Genetic Disorders/Inborn Errors Of Metabolism 2

Question 0

Disorders with unusual odors:

1. Mousy/musty
2. Sweet
3. Sweaty feet
4. Rotten cabbage

Answer 0

1. Phenylketonuria
2. Maple syrup urine disease
3. Isovaleric or glutaric
4. Hereditary tyrosinemia

Question 1

Typical presentations of inborn errors of metabolism?

Answer 1

1. Acute severe neonatal illness (apparently healthy newborn develops severe illness within the first few hours/weeks)
2. Recurrent intermittent episodes at times of stress (surgery, fasting, illness)
3. Chronic and progressive symptoms (mitochondrial)

Question 2

Increased plasma NH3 suggest?

Answer 2

1. Hypoxia
2. Severe dehydration
3. Urea cycle defects if > 200

Question 3

Family history suspicious for inborn errors of metabolism?

Answer 3

1. Neonatal deaths in siblings or males on maternal side
2. Parental consanguinity
3. Mental retardation
4. Unusual dietary preferences and relatives

Question 4

Ketones in newborns versus older?

Answer 4

Inborn errors of metabolism versus fatty acid oxidation defect

Question 5

Test suggestive for galactosemia?

Answer 5

Non-glucose-reducing substance on urine dipstick

Question 6

Baby with metabolic acidosis – order these tests?

Answer 6

1. Serum lactate and pyruvate (rule out lactic acidemias or organic acidemias)
2. Plasma amino acids (rule out aminoacidemias or organic acidemias)

Question 7

Baby with increased ammonia – test? Tx for hyperammonemia?

Answer 7

1. Plasma amino acids (if high suspect aminoacidemia)
2. Urine organic acids (elevated orotic acid suggests ornithine transcarbamylase deficiency)
3. Sodium benzoate and sodium phenylacetate to increase excretion
4. Oral Neosporin and lactulose to prevent bacterial production of ammonia in colon

Question 8

Homocystinuria – caused by? Inheritance? Clinical features? Diagnosis? Management?

Answer 8

Cystathionine synthase deficiency; autosomal recessive

1. Marfanoid body habitus without arachnodactyly
2. Downward lens subluxation (in Marfan’s, get upward lens subluxation)
3. Hypercoagulable state
4. Cardiovascular abnormalities – mitral or aortic regurgitation (unlike Marfan’s, no aortic dilatation)
5. Scoliosis and large joints
6. Developmental delay, mild mental retardation
7. Increased methionine in urine and plasma
8. Positive urinary cyanide nitroprusside test
9. Methionine restricted diet
10. Aspirin
11. Folic acid/B6 supplementation

Question 9

PKU – inheritance? Clinical features? Diagnosis? Management? Prognosis?

Answer 9

On some obsessive

1. Mental retardation/ADHD
2. Mousy/musty odor
3. Infantile hypotonia
4. Eczema
5. White hair and eyes (decreased pigment)

Phenylalanine: tyrosine ratio

Phenylalanine restricted diet

Near normal intelligence if diet restriction begins before one month

Question 10

Maple syrup urine disease – inheritance? Clinical features? Diagnosis? Management? Prognosis

Answer 10

Autosomal excessive

1. Progressive vomiting and poor feeding
2. Lethargy and hypertonia
3. Developmental delay
4. Maple syrup odor in urine
5. Hypoglycemia and acidosis during episodes

Sarah and urine BCAAs

Dietary protein restriction

Avert neurologic damage if protein restriction within two weeks

Question 11

Tyrosinemia – inheritance? Clinical features? Diagnosis? Management? Prognosis

Answer 11

Autosomal recessive

1. Prefold neuropathy
2. Chronic liver disease
3. Renal tubular dysfunction
4. Rotten cabbage/fish odor

Succinylacetone in urine

1. Dietary restriction of phenylalanine, tyrosine, NTBC
2. Liver transplant
3. Death in one-year if disease begins in infancy
4. HCC and cirrhosis

Question 12

Transient tyrosinemia of the newborn - Clinical features? Diagnosis? Management? Prognosis?

Answer 12

Poor feeding or lethargy

Elevated serum tyrosine and allowing

1. Decreased protein intake during acute episode
2. Vitamin C may help aluminate tyrosine

Resolution within one month

Question 13

Membrane transport defects? Clinical features?

Answer 13

1. Cystinuria – defect in the renal absorption of cystine, lysine, arginine, ornithine that leads to renal stones. (UTIs, dysuria, back pain, urinary urgency)
2. Hartnup Disease – defect in transport of neutral amino acids (ataxia, photosensitivity rash, mental retardation emotional lability)

Question 14

Transient hyperammonemia of the newborn – Presents when? Symptoms? Treatment?

Answer 14

Presents within 24-48 hours of life

Respiratory distress, alkalosis, vomiting, Lethargy

Aggressive anti- ammonia treatment

Question 15

Most common urea cycle defect? Inheritance? Clinical features? Diagnosis? Management? Prognosis?

Answer 15

Ornithine transcarbamylase deficiency; X-linked recessive

Vomiting, lethargy, coma

1. Elevated urine orotic acid, decreased serum situate, increased Ornstein
2. Liver biopsy

Low-protein diet and management of hyperammonemia; liver transplant

Prognosis depends on neurologic sequelae

Question 16

Galactosemia – suspect when? Mech? Clinical features? Management? Prognosis?

Answer 16

Any newborn with hepatomegaly and hypoglycemia

Galactose-1-phosphate uridyltransferase deficiency

1. Vomiting/diarrhea and FTT
2. Hepatic dysfunction with hepatomegaly
3. Cataracts with oil-droplets appearance
4. Renal tubular acidosis
5. Non-glucose-reducing substrate in urine
6. Enzyme deficiency and blood cells

Galactose-free diet

Normal intelligence is treated early, otherwise mental retardation, ovarian failure

Question 17

Von Gierke’s disease – inheritance? Defect? Presenting features? Management? Future risk for?

Answer 17

Autosomal recessive; glucose-6-phosphatase deficiency

1. Organomegaly
2. metabolic acidosis
3. Hypoglycemia
4. hypertriglyceridemia
5. Doll-like facies
   Highcomplex carbohydrate diet

HCC

Question 18

Pompeys disease – aka? deficiency? Features?

Answer 18

Acid maltase deficiency

Alpha-glucosidase deficiency

1. Muscular weakness (floppy baby) and cardiomegaly
2. Metabolic acidosis and hepatomegaly

Question 19

Sequela of fatty acid oxidation disorders? Most common fatty acid oxidation disorder? Diagnose by? Management?

Answer 19

1. Nonketotic hypoglycemia
2. Hyperammonia
3. Myopathy and cardiomyopathy

Medium chain acyl-CoA dehydrogenase deficiency

Tandem mass spectrometry detecting elevated plasma medium chain fatty acids

Frequent feedings with high carb, low-fat diet and carnitine supplementation

Question 20

Suspect if a disease involves three or more organ systems? Examples?

Answer 20

Mitochondrial disorders

Kearns-Sayre
MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes)

Question 21

Tay-Sachs - deficiency of? Clinical features? Diagnosis? Prognosis?

Answer 21

Hexosaminodase A deficiency

1. Cataracts
2. Hypotonia and motor weakness
3. Increased startle due to hyperacusis
4. Macrocephaly
5. Cherry red macula (NOT present in juvenile/adult onset)
6. Progressive blindness, seizures, mental retardation

Hexosaminidase a activity in leukocytes/fibroblasts

Infantile disease is untreatable and death occurs by four; adult/juvenile type results in chronic debilitated state

Question 22

Most common gangliosidosis? Characteristic findings? Tx? Prognosis?

Answer 22

Gaucher’s disease

Erlenmeyer flask-shape to distal femur

Enzyme replacement therapy

Death By four years

Question 23

Neumann-Pick disease – deficiency in? clinical features? Prognosis?

Answer 23

Sphingomyelinase

neurodegeneration, ataxia, seizures, hepatosplenomegaly, cherry red macula

Death by four years

Question 24

Metachromatic leukodystrophy – deficiency? Present features Prognosis?

Answer 24

Arylsulfatase A deficiency Araxua, seizures, progressive mental retardation Death before 20

Question 25

Dysistosis multiplex? Seen in?

Answer 25

Constellation of bony abnormalities thickened cranium, J-shaped sella turcica, beak-like vertebrae, short clavicles, oar-shaped ribs) Seen in mucopolysaccharidosis (lysosomal storage disorders with glucosaminoglycan accumulation)

Question 26

Most severe mucopolysaccharidosis? Inheritance? Deficiency? Clinical features? Diagnosis? Management? Prognosis?

Answer 26

Hurler syndrome; autosomal recessive; alpha-L-idoronidase deficiency 1. Hepatosplenomegaly, kyphosis 2. Course facial features 3. Corneal clouding 4. Developmental delay Dermatan and heparan sulfate in urine and decreased a-L-idoronidase activity Early bone marrow transplant to prevent neurodegeneration Death by 15

Question 27

Hunter syndrome – inheritance? Clinical features? Diagnosis? Prognosis?

Answer 27

X linked recessive 1. Hepatomegaly 2. Hearing loss 3. Dysostosis multiplex 4. No corneal clouding (unlike hurler) Dermatan and heparan sulfate in urine and decreased a-L-iduronidase No treatment, death by 20

Question 28

Sanfilippo syndrome – inheritance? Features?

Answer 28

Autosomal recessive; mental and motor retardation

Question 29

Marquino syndrome – clinical findings? Prognosis?

Answer 29

Unlike other mucopolysaccharidosis, no mental retardation Scoliosis meeting to cor pulmonale results in death by 40

Question 30

Hepatolenticular degeneration – defect? Clinical features? Diagnosis? Management

Answer 30

Wilson's disease; defect and copper excretion that results in Copper deposition into tissues 1. Kaiser-Fleischer rings - deposits in Descemet's membrane 2. Neurologic – dystonia, dysarthria, tremors, ataxia, seizures 3. Hepatic dysfunction 1. Decreased serum ceruloplasmin 2. Elevated serum/urine copper 3. Copper deposition in hepatocytes 1. Avoid copper containing food (nuts, liver, shellfish, chocolate) 2. Chelation therapy with oral penicillamine and zinc

Question 31

Menke's kinky hair disease – inheritance? Defect? Clinical features? Labs?

Answer 31

Excellent recessive disorder; abnormal copper transport 1. Myoclonic seizures 2. Kinky friable hair 3. Optic nerve atrophy 4. Mental retardation, neurologic degeneration Low serum ceruloplasmin and copper