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On physical examination, you find mod- erate hepatosplenomegaly. Treatment Elimination of galactose from the diet. Treatment and Experimental treatments include hepatic or bone marrow transplantation and enzyme Prognosis therapy. On physical examination, the child 4 is afebrile; however, you note that his Moro reflex is absent and that his muscle tone is rigid. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free.

ATP Because acetyl CoA is primarily formed in the CO2 CO2 mitochondria usually by pyruvate dehydroge- Pyruvate Pyruvate nase , the citrate shuttle is necessary to transport acetyl CoA into the cytosol, where fatty acid syn- thesis occurs. Furthermore, the citrate shuttle produces NADPH, which is subsequently used in the process of fatty acid synthesis.

The carnitine transport system shut- tles long-chain fatty acids from the cytosol into Fatty-acyl the mitochondria. The fatty acyl chain is enzymatically CoA Carnitine Carnitine attached to carnitine in the cytosol via carnitine Acyl Acyl acyl transferase I, and then shuttled across the Transferase I Transferase II mitochondrial membrane. Because long-chain fatty acids are unable to enter the mitochondria, the carnitine transport system allows for the movement of fatty acids in the mitochondrial matrix where fatty acid oxidation occurs.

Inherited defects in the carnitine shuttle present with hypoglycemia, muscle pain, and muscle atrophy because of the accumulation of fat in muscle tissue. Affected infants benefit from being fed fat with medium-chain triacylglycerols eg, butter fat because medium-sized fatty acids can bypass the carnitine shuttle. Dietary cholesterol and triglycerides are Intestine Chylomicron absorbed from the intestinal lumen into the mucosal Lip ipase Triglycerides cells of the small intestine, where they are incorpo- opr L rated into chylomicrons and released into the blood- ot e stream.

Chylomicrons are degraded by LPL, which in Glycerol is present on the capillary endothelium of muscle Chylomicron Remnant Free Fatty Acids and adipose tissue, into glycerol, free fatty acids, and 3 rich in cholesterol a chylomicron remnant. The free fatty acids are either stored in adipose cells or taken up by muscle or other Liver peripheral tissues.

The glycerol is transferred to the Peripheral Adipose liver. The remnant of the chylomicron, which is rich HDL Tissues Cells in cholesterol molecules, is then either directly taken up by the liver through endocytosis or transported to the liver by HDL. Either used as fuel in muscle or other peripheral tissues or stored as triacylgycer- ols in adipose tissue.

Transferred to the liver where it is used in glucose synthesis. Absorbed by the liver where the cholesterol within the remnant is either converted to bile acids or transformed to VLDLs. L i p i pa s e Triglycerides The free fatty acids are taken up by the peripheral tissues opr L for fuel or are stored in the adipose cells. If absorbed by the peripheral tissues, LDL is Chylomicron Remnant rich in cholesterol degraded intracellularly into cholesterol and cholesterol esters, which are then released into the bloodstream.

The Liver cholesterol esters are picked up by HDL with the help of Peripheral Adipose the cholesterol ester transfer protein and transported out of HDL Tissues Cells the bloodstream and back into the liver. Broken down to free fatty acids and LDL by lipoprotein lipase. Absorbed by liver or peripheral tissues via LDL receptors. Attached to HDL by cholesterol ester transfer protein and transported back to liver.

Acetyl CoA; acetoacetyl CoA. This enzyme is the pharmacologic target of lovastatin and other Mevalonic Acid drugs in that class. Cholesterol esterification by LCAT traps choles- terol in HDL and prevents membrane cholesterol uptake, which can lead to alterations in membrane permeability. Sphingolipid synthesis occurs in the cytosol. Serine; palmitoyl CoA. Principal lipid of nervous tissue Sphingosine membranes. Acidic glycosphingolipids found in ganglion cells of the nervous system.

Acidic glycosphingolipids found pri- UDP-galactose Ceramide marily in nervous tissue. There are two phases in sphingo- lipid synthesis. In general Sulfatides though, the second phase involves the addition of a specific compound eg, phosphocholine, glucose, galactose, sulfate, etc to the hydroxyl group on the terminal carbon of the ceramide molecule.

Normally degraded by lysosomes. Phospholipid synthesis occurs in the cytosol in the cells of the liver, intestine, and adipose tissue. Negatively charged phospholipid; when phosphorylated, it plays a major role in cell signaling. Most abundant phospholipid; it is neutral; acts as key component of lipoproteins, as well as membranes of cells in several types of tissues; may have a role in cell-signaling.

Found in membranes in the cells of the nervous tissue particularly white matter of the brain. Acidic phospholipid found mostly in membranes of myelin cells.

All phospholipids are derived from 1, 2-DAG. The addition of a phosphorylated ethanol- amine group to 1,2-DAG results in phosphatidyl ethanolamine.

The addition of an activated choline group to 1,2-FAG results in phosphatidyl choline. The addition of an inositol group to phosphorylated 1,2-DAG results in phosphatidylinositol. Phosphatidylserine is formed by the exchange of a serine group for the etha- nolamine group on phosphatidyl ethanolamine. Normally degraded by a family of enzymes known as phospholipases. The pain lasts for about 2 minutes at a time and radi- ates up to his left jaw. He reports that the pain is relieved by rest.

The patient reports that his father and two paternal uncles had heart attacks during their 30s.

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His symptoms and ECG are consistent with stable angina. While you prescribe nitroglycerin to treat the angina, you also order a serum lipid panel because you are concerned that this patient may have a codominant genetic disorder that is putting him at a very high risk for early-onset atherosclerotic heart disease.

This results in increased plasma LDL levels, leading to intracellular and extracellular deposits of cholesterol, which result in xanthomas and xanthelasmas as well as premature atherosclerotic disease. Clinical Homozygotes develop severe atherosclerosis with heart disease in early or middle age.

Manifestations Other symptoms include tendon xanthomas of the Achilles and knuckle extensor tendons, tuberous xanthomas soft, painless nodules on elbows and buttocks, and xanthelasmas barely elevated deposits of cholesterol on eyelids. Treatment Low-fat, low-cholesterol diet and exercise; HMG-CoA reductase inhibitor atorvastatin or simvastatin in combination with cholestyramine; nicotinic acid can be added as a third agent.

Notes The homozygous form of the LDL receptor mutation is rare 1: He 3 has a history of pancreatitis, but his current symptoms do not suggest an acute process. Upon taking a family history, you discover that several members of his family, including his mother and two sisters suffer from an inherited metabolic disease.

On funduscopic examination, you discover the presence of lipemia retinalis. Abdominal examination shows moderate hepatosplenomegaly. You are con- cerned that this patient may have a genetic disorder predisposing him to attacks of abdominal pain. You order serum studies, looking for elevated fasting plasma triglycerides, along with tests for elevated amylase and lipase.

In addition to a low-fat diet and exercise, you also start the patient on gemfibrozil. Pathophysiology Pathophysiology involves both reduced catabolism of triglyceride-rich lipopro- teins and overproduction of VLDL in the liver.

Also associated with an increased risk of vascular disease. Notes Obesity, inactivity, alcohol use, and insulin resistance are associated with hyper- triglyceridemia.

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Physical examination reveals small orange-red papules on his scalp, elbows, and knees that are not painful to the touch. You order serum studies, which demonstrate elevated triglyceride levels as well as elevated levels of chylo- microns and VLDL.

You explain to the patient that he likely has a partial genetic deficiency of an enzyme involved in lipid metabolism, and you start the patient on gemfibrozil and fish oil supple- ments. Mixed hypertriglyceridemia type V is a heterogeneous disorder caused by a partial deficiency as opposed to total deficiency in either LPL or apoprotein C-II. Treatment Lifelong fat-free diet; niacin, gemfibrozil, or fish oil supplements.

Notes Obesity, inactivity, alcohol use, and insulin resistance are associated with hypertriglyceridemia. Although she is feeling well during this visit, she is concerned about what may have led to a heart attack so early in her life.

She eats a regular diet and exercises twice a week. On physical examination, you notice cholesterol deposits in the palmar creases of both her hands. She also has two very small tuberous xanthomas near her buttocks.

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You believe that the patient may benefit from niacin and clofibrate treatment. Clinical Manifestations Tuberous xanthomas; striae palmaris deposits of cholesterol in palmar creases are pathognomonic; vascular disease is present usually by the fifth decade. Treatment Niacin and fibrates. He tells you that 3 his past medical history includes peripheral arterial disease, borderline diabetes mellitus, and high cholesterol.

Family history is significant for early-onset coronary artery disease as well as hyper- lipidemia in several family members. Routine laboratory studies reveal moderately elevated total cholesterol levels as well as moderately elevated triglyceride levels. The proband initial case discovered within a fam- ily typically has combined hyperlipidemia or isolated hypertriglyceridemia.

Pathophysiology The defect results in the overproduction of apo B lipoproteins, which results in the increased circulation of VLDL particles in the blood.

Clinical Manifestations Type IIb: Usually asymptomatic until premature vascular disease appears by fifth decade; insulin resistance; patients usually do not have xanthomas.

Moderately elevated triglyceride and total cholesterol levels. While evaluating the patient, you notice that he is small for his age, has a large tongue, and has mild coarsening of his facial features. On ophthalmo- logic examination, you find bilateral corneal opacities and papilledema. You believe that the patient may be suffering from an autosomal recessive trait caused by a deficiency in a lysosomal enzyme.

Although the patient may benefit from symptomatic treatment for his eyes, you fear that his prog- nosis is grim and that he will likely die in childhood. When this enzyme is deficient, there is a buildup of dermatan sulfate and heparan sulfate GAGs that are linked to proteins in connective tissue.

Dermatan sulfate and heparan sulfate tend to accumulate in the skin and bones leading to physical deformities , and in the heart, liver, and brain leading to abnormal functioning of these organs. Clinical Manifestations Affected infants are normal at birth but exhibit mild coarsening of facial features and growth retardation in the first year.

Distinguishing features include coarse facies, joint stiffness, short stature, and valvular heart disease. Other symptoms include hepatosple- nomegaly, corneal clouding, large tongue, developmental delay, dwarfism, hearing loss, and mental retardation. Dermatan sulfate and heparan sulfate in the urine. Treatment and Symptomatic therapies currently include corneal transplantation, heart valve replacement, Prognosis and physical therapy for joint contractures.

Bone marrow transplantation and enzyme replacement are experimental. Death usually occurs before age Hurler disease, Scheie syndrome, Hunter disease, Sly syndrome, and Sanfilippo disease are considered mucopolysaccharidoses. On physical examination, you find that the patient has coarse facial features, a large tongue, a small jaw, and marked hepatosplenomegaly. He also has a distinctive nonpainful, pebbly skin lesion on his upper back.

When asked to perform movements, he exhibits remarkable joint stiffness for his age and is unable to touch his toes from a standing position. You order a urinalysis, looking for dermatan sulfate and heparan sulfate, which you suspect will be present in the urine if the patient has a particular X-linked recessive disorder. Pathophysiology Iduronate sulfatase is a lysosomal enzyme that is involved in the breakdown of GAGs. When this enzyme is deficient, there is a buildup of dermatan sulfate and heparan sulfate GAGs that are linked to proteins in connective tissue as in Hurler disease.

Dermatan sulfate and heparan sulfate tend to accumulate in the skin and bones, leading to physical deformities, and in the heart, liver, and brain, leading to abnormal function- ing of these organs. Clinical Manifestations As in Hurler disease, affected Hunter disease infants are normal at birth but develop coarse facies, growth retardation, joint stiffness, hepatosplenomegaly, large tongue, small jaw, mental retardation, and valvular heart disease as they age.

Unlike Hurler disease, patients with Hunter disease have retinal degeneration but no corneal cloud- ing, mild or no mental retardation, and distinctive pebbly skin lesions. Treatment Symptomatic therapies currently include heart valve replacement and physical therapy for joint contractures.

Bone marrow transplantation has been unsuccessful, and enzyme replacement therapy is experimental. Notes Hurler disease, Scheie syndrome, Hunter disease, Sly syndrome, and Sanfilippo disease are considered mucopolysaccharidoses.

The patient was last seen 2 weeks ago for progressive behavioral problems, including lashing out at other children in the playground. On physical examination, you noticed that the child had mildly coarse facial features. When this enzyme is deficient, there is a buildup of heparan a GAG that is linked to proteins in connective tissue. Heparan sulfate tends to accumulate in the skin and bones leading to physical deformities , and in the liver and brain leading to abnor- mal functioning of these organs.

Clinical Manifestations Affected infants present with severe mental retardation, mild coarse facies, progressive behavioral problems, and CNS disease in the form of seizures. Treatment and Prognosis Psychotropic drugs to control behavior. Patients can survive into the third or fourth decade, although they will suffer from progressive CNS disease.

On physical examination, you note that the child is short for his age and that he has coarse facies. Spinal examination reveals mild kyphosis.

When you ask the mother how the child has been doing in school, she admits that he is behind his classmates in reading and writing and that his teachers have wondered if he has some form of a learning disability. Clinical Patients present in infancy with short stature, coarse facies, and spinal deformities Manifestations kyphosis or scoliosis.

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CNS disease is manifested as mental retardation. Bone marrow malfunctioning is manifested as recurrent infections as well as hepatosplenomegaly.

In its most severe form, hydrops fetalis can result prior to birth. Treatment and Supportive treatment with physical therapy to treat skeletal deformities. Survival to middle Prognosis age is possible with milder forms of the disease. On 3 physical examination, you notice that the child has an exaggerated startle reaction to noise while otherwise appearing quite limp and sleepy.

He has a fixed gaze and a larger-than-normal head size. On funduscopic examination, you identify macular pallor with a distinctive cherry-red spot. You begin to suspect that this patient may suffer from an autosomal recessive disorder that results in a progressive neurologic disease and death by age 3. Pathophysiology Hexosaminidase A is a lysosomal enzyme that is involved in the breakdown of gan- gliosides, a type of glycolipid that contains neuraminic acid and is found in high concen- tration in the ganglion cells of the CNS.

When this enzyme is deficient, there is the accumulation of GM2 gangliosides, which are toxic to neuronal cells and lead to progres- sive neurologic damage.

Clinical Manifestations There are several different clinical forms of this disorder. The infantile form is a neurode- generative disease characterized by macrocephaly, loss of motor skills, increased startle reaction to noise hyperacusis , hepatosplenomegaly, and macular pallor with cherry-red spot on retinal examination.

The juvenile-onset form presents with dementia and ataxia. The adult-onset form is characterized by childhood clumsiness, progressive motor weakness in adolescence, spinocerebellar or lower motor neuron symptoms in adulthood, and the eventual development of psychosis.

Treatment and Supportive treatment for symptoms. The infantile form usually results in death by age 3; Prognosis the juvenile form results in death by age Notes Screening for Tay-Sachs disease carriers is recommended among Ashkenazi Jews because 1 in 30 people of this descent carries the allele for this disease. Tay-Sachs disease and Sandhoff disease are considered GM2 gangliosidoses. On physical examination, you note that the child has an ataxic gait and is unable to write without shak- ing.

Ophthalmologic examination is significant for macular pallor with a cherry-red spot. You tell the parents that you believe that their son is suffering from an autosomal recessive disorder caused by defects in two lysosomal enzymes.

Pathophysiology Hexosaminidase A and B are lysosomal enzymes, which are involved in the break- down of gangliosides, a type of glycolipid that contains neuraminic acid and is found in high concentration in the ganglion cells of the CNS. When this enzyme is deficient, there is the accumulation of GM2 gangliosides, which are toxic to neuronal cells and lead to progressive neurologic damage. Clinical Manifestations Sandhoff disease is nearly identical to Tay-Sachs disease in that it is a fatal neurodegen- erative disorder.

In its infantile form, it is characterized by macrocephaly, loss of motor skills, seizures, and macular pallor with cherry-red spot on retinal examination. In its later- onset variants, patients suffer from progressive visceral and degenerative CNS disease.

Unlike Tay-Sachs disease, Sandhoff disease patients do not have hepatosplenomegaly or bony dysplasias, and the course of the disease is more rapid. Treatment Supportive treatment for symptoms. He tells you that she is caring for a year-old patient, who has developed the slow onset of dementia as well as gait ataxia over the last 2 years.

Neurologic workup for causes of early-onset Parkinson disease has been unrevealing, and your colleague is beginning to suspect that his patient may suffer from a genetic disease. When this enzyme is deficient, there is the accumulation of GM1 gangliosides, which are toxic to neuronal cells and lead to progressive neurologic damage. Clinical Manifestations There are three clinical subtypes of GM1 gangliosidosis. Type 1 infantile manifests at birth with hepatosplenomegaly, coarse facies, macular cherry-red spots, and CNS dysfunc- tion.

Type 2 juvenile presents within the first 3 years of life and is not marked by orga- nomegaly or macular spots, but does have coarse facies and skeletal deformities. Type 3 adult is marked by a normal childhood; however, dementia and CNS degeneration with gait ataxia develop by middle age. Treatment and No effective treatment is currently available. The infantile subtype is usually fatal by age 2. These painful episodes occur only after strenuous exercise or when he is sick with the flu.

On physical examination, you notice telangiectatic skin lesions on his back that are dark red, punctate, and nonblanching with pressure. He states that these lesions have grown in size and become more numerous over the years. His neurologic examination is normal.

You believe that he may be suffering from an X-linked recessive disorder that is associated with a lysosomal enzyme deficiency, and you prescribe pheny- toin and carbamazepine for treatment of his painful burning episodes while you await further genetic testing.

When this enzyme is deficient, globotriaosylceramide ceramide trihexoside accumulates in the skin, heart, kidneys, and CNS, leading to abnor- mal functioning of these organs. Clinical The disease presents in childhood with angiokeratomas telangiectatic skin lesions , acro- Manifestations paresthesia, and hypohidrosis sweating less than usual.

Angiokeratomas are small, punctate, and dark red to blue-black, do not blanch with pressure, and increase in size and number with age. The acroparesthesia presents as episodic burning pain of the hands, feet, and proximal extremities that is precipitated by exercise, fatigue, or fever. Corneal and lenticular lesions are detectable on slit-lamp examination, with tortuosity of conjunctival and retinal vessels.

Patients may eventually develop heart failure and renal failure as well. Elevated serum BUN and creatinine. Treatment Phenytoin and carbamazepine diminish acroparesthesia; dialysis and kidney transplantation for renal failure. Notes Fabry disease, Gaucher disease, and Niemann-Pick disease are classified as neutral glycosphingolipidoses. He has 3 been held back in school several times and has just recently begun forgetting common, everyday facts.

On further questioning, he informs you that he has also become more injury prone, sustaining small fractures over the last 2 years while playing sports. On physical examination, you find mod- erate hepatosplenomegaly.

Neurologic examination shows defects in his lateral gaze tracking. These findings lead you to suspect that he may suffer from an autosomal recessive disorder that is associated with a lysosomal enzyme deficiency. When this enzyme is deficient, glucosylceramide glucocere- broside accumulates in the brain, liver, spleen, and bone marrow, causing damage to those organs.

In the bone marrow specifically, there is the infiltration of Gaucher cells lipid-laden macrophages , which leads to infarction, necrosis, and cortical bone destruction. Clinical There are multiple clinical forms of this disorder. Patients exhibit hepatosplenomegaly as Manifestations well as variable manifestations in the CNS and viscera. Type I adult form presents in early adulthood with rapidly progressive, myoclonic seizures and aseptic necrosis with fractures of the femoral head.

Type II infantile form presents early with slowly progressive CNS involvement and mental retardation. Type III juvenile form presents in adolescence with dementia. Mild anemia and thrombocytopenia; bone marrow biopsy reveals Gaucher cells characteristic wrinkled tissue paper—appearing macrophages. Symptomatic management of the blood cytopenias; joint replacement surgeries. Notes Gaucher disease type I is the most common and most compatible with life.

Fabry disease, Gaucher disease, and Niemann-Pick disease are classified as neutral glycosphingolipidoses. Your initial physical examination demonstrated possible diminished vision in both eyes, dyspnea, hepatosplenomegaly, and a general failure to thrive. With this information, you inform the mother that her child has an autosomal recessive genetic disorder associated with a lysosomal enzyme deficiency.

Although there is no specific treatment, you inform the mother about possible clinical trials involving bone marrow transplantation and enzyme replacement therapy. Pathophysiology Sphinogomyelinase is a lysosomal enzyme that is responsible for converting sphingomy- elin to ceramide during glycosphingolipid catabolism. When this enzyme is deficient, sphingomyelin accumulates in the histiocytic lysosomes foam cells of the brain, liver, spleen, bone marrow, and lung, leading to dysfunction of these organs.

Clinical Manifestations Two clinical variants exist. NPD type A presents in the first 6 months of life with rap- idly progressive CNS deterioration seizures , spasticity, and failure to thrive. NPD type B has a later onset. In both types, patients develop mental retardation, hepatosple- nomegaly, osteoporosis, and macular degeneration.

There is also progressive pulmo- nary disease, which eventually leads to the development of pulmonary hypertension and cor pulmonale. Reticular infiltrative pattern on chest x-ray film.

Treatment and Experimental treatments include hepatic or bone marrow transplantation and enzyme Prognosis therapy. Death usually occurs during adolescence from pulmonary disease.

The 3 mother states that she has noted that her child has developed swollen glands and joints over the last few weeks. She also states that the child often chokes when feeding. Pathophysiology Acid ceramidase is a lysosomal enzyme that is responsible for converting ceramide to sphingosine during glycosphingolipid catabolism. When this enzyme is deficient, cer- amide accumulates in the histiocytic lysosomes foam cells of the musculoskeletal system, throat, liver, and central nervous system, leading to dysfunction of these organs.

Clinical Patients tend to present with the disease within the first few months of life, although phe- Manifestations notypic variability has had some patients presenting later in childhood. Symptoms include developmental delay, arthritis with joint swelling and contracture, hoarseness, dys- phagia, and hepatosplenomegaly. There are multiple clinical forms with variable progno- Prognosis ses, although most patients die of the disease by age 3. The child 3 has been small for his age and quite lethargic since birth.

He has not met his developmental mile- stones. On initial physical examination, you notice the child has significantly coarse facial features as well as significant deterioration of his gums. Fundoscopic examination reveals corneal clouding. When serum studies reveal highly elevated levels of lysosomal enzymes in the plasma, you imme- diately become concerned that the child may suffer from an autosomal recessive disorder caused by a deficiency in a lysosomal phosphotransferase.

Pathophysiology N-acetylglucosaminephosphotransferase is involved in the development of the mannosephosphate signal, which serves to sort lysosomal enzymes into the lyso- somes during enzyme production. When this enzyme is deficient, there is defective cell targeting of lysosomal hydrolases, which leads to numerous enzymes being secreted out- side the cell and accumulation of their substrate mucopolysaccharides outside the cell.

Clinical Manifestations Small, lethargic infants with mental retardation, corneal clouding, coarse facies, and gingival hypoplasia. Greatly elevated serum levels of lysosomal enzymes; absence of mucopoly- sacchariduria. Treatment Symptomatic treatment. Notes I-cell disease is categorized as a mucolipidosis. He states 3 that he developed his first seizure 6 months ago. He describes the seizures as whole-body jerks that last a few seconds. On neurologic examination, you note macular cherry-red spots as well as mild gait ataxia.

You tell the patient that his symptoms of myoclonic seizures in conjunction with his findings on neurologic examination may be consistent with a metabolic disorder that is caused by an abnormality in the degradation of glycoproteins. Pathophysiology Sialidase is involved in the degradation of glycoproteins with sialic acid moieties. When this enzyme is deficient, there is defective degradation of sialyloligosaccharides, resulting in the abnormal accumulation of these glycoproteins in lysosomes in the cells of the mus- culoskeletal system, central nervous system, and reticuloendothelial system.

Clinical There are two clinical forms of the disorder. Type I presents in early adulthood with myo- Manifestations clonic seizures, gait instability, and macular cherry-red spots. Type II presents in early childhood with coarse facies, skeletal abnormalities, hepatosplenomegaly, and developmen- tal delay. Only some patients with type II disease will have macular cherry-red spots. Treatment and Supportive treatment of symptoms.

Type I form of the disease is usually fatal by age 35, Prognosis whereas type II form of the disease is fatal by age 2. On physical examination, you discover that the patient is small for her age and has hyperactive deep tendon reflexes and marked hamstring rigidity.

She does not have much of a startle reflex, suggesting possible diminished visual or hearing acuity. Her suck reflex is also quite weak. Laboratory serum studies are within normal limits. You begin to wonder whether this child might suffer from a leukodystrophy disorder associated with demyelination in the CNS, and you refer the child and her family to a medical geneticist.

Pathophysiology Galactosylceramidase is a lysosomal enzyme that catalyzes the conversion of galactosyl- ceramide galactocerebroside to ceramide during glycosphingolipid catabolism. When this enzyme is deficient, there is an accumulation of galactosylceramide galactocerebro- side and galactosyl sphingosine in the brain, leading to neuronal damage white matter globoid cells on gross pathology and demyelination.

Clinical Optic atrophy blindness ; deafness; spasticity or paralysis; mental retardation; seizures. Manifestations Treatment and Symptomatic treatment. Prognosis This disease is usually fatal in childhood. Notes Krabbe disease and metachromatic leukodystrophy are classified as the leukodystrophies. The infant was born full term without any complications during pregnancy. He had met all developmental milestones up to this point.

On standing the patient up, you find a wide- based gait and ataxia. The child also has mildly hyperreflexive deep tendon reflexes. The parents were also concerned about possible seizure-like activity 1 week ago.

A lumbar puncture shows increased protein, thereby ruling out cerebral palsy. You become concerned about an autosomal recessive leukodystrophy that tends to present in this fashion, and you set out to diagnose this dis- order by demonstrating a deficiency of arylsulfatase A in nucleated cells.

Pathophysiology Arylsulfatase A is involved in the conversion of galactosylceramide sulfate to galactosylce- ramide during glycosphingolipid catabolism. When this enzyme is deficient, there is an accumulation of galactosylceramide sulfate or sulfatide in the nervous system especially CNS white matter and myelinated peripheral nervous system tracts , kidney, and liver.

Clinical There are several clinical variations of this disorder.

The infantile form presents by age 2 with Manifestations regression of developmental milestones and mental retardation. The juvenile and adult forms present with ataxia gait disturbances , mental regression, optic atrophy, peripheral neuropathy, and seizures. In adults, behavioral disturbances such as psychosis and demen- tia are common. Metachromasia of nerves with staining on microscopic examination. Treatment and Later-onset diseases respond to bone marrow transplantation.

The infantile and juvenile Prognosis forms of the disease are usually fatal by age Adrenal leukodystrophy is a rare, fatal X-linked recessive disorder characterized by the defective breakdown of very long-chain fatty acids, resulting in the accumulation of choles- terol esters in the CNS white matter, peripheral nerves, adrenal cortex, and testes. Patients present in early childhood with gait deterioration, spasticity resulting from demyelination, seizures, loss of vision, and Addison disease caused by adrenal gland degeneration.

These amino Acidic Aspartic acid Polar acids are called essential amino acids and include Glutamic acid phenylalanine, valine, tryptophan, threonine, iso- Uncharged Serine Glutamine leucine, methionine, histidine, leucine, and lysine. This can be done either via transamination or oxidative deamination see card This transport occurs with the help of alanine and glutamine see card Once in the liver, the ammonia moiety is transformed into urea via the urea cycle see card The remaining carbon skeleton are then degraded into intermediates of the citric acid cycle or can be used as building blocks for other molecules see card The branched-chain amino acids valine, isoleucine, leucine require specific enzyme complexes in order to be fully degraded see card Many tissues, especially liver, skeletal Alanine muscle, and kidney.

Pyridoxal phosphate vitamin B6. Deamination is the first step in amino acid metabolism and can occur either through trans- Glutamate Oxaloacetate amination or oxidative deamination. Almost every amino acid has a specific aminotransferase. Liver and kidney. Oxidative deamina- NAD P H tion acts to remove the amino group from glutamate and release it as ammonia. Skeletal muscle and liver. Skeletal muscle, brain, kidney, and liver.

Alanine transaminase. Glutamine synthetase; glutaminase. To transport free ammonium moieties formed removed from amino acids to the liver for metabolism in the tissues to the liver for metabolism. This reaction requires one ATP. This ammonium ion can then be directly the bloodstream to the liver. Cytosol and mitochondria of hepatocytes. Urea; fumarate; H2O. Converts ammonium and bicarbonate into carbamoyl phosphate. This is the rate-limiting step in the urea cycle. This reaction requires two ATP and occurs in the mitochondria.

Combines ornithine and carbamoyl phosphate to form citrulline. Located in mitochondria. Condenses citrulline with aspartate to form arginosuccinate. This reaction occurs in the cytosol and requires one ATP. Splits argininosuccinate into arginine and fumarate. Occurs in the cytosol. Cleaves arginine into one molecule of urea and ornithine in the cytosol.

The ornithine is then transported back into the mitochondria for entry back into the cycle. Carbamoyl phosphate synthetase I catalyzes the rate-limiting step of the cycle and is stimu- lated by N-acetylglutamate. Ammonia intoxication leads to CNS deterioration in the form of men- tal retardation, seizure, coma, and death.

The amino acid carbon skeletons undergo a series of reactions in order to be used as a fuel source or they can be used as building blocks to make other molecules. If an amino acid is keto- genic, its carbon skeleton will be used for ketogenesis. If an amino acid is glucogenic, its carbon skeleton will be used for glucogenesis. Lysine and leucine are strictly ketogenic. Isoleucine, phenylalanine, tryptophan, and tyrosine are both glucogenic and ketogenic. All other amino acids are strictly glucogenic.

Mitochondria of skeletal muscle cells. Branched-chain amino acids valine, isoleucine, leucine require the use of two common enzyme complexes to catalyze their degradation. The products of degradation are intermediates in the pathways for fatty acid synthesis or the citric acid cycle and hence are converted to energy. This enzyme uses pyridoxal phosphate as a cofactor.

This enzyme complex requires lipoate and thiamine pyrophosphate as cofactors. Phenylalanine can be converted into one of two products. Alternatively, phenylalanine can be used to synthesize tyro- sine. The conversion of phenylalanine to tyrosine is catalyzed by phenylalanine hydroxylase. Hydroxylates phenylalanine to tyrosine. Requires tetrahydrobiopterin and O2 as cofactors. Regenerates tetrahydrobiopterin by reducing dihydrobiopterin to form tetra- hydrobiopterin.

When phenylalanine hydroxylase or dihydropteridine reductase is deficient, phenylketonuria results see card Methionine is the precursor for the formation of SAM, which is used as a methylating agent in many reactions. Furthermore, after several more reactions, methionine can be transformed into homocysteine, which can then either be converted back to methionine with the help of N5-methyl-tetrahydrofolate and methyltransferase with vitamin B12 or can be converted into cysteine with the help of cystathionine synthase.

Converts methionine to SAM. Uses one ATP. Converts excess homocysteine back into methionine. Requires vitamin B12 as cofactor as well as a molecule of N5-methyl-tetrahydrofolate. Combines serine and homocysteine to form cystathionine, which is eventually converted to cysteine. Requires pyridoxal phosphate as a cofactor. When either cystathionine synthase or methyltransferase is deficient or there is a decreased affinity of cystathionine synthase for pyridoxal phosphate which results in decreased function of the enzyme , homocystinuria results see card He has just moved to the area and tells you that has avoided physicians most of his young life.

He reports that his knee pain is a chronic issue along with chronic back pain. On 4 physical examination, he has limited range of motion of both his spine and knees. He also has dark spots in his conjunctiva and nasal bridge. On further questioning, you learn that the water in his toilet bowl turns black if he forgets to flush it after urination. You order x-ray films of his back and knees and send his urine for analysis, expecting to find premature arthritic changes on x-ray film and elevated urine homogentisic acid in the urinalysis.

Pathophysiology Homogentisic acid oxidase is responsible for the degradation of tyrosine. When this enzyme is defective, there is a buildup of tyrosine, phenylalanine precursor to tyrosine , and homo- gentisic acid intermediate in tyrosine breakdown.

The accumulation of homogentisic acid causes degeneration of cartilage, leading to a dark blue discoloration of connective tissue ochronosis and degenerative joint disease. Clinical Increased pigmentation of ears, nasal bridge, conjunctiva, neck, and anterior thorax; Manifestations arthralgias and incapacitating arthritis of knee joints, spine, and fingers. Elevated urine homogentisic acid; dark urine caused by polymers of homo- gentisate.

Premature arthritic changes and cartilaginous calcifications seen on x-ray film. Treatment Symptomatic treatment of arthritis. Physical examination is remarkable for a slight fever, tachycardia, and tenderness in the right upper quadrant of the abdomen and right flank.

His 4 routine urinalysis shows hematuria. After three-way films of the abdomen revealing a radiopaque stone in the area of the right kidney, you begin treating him for kidney stones. When further urinalysis testing reveals the presence of cysteine crystals, you begin to wonder whether this patient might suffer from an autosomal recessive disorder that is associated with abnormal renal and intestinal transport of four amino acids.

Pathophysiology The amino acid transporter is responsible for transporting cysteine, ornithine, lysine, and arginine. Defective tubular reabsorption of these amino acids in the kidneys results in increased cysteine in the urine, which can precipitate and cause kidney stones.

Clinical Cysteine kidney stones presenting with severe, intermittent flank pain and hematuria. Manifestations Lab findings: Increased urinary excretion of cysteine, ornithine, arginine, and lysine on urine amino acid chromatography; hematuria and cysteine crystals hexagonal on cooling of acidified urine sediment. Radiopaque kidney stones on CT scan.

Treatment Low-methionine diet; increased fluid intake; acetazolamide to alkalinize the urine. Notes Cystinosis is a rare disorder characterized by the intralysosomal accumulation of free cys- teine in body tissues. One variant of cystinosis is the infantile nephropathic autosomal recessive form, which manifests as Fanconi syndrome. Fanconi syndrome is characterized by renal proximal tubular dysfunction, leading to hypophosphatemia, renal glycosuria, generalized amino aciduria, and hypokalemia.

Clinical manifestations include growth retar- dation, vomiting, rickets, polyuria, dehydration, metabolic acidosis, and photophobia.

Death usually occurs as a result of uremia or infection by age He reports that the rash is usually worse after he spends the day outside. On further question- ing, he also reveals that he has been feeling more irritable than usual. Physical examination is sig- 4 nificant for mild photophobia, an ataxic gait, and the presence of a scaly, red rash on the face, back of the neck, and extensor surfaces of his limbs.

You feel as though his symptoms are rather consis- tent with niacin vitamin B6 deficiency, although he reports eating a healthy and well-balanced diet. You prescribe nicotinic acid supplements and concurrently refer him to a geneticist for workup of a rare autosomal recessive disease that causes defective transport of certain amino acids in the intestine and kidney.

Pathophysiology The neutral amino acid transport channel is present in both the proximal tubule of the nephron and the brush border of the small intestine. If this transport channel is defec- tive, neutral amino acids cannot be absorbed in the intestine or reabsorbed by the kidney after filtration, thereby resulting in a relative deficiency of the neutral amino acids, such as tryptophan.

If the body is deficient in tryptophan a precursor for niacin , symptoms can arise that mimic niacin deficiency ie, pellagra. Clinical Symptoms appear intermittently and tend to decrease with age.

Symptoms include a pho- Manifestations tosensitive dermatitis that affects face, neck, and extensor surfaces of limbs and neuro- logic signs headaches; personality disturbances; photophobia; mental retardation; cere- bellar ataxia.

Renal aminoaciduria; indoles in the urine. Treatment Nicotinic acid supplements. He was born in Southeast Asia and immigrated to the United States 1 year ago. On physical examination, you find that he has lenticular dislocation on ophthalmologic examination and abnormally long 4 fingers.

His concerned parents also report that he was far behind his peers in terms of developmental milestones and seems to suffer from some mild mental retardation. While you await an emergent pediatric ophthalmology consult, you order serum and urine studies, expecting elevated serum methionine and urine homocysteine levels. You suspect that the patient will need high-dose pyridoxine, cysteine, folate supplements, and a methionine-restricted diet.

The disorder can be caused by either a deficiency of either enzyme or decreased affinity of cystathionine synthase for pyridoxal phosphate vitamin B6 , a necessary cofactor for the enzyme.

Pathophysiology Homocysteine is converted to either methionine by NPTHM or to cystathionine and eventually cysteine by cystathionine synthase with vitamin B6. Homocysteine is a toxin to the vascular endo- thelium, leading to increased atherosclerosis and increased platelet adhesiveness to the vessel wall and thus increased incidence of thrombus formation. Elevated homocysteine levels also interfere with normal collagen formation, thereby resulting in ocular and skeletal malformations.

Clinical Marfanoid appearance with elongated limbs; can cause mental retardation, neuropsychiatric Manifestations dysfunction, osteoporosis, and characteristic lens dislocation ectopia lentis. Patients with this disorder are at increased risk for thromboembolism and coronary artery disease. Increased methionine in serum; excess homocysteine in urine.

Treatment Enzyme deficiency: Decreased methionine and increased cysteine and folate in diet. Decreased affinity of synthase for pyridoxal phosphate: On further questioning, she tells you that the child is urinating regularly, but that the urine has a strange odor reminiscent of pancake syrup. On physical examination, the child 4 is afebrile; however, you note that his Moro reflex is absent and that his muscle tone is rigid.

Pathophysiology BCKD is the second enzyme in the pathway of the breakdown of the three branched- chain amino acids: When this enzyme is defective, branched-chain ketoacids build up, resulting in a metabolic acidotic state. Also, the elevated levels of these ketoacids are toxic to the brain and lead to brain edema with gliosis and white matter demyelination.

Clinical Symptoms include those associated with metabolic acidosis, psychomotor retardation Manifestations muscular rigidity, loss of Moro reflex , brain damage, and a maple syrup odor of the urine caused by branched-chain amino acids in urine. Increased serum and urine levels of branched-chain amino acids isoleucine, leucine, valine. Treatment and Protein-modified diet restricting intake of branched-chain amino acids; dialysis; thiamine Prognosis supplementation.

Associated with high mortality rate. The child appears small for his age and has slight micro- cephaly. His parents report some concern about possible developmental delays. Physical examination 4 is significant for hypertonia and hyperreflexia in all limbs. In addition to ordering a CBC and uri- nalysis, you order a Guthrie test, which you suspect will be positive. While you await the results of the laboratory testing, you tell the parents that the patient will likely need to avoid foods containing Nutrasweet.

Pathophysiology Phenylalanine hydroxylase is responsible for converting phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine builds up. High levels of phenylalanine lead to severe brain damage by competitively inhibiting amino acid transport required for pro- tein synthesis, impairing polyribosome stabilization, reducing myelin production, and decreasing the formation of norepinephrine and serotonin.

Phenylalanine is also a com- petitive inhibitor of tyrosinase, a key enzyme in the pathway of melanin synthesis, and thereby leads to hypopigmentation of the hair and skin. Phenylketones detected in urine phenylacetate, phenyllactate, and phenyl- pyruvate ; positive Guthrie test measures phenylalanine in blood at birth. Treatment Decreased intake of phenylalanine avoid aspartame, which is found in Nutrasweet and increased dietary tyrosine essential amino acids for patients with this disorder.

Thus, there are elevated levels of histidine in the blood.

Lange Biochemistry and Genetics Flash Cards, 2nd Edition | Shafinewaz RPh -

The disorder is characterized by both hearing and speech deficits. Glycine C6: Aspartate N N C2, N3: Glutamine C4, C5, C6, N1: Purine synthesis occurs in all tissues. This reaction is catalyzed by glutamine PRPP amidinotransferase.

Inhibited by GMP. Inhibited by AMP. Although not shown, tetrahydrofolate is involved in two reactions of de novo purine synthesis. Folic acid analogs, such as methotrexate, inhibit the formation of tetrahydrofolate and thus interfere with purine synthesis. Purine synthesis via the salvage pathways occurs in all tissues. Hypoxanthine; PRPP; guanine; adenine. De novo pyrimidine synthesis occurs in the cytosol of cells in all tissues. This reaction is catalyzed by carbamoyl phosphate synthetase II, which is the major regulated step for this pathway.

Inhibited by CTP. Pyrimidines can be salvaged from orotic acid, uracil, and thymine but not from cytosine. Salvage is accomplished by the enzyme pyrimidine phosphoribosyl transferase. Deficiencies in orotate phosphoribosyl transferase or OMP decarboxylase can lead to orotic aciduria see card 78 , which is characterized by growth retardation and anemia. Purine degradation takes place in most tissues.

Uric acid excreted in the urine. Pyrimidine degradation can take place in many tissues. Unlike purine nucleotides, pyrimidine reduction, ring-opening, nucleotides can be completely degraded into precur- deamination-decarboxylation sors for intermediates of other metabolic processes, such as the citric acid cycle.

The two sulfhydryl groups of thioredoxin provide reducing power for ribonucleotide reductase, Deoxyribonucleoside Diphosphate and thioredoxin becomes oxidized in the pro- cess. Allosterically inhibited by dATP and other deoxy- nucleotide triphosphates. Deoxythymidylate dTMP synthesis occurs in all body tissues. Tetrahydrofolate is then remethyl- ated with the aid of serine to form FH4, which can subsequently be used again by thymidylate synthase.

Folic acid analogs such as methotrexate act to inhibit dihydrofolate reduc- tase, which results in a lack of tetrahydrofolate and thus inhibition of this pathway. Over the last month, the child was admitted to the hospital twice for the treatment of bacterial and viral pneumonias as well as for positive fungal growth from past stool samples. While hospitalized, the child was found to have a significantly deficient lymphocyte count.

You suspect that the child has an immune deficiency and will not be able to survive past his first birthday without extraordi- nary treatment. You inform the concerned parents that the child may need a bone marrow transplan- tation and raise the possibility of experimental gene therapy. Pathophysiology ADA is involved in converting adenosine to inosine during purine degradation.

When ADA is deficient, adenosine accumulates. This accumulation of adenosine even- tually results in an excess of dATP, which serves to inhibit ribonucleotide reductase, a key enzyme in the synthesis of DNA.

Defective DNA synthesis results in deficient lymphoid differentiation and results in dysfunctional T and B cells. SCID is associated with severe and repeated fungal, bacterial, viral, and pro- tozoal infections during the first year of life. The disorder commonly presents with Pneumocystis carinii pneumonia and failure to thrive. Graft-versus-host disease will often develop after transfusions. Treatment and Prognosis Bone marrow transplantation as a source of stem cells.

Administration of exogenous ADA prognosis ADA conjugated to polyethylene glycol may improve immunologic function and clinical status. ADA gene therapy is also used with limited success. Affected infants rarely survive beyond 1 year without treatment. His parents are concerned about his propensity for biting himself and strange writhing body movements. On physical examination, the patient is quite spastic in his movements with marked hyperreflexia in all limbs.

His fingers are notably disfigured from his constant self- biting. When questioned further, the mother admits that the child produces reddish-orange urine in 5 his diapers but states that this has been a constant phenomenon since birth. You ask the nurse to collect urine from the child, suspecting marked hyperuricemia and uric acid crystals on analysis.

Hyperuricemia then leads to nephrolithiasis and arthritis. Excessive levels of purines can lead to CNS damage and neurologic problems. Clinical Manifestations Self-mutilative behavior; aggression; spasticity; choreoathetosis involuntary writhing ; kidney stones; arthritis; hyperreflexia; gout; mental retardation; orange or red urine.

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