Biochemistry - Enzyme deficiencies

What enzyme is defective in McArdles disease and what is the clinical presentation?

Glycogen storage disease: defect in myphosphorylase (an isoenzyme of glycogen phosphorylase) that converts muscle glycogen to glucose 1 phosphate (which is converted to glucose-6-phos and used by the muscle for energy)

Muscle cramps with exercise

What is are the primary signs and symptoms in patients with fructokinase deficiency?

This disease is asymptomatic, however large amounts of fructose will be found in the urine

How to patients with fructokinase deficiency process fructose?

Hexokinase in the liver catalyzes the conversion of fructose to fructose-6-phosphate. This pathway is not usually used in normal people.

F6P can then be used in the glycolytic pathway or converted to glucose-6-phosphate by phosphoglucoisomerase.

Name the enzyme that is defective in Maple Syrup Urine Disease. What is the result of this enzyme deficiency?

Caused by a defect in alpha-keto acid dehydrogenase

This leads the the defective breakdown of leuine, isoleucine, and valine (the branched chain amino acids)

The increase in alpha-keto acids leads to neuro toxicity

What is ornithine transcarbamylase deficiency? How is it inherited?

Carbamoyl phosphate + ornathine ---X---> citruline

Most common inherited urea cycle disorder is a deficiency of ornithine transcarbamylase (X-linked recessive unlike the other urea cycle enzyme deficiencies which are autosomal recessive)

List a few signs and symptoms of ornithine transcarbamylase deficiency:

- often evident in the first few days of life (but may appear later)
- ↑ orotic acid in blood and urine (excess carbomyl phosphate converted to orotic acid, a pyrimidine synthesis intermediate)
- ↓ BUN (no urea produced due to enzyme deficiency)
- symptoms of hyperammonemia (should be distinguished from orotic aciduria which has ↑ orotic acid with no hyperammonemia)

Build up of carbamoyl phosphate in ornithing transcarbamylase deficiency leads to excess of what product?

excess carbomyl phosphate converted to orotic acid, a pyrimidine synthesis intermediate

↑ orotic acid in blood and urine

Deficiency of Aldolase B leads to what disease? How is the enzyme deficiency inherited?

Hereditary fructose intolerance - Auto Recessive

A deficiency in aldolase B leads to accumulation of phosphorylated fructose → available phosphate levels drop → gluconeogenesis is blocked

List three symptoms of hereditary fructose intolerance

Symptoms: hypoglycemia, vomiting, jaundice, and cirrhosis

How is aldolase B deficiency treated?

Patients usually asymptomatic until challenged, in infancy, with fructose

Treatment: avoid intake of fructose or sucrose (combination of glucose and fructose)

Defects in hepatic fructokinase leads to what disease?

Essential fructosuria - Auto Recessive

Fructose can not be phosphorylated, so it is unable to be sequestered in the cell → elevated serum fructose levels → fructosuria

Autosomal recessive deficiency in GALT (galactose-1-phosphate uridyl transferase leads to what disease?

Classic galactosemia

GALT converts galactose-1-phosphate to glucose-1-phosphate

Absence of GALT leads to galactose-1-phosphate accumulation → toxic

List a 3 sx of classic galactosemia. These infants are at risk of what??

1) Jaundice
2) Suseptibility to bleeding (bleeding diathesis)
3) Feeding intolerance
4) Hypotension
5) Death

These infants also have an ↑ risk for E. coli septicemia.

What is the treatment for classic galactosemia (GALT deficiency)

All states mandate neonatal screening because lactose (i.e. milk) is metabolized to glucose and galactose

Treatment: galactose-free diet

What is galactokinase deficiency. How does it differ from classic galactosemia?

Autosomal recessive deficiency in galactokinase, which phosphorylates galactose to make galactose-1-phosphate.

This disorder leads to an overload in glactose, NOT an overload in glactose-1-phosphate (such is the case in classic galactosemia) --> Cateracts

List one common clinical complication from galactokinase deficiency

Accumulation of galactose → galactosemia → galactosuria

Galactosemia → cataracts because the lens of the eye contains aldose reductase, which converts galactose to galactitol, an osmotically active alcohol

What is lactose deficiency?

Age-related or hereditary lactose intolerance due to ↓ expression of lactase (a brush-border enzyme) or transient ↓ expression following gastroenteritis

Symptoms: osmotic diarrhea, bloating/cramps

Tx: lactase supplementation or lactose avoidance

Phenylketonuria (PKU)

Autosomal recessive defects in the enzyme phenylalanine hydroxylase (PAH)

Phenylalanine accumulates

List three signs/sx of PKU

- neurologic defects (e.g. seizures and mental retardation)
- albinism (tyrosine required for melanin synthesis)
- "musty odor" to their sweat & urine (due to accumulated phenylalanine conversion to phenylketones)

When is PKU screened for? What complications can this cause?

Screened for on the 2 nd or 3 rd day of life due to presence of maternal enzyme at birth

Look for questions that say pt was screened on the first day! This can easily miss PKU!

What is the treatment for PKU

restrict phenylalanine and aspartame (contains phenylalanine) in diet and ‚ increased tyrosine intake (becomes an essential amino acid)

What is maternal PKU? List three clinical features.

Maternal PKU : lack of proper dietary treatment in a pregnant woman with PKU ‚ infant born with microcephaly, congenital heart defects, mental and growth retardation

Defects in the enzyme dihydrobiopterin reductase causes what disease?

Malignant PKU : autosomal recessive defects in the enzyme dihydrobiopterin reductase (called malignant because restricting phenylalanine does not correct neurological problems)

Albinism is caused by the deficiency of what enzyme?

Tyrosinase: results in the production of melanin from DOPA

Autosomal recessive defects in tyrosinase or albinism : absence of melanin in hair (white hair), eyes (photophobia), and skin (increased risk of UV related skin cancer

What reaction is catalyzed by Homogentisic acid deoxygenase?

Homogentisic acid deoxygenase is part of the degradative pathway of tyrosine into fumarate

Defect = alkaptonuria
- Benign disease characterized by dark connective tissue, brown sclera, dark urine. May cause arthralgias.

List four causes of homocystineuria

1) Deficiency of cystathionine synthase
2) Decreased affinity of cystathionine synthase for pyridoxal phosphate
3) Homocysteine methyltransferase deficiency
4) Methylenetetrahydrofolate reductase (MTHFR) deficiency:

1) Deficiency of cystathionine synthase
2) Decreased affinity of cystathionine synthase for pyridoxal phosphate
3) Homocysteine methyltransferase deficiency
4) Methylenetetrahydrofolate reductase (MTHFR) deficiency:

ALL CAUSE HOMOCYSTINURIA!!

What is the cause of classical homocystinuria and how is it treated?

Classical homocystinuria (most common cause of homocystinuria): deficiency of cystathionine synthase → can be treated with ↓ methionine and ↑ cysteine intake with supplementation of B₁₂ and folate

How do you treat Decreased affinity of cystathionine synthase for pyridoxal phosphate?

Can be treated with high does of pyridoxal phosphate (vitamin B₆) to overcome the decreased affinity

List four clinical findings in patients with homocystinuria

1) Mental retardation
2) Atherosclerosis leading to vascular thrombosis
3) Long thin extremities with eunochoid features (reminiscent of Marfan's habitus)
4) Lens dislocation
5) Osteoporosis

How can you distinguish marfans syndrom from homocystinuria?

Patients with Marfan's syndrome usually have a lens that is dislocated in an up-and-out direction, while patients with homocystinuria have lens dislocation in a down-and-in direction

How could you acquire a homocystinuria?

Seen in both B₁₂ and folate deficiency (both are needed for the remethylation of homocysteine to methionine)

Homocystine is associated with what other common pathology?

Homocysteine is thought to promote atherosclerosis → explaining vascular disease in patients with homocystinuria and elevated cardiovascular disease risk in people with B₁₂ or folate deficiency ^[1]

What is the cause of cystinuria?

Defect in cysteine transport proteins in renal proximal tubule and small intestine → ↑ urine levels of cysteine lead to dimerization of cysteine to cystine

Same amino acid transporter is responsible for the dibasic amino acids (ornithine, lysine, and arginine)

What is the primary problem with cystinuria? Explain what this problem looks like.

Cystine precipitates in acidic (less than pH 7.5) urine → patients suffer from recurrent cystine renal stones

Hexagonal or benzene crystals in the urine are pathognomonic of cystinuria

How do you treat cystinuria?

Treatment: hydration and alkalization of the urine using potassium citrate or acetazolamide

Name the three amino acids that build up in branched chain ketoaciduria (maple syrup urine disease)

Defect in the branched-chain α-ketoacid dehydrogenase complex that catalyzes the breakdown of Isoleucine, Leucine, and Valine

I Love Vermont maple syrup from trees with branches

List four signs and sx of brached chain ketoaciduria. When do these sx usually present?

Symptoms typically present in the first few days of life (days 4-7) and include
1) Poor feeding, poor weight gain
2) Vomiting
3) Lethargy
4) Maple syrup odor to the urine (burnt sugar smell)

What is the long term complication of branched chain ketoaciduria?

Defective BCKD → accumulation of branched chain amino acids in the blood and the brain → irreversible neurological damage

Which aa causes the characteristic maple syrup odor of the urine

Isoleucine

Which aa is responible for the neurologic sx in maple syrup urine disease?

Leucine: readily crosses the blood-brain barrier and is responsible for the neurological symptoms

List two treatments for Maple Syrup Urine Disease

Treatment: restrict amino acid intake, and a small number of patients respond to thiamine (vitamin B₁) supplementation

Propionyl carboxylase is responsible for what reaction? Deficiency of this enzyme leads to what?

Pathway: propionyl CoA → methylmalonyl CoA → succinyl CoA

Propionyl carboxylase: enzyme that catalyzes the conversion of proprionyl CoA to methylmalonyl CoA (deficiency of this enzyme leads to propionic acidemia)

Methylmalonyl CoA mutase is responsible for what reaction? What cofactor does this enzyme need?

Pathway: propionyl CoA → methylmalonyl CoA → succinyl CoA

Methylmalonyl CoA mutase: enzyme that catalyzes the conversion of methylmalonyl CoA to succinyl CoA, requiring vitamin B₁₂ as a cofactor (deficiency of this enzyme leads to methylmalonic acidemia

List 5 sx of methymalonic and proprionic aciduria

Symptoms of both include:
1) Ketosis
2) Metabolic acidosis
3) Vomiting
4) Lethargy
5) Ppoor feeding
6) Neutropenia
7) Developmental/neurological complications

What is the treatment for methylmalonic & propinoic aciduria? Which amino acids should be avoided?

Treatment for both:
1) low-protein diet
2) ↓ intake of methionine, valine, threonine, isoleucine, and odd-chain fatty acids because they are all broken down into propionyl CoA
3) carnitine supplementation (improves β-oxidation of fatty acids)

Glucose 6 phosphatase deficiency leads to what disease? Describe the basic pathophysiology of this disease.

Type I (von Gierke’s) glycogen storage disease

Deficient glucose-6-phosphatase (liver, kidney) → defective glycogenolysis and gluconeogenesis → severe fasting hypoglycemia (seizures, hypoxic brain damage)

You can make glycogen, but cant break it down!

List 6 clinical features of Von Girkes

1) Hepatorenomegaly - with fatty liver!
2) Hyperlipidemia → skin xanthomas and ↑ VLDL
3) Hyperuricemia
4) Fasting lactic acidosis
5) Ingestion of galactose or fructose → no increase in blood glucose
6) Administration of glucagon, epinephrine, or other gluconeogenic stimulus → no increase in blood glucose

What is the cause of hepatorenalmegally in von Gierkes disease?

Hepatorenomegaly - glycogen accumulates in liver and kidney because excess G-6-P stimulates glycogen synthesis and inhibits glycogenolysis

What is the cause of hyperuricemia in von Giekes disease?

↓ free phosphate due to G6-Pase defect → ↑ AMP → AMP degraded to uric acid → ↑ uric acid → predisposes to gout

glucose 6-phosphatase

Enzyme in liver smooth ER (NOT present in muscle!) that carries out final rxn in glucose production. Glucose 6-phosphate is dephosphorylated so it can cross cell membrane and go to other cells. In muscle, glucose is retained to meet nrg needs.

A defective lysosomal α-1,4-glucosidase enzyme (also known as acid alpha glucosidase or acid maltase!) leads to what disease?

Type II glycogen storage diseae (Pompe’s disease): defective lysosomal α-1,4-glucosidase → enzyme is responsible for digesting glycogen → glycogen deposits accumulate in lysosomes

What 3 organs are effected by pompe's disease. What classic complication does this lead to?

Organs most affected are those that store glycogen (liver, heart, skeletal muscle)

Left ventricular hypertrophy leads to outflow tract obstruction and cardiac failure

Pompe’s trashes the Pump (heart)

α-1,6-glucosidase (glycogen debrancher enzyme) deficiency leads to what disease?

Type III glycogen storage disease (Cori’s disease): defective α-1,6-glucosidase (glycogen debrancher enzyme) → fasting hypoglycemia → milder than Type I (von Gierke’s), normal blood lactate level

Glycogenolysis is defective but gluconeogenesis is still functional.

How does Cori's disease (aka Forbes disease) present clinically?

1) Hepatosmegally
2) Hypoglycemia
3) Ketosis
4) Distinguished from other glycogen storage disease by the identification of short dextrin-like molecules on liver biopsy

Type IV glycogen storage disease or Andersons disease, is cause by defects in what enzyme?

Type IV (Andersen’s): defective α-4,6-glucosidase (glycogen branching enzyme)

Inability to form branches → accumulation of long, insoluble glycogen chains → hepatosplenomegaly and cirrhosis

How does Andersen's disease present clinically?

Causes infantile cirrhosis failure to thrive and hypotonia → usually fatal

What enzyme is defective in Type V glycogen storage disease (McArdles Disease)?

Type V (McArdle’s): defective skeletal muscle glycogen phosphorylase→ unable to complete 1st step in glycogen breakdown → ↑ glycogen in muscle → muscle cramps/weakness with exercise → can lead to myoglobinuria

How does McArdles disease present on a USMLE question?

Young kid who cramps up when he exercises who experiences color changes in his urine.

Name the enzyme that is deficient in type VI glycogen storage disorder (Hers' disease)

Deficient Hepatic glycogen phosphorylase → gluconeogenesis but no glycogenolysis → fasting hypoglycemia (mild) and hepatomegaly/cirrhosis

Hers' = Hepatic phosphorylase

How does hepatic glycogen phosphorylase present clinically? Do these sx ever improve?

Early childhood presentation of hepatomegaly and growth retardation → hepatomegaly may improve with ↑ age

What does carnitine deficiency lead to?

Decreased ability to utilize long chain fatty acids as a fuel source. Can be due to environmental (e.g. malnutrition) or genetic factors (e.g. CAT-I deficiency).

What are two sx of carnatine deficiency?

Muscle aches and fatigue following exercise, ↑ free fatty acid levels in the blood, hypoketotic hypoglycemia.

The last piece is key. Anyone with hypoglycemia with low ketone levels = fat metaboism problem!

What is MCADD (medium-chain acyl-CoA dehydrogenase deficiency)? What is the most common symptom?

MCAD is a enzyme required for complete oxidation of medium length fatty acids. Deficiency → inability to oxidize fatty acids with <12 carbons.

Presents with symptoms of hypoglycemia.

Medium-chain acyl-CoA dehydrogenase deficiency

Treatment: Avoid prolonged fasting, ↑ carbohydrate and protein intake, ↓ fat intake.

7-dehydrocholesterol reductase deficiency causes what disease? List 4 clinical features.

SLOS (Smith-Lemli-Opitz-Syndrome) is an autosomal recessive deficiency in DHCR-7 (7-dehydrocholesterol reductase), an enzyme used in the synthesis of cholesterol → ↓ cholesterol levels.

Symptoms include abnormal facial features, mental retardation and characteristics of autism, and congenital malformations.

Deficiency in lipoprotein lipase (or what cofactor) causes what disease?

Hyperchylomicronemia - autosomal recessive; deficiency of LPL or mutation in apoC-II

LPL normally degrades TGs in circulating chylomicrons and VLDL.

Deficiency of LPL → ↑ serum TG and ↑ chylomichrons

Patient Present with: fatty liver changes, chylomicron-induced acute pancreatitis, red-orange xanthomas (cholesterol-laden deposits), milky, lipid-laden supernatant in centrifuged blood sample... name this disease & enzyme deficieny.

Type I Familial Dyslipidemias/Hyperlipidemias
Hyperchylomicronemia - autosomal recessive; deficiency of LPL or mutation in apoC-II (required co-factor for LPL)

Are patient with hyperchylomicronemia at risk for atherosclerosis?

No increased risk of atherosclerosis

Absence or decrease in LDL recptors leads to what disease? What is the inheritance pattern?

Type IIa: Familial hypercholesterolemia - autosomal codominant absence or ↓ in LDL receptors

What would the blood work look like in a patient with Type IIa: Familial hypercholesterolemia? What are these patients at risk for?

↑ cholesterol and ↑ LDL → marked ↑ risk of atherosclerosis and CAD

1) Corneal arcus - gray or white arcs visible around the entire cornea → lipid deposits at edge of cornea
2) Xanthomas on the tendons - classic locations → Achilles’ heel, elbows

List two treatments for type II familial hypercholesterolemia. How do they work?

1) Cholestyramine and other drugs that ↑ bile salt synthesis from cholesterol → ↓ cholesterol concentration within hepatocytes → ↑ LDL receptor expression → ↑ cholesterol removal from circulation.
2) Statins ↓ de novo synthesis of cholesterol → increases LDL receptor expression

Type IIa familial hypercholesterolemia is codominant. What does this mean for heterozygotes v homozygotes?

Prevalence: heterozygotes = 1/500 (cholesterol ≈ 300 mg/dL); homozygotes = 1/10⁶ (cholesterol ≈ 700+ mg/dL)

Homozygous condition usually lethal before age 20 from MI

People who are homozygous expression of apoE2 develop what disease? What else is needed for the disease to progress?

Type III Familial Dyslipidemias
Dysbetalipoproteinemia
Homozygous expression of apoE2. Second hit → metabolic disorder (e.g. diabetes, obesity)

Why does homozygous expression of ApoE2 lead to dysbetalipoproteinemia?

ApoE2 has decreased affinity for LDL receptor (on liver) → ↑ chylomicron and IDL remnants in the blood → ↑ cholesterol and TGs.

What is one key feature of dysbetalipoproteinemia?

Presents with tuberoeruptive xanthomas and peripheral vascular disease

Tuperoeruptive xanthomas, as the name suggests, are large grapelike nodules that appear inflamed and coalesce.

How does hyperlipidemia occur (biochemically). What "conditions" are associated with this biochemical process?

↑ hepatic VLDL production leads to ↑ serum VLDL and ↑ serum TG

High VLDL levels are also frequently associated with chronic alcoholism and estrogen therapy.

Describe the relative lipid values in a patient with Familial Combined Hyperlipidemia (FCH)

↑ LDL and/or ↑ VLDL, ↓ HDL

Mechanism not fully elucidated; may be due to ↑ apoB-100 production → VLDL packaging ↑ → serum VLDL levels ↑

What is abetalipoprotinemia?

Deficiency of lipoproteins → disorder of lipid, cholesterol, and fat soluble vitamin absorption.

List 5 clinical features associated with abetalipoproteinemia

1) Steatorrhea
2) acanthocytes (star shapped blood cells)
3) Failure to thrive
4) Ataxia (due to the vit E deficiency)

Disruption of what pathway leads to porphyrias?

Disruption at 4 points on the heme synthesis pathway leads to accumulation of intermediates → porphyrias

Name the enzyme deficiency responsible for acute intermittent porphyria

Autosomal dominant defect of porphobilinogen deaminase (aka uroporphyrinogen I synthase?)

Describe how actute intermittent porphyria presents clinically and list four common signs/sx.

Characterized by attacks of peripheral/autonomic neuropathies with intermittent, symptom free periods.

SX: abdominal pain (severe and several days’ duration), seizures, tachycardia, hypertension, coma and psychiatric manifestations (e.g. depression).

Name the enzyme deficiency responsible for Porphyria Cutanea Tarda

Autosomal dominant defect of uroporphyrinogen decarboxylase

Lead interferes with which two heme related enzyme?

Inhibition of ALA dehydratase → accumulation of ALA; if ferrochelatase is inhibited, protoporphyrin IX accumulates.

What are the initial sx of porphyria cutanea tarda?

Initial symptoms: fragile skin that blisters with minimal sun exposure

List two things that can exacerbate porphyria cutanea tarda

Episodes are precipitated by hepatotoxic agents (e.g. EtOH, hepatitis)

Barbiturates (and other inducers) induce the P450 system → consumption of heme → loss of heme's negative feedback on ALA synthase (the rate limiting step of heme biosynthesis) → accumulation of heme intermediates.

Epidermolysis bullosa simplex is caused by defects in what protein?

Keratin 5 and 14

Defects in the enzyme histidase cause what disease? List 4 symptoms.

Histidinemia:
1) Speech defects
2) Psychomotor and generalized retardation
3) Emotional disturbances

This is the most common inborn metabolic error in Japan

Biochemistry - Enzyme deficiencies

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