the orange area are nonpolar and hydrophobic.The other amino acids are polar and hydrophilic ("water loving").The two amino acids in the magenta box are acidic ("carboxy" group in the side chain).The three amino acids in the light blue box are basic ("amine" group in the side chain).
ACIDIC AMINOACIDS BASIC AMINOACIDS
ESSENTIAL AA Glucogenic amino acids: Their carbon skeletons are degraded to pyruvate, or to one of the 4- or 5-carbon intermediates of Krebs Cycle that are precursors for gluconeogenesis. Glucogenic amino acids are the major carbon source for gluconeogenesis when glucose levels are low.They can also be catabolized for energy or converted to glycogen or fatty acids for energy storage. Ketogenicamino acids: Their carbon skeletons are degraded to acetyl-CoA or acetoacetate. Acetyl CoA, and its precursor acetoacetate, cannot yield net production of oxaloacetate, the precursor for the gluconeogenesis pathway. For every 2-C acetyl residue entering Krebs Cycle, two carbon atoms leave as CO2. (For review, see notes on Krebs Cycle.) Carbon skeletons of ketogenic amino acids can be catabolized for energy in Krebs Cycle, orconverted to ketone bodies or fatty acids. They cannot be converted to glucose.
Glucogenic amino acids: Their carbon skeletons are degraded to pyruvate, or to one of the 4- or 5-carbon intermediates of Krebs Cycle that are precursors for gluconeogenesis. Glucogenic amino acids are the major carbon source for gluconeogenesis when glucose levels are low.They can also be catabolized for energy or converted to glycogen or fatty acids for energy storage. • Ketogenicamino acids: Their carbon skeletons are degraded to acetyl-CoA or acetoacetate. Acetyl CoA, and its precursor acetoacetate, cannot yield net production of oxaloacetate, the precursor for the gluconeogenesis pathway. For every 2-C acetyl residue entering Krebs Cycle, two carbon atoms leave as CO2. (For review, see notes on Krebs Cycle.) Carbon skeletons of ketogenic amino acids can be catabolized for energy in Krebs Cycle, orconverted to ketone bodies or fatty acids. They cannot be converted to glucose. STRICTLY KETOGENIC: LEUCINE , LYSINE KETO and GLUCOGENIC: ISOLEUCINE, THREONINE,TRYPTOPHAN, PHENYLALANINE
The synthesis of serotonin, dopamine, norepinephrine, and epinephrine from amino acid precursors.
DISORDERS OF AMINO ACID METABOLISM • This is a group of inherited defects of the degradation of amino acids. They include the urea cycle disorders, in which the defect involves conversion of the amino group to urea, and many of the organic acidemias, which are caused by defects in the disposal of the carbon skeletons of the branched chain amino acids after the initial transamination step. With the exception of ornithine transcarbamylase deficiency, which is X-linked, all amino acid disorders are autosomal recessive.
Clinical findings. Most amino acid disorders present in the neonatal period with a severe or fatal metabolic encephalopathy, which mimics perinatal asphyxia and sepsis. This encephalopathy is caused by the toxic effects of the accumulating amino acids and their intermediates, hyperammonemia, impairment of energy and synthetic pathways, and defective synthesis of neurotransmitters. The metabolic encephalopathy is often accompanied by respiratory depression, seizures, and hypoxic-ischemic brain injury. Survivors have psychomotor retardation, and suffer from recurrent neurotoxic episodes, which are triggered by metabolic stress, e.g., infections. The clinical picture in older patients resembles cerebral palsy. Less severe mutations cause milder illness, which presents later in life with developmental delay, episodes of metabolic decompensation, seizures, and ataxia. A few amino acid disorders (phenylketonuria, homocystinuria) have an insidious onset and a chronic course.
The clinical, biochemical, and pathological findings in the most common amino acid disorders are summarized below. • Nonketotic hyperglycinemia (defects of the glycine cleavage system)Elevated glycine in plasma and CSF Neonatal encephalopathy, psychomotor retardationSpongy myelinopathy, agenesis of the corpus callosum • Urea cycle disorders(5 enzymes of the urea cycle)HyperammonemiaSeizures Neonatal encephalopathyBrain swelling, Alzheimer type II astrocytes • Maple Syrup Urine Disease(defects of branched-chain ketoacid dehydrogenase complex)Accumulation of branched-chain amino acids and their ketoacidsNeonatal encephalopathy, psychomotor retardationBrain swelling, spongy myelinopathy • Homocystinuria (cystathionine beta synthase deficiency)Elevated homocysteineThrombosis, Marfanoid habitus, dislocation of lensVenous and arterial thrombosis and cerebral infarcts
INHERITED METABOLIC DISORDERS • This section deals with the principles of lysosomal, peroxisomal, mitochondrial, and amino acid disorders, and highlights some important entities in these groups. There are many more inherited metabolic diseases that are beyond the scope of this web site. Many neurodegenerative diseases and muscle diseases are inherited metabolic disorders, the molecular and biochemical pathways of which we are now beginning to understand.
The diseases covered in this section are, for the most part, childhood disorders. In most of them, patients are normal at birth and have progressive neurological deterioration beginning at some later time. In some of them, the disease is manifested in adulthood. The clinical phenotype depends on the type and severity of the biochemical defect, i.e., what functions are lost and whether the loss is total or partial, and on structural-functional reserves, i.e., what resources are available to replace or cope with the loss. Most inherited metabolic disorders are autosomal recessive.
LYSOSOMAL STORAGE DISORDERS-GENERAL PRINCIPLES • The lysosomal storage disorders (LSDs) are due to deficiencies of lysosomal enzymes caused by mutations of genes that encode the enzyme proteins and related cofactors. Lysosomal enzymes degrade most biomolecules. The products of this degradation are recycled. This process is crucial for the health and growth of cells and tissues. LSDs result in accumulation (storage) of undegraded products in lysosomes. This causes enlargementof cells(ballooning), cellular dysfunction, and cell death. On electron microscopic examination, the stored products are membrane-bound because they are contained within lysosomes.
LSDs are rare. The most common among them are the mucopolysaccharidoses (MPS), which affect one in every 100,000 to 200,000 liveborn infants. The single most common LSD is Gaucher disease. Most LSDs are autosomal recessive. A few are X-linked. Patients are normal at birth. Manifestations of neurological disease begin in infancy or childhood. Initially, there is delay and then arrest of psychomotor development, neurological regression, blindness, and seizures. Inexorable progression leads to a vegetative state.
CLINICAL MANIFESTATIONS AND PATHOLOGY • The clinical manifestations of LSDs depend on which cells and tissues use the deficient enzyme and when is the period of its peak demand. For instance, neurons recycle large amounts of certain gangliosides which are components of their membranes and synapses. Enzymes of ganglioside degradation are highly expressed in brain tissue and are in great need at all times but especially in the first few years of life when axons elongate, dendrites branch, and synapses develop. Deficiency of these enzymes causes neuronal storage of gangliosides. Other gangliosides are components of myelin and their storage causes white matter disease.
LSDs have diverse clinical manifestations. Some of them share certain clinical and pathological features, on the basis of which four basic clinical-pathological phenotypes can be defined: neuronal lipidosis, leukodystrophy, mucopolysaccharidosis, and storage histiocytosis. The most prevalent phenotype is neuronal lipidosis. A few LSDs have distinct clinical features.
CLASSIFICATION • The classification of the LSDs is based either on the deficient enzyme or on the chemical composition of the storage material. Eponymic and clinical terms supplement the biochemical nomenclature. In terms of the storage material, LSDs can be divided into three large groups, the sphingolipidoses, mucopolysaccharidoses, and glycoproteinoses and several other individual entities. Sphingolipids consist of a backbone of ceramide with attached oligosaccharide side chains. They are major constituents of cell membranes. Gangliosides have sialic acid side chains and are especially abundant in neuronal membranes. Galactosylceramide and sulfatide are myelin lipids. Glycosaminoglycans (mucopolysaccharides) are long unbranched molecules of repeating disaccharides. They are attached to core proteins forming proteoglycans. They are produced by most cells and are found mainly on the surface of cells and in the extracellular matrix. They are primarily structural molecules. Glycoproteins are also stuctural molecules, components of mucinous secretions, and have a variety of other functions. • Most LSDs are caused by deficiencies of enzymes that degrade carbohydrate side chains and their storage materials are carbohydrates or other glycocompounds. The table below gives a simplified classification of the most common LSDs.
LABORATORY DIAGNOSIS OF LSDs • The gold standard for diagnosis of LSDs is enzyme assay. For most LSDs, this can be performed on leukocytes with fast turnaround. It is important to narrow down the differential diagnosis to help decide which assay to order. Cultured fibroblasts are required in a few LSDs. Cultured amniocytes or chorionic villus cells may be used for prenatal diagnosis. Biochemical determination of storage products is cumbersome, but has some applications. For instance, demonstration of GAGs in urine is a useful screening test for GAG storage. Storage of abnormal products can be detected by light and electron microscopy. In addition to neurons, gangliosides and ceroid-lipofuscin are stored in somatic cells and may be detected by nerve, muscle, skin, conjunctival, and other biopsies. Tissue diagnosis (detection of specific storage materials by electron microscopy) is still the standard for some NCLs because no other laboratory tests are available. The gene mutations of LSDs can be detected by DNA analysis. Mutation analysis is used mainly for carrier detection.
GLOBOID CELL LEUKODYSTROPHY (KRABBE'S DISEASE) • About one third of myelin lipid consists of galactocerebroside and its sulfated variant sulfatide. Deficiency of galactocerebrosidase (GALC) causes a severe infantile leukodystrophy, Globoid cell leukodystrophy (GCL) or Krabbe's disease. Children with the most common infantile form of GCL appear normal at birth but, in a few months, develop irritability, spasticity, progressive neurological regression, peripheral neuropathy and seizures and usually die in one or two years, many in a few months. Patients with late onset forms have a more protracted course eventually leading to severe disability and death.
Krabbe's disease In GCL, brain macrophages store galactocerebroside and are transformed into globoid cells. Most of the damage, however, is caused by accumulation in the white matter of a related metabolite galactosylsphingosine (psychosine), which is toxic to oligodendrocytes. The combined effects of lipid imbalance and toxicity result in early and severe myelin degeneration. The white matter in GCL is devoid of myelin and axons (except for the subcortical fibers), firm because of gliosis, and contains globoid cells, which tend to accumulate around vessels. The cortex is normal and there is no galactocerebroside storage in neurons. There is neuronal loss in the thalamus, cerebellum and brainstem. Peripheral nerves show a demyelinative and axonal neuropathy with accumulation of galactocerebroside in Schwann cells and macrophages.
GAUCHER DISEASE • Gaucher disease (GD) is due to deficiency of glucocerebrosidase (glucosylceramidase) and is characterized by storage of glucocerebroside (glucosylceramide) in monocyte-macrophage cells. Three clinical phenotypes are recognized. The most common is type 1 which is especially prevalent in Ashkenazi Jews. Type 1 GD presents from childhood to early adulthood and causes hepatosplenomegaly, bone disease (osteopenia, focal lytic or sclerotic lesions, osteonecrosis, pathologic fractures, chronic bone pain), anemia and thrombocytopenia due to hypersplenism, and pulmonary interstitial infiltrates. Spinal cord and root compression secondary to bone disease may also develop but there is no storage in the CNS. Type 2 (acute neuronopathic) GD patients have hepatosplenomegaly similar to type 1, but develop also neurological manifestations (stridor, strabismus and other oculomotor abnormalities, swallowing difficulty, opisthotonus, spasticity) which cause their death by 2 to 4 years of age. There is no special ethnic prevalence for type 2 GD. Type 3 (subacute neuronopathic) GD is frequent in Northern Sweden and has hematological and neurological manifestations similar to type 2 but milder and more slowly progressive. GD is the first LSD to be successfully managed by enzyme replacement.
Gaucher cells GD is the prototype of storage histiocytosis. Lysosomal storage of glucocerebroside in cells of the monocyte-macrophage system leads to a characteristic cellular alteration of these cells. Gaucher cells (GC) have a large cytoplasmic mass with a striated appearance that has been likened to "wrinkled tissue paper" or "crumpled silk". GCs are present in the bone marrow, spleen, lymph nodes, hepatic sinusoids, and other organs and tissues in all forms of GD. An increased incidence of cancer including lymphoma, myeloma, and bone tumors has been reported in GD patients. There is no storage in neurons or glial cells. In type 2 and 3 GD, there are numerous GCs in perivascular CNS spaces and rare GCs in brain parenchyma. No part of the CNS is spared but the brainstem and deep nuclei are more severely affected than the cortex and account for most neurological deficits. Along with the presence of GCs, type 2 and 3 GD shows also neuronophagia, neuronal loss, and gliosis. No neuronal storage is seen. Neuronal degeneration and loss have been attributed to the neurotoxic action of glucosyl sphingosine, a by-product of glucocerebroside not normally present in the brain.
MUCOPOLYSACCHARIDOSES (MPS) • Mucopolysaccharides (now called Glycosaminoglycans-GAGs) are synthesized in the Golgi apparatus and secreted and assembled in the extracellular space. They are produced by all cells, and are especially abundant in connective tissues. They are an important component of the matrix of connective tissue, cartilage and bone. For recycling, GAGs are internalized and degraded in a stepwise fashion by lysosomal enzymes. Deficiency of these enzymes causes lysosomal storage of GAGs. There are six clinical groups of MPS caused by deficiencies of ten GAG-cleaving enzymes.
Intracellular storage of GAGs in hepatocytes and other cells causes hepatomegaly, cellular dysfunction, and cell death. The most severe somatic changes in the MPS are due to accumulation of GAGs in matrix due to impaired recycling and to discharge of GAGs from dying mesenchymal cells. Because they are negatively charged, GAGs attract a lot of water that causes their molecules to swell to tremendous volumes. High GAG content of connective tissues affects collagen synthesis and causes increased collagen deposition. MPS MPS: thickened cardiac valves MPS-coronary artery: intimal thickening
The skin, connective tissues, and cartilage become swollen and distorted. The connective tissue and cutaneous changes cause facial deformity and macroglossia which gave rise to the insensitive term gargoylism. Cardiac valves and chordae tendineae become thickened and stiff. Endocardial and interstitial myocardial fibrosis develops. The intima of coronary arteries may be thickened to the point of occlusion and the aorta develops fibrous intimal plaques without lipid deposition. These changes cause a fatal cardiomyopathy and ischemic heart disease. GAG storage causes joint stiffening and swelling and complex skeletal deformities known as dysostosis multiplex. Storage in corneal fibroblasts causes corneal clouding. MPS: Hydrocephalus MPS: "zebra bodies"
GAG deposition in connective tissues of the brain and spinal cord causes thickening of the dura which along with distortion of vertebraeresults in compression myelopathy. Thickening of the arachnoid membrane impairs CSF flow, causing communicating hydrocephalus. But the most devastating neurological effects of MPS are due to neuronal storage of gangliosides. The mechanism of this storage is poorly understood. It is probably due to inhibition of neuraminidase and other lysosomal enzymes induced by the storage of GAGs. Thus, in addition to the skeletal, cardiovascular and other lesions, many MPS also cause neuronal lipidosis. Gangliosides stored in nerve cells take the form of concentric membranes (membranous cytoplasmic bodies) or stacks of membranes (zebra bodies).
NIEMANN-PICK DISEASE TYPE C • Type A and B Niemann-Pick disease are neurovisceral storage diseases caused by deficiency of sphingomyelinase. Niemann-Pick type C (NPC) is an LSD with protean clinical manifestations including neonatal hydrops, neonatal hepatitis, storage histiocytosis and neuronal lipidosis. The material that is stored in lysosomes in NPC is not sphingomyelin but cholesterol. Patients with NPC can import LDL cholesterol into lysosomes and remove the cholesteryl ester generating free cholesterol, but they cannot move free cholesterol to its normal cellular destinations. Thus, cholesterol accumulates in lysosomes. The mutant gene is located on 18q and its product, the NPC1 protein, is a transmembrane protein which acts as "gatekeeper" in the transport of lysosomal cholesterol to its other cellular targets. The "filipin test", which is used for diagnosis of NPC, consists of feeding cultured fibroblasts with LDL cholesterol tagged with the fluorescent dye filipin. The fibroblasts show bright fluorescence due to accumulation of cholesterol. NPC is rare but its study has produced some important insights into intracellular cholesterol homeostasis and trafficking.
Carbohydrates - Sugars and Polysaccharides • Monosaccharides - simple sugars, with multiple hydroxyl groups. Based on the number of carbons (e.g., 3, 4, 5, or 6) a monosaccharide is a triose, tetrose, pentose, or hexose, etc. • Disaccharides - two monosaccharides covalently linked • Oligosaccharides - a few monosaccharides covalently linked. • Polysaccharides - polymers consisting of chains of monosaccharide or disaccharide units.
Common monosaccharides found in vertebrates. N-Acetylneuraminic acid is the most common form of sialic acid.
HEZOSE KINASES These enzymes phosphorylate glucose to glucose-6-phosphate, which cannot get Out of the cell. Glucokinase of the liver has a lowe affinity, removing glucose when Blood concentrations are high.
Saccharide disorders Inborn errors of metabolism that prevent digestion or carbolism of saccharides. Clinical symptoms are mostly due to accumulation of metabolites Diarrhea of any cause can result in temporary laxtase deficiency
Hereditary fructose intolerance disease Hepatic fructose metabolism is quite rapid. That is, the initial step, phosphorylation by fructokinase is rapid. Further metabolism of fructose is dependent upon aldolase B. Normally, fructose consumption leads to a rapid flux into glycolysis at the triose phosphate level, enhancinggluconeogenesis, glycolysis and triglyceride synthesis . However, individuals who have reduced levels of aldolase B exhibit so-called fructose intolerance. They build up excessively high hepatic fructose-1-phosphate levels, trapping inorganic phosphate and reducing ATP synthesis accordingly. In these people, fructose is not a good substrate for glycolysis or gluconeogenesis. While the statistics on this are not clear, it appears that somewhere between 1 in 10,000 to 1 in 50,000 persons exhibit fructose intolerance. Declining ATP levels interfere with many of the liver's functions, among these are ureogenesis and gluconeogenesis.
Glycogen storage diseases The most common glycogen storage disease is Type I — von Gierke’s, or hepatorenal glycogen storage disease — which results from a deficiency of the liver enzyme glucose-6-phosphatase. This enzyme converts glucose-6-phosphate into free glucose and is necessary for the release of stored glycogen and glucose into the bloodstream, to relieve hypoglycemia. Infants may die of acidosis before age 2; if they survive past this age, with proper treatment, they may grow normally and live to adulthood, with only minimal hepatomegaly. However, there’s a danger of adenomatous liver nodules, which may be premalignant. Signs and symptoms Primary clinical features of the liver glycogen storage diseases (Types I, III, IV, VI, and VIII) are hepatomegaly and rapid onset of hypoglycemia and ketosis when food is withheld. Symptoms of the muscle glycogen storage diseases (Types II, V, and VII) include poor muscle tone; Type II may result in death from heart failure. (See Rare forms of glycogen storage disease.)
Diagnosis Confirming diagnosis Liver biopsy confirms the diagnosis by showing normal glycogen synthetase and phosphorylase enzyme activities but reduced or absent glucose-6-phosphatase activity. Glycogen structure is normal but amounts are elevated. Spectroscopy may be used to show abnormal muscle metabolism with the use of magnetic resonance imaging in specialized centers. ❑ Laboratory studiesof plasma demonstrate low glucose levels but high levels of free fatty acids, triglycerides, cholesterol, and uric acid. Serum analysis reveals high pyruvic acid levels and high lactic acid levels. Prenatal diagnoses are available for Types II, III, and IV. ❑ Injection of glucagon or epinephrine increases pyruvic and lactic acid levels but doesn’t increase blood glucose levels. Glucose tolerance test curve typically shows depletional hypoglycemia and reduced insulin output. Intrauterine diagnosis is possible.
Mucopolysaccharidoses • The mucopolysaccharidoses are a group of inherited metabolic diseases caused by the absence or malfunctioning of certain enzymes needed to break down molecules called glycosaminoglycans - long chains of sugar carbohydrates in each of our cells that help build bone, cartilage, tendons, corneas, skin, and connective tissue. Glycosaminoglycans (formerly called mucopolysaccharides) are also found in the fluid that lubricates our joints. • People with a mucopolysaccharidosis either do not produce enough of one of the 11 enzymes required to break down these sugar chains into proteins and simpler molecules or they produce enzymes that do not work properly. Over time, these glycosaminoglycans collect in the cells, blood, and connective tissues. The result is permanent, progressive cellular damage that affects the individual's appearance, physical abilities, organ and system functioning, and, in most cases, mental development. • Who is at risk? It is estimated that one in every 25,000 babies born in the United States will have some form of the mucopolysaccharidoses. It is an autosomal recessive disorder, meaning that only individuals inheriting the defective gene from both parents are affected. (The exception is MPS II, or Hunter syndrome, in which the mother alone passes along the defective gene to a son.) When both people in a couple have the defective gene, each pregnancy carries with it a one in four chance that the child will be affected. The parents and siblings of an affected child may have no sign of the disorder. Unaffected siblings and select relatives of a child with one of the mucopolysaccharidoses may carry the recessive gene and could pass it to their own children.
