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Must-Know Biochemistry Concepts: Enzymatic Defects and Associated Key Concepts

Defective Enzymes and their Associated Key Concepts

Adenosine Deaminase Deficiency

•SCID (Severe Combined Immuno-Deficiency)

•AKA: Swiss-type agammaglobulinemia

•Humoral and cell-mediated defects.

•T and B cell deficiency.

•Autosomal recessive

Arylsulfatase A Deficiency

•Metachromatic leukodystrophy

•Sphingolipidoses

•Deficient enzyme activity in leukocytes

•Demyelinating disease

•Autosomal recessive

Carbamoyl Phosphate Synthase Deficiency

•Hyperammonemia, metabolic alkalosis and mental retardation

•Ceramidase Deficiency

•Farber’s Disease

•Ceramide is not converted to sphingosine

•Ceramide accumulation

•Deformed joints; fatal

•Autosomal recessive

Carnitine-acyl Transferase Deficiency

•Genetic inability to use long chain fatty acids as a source of energy by muscle

•Muscle cramp and fatigability

•Rhabdomyolysis

Cystathionine Synthase Deficiency

•Homocystinuria

•Body deprived of pyridoxine (vitamin B₆)

•Increased blood methionine

Citrate Synthase Deficiency

•Kreb’s malfunction

•Lack of ATP production.

α1-4, 1-6 Glucosidase Deficiency

•Branching enzyme

•Anderson’s disease

•Glycogen Storage Disease Type IV

•Cirrhosis; Accumulation of long-outer branch glycogen in the liver and spleen.

•Fatal

•Autosomal recessive

α-1,6-Glucosidase Deficiency

•De-branching enzyme

•Cori’s Disease

•Glycogen Storage Disease Type III

•Glycogen accumulation in liver, heart and skeletal muscles

•Mild hypoglycemia, little or no cardiomegaly.

Enolase Deficiency

•Hemolytic Anemia

•Glycolytic anomaly

•Not commonly tested on the exam

Fructose-1-P Aldolase Deficiency

•AKA: Aldolase B

•Fructose Poisoning

•Accumulation of fructose 1-P

•Hypoglycemia; hepatic and renal damage

•Fructosemia and fructosuria

•Autosomal recessive

Fructokinase Deficiency

•Essential Fructosuria

•Fructose accumulation.

•Benign

•Autosomal recessive

Fructose-1, 6-Diphosphatase Deficiency

•Lactic Acidosis

•Failure of gluconeogenesis and hypoglycemia

Galactosamine Sulfate Sulfatase Deficiency

•Morquio’s Syndrome

•Mucopolysaccharidoses

•Increased keratan sulfate

•Severe nervous system anomaly

•Autosomal recessive

α-Galactosidase Deficiency

•Fabry’s Disease

•Ceramide accumulation

•Neuropathy, vascular thromboses, and renal failure (nephritic sysndrome)

•The most benign lipid storage disease

•X-linked

Galactosyl Uridyl Transferase Deficiency

•Classic Galactosemia

•Galactose 1-P accumulation, mental retardation, hepatomegaly, jaundice and mental retardation

•Autosomal recessive

β-Gangliosides A Deficiency

•GM1-Gangliosidosis (Sphingolipidoses)

•GM1 to GM2 transformation is affected

•Autosomal recessive

Glucocerebrosidase Deficiency

•Gaucher’s Disease

•Glucocerebroside accumulation in brain, spleen and bone marrow

•Hepatosplenomegaly

•Gaucher cells (in bone marrow)

•Autosomal recessive

Glucose Phosphate Isomerase Deficiency

•Hemolytic anemia

•A glycolytic anomaly

Glucose 6-Phosphatase Deficiency

•Von-Gierke’s Disease

•Most common glycogen storage disease (Type I)

•Increased Liver and kidney glycogen; hypoglycemia; Gout; prolonged PT, hypertriglyceridemia

•Autosomal recessive

Galactosamine-6-Sulfate Sulfatase Deficiency

•Morquio’s Syndrome

•Mucopolysaccharidoses

•Increased keratan sulfate

•Severe nervous system anomaly

•Autosomal recessive

Glucose-6-Phosphate Dehydrogenase Deficiency

•Hemolytic Anemia

•Hexose monophosphate shunt defect.

•Low NADPH leads to low reduced glutathione that in turn leads to damage to RBC membrane (hemolysis)

•X-linked recessive

•Reduced RBC defense against oxidizing agents.

•X-linked

α-1, 4-Glucosidase Deficiency

•Pompe’s

•Glycogen Storage Disease Type II

•Accumulation of glycogen in liver, kidney, heart (main) and muscle

•Cardiomegaly

•Early fatality due to cardiac or respiratory failure

•Enzyme replacement therapy is available

•Autosomal recessive

Heparan N-Sulfatase Deficiency

•Sanfilippo’s Disease

•Mucopolysaccharidoses III

•Heparan accumulation

•Nervous system anomaly

•Autosomal recessive

Hypoxanthine-Guanine Phosphoribosyl Transferase Deficiency

•HGPRT deficiency

•Lesch-Nyhan Syndrome

•Mental retardation

•Self-mutilation

•Purine salvage disorder

•Increased serum uric acid

•X-linked

Hexokinase Deficiency

•Hemolytic anemia

•Glycolytic anomaly

•Low 2,3 diphosphoglycerate level in the red cells

•Left shift of oxygen saturation

Hexosaminidase-A Deficiency

•Tay-Sachs Disease

•Ashkenazi Jewish

•GM₂-ganglioside accumulation.

•Autosomal recessive

•Cherry-red spots

•Autosomal recessive

HMG CoA Reductase Deficiency

•Lack of cholesterol synthesis.

•Homogentisic Acid Oxidase Deficiency

•Alkaptonuria

•Tyrosine degradation anomaly

•Homogentisate accumulation

•Dark tissue coloration and arthritis

21-Hydroxylase Deficiency

•Female pseudohermaphroditism

•Male phenotype

•Most common congenital adrenal hyperplasia

•Decreased cortisol, increased ACTH and enlarged male genitalia

•Hyperkalemia, increased 17-alpha-hydroxy progesterone, increased 17-ketosteroids and 21-deoxysteroids

•Ambiguous genitalia in females

• Hypotension.

•Autosomal recessive

17-Hydroxylase Deficiency

•Congenital Adrenal Hyperplasia

•Hypertension. Sodium and water retention

•Lack of androgens

•Female phenotype exaggerated

11-Hydroxylase Deficiency

•Congenital Adrenal Hyperplasia

•Hypertension. Sodium and water retention

•Male phenotype exaggerated

•Autosomal recessive

Liver Glycogen Phosphorylase Deficiency

•Her’s Disease

•Glycogen storage disease type VI

•Glycogen accumulation in the liver

•Muscle phosphorylase is normal

•Hyperglycemia.

•Autosomal recessive

Muscle Glycogen Phosphorylase Deficiency

•McArdle’s Syndrome

•Glycogen Storage Disease Type V

•Glycogen Accumulation in skeletal muscles, and muscle cramps.

•Autosomal recessive

α-L-Iduronidase Deficiency

•Hurler’s Syndrome (Gargoylism)

•Most common mucopolysaccharidosis

•Iduronidase deficiency in WBC.

•Accumulation of heparan and dermatan sulfate in liver, heart, and brain

•Retinal clouding; hepatomegaly, cardiomegaly, and kyphoscoliosis

•Dwarfism, mental retardation, and death

•Autosomal recessive

Iduronosulfate Sulfatase Deficiency

•Hunter’s Syndrome

•Similar to but less severe than Hurler’s

•Heparan and dermatan sulfates accumulation

•Hepatosplenomegaly, Mild mental retardation and no corneal opacity

•Deafness

•X-linked

α-Ketoacid Decarboxylase Deficiency

•Maple Syrup Urine Disease

•Alpha-ketoacidemia

•Increased branched amino acids—Isoleucine, Leucine and Valine

• Neurological symptoms: seizures

•Muscular rigidity

•Maple sugar odor of urine

•Mental retardation

•Neonatal screening

•Autosomal recessive

Lysosomal Hydroxylase Deficiency

•I-Cell Disease (Pseudo-Hurler’s)

•Deficient phosphorylation of mannose residues of lysosomal hydroxylase

•Elevated serum lysosomal enzymes

•Autosomal recessive

Lactase Deficiency

•Lactose Intolerance

•Early adolescence onset

•Cramping and diarrhea

•Benign

•Autosomal recessive

LCAT Deficiency

•Lecithin: Cholesterol Acyl-transferase Deficiency

•AKA. PCAT

•HDL cholesterol is not esterified

•Atherosclerosis

Lipoprotein Lipase Deficiency

•Familial Lipoprotein Lipase or apo C-II Deficiency

•Pancreatitis

•Chylomicronemia

•Xanthomas

•Autosomal recessive

NADPH Oxidase Deficiency

•Chronic Granulomatous Disease (CGD)

•Multiple infections in particular by catalase-positive microorganisms

•Lack of respiratory burst

•X-linked

NADPH Dehydrogenase Deficiency

•Hereditary Methemoglobinemia

•Methemoglobin is not converted back to hemoglobin

•Oxygen binding capacity affected

•Dyspnea and cyanosis.

Orotidine Decarboxylase Deficiency

•Sialidosis

•Decreased RBC and WBC production

•Anemia and immune deficiency

•Pyrimidine synthetic deficiency

Ornithine Transcarbamoylase Deficiency

•Hyperammonemia

•Most common hyperammonemia

•Mental retardation

•X-linked

Phenylalanine Hydroxylase Deficiency

•Phenylketunuria (PKU)

•Phenylalanine is not converted to tyrosine

•Tyrosine becomes essential

•Deficiency of pigmentation

•Musty urine odor, mental retardation, blue eyed and blonde children

•Guthrie test for neonatal screening

Phosphoglycerate Kinase Deficiency

•Hemolytic Anemia

•Glycolytic anomaly

•Hemolytic anemia

Pyruvate Dehydrogenase Deficiency

•Lactic Acidosis

•Metabolic acidosis

•Increased serum lactate; hyperphosphatemia, and Increased anion gap

Pyruvate Kinase Deficiency

•Hemolytic anemia

•Accumulation of 2,3 Phosphoglycerate

•Binding of oxygen to Hb affected

•Right shift of oxygen saturation curve

5-α-Reductase Deficiency

•Male Pseudo-hermaphroditism

•Elevated testosterone/DHT ratio

•Virilization

•Marked reduced dihydrotestosterone

•Small genitalia

•Autosomal recessive

Sphingomyelinase Deficiency

•Niemann-Pick Disease

•Ashkenazi Jewish Population

•Diminished visual acuity

• Sphingomyelin and cholesterol accumulation in lysosomes of brain cells, and reticuloendothelial cells in bone marrow, spleen and liver

• “Foam cells”; Cherry red spots on macula

•Autosomal recessive

Tyrosinase Deficiency

•Albinism

•Tyrosine is not converted to melanin

•Skin cancers

UDP-Glucuronyl Transferase Deficiency

•Crigler-Najjar Syndrome, Type I

•Early onset

•Increased unconjugated bilirubin; Jaundice, kernicterus, death at early age

•Autosomal recessive

UDP-Glucuronyl Transferase Deficiency

•Gilbert’s Syndrome

•Mild decrease in UDP-glucuronyl transferase activity

•Mild unconjugated bilirubinemia

•Jaundice

•Moderately dark urine

•Autosomal dominant

Uroporphyrinogen III Co-Synthetase Deficiency

•Congenital Erythropoietic Porphyria (EPP)

•Heme synthesis affected

•Increased serum and urine uroporphyrins and coproporphyrins

•Marked hemolytic anemia

•Marked photosensitivity

•Most fatal porphyria

•Red teeth

•Autosomal recessive

Uroporphyrinogen III Synthetase Deficiency

•Acute Intermittent Porphyria

•Prototype of porphyrias

•Mostly in females

•Low or moderate photosensitivity

•Colicky attacks

•Precipitated by drugs

•[AD]

Uroporphyrinogen Decarboxylase Deficiency

•Porphyria Cutanea Tarda

•Mostly acquired with late onset (often after 55 years of age)

•Most common porphyria

•Mostly in men and mostly acquired

•No acute attacks

•Serious photosensitivity

•History of alcoholism

•Skin rash

Xanthine Oxidase Deficiency

•Hereditary Xanthinuria

•Hypoxanthine is not converted to uric acid

•Hypo-uricemia

•Autosomal recessive