Genetic Disorders/Inborn Errors Of Metabolism 2 Flashcards
Disorders with unusual odors:
- Mousy/musty
- Sweet
- Sweaty feet
- Rotten cabbage
- Phenylketonuria
- Maple syrup urine disease
- Isovaleric or glutaric
- Hereditary tyrosinemia
Typical presentations of inborn errors of metabolism?
- Acute severe neonatal illness (apparently healthy newborn develops severe illness within the first few hours/weeks)
- Recurrent intermittent episodes at times of stress (surgery, fasting, illness)
- Chronic and progressive symptoms (mitochondrial)
Increased plasma NH3 suggest?
- Hypoxia
- Severe dehydration
- Urea cycle defects if > 200
Family history suspicious for inborn errors of metabolism?
- Neonatal deaths in siblings or males on maternal side
- Parental consanguinity
- Mental retardation
- Unusual dietary preferences and relatives
Ketones in newborns versus older?
Inborn errors of metabolism versus fatty acid oxidation defect
Test suggestive for galactosemia?
Non-glucose-reducing substance on urine dipstick
Baby with metabolic acidosis – order these tests?
- Serum lactate and pyruvate (rule out lactic acidemias or organic acidemias)
- Plasma amino acids (rule out aminoacidemias or organic acidemias)
Baby with increased ammonia – test? Tx for hyperammonemia?
- Plasma amino acids (if high suspect aminoacidemia)
- Urine organic acids (elevated orotic acid suggests ornithine transcarbamylase deficiency)
- Sodium benzoate and sodium phenylacetate to increase excretion
- Oral Neosporin and lactulose to prevent bacterial production of ammonia in colon
Homocystinuria – caused by? Inheritance? Clinical features? Diagnosis? Management?
Cystathionine synthase deficiency; autosomal recessive
- Marfanoid body habitus without arachnodactyly
- Downward lens subluxation (in Marfan’s, get upward lens subluxation)
- Hypercoagulable state
- Cardiovascular abnormalities – mitral or aortic regurgitation (unlike Marfan’s, no aortic dilatation)
- Scoliosis and large joints
- Developmental delay, mild mental retardation
- Increased methionine in urine and plasma
- Positive urinary cyanide nitroprusside test
- Methionine restricted diet
- Aspirin
- Folic acid/B6 supplementation
PKU – inheritance? Clinical features? Diagnosis? Management? Prognosis?
On some obsessive
- Mental retardation/ADHD
- Mousy/musty odor
- Infantile hypotonia
- Eczema
- White hair and eyes (decreased pigment)
Phenylalanine: tyrosine ratio
Phenylalanine restricted diet
Near normal intelligence if diet restriction begins before one month
Maple syrup urine disease – inheritance? Clinical features? Diagnosis? Management? Prognosis
Autosomal excessive
- Progressive vomiting and poor feeding
- Lethargy and hypertonia
- Developmental delay
- Maple syrup odor in urine
- Hypoglycemia and acidosis during episodes
Sarah and urine BCAAs
Dietary protein restriction
Avert neurologic damage if protein restriction within two weeks
Tyrosinemia – inheritance? Clinical features? Diagnosis? Management? Prognosis
Autosomal recessive
- Prefold neuropathy
- Chronic liver disease
- Renal tubular dysfunction
- Rotten cabbage/fish odor
Succinylacetone in urine
- Dietary restriction of phenylalanine, tyrosine, NTBC
- Liver transplant
- Death in one-year if disease begins in infancy
- HCC and cirrhosis
Transient tyrosinemia of the newborn - Clinical features? Diagnosis? Management? Prognosis?
Poor feeding or lethargy
Elevated serum tyrosine and allowing
- Decreased protein intake during acute episode
- Vitamin C may help aluminate tyrosine
Resolution within one month
Membrane transport defects? Clinical features?
- Cystinuria – defect in the renal absorption of cystine, lysine, arginine, ornithine that leads to renal stones. (UTIs, dysuria, back pain, urinary urgency)
- Hartnup Disease – defect in transport of neutral amino acids (ataxia, photosensitivity rash, mental retardation emotional lability)
Transient hyperammonemia of the newborn – Presents when? Symptoms? Treatment?
Presents within 24-48 hours of life
Respiratory distress, alkalosis, vomiting, Lethargy
Aggressive anti- ammonia treatment
Most common urea cycle defect? Inheritance? Clinical features? Diagnosis? Management? Prognosis?
Ornithine transcarbamylase deficiency; X-linked recessive
Vomiting, lethargy, coma
- Elevated urine orotic acid, decreased serum situate, increased Ornstein
- Liver biopsy
Low-protein diet and management of hyperammonemia; liver transplant
Prognosis depends on neurologic sequelae
Galactosemia – suspect when? Mech? Clinical features? Management? Prognosis?
Any newborn with hepatomegaly and hypoglycemia
Galactose-1-phosphate uridyltransferase deficiency
- Vomiting/diarrhea and FTT
- Hepatic dysfunction with hepatomegaly
- Cataracts with oil-droplets appearance
- Renal tubular acidosis
- Non-glucose-reducing substrate in urine
- Enzyme deficiency and blood cells
Galactose-free diet
Normal intelligence is treated early, otherwise mental retardation, ovarian failure
Von Gierke’s disease – inheritance? Defect? Presenting features? Management? Future risk for?
Autosomal recessive; glucose-6-phosphatase deficiency
- Organomegaly
- metabolic acidosis
- Hypoglycemia
- hypertriglyceridemia
- Doll-like facies
Highcomplex carbohydrate diet
HCC
Pompeys disease – aka? deficiency? Features?
Acid maltase deficiency
Alpha-glucosidase deficiency
- Muscular weakness (floppy baby) and cardiomegaly
- Metabolic acidosis and hepatomegaly
Sequela of fatty acid oxidation disorders? Most common fatty acid oxidation disorder? Diagnose by? Management?
- Nonketotic hypoglycemia
- Hyperammonia
- 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
Suspect if a disease involves three or more organ systems? Examples?
Mitochondrial disorders
Kearns-Sayre
MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes)
Tay-Sachs - deficiency of? Clinical features? Diagnosis? Prognosis?
Hexosaminodase A deficiency
- Cataracts
- Hypotonia and motor weakness
- Increased startle due to hyperacusis
- Macrocephaly
- Cherry red macula (NOT present in juvenile/adult onset)
- 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
Most common gangliosidosis? Characteristic findings? Tx? Prognosis?
Gaucher’s disease
Erlenmeyer flask-shape to distal femur
Enzyme replacement therapy
Death By four years
Neumann-Pick disease – deficiency in? clinical features? Prognosis?
Sphingomyelinase
neurodegeneration, ataxia, seizures, hepatosplenomegaly, cherry red macula
Death by four years
Metachromatic leukodystrophy – deficiency? Present features Prognosis?
Arylsulfatase A deficiency
Araxua, seizures, progressive mental retardation
Death before 20
Dysistosis multiplex? Seen in?
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)
Most severe mucopolysaccharidosis? Inheritance? Deficiency? Clinical features? Diagnosis? Management? Prognosis?
Hurler syndrome; autosomal recessive; alpha-L-idoronidase deficiency
- Hepatosplenomegaly, kyphosis
- Course facial features
- Corneal clouding
- Developmental delay
Dermatan and heparan sulfate in urine and decreased a-L-idoronidase activity
Early bone marrow transplant to prevent neurodegeneration
Death by 15
Hunter syndrome – inheritance? Clinical features? Diagnosis? Prognosis?
X linked recessive
- Hepatomegaly
- Hearing loss
- Dysostosis multiplex
- No corneal clouding (unlike hurler)
Dermatan and heparan sulfate in urine and decreased a-L-iduronidase
No treatment, death by 20
Sanfilippo syndrome – inheritance? Features?
Autosomal recessive; mental and motor retardation
Marquino syndrome – clinical findings? Prognosis?
Unlike other mucopolysaccharidosis, no mental retardation
Scoliosis meeting to cor pulmonale results in death by 40
Hepatolenticular degeneration – defect? Clinical features? Diagnosis? Management
Wilson’s disease; defect and copper excretion that results in Copper deposition into tissues
- Kaiser-Fleischer rings - deposits in Descemet’s membrane
- Neurologic – dystonia, dysarthria, tremors, ataxia, seizures
- Hepatic dysfunction
- Decreased serum ceruloplasmin
- Elevated serum/urine copper
- Copper deposition in hepatocytes
- Avoid copper containing food (nuts, liver, shellfish, chocolate)
- Chelation therapy with oral penicillamine and zinc
Menke’s kinky hair disease – inheritance? Defect? Clinical features? Labs?
Excellent recessive disorder; abnormal copper transport
- Myoclonic seizures
- Kinky friable hair
- Optic nerve atrophy
- Mental retardation, neurologic degeneration
Low serum ceruloplasmin and copper
