Disorders of metabolism

Question 1

What causes PKU

Answer 1

AR
phenylalanine can not be converted to tyrosine
enzyme defect is phenylalanine hydroxylase

Question 2

What is the common presentation of PKU and what would be seen in the blood and in the urine?

Answer 2

vomiting
irritability
eczematoid rash
mousy, wolf like or musty odor
(often fair hair with fair skin)
high levels of phenylalanine in blood
high levels of phenyl-pyruvic acid in urine

Question 3

What does an infant have if mother has untreated PKU?

Answer 3

growth deficiency, microcephaly, intellectual disability and congenital heart defects

Question 4

What can cause hyperphenylalaninemia

Answer 4

could have a milder deficiency is the PAH enzyme

defect in synthesis or recycling or biopterin a cofactor of the PAH enzyme needed to make tyrosine

Question 5

What are the symptoms of hyperphenylalaninemia and what is the treatment?

Answer 5

neurologic symptoms despite low ingestion of phenylalanine.
also affects ability to make serotonin, dopa and norepinephrine
treatment includes phenylalanine restriction and biopterin supplementation, and supplementation of precursors like dopa and 5-hydroxytryptophan

Question 6

What is seen in hereditary tyrosinemia Type 1

Answer 6

AR
deficiency of fumarylacetoacetate hydroxylase (tyrosine metabolism)
accumulation of succinylacetone
rapid course to death or FFT, liver failure, hepatomegaly with hepatoblastoma, renal tubular acidosis, xr findings consistent with rickets

Question 7

How is hereditary tyrosinemia type 1 diagnosed and treated?

Answer 7

elevated plasma tyrosine
succinylacetone in the urine
liver failure and Fanconi syndrome treated with NTBC {2-(nitro-4-trifuoro-methylbenzoyl)-1,3cyclohexanedione}
and low tyrosine diet

Question 8

How does tyrosinemia type 2 present

Answer 8

AR
oculocutaneous tyrosinemia
deficiency of tyrosine aminotransferase 
corneal ulcers or dendritic keratitis
red papular or keratotic lesion on their palms and soles
50% have intellectual disability

Question 9

What is alkaptonuria?

Answer 9

deficiency in homogentisic acid dioxygenase
3rd step in tyrosine metabolism
urine darkens as it sits due to oxygenation of the homogentisic acid in the urine

Question 10

What are the symptoms of alkaptonuria?

Answer 10

pigment deposition in ears and sclera as an adult: ochronosis
can also cause ochronosis arthritis
some have aortic root dilatation or valvular involvement

Question 11

How does maple syrup urine disease present?

Answer 11

urine, hair or skin smells like maple syrup
symptoms start day 3-5 with progression to death in 2-4 weeks
feeding difficulties, irregular breathing, loss of the moro reflex, seizures, opisthotonos and rigidity

Question 12

What is the defect in maple syrup urine disease and what is the treatment?

Answer 12

defect in oxidative decarboxylation of ketoacids formed from the catabolism of branched amino acids:
leucine, isoleucine and valine
increased amounts of valine, leucine and isoleucine in the urine, or alloisoleucine in the urine
decrease intake of these proteins

Question 13

What is the clinical presentation of homocystinuria

Answer 13

AR
elevation in homocysteine
in those with the cystathionine beta-synthetase deficiency have a marfanoid habitus, developmental delay, lens dislocation and increased risk of thromboembolism (both venous and arterial)
joints are NOT hypermobile, osteoporosis

Question 14

What is the treatment for homocystinuria

Answer 14

pyridoxine in the vitamin responsive form

diet low in methionine

Question 15

What is nonketotic hyperglycinemia

Answer 15

large amounts of glycine in the body and in the CSF, with highest amounts being in the CSF
intractable seizures in the neonatal period, with hiccups in utero
results in severe intellectual disability

Question 16

What are the six main enzyme defects that can cause hyperammonemias?

Answer 16

1. N acetylglutamate synthetase deficiency
2. carbamoyl phosphate synthase deficiency
3. ornithine transcarbamylase deficiency (X-linked)
4. argininosuccinate synthetase deficiency (citrullinemia)
5. argininosuccinate lyase deficiency
6. arginase deficiency (argininemia)

Question 17

How does a urea cycle disorder present?

Answer 17

intoxication
lethargy, vomiting, confusion to coma
more proximal the defect, the more severe

Question 18

What labs should be ordered to help determine the location of the defect

Answer 18

plasma and urine organic acids
arginine is low except in argininemia
citrulline level: low if a proximal disorder (otc or cps)
check a urinary orotic acid level:
elevated in ornithine transcarbamylase , low in carbamoyl phosphate synthase deficiency

Question 19

What are some clinical findings in someone with Argininemia

Answer 19

progressive spastic diplegia/quadriplegia, tremor, ataxia, choreoathetosis

Question 20

What are some of the clinical findings in HHH syndrome

Answer 20

hyperammonemia, hyperorniththinemia, homocitrullinuria
defect in mitochondrial ornithine transporter
progressive spastic diplegia/quadriplegia, retinal depigmentation, chorioretinal thinning

Question 21

What are some of the clinical findings of LPI, Lysinuric protein intolerance

Answer 21

defect in amino acid transporter gene SLC7A7

interstitial pneumonia, glomerulonephritis, osteoporosis, underlying immune deficiency

Question 22

What are some of the clinical findings of Argininosuccinic aciduria.

Answer 22

trichorrhexis nodose (node-like appearance of fragile hair) episodic coma

Question 23

What is seen in propionic acidemia?

Answer 23

AR
severe ketoacidosis with or without hyperammonemia
encephalopathy, bone marrow suppression, vomiting
due to inability to catabolize valine, methionine, isoleucine and threonine

Question 24

What are the common presenting symptoms of fatty oxidation defects?

Answer 24

hepatic, skeletal muscular like rhabdomyolysis after exercise, cardiac arrhythmias and sudden death

Question 25

What main laboratory studies are done to detect fatty oxidation defect disorders?

Answer 25

CBC, CMP, ammonia, lactate CPK, urine ketones free and acylcarnitine levels in the blood GC-MS analysis of organic acids analysis of plasma acylcarnitine and urine acylglycines by specialized techniques

Question 26

How does MCAD present?

Answer 26

fasting induced lethargy and hypoglycemia seizures | elevated LFTs and CPK

Question 27

How do you diagnose and treat MCAD

Answer 27

finding elevated C8, C8:1 and C10:1 esters restrict medium chain triglycerides from the diet avoid fasting

Question 28

How does Type 1 glycogen storage disease (von Gierke disease) present?

Answer 28

Age 3-4 months with hepatomegaly, failure to thrive and hypoglycemia with seizures short stature, hypertrophied kidneys

Question 29

What abnormal laboratory findings are seen in Type 1 glycogen storage disease (glucose-6-phosphatse deficiency)?

Answer 29

hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia

Question 30

What is seen as patients with Type 1 glycogen storage disease (von Gierke disease) grow older

Answer 30

``` liver is affected gout pancreatitis due to the hypertriglyceridemia, triglycerides remain elevated even after dietary modification hepatic adenomas HTN, proteinuria focal segmental glomerular nephritis ```

Question 31

What is the treatment for Type 1 glycogen storage disease (glucose-6-phosphatse deficiency)

Answer 31

prevent hypoglycemia with gastric feeds, uncooked corn starch must avoid galactose and fructose allopurinol for the hyperuricemia

Question 32

What is seen in Type IV glycogen storage disease, (branching enzyme deficiency, amylopectionosis or Andersen disease)

Answer 32

cirrhosis of the liver with hepatomegaly and FTT in the first 18 months of life. There is no specific therapy and treatment is supportive

Question 33

What is seen in Type 0 glycogen storage disease, or glycogen synthase deficiency

Answer 33

enzyme deficiency leads to a decrease in glycogen stores early morning drowsiness and fatigue and sometimes with seizures, hypoglycemia and hyperketonemia treatment: frequent feedings, uncooked cornstarch

Question 34

What is Fanconi-Bickel Syndrome and how does it present?

Answer 34

AR defect in the glucose transporter 2, which transports glucose out of liver, pancreas, kidney cells, intestinal cells proximal renal tubule disfunction and accumulation in liver and kidney children have FTT, rickets and a large protuberant abdomen due to the hepatomegaly

Question 35

How does Type V glycogen storage disease or McArdle disease present?

Answer 35

AR symptoms in 20s and 30s of exercise induced cramps and exercise intolerance with a second wind phenomena of being able to resume after resting burgundy colored urine after exercise-myoglobinuria due to rhabdomyolysis CPK elevated and increases after exercise

Question 36

How is McArdle disease diagnosed and how is it treated

Answer 36

increase in ammonia as opposed to lactic acidosis after exercise enzymatic essays on muscle biopsy avoid strenuous exercise, oral fructose or glucose prior to exercise is helpful

Question 37

What is galactosemia

Answer 37

deficit in glactose-1-phosphate uridyl transferase results in: jaundice, hepatosplenomegaly hypoglycemia irritability, cirrhosis, asceites cataracts, vitreous hemorrhage intellectual disability vomiting, seizures, poor weight gain

Question 38

What is an infectious disease that is associated with galactosemia?

Answer 38

E.coli sepsis

Question 39

What symptoms are still present even if galactose is removed from the diet?

Answer 39

ovarian failure, amenorrhea, developmental delay and learning disabilities that increase with age

Question 40

What is the only manifestation of galactokinase deficiency?

Answer 40

cataracts | treat with restriction of galactose

Question 41

What is the significance of fructokinase deficiency

Answer 41

find fructose in urine when screening for urinary reducing substances. benign disorder

Question 42

How does deficiency of fructose 1,6-bisphosphate aldolase or hereditary fructose intolerance present and how is it treated?

Answer 42

presents when child is old enough to eat sugared cereal or juice (fructose or sucrose). Looks kind of like galactosemia: jaundice, hepatomegaly, vomiting, lethargy, seizures and irritability prolonged clotting time, low albumin, elevated bilirubin, proximal tubule dysfunction diet free of sucrose and fructose

Question 43

What is seen in Fredrich Ataxia?

Answer 43

``` AR hypoactive or absent tendon reflexes ataxia corticospinal tract dysfunction impaired vibratory and proprioceptive function hypertrophic cardiomyopathy diabetes ```

Question 44

What is Pompe disease

Answer 44

deficiency in the lysosomal acid alpha 1.4-glucosidase | results in accumulation of glycogen in lysosomes

Question 45

Describe the three forms of Pompe disease

Answer 45

Infantile-onset: most severe, cardiomegaly, hypotonia, muscle weakness, macroglossia, hepatomegaly and CHF from hypertrophic cardiomyopathy Juvenile/late childhood: skeletal muscular manifestations (no cardiac defects) delayed walking, swallowing difficulties, proximal muscle weakness, respiratory muscle weakness Adult form: slowly progressive myopathy proximal muscle weakness

Question 46

What labs are seen in Pompe disease

Answer 46

elevated LDH, CPK, AST and LDH

Question 47

What is seen in Hurler syndrome or mucopolysaccharidosis Type 1

Answer 47

``` usually diagnosed prior to age 2 coarsened facial features with mid face hypoplasia, large tongue sleep apnea large head with communicating hydrocephalus growth retardation hepatosplenomegaly cardiomyopathy corneal clouding deafness intellectual disability atlanto-axial subluxation ```

Question 48

How is hurler syndrome treated

Answer 48

enzyme replacement therapy or hematopoietic stem cell transplant for those severely affected

Question 49

What is seen in Hunter syndrome of mucopolysaccharidosis type 2

Answer 49

``` x linked recessive No corneal clouding (hunters need good eye sight) nodular rash around the scapulae and extensor surfaces is pathognomonic rare cardiomyopathy otherwise similar to type 1: intellectual disability coarse facial appearance hepatosplenomegaly NO atlanto-axial instability sleep apnea ```

Question 50

What is seen in Sanfilippo syndrome, mucopolysaccharidosis type 3

Answer 50

disproportionate CNS involvement Phase 1: developmental delay with recurrent URI, diarrhea, and sleep disturbance before 1 year of age Phase2: severe challenging behavior where child has no understanding of danger and is aggressive. Precocious puberty, loss of motor skills Phase 3: swallowing dysfunction and progression to vegetative state

Question 51

What is seen in Morquio syndrome or mucopolysaccharidosis Type IV

Answer 51

``` short trunk dwarfism fine corneal deposits normal intelligence skeletal dysplasia as and adult: sternal protrusion short neck odontoid dysplasia ```

Question 52

What is seen in Gaucher disease Type 1

Answer 52

deficiency of lysosomal glucocerebrosidase splenomegaly thrombocytopenia bone infiltration with growth retardation will find deficiency of beta glucosidase in leukocytes very common in Ashkenazi jew population

Question 53

What is seen in Tay-Sachs disease

Answer 53

Infantile: enhanced startle reflex with moro that does not diminish with repeated stimuli-> delayed motor skills, axial hypotonia with extremity hypertonia cherry red spot seizures Adult: Ashkenazi jews: initially clumsy, then proximal muscle weakness with fasciculations and atrophy

Question 54

What is seen in Niemann-Pick disease type C?

Answer 54

ataxia hepatosplenomegaly poor school performance and impaired fine motor skills cataplexy and narcolepsy vertical gaze palsy intralysosomal accumulation of cholesterol in cultured fibroblasts

Question 55

What is seen in Fabry disease

Answer 55

``` X linked neuropathic pain heat exposure makes pain worse, does not sweat angiokeratoma corneal opacities renal disease coronary artery disease and stroke autonomic dysfunction with diarrhea, constipation, ```

Question 56

What is Zellweger syndrome?

Answer 56

AR peroxisome is not able to handle very long chain fatty acids progressive loss of skills high forehead, broad based nasal bridge, micrognathia cataracts pigmented retinopathy hearing and vision loss abnormal LFTs and jaundice calcific stippling in patella and long bones

Question 57

What is seen with Menke disease

Answer 57

x linked recessive seizures, loss of milestones or no progression kinky hair, sparse, breaks easily due to impaired copper uptake, decreased copper and decreased ceruloplasmin

Question 58

What is seen in Smith-Lemli-Opitz syndrome

Answer 58

``` AR defect in cholesterol biosynthesis microcephaly hypertelorism broad nasal tip micrognathia, cleft palate low set ears narrow bifrontal diameter ptosis anteverted nostrils postaxial polydactyly hypospadias, ambiguous genitalia intellectual disability congenital heart defects ```

Question 59

What are the symptoms of acute intermittent porphyria

Answer 59

``` AD deficiency of HMB synthetase (uroporphyrinogen 1 synthetase abdominal pain, nausea and vomiting limb pain dysuria and urinary retention progressive weakness starting with proximal muscles anxiety, insomnia, depression seizures ```

Question 60

What medications can precipitate an attack of acute intermittent porphyria?

Answer 60

``` barbiturates sulfonamide antibiotics anti seizure medications (valproic acid, carbamazepine griseolfulvin synthetic estrogens (OCPs) ```

Question 61

How can acute intermittent porphyria be diagnosed and treated?

Answer 61

normal porphobilinogen level in the stool rules it out HMB syntetase in RBCs give heme during acute crisis heme albumin or heme arginate)

Question 62

What is seen in porphyria cutanea tarda

Answer 62

URO decarboxylase deficiency cutaneous photosensitivity with fluid filled vesicles and bullae on sun exposed areas hypertrichosis and hyper pigmentation liver damage with risk of hepatocellular carcinoma

Question 63

What is seen in erythropoietic protoporphyria

Answer 63

skin photosensitivity | in minutes of sun exposure, redness, burning, itching and swelling

Question 64

What is seen in Lesch-Nyhan disease

Answer 64

x linked recessive deficiency in hypoxanthine guanine phosphoribosyltransferase normal at birth but 3-6 months with FTT, emesis and irritability 2-3 years self mutilation with bitting fingers and lips renal stones gout