Chapter 8 Enzyme & Collagen Disorders (Inborn orders of metabolism)

Genetic Lysosomal Storage Disease: Mucopolysaccharidoses Type 1 (Hurler Syndrome) S/S:

-Appear normal at birth. -Physical appearance begins to change w/in the 1st 6months -Umbilical hernias common -Coarse facial features, micrognathia, macroglossia -corneal clouding -Short stature -Spinal deformity -Hepatosplenomegaly -Intellect limited and deteriorates over time -Cardiac dysfunction (accumulation in coronary arteries), respiratory obstruction, or pneumonia lead to death b/w ages 5-10yrs

Genetic Lysosomal Storage Diseases

-Enzyme disorders -Present from conception but manifestations usually not present till after birth

Genetic Lysosomal Storage Disease: Mucopolysaccharidoses: Type 2 Hunter Syndrome S/S:

-Normal at birth. Slower development. -Similar to Hurler syndrome but intellect less affected -Gradual hearing loss -Severe form: live 10-20 yrs -Mild form: live 20-60 yrs

Genetic Lysosomal Storage Disease: Tay-Sachs S/S

-Normal at birth=normal muscle tone & cognitive development first few months -cognitive regression (loss of learned skills) -Progressive muscle weakness to flaccid paralysis (see loss of smile, crawl, grab) -Retinal cells pale & you get the cherry-red spot in macula -Blindness - seizure activity

Connective Tissue Disorder: Marfan Syndrome S/S:

-Ocular defects: myopia (nearsighted), Ectopia (lense dislocation of the eye) -Skeletal defects: Long slender limbs, hallow chest, scoliosis, hypermobile joints, arachnodactyly -Cardiovascular defects: mitral valve prolapse or regurgitation, aortic dilation or dissection

Genetic Lysosomal Storage Disease: Fabry Disease S/S

-Seen later in childhood -At first S/S related to poor perfusion: -Cold intolerance -Insufficient sweating in hot environments -Pain -Adolescents have affected blood vessels affecting the heart, kidneys, brain, and peripheral nerves -Angiokeratomas -Spoke wheel posterior cataract -Strokes -Hearing loss or tinnitus -Cardiac problems lead to early death

Phenylketonuria Management:

-Strict dietary managment of phenylalanine levels: low-phenylalanine infant formula then less than 300-500mg daily (adjustment needed for body size and growth spurts) -After brain development is complete less restriction of phenylalanine is needed (controversial)

Alcaptonuria

-Variant form of metabolism -Lose of function mutation - They don't have the enzyme HGO so they can't break down the amino acid, phenylalanine, so the intermediate metabolite HGA will accumulate and be excreted in urine turning it black

The metabolic process consist of:

A sequence of steps catalyzed by enzymesthat are encoded by the genes in our DNA

Enzyme: What is it and what does it do ?

Biological catalyst (protein) that: 1) causes a biochemical reaction to occur or 2) increases the rate of a biochemical reaction within a cell, body tissue, or organ. --> ALL enzymes are gene products. A mutation in a gene coding for a specific enzyme usually reduces the enzyme's activity resulting in a physiologic problem.

Elastin

Provides stretch

Inborn errors of metabolism: Hyperammonemia

Urea cycle defect -treatable

Inheritance of Metabolic Defects:

- Most are autosomal recessive -Mutant allele usually leads to loss of function -Heterozygous carriers usually unaffected

Pathological Effects Of A Blocked Pathway

1) Absence of a functioning enzyme- does not catalyze the reaction 2) Accumulation of a substrate as a result of an inactive enzyme 3) Accumulation of a product due to an overactive enzyme

S/S Of Decrease/Lack Of Tyrosine:

1) Disrupts essential CNS processes in the developing nervous system, myelination, and protein synthesis = severe mental retardation, seizure activity, & tremors 2) Growth retardation in the skin pigment, eyes, & hair color (decrease color of each) 3)Musty/mousy odor of sweat, breath, & urine. Urine will have phenylalanine & phenylpyruvate in it.

Two Types of Amino Acids

1) Essential: Our cells can't synthesize them so we have to get them in our diet 2) Nonessential: Our cells can synthesize them

Collagen Gene Mutations: Ehlers-Danlos: Two Major Types

1) Hypermobility & Vascular (type 3 collagen mutation) -autosomal dominant 2)Kyphoscoliosis (kyphosis = abnormally rounded upper back) (mutation in gene responsible for modifying collagen) - autosomal recessive

Genetic Lysosomal Storage Disease: Gaucher Disease Management:

1) Manage anemia & thrombocytopenia with growth factors & transfusion 2)Enzyme replacement therapy for splenomegaly & hepatomegaly -sometimes works for bone pain ( life long replacement - very expensive) 3) Cure requires hematopoietic stem cell transplant (HSCT) for severe cases (has 50% mortality rate)

Classification of Metabolic Disorders

1) Pathological effects of the pathway blocked 2) Functional classes of proteins (receptor, hormone, enzyme) 3)Co-factors (metals vs. vitamins) 4) By the pathway that is effected = best way (And if it is catabolic [oxidation] or anabolic pathway of one of the 4 macromolecules)

A DNA mutation that inactivates a single enzyme in a pathway can:

1) Stop production of the final product 2)Lead to accumulation of an intermediate product : toxic metabolite

Genetic Enzyme Disorders: Lysosomal storage disease:

1) The degradative enzyme within Lysosomes is defective or deficient leading to the build up of protein and lipid by-products (metabolite/substrate) 2) There is defective transport of the enzyme to the lysosome

Genetic Lysosomal Storage Disease: Gaucher Type 1 Nonneuronopathic S/S:

1) Visceromegaly: Large protruding abdomen with pain (splenomegaly/hepatomegaly) 2)Enlarged macrophages infiltrate bone marrow and decrease RBC (anemia) & platelets (thrombocytopenia) production 3)Mutli organ failure 4)Debilitating skeletal disease

Enzymes in Lysosomes Breakdown:

1) sphingolipids 2)Glycosaminoglycans & MPS 3)Glycoproteins 4)Glycolipids

Collagen Gene Mutations: Ehlers-Danlos Syndrome (ED)

A group of 6 different genetic disorders due to mutations in genes for type I, III, & V collagen.

Collagen Gene Mutations: Osteogenesis Imperfecta

A group of disorders that impair type 1 collagen formation. Loss of or defective procollagen does not combine and form functional fibers. The developing bones have decrease integrity / strength and increase fractures -No cure. Management only. Try to prevent fractures. Brace skeletal structures (surgical rod placement, braces around joints). Bisphosphonate based drugs to improve bone strength. Safe exercise(swimming).

Genetic Lysosomal Storage Disease: Mucopolysaccharidoses

An enzyme in the pathway to breaking down mucopolysacchardies, also called glucosaminoglycans (GAGS) is inactive. GAG accumulates & the cell dies. Which syndrome depends on the specific enzyme that's deficient in this process of breaking down/recycling mucopolysaccharides (GAG'S).

Genetic Lysosomal Storage Disease: Fabry Disease

Deficiency in enzyme A-GAL(also called ceramide trihexosidase) resulting in accumulation of GL-3s in lysosomes and in the blood -Due to mutation in gene located on chromosome xq22 -X-linked recessive (males affected & females carriers but may have symptoms with this disease due to skewed X chromosome inactivation in different tissues) Tx- Enzyme replacement therapy q 2 weeks

Genetic Lysosomal Storage Disease: Gaucher

Deficiency in the enzyme glucosylceraMIDASE (beta glucosidase =GBA gene) leading to an accumulation of glucosylceraMIDE in macrophages of liver, spleen, bone marrow, and lungs. Macrophages become excessively large and exert pressure on nearby organ cells. The organs also enlarge due to the continually increasing size of macrophages decreasing oxygen/perfusion to the organ. --> Most common lysosomal storage disease. --> Usual onset during childhood

Genetic Lysosomal Storage Disease: Tay-Sachs Pathophysiology

Deficiency of the enzyme hexosamindase (hex-a)resulting in failure to degrade GM-2 Ganglioside particularly in brain cells but other cells too (retinal & muscle). Brain cells swell, increase the cell size, and destroys cell function. When enough brain cells are destroyed death occurs. Death usually occurs between 2-4 years. -No treatment. Try to delay muscle weakness. Genetic counseling for parents & siblings.

Inborn errors of metabolism: Reye Syndrome

Fatty acid oxidation syndrome -Not really treatable (Some cases of SIDS are found to have fatty acid metabolism defect)

Fibrillin Function And Where It's Chiefly Found:

Fibrillin interacts with collagen and elastin to provide recoil strength to tissues during and after stretching. It allows stretching to occur without breaking and a return to the size it was before stretching. Prevents too much stretching. -There are 3 major types of fibrillin -It is an essential component of CT in muscles, tendons, and in tissues that are around large arteries -Plays a role in skin and eye development

Genetic Lysosomal Storage Disease: Fabry Disease Pathophysiology

GL-3s accumulates in lysosomes and in the blood due to enzyme A-GAL deficiency. Accumulation in the blood is because GL-3s degradation is part of the normal RBC recycling process. -Lysosomes swell, increase in size, and disrupt function -GL-3s accumulation in the blood causes damaged blood vessels inducing inflammation, poor tissue perfusion, ischemia, and organ failure

Collagen

Group of glycoprotein fibers that form the major component of the connective tissue found in nearly all body tissue. It is the most abundant protein in humans. Starts out as procollagen. -16 types of collagen. Type 1-4 makeup 90% of the collagen in our bodies.

Genetic Lysosomal Storage Disease: Mucopolysaccharidoses Type 2

Hunter Syndrome: Deficiency in the enzyme IDS resulting in accumulation of mucopolysaccharides (GAG's) in lysosomes in most cells. -Lysosomes swell, increase cell size, disrupt cell function -Due to mutation in gene on chromo Xq28 -X-Linked recessive (So males affected. F just carriers) -Tx: Enzyme replacement until HSCT

Genetic Lysosomal Storage Disease: Mucopolysaccharidoses Type 1:

Hurler Syndrome: Deficiency in the enzyme alpha-L-Iduronidase (IDUA) resulting in accumulation of mucopolysaccharides (GAG's) in the lysosomes. In type 1 the lysosomes of almost all cells are eventually affected. -Accumulation of GAG's: heparan & dermatan sulfate -Lysosomes swell increasing cell size and disrupting function -Due to mutation in gene on chromo 4p16.3 -Autosomal Recessive -Treatment is aimed at slowing progression w/ weekly enzyme replacement (wont prevent CNS deterioration) until you can do a HSCT and hope that it takes. HSCT must be done within 18months.

Mucopolysaccharides

Large glucosaminoglycans (GAGS=protein &sugar) that make up a large part of the extracellular matrix (basement membranes) of different tissues. They hold cells & tissues together. -They must be broken down / recycled in lysosomes of many diff. cells by a specific enzyme. They are recycled (broken down into its constituent parts) almost daily.

Collagen Gene Mutations: Kyphoscoliosis Ehlers-Danlos S/S

Lax joints Declining muscle weakness Premature Death

Type 1 Collagen Formation

Most common & major component of: -bone -dermal layer of skin -tendons -ligaments -corneas -intervertebral disks -walls of arteries & other blood vessels

Hyperaminoacidemias

One amino acid accumulates to a toxic level

Collagen Function

Procollagen is modified in multiple ways to form different types of mature collagen fibers that combine and work with other fibrous tissue to form cables that add strength and structure to most tissues. Collagen fibers are part of the extra cellular matrix between cells and tissues that function to hold cells together & promote communication between cells. Collagen forms fibrils that withstand stretching Provides static strength

Collagen Gene Mutations: Osteogenesis Imperfecta S/S for Types I-IV

Severity of phenotype depends on amount of collagen lost / how abnormal the collagen is Type I:Collagen is normal but less present = increase fractures during life but usually not infancy - blue tinged sclera Type II: Most severe and lethal in utero -no normal collagen Type III: Fractures during development & life- Bone deformities Type IV: Abnormal collagen but milder since there is collagen-fewer deformities

Collagen Gene Mutations: Hypermobility Ehlers-Danlos S/S

Stretchy skin Hyperextensible joints Bruise easy

Connective Tissue Disorder: Marfan Syndrome

Technically not a collagen disorder but a connective tissue disorder where the gene for fibrillin is mutated. Most cases of Marfan Syndrome are mutation of FBN1 Gene. It is large & many different mutations can occur- wide variations in phenotype - It is autosmal dominant

Inheritance of Metabolic Defects: Most common for of testing:

Testing dried blood of a newborn for increase levels of metabolites. -Currently we screen for >24 abnormal metabolites in newborns. Ex's: PKU (amino acid metabolism disorder) & Galactosemia (cant metabolize galactose sugar)

Defects In Amino Acid Metabolism/ Genetic Enzyme Disorders: Mutation in an enzymes of the phenylalanine (phe) hydroxylation pathway which results in what disorder?

The enzyme PAH is deficient so phenylalanine (phe) can't be enzymatically converted to tryrosine. Leads to increase serum levels of phenylalanine and decrease levels of tyrosine resulting in the disorder: phenylketonuria (excess phe metabolized into ketoacid lowering the blood pH). Tyrosine is nonessential ( made by body from phenylalanine not gotten through diet).

Collagen Gene Mutations: Vascular Ehlers-Danlos S/S

Thin mid-size and large arteries leading to rupture. Most common cause of death is hemorrhage from arterial rupture or sepsis from intestinal rupture usually by age 30.

Genetic Lysosomal Storage Disease: Mucopolysaccharidoses Type 1,2,3

Type 1 :Hurler Syndrome Type 2: Hunter Syndrome Type 3: Sanfilippo A,B,C (all three have similar s/s

Genetic Lysosomal Storage Disease: Gaucher Type 1-3

Type 1: CNS not affected -most common Type 2: Most severe -death by 2 yrs Type3: Somewhere b/w type 1&2

Functions Of Tyrosine In The Body

Tyrosine is an important amino acid for the production of: 1) thyroid hormones 2) melanin 3) neurotransmitters (dopamine & catecholamines like epi & nepi)

Genetic Enzyme Disorder

Usually neither parent has an obvious problem, and the newborn does not have symptoms at birth because the maternal enzymes cross the placenta and perform their specific functions in the cells of the fetus. S/S are seen shortly after birth.

Executive Functions:

Behavioral functions associated prefrontal lobe activity. -problem solving -controlling impulses -planning -goal directed impulses (Even with good control over phenylalanine levels executive functions are diminished)

Collagen Gene Mutations

Could have a mutation in: 1) The collagen gene 2)The enzyme that modify the procollagen 3) Assembly process 4) Association with other molecules -Mutation in one gene can effect many tissues and there are many different mutations so there's a great variation in disease severity -No cure. Managment treatment only .

Genetic Enzyme Disorder: Defects In Amino Acid Metabolism: Hyperphenylalaninemias

Defects in the metabolism of the amino acid phenylalanine (PHE) due to different gene mutations