Genetic disorders of Metabolism

Question 1

Phenylketonuria

• what is it
• genetics
• presentation
• dx
• tx

Answer 1

Defect hydroxylation phenylalanine –> tyrosine

AR trait

Nl at birth until buildup toxic metabolites

• mental retardation
• vomiting (projectivle)
• eczematous rash
• musty odor
• fair haired + skinned + blue eyes

Dx

• Blood screening after 48-72 hrs of life after protein intake
• High phenylalanine, normal tyrosine
• Guthrie test to detect metabolic products of phenylalanine in urine

Tx

• diet low in phenyalanine
• eat tyrosine

Complications:

• infants born to moms with uncontrolled PKU –> risk MR, microcephaly, congential heart dz
• high rate of spontaneous abortions
• screen babies for 2-3 days after birth (nl if mom is ok since they have maternal enzymes)

Question 2

Galactosemia

• etiology
• presentation
• dx
• tx

Answer 2

Deficiency of galactose-1-phosphate uridyl transferase
Galactose 1 phosphate accumulates

–> Kidney, liver, brain, injury

AR inherit

Sx: jaundice, vomiting, cataracts, HSM, E. coli sepsis

Dx:

• newborn screening
• reducing substances in urine

Tx:
- galactose elim

Question 3

Ways to remember lysosomal storage diseases

Answer 3

Gaucher and Krabbe are friends
- gluco vs galacto

Taysachs and N-P are friends cause they have cherry red foveas

• but TaysaX lacks heXosaminidase deficiency
• you never PICK your nose with your sphinger (sphingomyelinase deficiency for Neimann pick)
• but your liver is BIG with NP

Fabry likes ACTs = deficiency in a-galactosidase A, accumulates ceramide trihexoside

Metachromatic leukodystrophy like ARYLcs = deficiency in arylfulfatase A, accumulates cerebroside sulfate

FABRY is the only X linked recessive - all other are AR

Question 4

Hepatomegaly

Aseptic necrosis of femur

Bone crises

Xray = erlenmeyer flask appearance of long bones

Answer 4

Gaucher’s disease

Autosomal Recessive

Also have gaucher’s cells - macrophages looking like crumpled tissue paper

Confirm with absence of glucocerebrosidase in leukocytes, skin fibroblasts, and liver cells

Question 5

Gaucher’s disease

• deficiency enzyme
• accumulated substance

Answer 5

Deficiency:
Glucocerebrosidase

Accumulate:
Glucocerebroside

Question 6

Peripheral neuropathy

Developmental delay

Optic atrophy

Globoid cells

Opsithotonus

Answer 6

Krabbe’s disease

Autosomal Recessive

Question 7

Krabbe’s disease

• deficiency enzyme
• accumulated substance

Answer 7

Deficiency:
Galactocerebrosidase

Accumulate:
Galactocerebroside

Question 8

Progressive neurodegeneration

Hepatosplenomegaly

Cherry red spot on macula

Answer 8

Neimann Pick disease

Autosomal recessive

Also have foam cells

Question 9

Neimann-Pick disease

• deficiency enzyme
• accumulated substance

Answer 9

Deficiency:
Sphingomyelinase

Accumulate:
Sphingomyelin

Question 10

Progressive neurodegeneration

Developmental delay

Cherry red spot on macula

NO hepatosplanomegaly

Answer 10

Tay Sachs disease
Also in sandoff disease

Autosomal recessive

Also have lysosomes w/ onion skin

Question 11

Tay Sachs disease

• deficiency enzyme
• accumulated substance

Answer 11

Deficiency:
Hexosaminidase A

Accumulates:
GM2 ganglioside

Question 12

Peripheral neuropathy of hands/feet

Angiokeratomas

Cardio/renal disease

Answer 12

Fabry’s disease

X linked recessive

Question 13

Fabry’s disease

• deficiency enzyme
• accumulated substance

Answer 13

Deficiency:
a-galactosidase A

Accumulate:
Ceramide trihexoside

Question 14

Central and peripheral demyelination w/ ataxia

Dementia

Answer 14

Metachoromatic leukodystrophy

Autosomal recessive

• neurodegen disorder of white matter
• problems with myelin metabolism

Question 15

Metchromatic leukodystrophy

• deficiency enzyme
• accumulated substance

Answer 15

Deficiency:
Arylsulfatase

Accumulate:
Cerebroside sulfate

Question 16

Developmental delay

Gargoylism

Airway obstruction

Corneal clouding

HSM

Answer 16

Hurler’s syndrome

Autosomal recessive

Question 17

Hurler’s syndrome

• deficiency enzyme
• accumulated substance

Answer 17

Deficiency:
a-L-iduronidase

Accumulate:
Heparan sulfate
Dermatan sulfate

Question 18

Aggressive behavior

NO corneal clouding

Mild:
Developmental delay
Gargoylism

Answer 18

Hunter’s syndrome

X linked recessive

You can’t have corneal clouding to see as a HUNTER as you aim for the X

Question 19

Hunter’s syndrome

• deficiency enzyme
• accumulated substance

Answer 19

Deficiency:
Iduronate sulfatase

Accumulate:
Heparan sulfate
Dermatan sulfate

Question 20

Carnitine deficiency

Answer 20

Inability to transport long chain fatty acids into mitochondria to get broken down

Causes:

• weakness
• hypotonia
• hypoketotic hypoglycemia

Question 21

Alkaptonuria

Answer 21

Autosomal recessive

Congenital deficiency of homogentisic acid oxidase

Can’t degrade tyrosine –> fumarate

Benign disease

Findings:

• dark connective tissue
• brown pigmented sclera
• urine turns black on prolonged exposure to air
• can have arthritis –> hoomogentisic acid toxic to cartilage

Question 22

Essential fructosuria

Answer 22

AR

Defect in fructokinase

Benign, asymptomatic

Question 23

Fructose intolerance

Answer 23

AR

Deficiency of aldolase B

Hypoglycemia
Jaundice
Cirrhosis
Vomiting

Tx:
- decrease fructose and sucrose intake

Question 24

Galactokinase deficiency

Answer 24

AR

Deficiency of galactokinase

MIld condition
Infantile cataracts

Question 25

Classic galactosemia

Answer 25

AR Absence of galactose-1-phosphate uridyltransferase Present in 1st wk of life ``` FTT Jaundice Hepatomegaly Infantile cataracts MR ``` Tx: - no galactose and lactose in diet

Question 26

Ornithine transcarbamoylase deficiency

Answer 26

X linked recessive #1 urea cycle disorder Can't eliminate ammonia Increased orotic acid in blood and urine Dec BUN Sx of hyperammonemia (tremor, somnolence, vomiting) Tx: - supplement with citrulline - protein restrict

Question 27

Homocystinuria

Answer 27

AR Can't convert Homocysteine --> Cystathione 3 forms: - cystathione synthase deficiency - dec affinity of cystathione syntahse for B6 - Homocysteine methyltransferase deficiency Cysteine becomes essential!! - NOrmal at birth - Increased homocysteine in urine - MR - strokes*** - Marfanoid habitus - downward dislocation of lens Tx: - give high doses of B6 - restric methionine - supplement cysteine

Question 28

Cystinuria

Answer 28

AR Defect of renal tubular AA for cysteine, ornithine, lysine, arginine in PCT Tx: - good hydration - urinary alkalinization

Question 29

Maple syrup urine disease

Answer 29

AR Blocked degradation of branched amino acids (Ile, Leu, Val) - CNS defects - MR - Death

Question 30

Hartnup disease

Answer 30

AR Defective neutral aa transporter on renal and intestinal epithelial cells Tryptophan excretion in urine and dec absorption in gut Leads to pellagra!!!

Question 31

Von Gierke's disease

Answer 31

AR Glycogen storage disease Findings: - severe fasting hypoglycemia - inc glycogen in liver --> hepatomegaly - inc blood lactate - hyperURICemia - hyperLIPIDemia - nl LFTs - fat cheeks - thin extremities - short stature - protuberant abdomen - nl spleen and heart Deficiency: - Glucose-6-phosphatase

Question 32

Pompe's disease

Answer 32

AR = Acid maltase deficiency Findings: - Cardiomegaly - early death - hepatomegaly - floppy baby w/ feeding difficulties - macroglossia Deficiency: - lysosomal a-1,4 glucosidase

Question 33

Cori's disease

Answer 33

AR Findings: - friends with Von Gierke but not as bad! - increased LFTs - normal blood lactate + uric acid - splenomegaly - nl kidneys Deficiency: - debranching enzyme Gluconeogenesis ok

Question 34

McArdle's disease

Answer 34

AR Findings: - increased glycogen in muscle but can't break down - painful muscle cramps - myoglobinuria w/ exercise lots Deficiency: - muscle glycogen phosphorylase

Question 35

Marfan features MR Thromboembolic events Downward dislocation of lens

Answer 35

Homocystinuria