FA Biochem 10

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Catecholamine synthesis

Reaction
Breakdown products

Phenylalanine → (Phenylalanine hydroxylase) → Tyrosine → (Tyrosine hydroxylase) → Dihydroxyphenylalanine, aka "dopa" → (Dopa decarboxylase, with vitamine B₆) → Dopamine → (Dopamine β-hydroxylase, with vitamin C) → Norepinephrine → (Phenylethanlolamine N-methyl transferase with SAM) → Epinephrine

Enzyme legend:
Hydroxylase adds OH
Decarboxylase removes COOH
SAM adds CH₃

Breakdown products via MAO and COMT
Dopamine → HVA (homovanillic acid)
Norepinephrine → VMA (vanillylmandelic acid)
Epinephrine → Metanephrine

Phenylketonuria

Pathogenesis

Due to ↓ phenylalanine hydroxylase or ↓ tetrahydrobiopterin cofactor.

Tyrosine becomes essential.

↑ phenylalanine leads to excess phenylketones in urine.

Disorder of AROMATIC amino acid metabolism → musty body ODOR

Phenylketonuria

Findings (6)

1. Mental retardation
2. Growth retardation
3. Seizures
4. Fair skin
5. Eczema
6. Musty body odor

Phenylketonuria

Treatment

↓ PHENYLALANINE (contained in aspartame, e.g. NutraSweet)

↑ TYROSINE in diet

Phenylketonuria

Maternal PKU

Mechanism
Findings in infant (4)

Lack of proper dietary therapy during pregnancy.

Findings in infant:
1. Microcephaly
2. Mental retardation
3. Growth retardation
4. Congenital heart defects

Phenylketonuria

Screening
Ketones
Genetics

Screened for 2-3 days after birth (normal at birth because of maternal enzyme during fetal life)

Phenylketones - phenylacetate, phenyllactate, and phenylpyruvate.

Autosomal recessive. Incidence - I:10,000

Alkaptonuria (ochronosis)

Pathogenesis
Prognosis

Congenital deficiency of HOMOGENTISIC ACID OXIDASE in the degradative pathway of tyrosine to fumarate.

Autosomal recessive.

Benign disease

Alkaptonuria (onchronosis)

Findings (4)

1. Dark connective tissue
2. Brown pigmented sclera
3. Urine turns black on standing
4. May have debilitating arthralgias (homogentistic acid toxic to cartilage)

Albinism

Pathogenesis
Findings
Genetics

Congenital deficiency of either of the following:
1. Tyrosinase (inability to synthesize melanin from tyrosine) - autosomal recessive
2. Defective tyrosine transporters (↓ amounts of tyrosine and thus melanin)

Can result from a lack of migration of neural crest cells.

Lack of melanin results in an ↑ risk of skin cancer.

Variable inheritance due to locus heterogeneity (vs. ocular albinism - X-linked recessive)

Homocystinuria

Pathogenesis (3)

3 forms (all autosomal recessive)
1. Cystathionine synthase deficiency (treatment: ↓ Met and ↑ Cys, and ↑ B₁₂ and folate in diet)
2. ↓ affinity of cystathionine synthase for pyridoxal phosphate (treatment: ↑↑ vitamin B₆ in diet)
3. Homocysteine methyltransferase deficiency

All forms result in excess homocysteine.

Cysteine becomes essential

Homocystinuria

Findings

1. ↑↑ homocysteine in urine
2. Mental retardation
3. Osteoporosis
4. Tall stature
5. Kyphosis
6. Lens subluxation (downward and inward)
7. Atherosclerosis (stroke and MI)

Homocystinuria

Pathway

Homocysteine → (Cystathionine synthase, with B₆) → Cystathionine → Cysteine

Homocysteine → (Homocysteine methyltransferase with B₁₂) → Methionine

Cystinuria

Pathogenesis
Findings

Hereditary defect of renal tubular amino acid transporter for cysteine, ornithine, lysine, and arginine in the PCT of the kidneys.

Excess cystine in urine can lead to the precipitation of CYSTINE KIDNEY STONES (cystine staghorn calculi).

Autosomal recessive. Common (1:7000).

Cystine is made of 2 cysteines connected by a disulfide bond.

Cystinuria

Treatment

Acetazolamide to alkalinize the urine.

Hartnup disease

Pathogenesis, findings

An autosomal-recessive disorder characterized by defective neutral amino acid transporter on renal and intestinal epithelial cells.

Causes tryptophan excretion in urine and ↓ absorption from the gut.

Leads to PELLAGRA (diarrhea, dermatitis, dementia, death).

Glycogen

Types of bonds
Function

Branches have α (1,6) bonds; linkages have α (1,4) bonds.

Skeletal muscle - glycogen undergoes glycogenolysis to form glucose, which is rapidly metabolized during exercise.

Hepatocytes - glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels.

Glycogen storage diseases

Name 4

12 types, all resulting in abnormal glycogen metabolism and an accumulation of glycogen within cells.

Von Gierke's disease (type I)
Pompe's disease (type II)
Gori's disease (type III)
McArdle's disease (type V)

"Very Poor Carbohydrate Metabolism"

Von Gierke's disease

Findings
Deficient enzyme

Type I glycogen storage disease

Findings:
1. Severe fasting hypoglycemia
2. ↑↑ glycogen in liver
3. ↑ blood lactate
4. hepatomegaly

Deficient enzyme:
Glucose-6-phosphatase: breaks glucose-6P to glucose + Pi

Pompe's disease

Findings
Deficient enzyme

Type II glycogen storage disease

Findings:
1. Cardiomegaly
2. Systemic findings leading to early death

Deficient enzyme:
Lysoomal α-1,4-glucosidase (acid maltase): breaks glycogen down into glucose + Pi

"Pompe's trashes the Pump (heart, liver, and muscle)"

Cori's disease

Findings
Deficient enzyme

Type III glycogen storage disease

Findings:
Milder form of type I with normal blood lactate levels.

Deficient enzyme:
Debranching enzyme (α-1,6-glucosidase): converts limit dextran (4-glucose residues in branched configuration) to glucose.

Gluconeogenesis is intact

McArdle's disease

Findings
Deficient enzyme

Type V glycogen storage disease

↑ glycogen in muscle, but cannot break it down, leading to:
1. Painful muscle cramps
2. Myoglobinuria with strenuous exercise

Deficient enzyme:
Skeletal muscle glycogen phosphorylase: converts glycogen to limit dextran

"McArdle's = Muscle"

Lysosomal storage diseases

Name 8

Each is caused by a deficiency in one of the many lysosomal enzymes. Results in an accumulation of abnormal metabolic products.

Sphingolipidoses:
1. Fabry's disease
2. Gaucher's disease (most common)
3. Niemann-Pick disease
4. Tay-Sachs disease
5. Krabbe's disease
6. Metachromatic leukodystrophy

Mucopolysaccharidoses
1. Hurler's syndrome
2. Hunter's syndrome

↑ incidence of Tach-Sachs, Niemann-Pick, and some forms of Gaucher's disease from Ashkenazi Jews.

Fabry's disease

Category
Deficient enzyme
Accumulated substrate
Inheritance

Sphingolipidoses

Deficient enzyme:
α-galactosidase A (ceremide trihexoside → glucocerebroside)

Accumulated substrate:
Ceramide trihexoside

Inheritance:
XR

Fabry's disease

Findings (3)

1. Peripheral neuropathy of hands/feet
2. Angiokeratomas
3. Cardiovascular/renal disease

Gaucher's (most common)

Category
Deficient enzyme
Accumulated substrate
Inheritance

Sphingolipidoses

Deficient enzyme:
β-glucocerebrosidase

Accumulated substrate:
Glucocerebroside

Inheritance:
AR

Gaucher's disease (most common)

Findings (4)

1. Hepatosplenomegaly
2. Aseptic necrosis of femur
3. Bone crises
4. Gaucher's cells (macrophages that look like crumpled tissue paper)

Niemann-Pick disease

Category
Deficient enzyme
Accumulated substrate
Inheritance

Sphingolipidoses

Deficient enzyme:
Sphingomyelinase (sphingomyelin → ceramide)

Accumulated substrate:
Sphingomyelin

Inheritance:
AR

"NO MAN PICKS (Niemann-Pick) his nose with his SPHINGER (SPHINGomyelinase)"

Niemann-Pick disease

Findings (4)

1. Progressive neurodegeneration
2. Hepatosplenomegaly
3. Cherry-red spot on macula
4. Foam cells

Tay-Sachs disease

Category
Deficient enzyme
Accumulated substrate
Inheritance

Sphingolipidoses

Deficient enzyme:
Hexosaminidase A (GM₂ → GM₃)

Accumulated substrate:
GM₂ ganglioside

Inheritance:
AR

"Tay-SaX (Tay-Sachs) lacks heXosaminidase"

Tay-Sachs disease

Findings (5)

1. Progressive neurodegeneration
2. Developmental delay
3. Cherry-red spot on macula
4. Lysosomes with onion skin
5. No hepatosplenomegaly (vs. Niemann-Pick)

Krabbe's disease

Category
Deficient enzyme
Accumulated substrate
Inheritance

Sphingolipidoses

Deficient enzyme:
Galactocerebrosidase (galactocerebroside → ceramide)

Accumulated substrate:
Galactocerebroside

Inheritance:
AR

Krabbe's disease

Findings (4)

1. Peripheral neuropathy
2. Developmental delay
3. Optic atrophy
4. Globoid cells

Metachromatic leukodystrophy

Category
Deficient enzyme
Accumulated substrate
Inheritance

Sphingolipidoses

Deficient enzyme:
Arylsulfatase A (sulfatides → galactocerebroside)

Accumulated substrate:
Cerebroside sulfate

Inheritance:
AR

Metachromatic leukodystrophy

Findings (3)

Central and peripheral demyelination with ataxia, dementia

Hurler's syndrome

Category
Deficient enzyme
Accumulated substrate
Inheritance

Mucopolysaccharidoses

Deficient enzyme:
α-L-iduronidase

Accumulated substrate:
Heparan sulfate, dermatan sulfate

Inheritance:
AR

Hurler's syndrome

Findings (4)

1. Developmental delay
2. Gargoylism
3. Airway obstruction
4. Corneal clouding

Hunter's syndrome

Category
Deficient enzyme
Accumulated substrate
Inheritance

Mucopolysaccharidoses

Deficient enzyme:
Iduronate sulfatase

Accumulated substrate:
Heparan sulfate, dermatan sulfate

Inheritance:
XR

Hunter's syndrome

Findings (3)

Mild Hurler's + aggressive behavior

No corneal clouding

"HUNTERS see clearly (no corneal clouding) and aim for the X (X-linked recessive).

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