Disorders of metabolism Flashcards
What causes PKU
AR
phenylalanine can not be converted to tyrosine
enzyme defect is phenylalanine hydroxylase
What is the common presentation of PKU and what would be seen in the blood and in the urine?
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
What does an infant have if mother has untreated PKU?
growth deficiency, microcephaly, intellectual disability and congenital heart defects
What can cause hyperphenylalaninemia
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
What are the symptoms of hyperphenylalaninemia and what is the treatment?
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
What is seen in hereditary tyrosinemia Type 1
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
How is hereditary tyrosinemia type 1 diagnosed and treated?
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
How does tyrosinemia type 2 present
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
What is alkaptonuria?
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
What are the symptoms of alkaptonuria?
pigment deposition in ears and sclera as an adult: ochronosis
can also cause ochronosis arthritis
some have aortic root dilatation or valvular involvement
How does maple syrup urine disease present?
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
What is the defect in maple syrup urine disease and what is the treatment?
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
What is the clinical presentation of homocystinuria
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
What is the treatment for homocystinuria
pyridoxine in the vitamin responsive form
diet low in methionine
What is nonketotic hyperglycinemia
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
What are the six main enzyme defects that can cause hyperammonemias?
- N acetylglutamate synthetase deficiency
- carbamoyl phosphate synthase deficiency
- ornithine transcarbamylase deficiency (X-linked)
- argininosuccinate synthetase deficiency (citrullinemia)
- argininosuccinate lyase deficiency
- arginase deficiency (argininemia)
How does a urea cycle disorder present?
intoxication
lethargy, vomiting, confusion to coma
more proximal the defect, the more severe
What labs should be ordered to help determine the location of the defect
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
What are some clinical findings in someone with Argininemia
progressive spastic diplegia/quadriplegia, tremor, ataxia, choreoathetosis
What are some of the clinical findings in HHH syndrome
hyperammonemia, hyperorniththinemia, homocitrullinuria
defect in mitochondrial ornithine transporter
progressive spastic diplegia/quadriplegia, retinal depigmentation, chorioretinal thinning
What are some of the clinical findings of LPI, Lysinuric protein intolerance
defect in amino acid transporter gene SLC7A7
interstitial pneumonia, glomerulonephritis, osteoporosis, underlying immune deficiency
What are some of the clinical findings of Argininosuccinic aciduria.
trichorrhexis nodose (node-like appearance of fragile hair) episodic coma
What is seen in propionic acidemia?
AR
severe ketoacidosis with or without hyperammonemia
encephalopathy, bone marrow suppression, vomiting
due to inability to catabolize valine, methionine, isoleucine and threonine
What are the common presenting symptoms of fatty oxidation defects?
hepatic, skeletal muscular like rhabdomyolysis after exercise, cardiac arrhythmias and sudden death
What main laboratory studies are done to detect fatty oxidation defect disorders?
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
How does MCAD present?
fasting induced lethargy and hypoglycemia seizures
elevated LFTs and CPK
How do you diagnose and treat MCAD
finding elevated C8, C8:1 and C10:1 esters
restrict medium chain triglycerides from the diet
avoid fasting
How does Type 1 glycogen storage disease (von Gierke disease) present?
Age 3-4 months with hepatomegaly, failure to thrive and hypoglycemia with seizures
short stature, hypertrophied kidneys
What abnormal laboratory findings are seen in Type 1 glycogen storage disease (glucose-6-phosphatse deficiency)?
hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia
What is seen as patients with Type 1 glycogen storage disease (von Gierke disease) grow older
liver is affected gout pancreatitis due to the hypertriglyceridemia, triglycerides remain elevated even after dietary modification hepatic adenomas HTN, proteinuria focal segmental glomerular nephritis
What is the treatment for Type 1 glycogen storage disease (glucose-6-phosphatse deficiency)
prevent hypoglycemia with gastric feeds, uncooked corn starch
must avoid galactose and fructose
allopurinol for the hyperuricemia
What is seen in Type IV glycogen storage disease, (branching enzyme deficiency, amylopectionosis or Andersen disease)
cirrhosis of the liver with hepatomegaly and FTT in the first 18 months of life.
There is no specific therapy and treatment is supportive
What is seen in Type 0 glycogen storage disease, or glycogen synthase deficiency
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
What is Fanconi-Bickel Syndrome and how does it present?
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
How does Type V glycogen storage disease or McArdle disease present?
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
How is McArdle disease diagnosed and how is it treated
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
What is galactosemia
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
What is an infectious disease that is associated with galactosemia?
E.coli sepsis
What symptoms are still present even if galactose is removed from the diet?
ovarian failure, amenorrhea, developmental delay and learning disabilities that increase with age
What is the only manifestation of galactokinase deficiency?
cataracts
treat with restriction of galactose
What is the significance of fructokinase deficiency
find fructose in urine when screening for urinary reducing substances.
benign disorder
How does deficiency of fructose 1,6-bisphosphate aldolase or hereditary fructose intolerance present and how is it treated?
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
What is seen in Fredrich Ataxia?
AR hypoactive or absent tendon reflexes ataxia corticospinal tract dysfunction impaired vibratory and proprioceptive function hypertrophic cardiomyopathy diabetes
What is Pompe disease
deficiency in the lysosomal acid alpha 1.4-glucosidase
results in accumulation of glycogen in lysosomes
Describe the three forms of Pompe disease
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
What labs are seen in Pompe disease
elevated LDH, CPK, AST and LDH
What is seen in Hurler syndrome or mucopolysaccharidosis Type 1
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
How is hurler syndrome treated
enzyme replacement therapy or hematopoietic stem cell transplant for those severely affected
What is seen in Hunter syndrome of mucopolysaccharidosis type 2
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
What is seen in Sanfilippo syndrome, mucopolysaccharidosis type 3
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
What is seen in Morquio syndrome or mucopolysaccharidosis Type IV
short trunk dwarfism fine corneal deposits normal intelligence skeletal dysplasia as and adult: sternal protrusion short neck odontoid dysplasia
What is seen in Gaucher disease Type 1
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
What is seen in Tay-Sachs disease
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
What is seen in Niemann-Pick disease type C?
ataxia
hepatosplenomegaly
poor school performance and impaired fine motor skills
cataplexy and narcolepsy
vertical gaze palsy
intralysosomal accumulation of cholesterol in cultured fibroblasts
What is seen in Fabry disease
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,
What is Zellweger syndrome?
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
What is seen with Menke disease
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
What is seen in Smith-Lemli-Opitz syndrome
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
What are the symptoms of acute intermittent porphyria
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
What medications can precipitate an attack of acute intermittent porphyria?
barbiturates sulfonamide antibiotics anti seizure medications (valproic acid, carbamazepine griseolfulvin synthetic estrogens (OCPs)
How can acute intermittent porphyria be diagnosed and treated?
normal porphobilinogen level in the stool rules it out
HMB syntetase in RBCs
give heme during acute crisis heme albumin or heme arginate)
What is seen in porphyria cutanea tarda
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
What is seen in erythropoietic protoporphyria
skin photosensitivity
in minutes of sun exposure, redness, burning, itching and swelling
What is seen in Lesch-Nyhan disease
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
