Metabolic Disorders Flashcards
Glycogen storage disease type 1
Von-Gierke’s disease
Autosomal recessive genetic disorder
Mutation = glucose-6-phosphatase gene on chromosome 17
Produces inability to break G6P -> free glucose in glycogenolysis during fasting/strenuous exercise states
- instead uses glycolysis of excess G6P to break it down and produce Acetyl-CoA and pyruvate to go into TCA
- or funnels excess G6P into HMP shunt and PPP to produce high levels of R5P and uric acid
Symptoms:
- general weakness
- low blood sugar
- failure to thrive
- hepatomegaly (build up of G6P in liver)
- lactic acidosis (decreased blood pH)
- hyperetriglycerdiemia (type 1)
- hyperlipidemia (type 1)
- hyperuricemia (type 1)
- seizures (type 1)
- lethargy
Treatment:
- very complex
- control diet
Glycogen storage disease type 2
Pompe disease
Autosomal recessive disorder
Mutation = acid 1,4-alpha-glucosidase on GAA gene on chromosome 25
Produces a build up of glycogen molecules in lysosomes from the natural process of glycogenolysis
- usually, small amounts of glycogen somehow end up in lysosomes, and are broken down by acid-a(1,4)-glucosidase
Two types: 1) infantile form - none- or super low amounts of enzyme present - cardiac Hypertrophy of CHF signs - large tongue and hepatomegaly = generalized hypotonia - respiratory distress/failure - increased CK levels (MM or MB)
2) juvenile/ adult
- reduced amounts of enzyme, but noticeable amounts
- NO HEART SYMPTOMS
- proximal muscle weakness
- dyspnea and respiratory distress
- increased CK levels (MM only)
Treatment:
- enzyme replacement therapy via alglucosidase-alfa
- mechanical ventilation and physcial therapies
Glycogen storage disease type 3
cori/forbes disease
Autosomal recessive genetic disorder
Mutation = glycogen debranching enzymes (GDEs), amylo-a(1,6)-glucosidase
Results in a build up of detains which is a intermediate product of glycogenolysis
- causes swelling of cell due to increased osmotic pressure (hypotonic cells burst)
Affects liver/skeletal muscles/cardiac muscles Types: - 3a = all 3 affected - 3b = just liver - 3c = all 3 affected
Symptoms:
- hepatosplenomegaly
- cardiomegaly (not in 3b)
- liver failure
- failure to thrive
- hypoglycemia
- hypotonia
- arrhythmias (not in type 3b)
- Rhabdomyolysis
- *symptoms similar to Von grenkles (type 1)
Treatment:
- high glucose and protein diet
Glycogen storage disease type 4
Andersen’s disease
Autosomal recessive disorder
Mutation = (1,4)-a-glucan branching enzyme (1,4GBE) mutation on chromosome 3
Results in improper glycogen synthesis and an intracellular buildup of abnormal formed glycogen
- precipitates “polyglucosan bodies” to form intracellular and leads to increased osmotic pressure -> cell swelling
5 subtypes (only 1 allows life into adulthood)
4a) fatal perinatal neuromuscular
- fetal hydrops
- hydramnion
- hypotonia
- failure to thrive
- immobility
- cardiomyopathy @ birth
* dies within 1 month of birth*
4b) childhood neuromuscular
- myopathies
- cardiomyopathies
- generalized weakness and hypotonia
* dies sometime within childhood pending on severity of symptoms*
4c) progressive hepatic
- failure to thrive
- liver cirrhosis
- portal HTN
- ascites
* kills within 3 months of birth*
4d) non-progressive hepatic
- less intense 4c symptoms w/ NO CIRRHOSIS
* only one to live into adult hood*
4e) congenital muscular
- similar to 4b but presents earlier
* dies within a 3 months of birth
Treatment:
- symptomatic only
Glycogen storage disorder type 5
McArdles disease
Autosomal recessive disorder
Mutation = myophosphorylase
Results in accumulation of glycogen in skeletal muscle ONLY since skeletal muscles cannot release G1P in glycolysis
- disrupts NA/K pumps and increases skeletal muscle osmotic pressures
Symptoms/signs:
- renal failure
- myoglobinuria
- rhabdomyolysis
- muscle fibrosis
- muscle contracture
- exercise intolerance
- “second-wind” phenomenon
Treatment: symptomatic only
Homocystinuria
Homocysteine builds up in the urine from the excessive conversion of methionine AA
Two types:
1) familial homocystinuria
- autosomal recessive disorder
- caused by lack of cystathionine B-synthase or/and decreased B6 affinity for the enzyme (which is used to convert homocysteine -> cysteine)
2) acquired homocystinuria
- not genetic at all
- caused by poor diet with lack of vitamins B6/9/12 (pyridoxine, folate, and cobalamin)
- decreases cystathionine B-synthase activity and methionine synthase activity (leading to build up of homocysteine)
Symptoms:
- Signs of chronic inflammation and atherosclerosis
- signs of blood clotting
- bone weakening/deformities
- degenerative macula
- ectopia lentis(downward retraction of lens)
- developmental delay
- marfanoid habitus (looks like Marfan syndrome)
- pectus excavatum/carinatum
- genu valgu
- kyphosis
- seizures
- nearsightnedness and blurred vision
- signs of TIAs/strokes (even in children)
- HTN
Treatment:
- increased homocystinuria and increased methionine and homocysteine in the blood diagnosis this
- diet high in vitamins B6/9/12 and cysteine
Phenylketonuria (PKN)
Excess build up of phenylalanine in the urine due to inability of phenylalanine enzymes to work
- all three types lead to decreased levels of tyrosine and increased phenylalanine
3 types:
1) classic
- autosomal recessive disorder
- phenylalanine hydroxylase levels are low
- can take in some phenylalanine in diet
2) tetrahydrobiopterin (THBP) deficient
- autosomal recessive disorder
- phenylalanine hydroxylase does not function at all due to THBP not being present
- cant take in phenylalanine in diet
3)
Symptoms: (appear in 1st few months)
- *seizures (low dopamine serotonin, and NE levels)
- *hypo-pigmentation of skin/hair/eyes
- intellectual disabilities (low dopamine serotonin, and NE levels)
- psychiatric disorders (low dopamine serotonin, and NE levels)
- *low levels of LDL/HDL (since increased phenylalanine impairs cholesterol synthesis)
- poor immune system
- signs of inflammation
- *Musty Odor of sweat and urine
in pregnant patients specifically, can cause in the fetus:
- heart issues
- mental retardation
- microcephaly
Treatment:
- blood shows increased phenylalanine and decreased tyrosine levels
- avoid egg whites, chicken, fish, shrimp, turkey, artificial sweeteners
- use tyrosine and THBP supplements in diet
Maple syrup urine disease
Branched-chain ketoacid dehydrogenase deficency (BCKD)
autosomal recessive disorder in one of the 4 genes assocaited with BCKD
Results from the inability of the body to break down branched AAs and leads to buildup of these AAS
- valine
- leucine
- Isoleucine
Specifically the body cant breakdown the 3 carbon side chains found on the above AAs due to inaction of Branched-chain alpha ketoacid dehydrogenase complex (BCKD)
- leads to increased 3 above AAs and decreased glutamate levels
Two forms
1) classical:
- no functional BCKD
- worse
- symptoms are 48hrs after birth
2) intermediate form
- 10% functional NCKD
- better
- symptoms appear later in life after a stress trigger such as extraneous exercise/fasting.infections
Symptoms:
- *elevated levels of valine, isoleucine, leucine ,alloisoleucine and Sotolone in urine/blood (gives maple syrup odor)
- opisthotonos (muscle spasms while lying down which looks like bicycle riding)
- lethargy
- inability to thrive
- delayed growth
- irritability
- cerebral edema/ seizures/coma (within 7-10 days and usually only in classical form)
Treatment:
- strict diet that limits protein consumption
- hemodialysis (severe only)
- ONLY cure is liver transplant (super rare though and not done often)
Lesch-Nyhan syndrome
X-linked recessive disease
Rare genetic condition that causes Excessive uric acid build up in the blood
- due to inactivity of HGPRT enzymes (function is to salvage adenosine and guanine nucleotides in the purine salvage pathway
- this activity causes all nucleotides to be pushed through catabolism, increasing uric acid levels
Symptoms: (usually within 1 yr of birth)
- joint pain
- gout symptoms (tophi nodules and podagra especially)
- irritability
- hyperuricemia
- hypotonia w/ dystonia
- chorea
- ballismus (spontaneously flinging of limbs)
- aggression
- kidney damage
- hematonuira
- painful urination
- low dopamine levels = emotional and behavioral disturbances
- very high uric acid in blood and urine
Treatment:
- xanthine oxidase Inhibtors (allopurinol)
- shock wave lithotripsy (for kidney stones)
- anti-anxiety meds (behavioral symptoms)
Familial hypercholesterolemia
Autosomal dominant Mutations occur in LDL receptor gene, preventing LDL to bind to liver efficiently and be degraded into free cholesterol
5 classes/causes:
1) affects quantity of LDL receptors (less receptors available)
2) affects ability of LDL receptors to be transported to the membrane (number is normal)
3) affects binding of LDL to the receptors (number is normal)
4) affects location fo the LDL on the liver (there are not in the coated pit regions, bind perfectly though and number is usually okay)
5) affects LDL receptor recycling (lowers number found on liver surface)
Symptoms/signs: (homozygotes have worse symptoms and earlier onset)
- xanthoma presence throughout the body, especially eyelids and tendons (build up of LDL deposits)
- HTN and ischemic signs
- angina (stable/unstable)
- TIAs
- past strokes
- high levels of total cholesterol and LDL
Treatment:
- lower LDL diet
- quit smoking
- quit alcohol
Gaucher disease
Autosomal recessive Glucocerebrosidase/ B-glucosidase deficiency due to mutation in the GBA gene
- leads to build up of byproduct glucocerebroside from sphingomyelin breakdown
3 types:
Type 1: asymptomatic usually except in times of stress
Type 2: (acute neuronopathic gaucher disease)
- symptoms are usually always present
- has same potential symptoms as type 1 but also neurological symptoms
Type 3: (chronic neuronopathic gaucher disease)
- same as type 2 except takes longer to show symptoms
- also usually presents with seizures
Symptoms: all are type 1 unless said otherwise
- macrophages look “crumpled paper-like” (gaucher cells)
- (+) B-glucosidase enzyme blood test
- signs of inflammation
- bone marrow fibrosis
- bone pain due to bone infarcts
- osteoporosis
- leukopenia
- anemia/fatigue
- thrombocytopenia
- hepatosplenomegaly
- loss of motor skills (type 2)
- hypotonia (type 2)
- dysphagia (type 2)
- muscle spasms (type 2)
- dyspnea/respiratory failure (type 2)
- seizures (usually type 3 only)
Treatment:
- enzyme replacement therapy with synthetic glucocerebrosidase
- substrate reduction therapies
- supportive therapies for symptoms
Hartnup Disease
Autosomal recessive metabolic disorder that prevents metabolism of nonpolar AAs
- especially tryptophan
This is due to a renal and intestinal deficiency of non-polar AA transporters present
- decreased absorption from both intestines and kidneys
Results physiologically in decreased tryptophan, non-polar AA and niacin levels in the blood
Signs/symptoms:
- pellagra-like symptoms
- photosensitive
- diarrhea
- ataxia
- tremors
- headaches
- mental retardation
- ocular manifestations (nystagmus and double vision most common)
- increased levels of non-polar AAs in the urine
Treatment:
- high protein diet and isotonic acid supplements
- avoid sunlight
Ornithine transcarbamylase deficiencies
X-linked recessive disorder that causes a deficiency in the level/action of ornithine transcarbamylase.
Results in disorder of the urea cycle and accumulation of ammonia in the urine and blood
- also increased orotic acid concentrations due to inability to convert carbamoyl phosphate into anything else
Symptoms/signs:
- 2 forms*
1) neonatal form (most common) - lethargy
- irritability
- failure to thrive
- hyperventilation/ respiratory alkalosis
- cerebral edema
- coma/death (if left untreated)
2) adult form
- headaches
- nausea/vomiting
- psychiatric disorders
- both show elevated ammonia, BUN and citrulline levels in urine and plasma as well as orotic acid in urine*
Treatment:
- liver transplant
- low protein diet and sodium benzoate
Alkaptonuria
Autosomal recessive mutation in the homogentisic oxidase gene and therefore deficit homogentisate oxidase enzyme.
- leads to increases in homogentisic acid levels in blood and inability to properly breakdown phenylalanine and tyrosine AAs (instead breaks them down to homogentisic acid intermediate).
Sings/symptoms
- *“black nappies” in infants (urine in diapers turns to a dark brown/black color due to homogentisic acid levels in urine)
- blue sclera/ear
- pain in spine/hip/knees
- calcification of IVDs on imaging
Treatment:
- herbicide nitisinone (prevents tyrosine -> homogentisic acid)
- low protein diet and restrict tyrosine/phenylalanine consumption.
Orotic aciduria
Extremely rare autosomal recessive disorder which causes impaired Cytosol/uracil and thymine synthesis
- caused by inactivity of UMPS and OMP-de carboxylase enzymes
- all are instead stopped at orotic acid intermediate
Signs/symptoms:
- glossitis
- mental retardation
- failure to thrive
- immunodeficiencies
- *megaloblastic anemia which DOESNT respond to colabaumin and/or folic acid supplements
- *increased orotic acid in ursine (without ammonia increases)
Treatment:
- pyrimidine replacement therapy via uridine monophosphate
Abetalipoproteinemia
Bassein-Kornzweig disease
Autosomal recessive disorder caused by MTTP gene mutations encoding for microsomal triglyceride transfer protein (MTP)
- this protein is required for hepatic and intestinal production of apolipoprotein-B
- results in decreased chylomicrons, LDL and VLDL levels and impaired DEAK vitamin transport (fat soluble)
- most susceptible vitamin deficiency is E
Signs/symptoms:
- impaired fat absorption (steatorrhea, nausea, abdominal distention, weight gain and FTT)
- hyporeflexia
- ataxia
- dysarthria
- vision impairment
- retinitis
- opthalmoplegia
- neuropathies
- decreased triglycerides, total cholesterol, VLDL and LDL
Treatment:
- vitamin DEAK replacements
- reduced fat diet
-
Hyperlipidemia
Primary (genetics) or secondary causes of increased serum total cholesterol and LDL levels
Secondary causes are as follows:
- Cushing syndrome
- excessive alcohol intake
- uncontrolled diabetes
- chronic kidney/liver disease
- BBs, thiazide usage
- HIV regiment usage
- oral estrogen therapies
Risk factors are as follows:
- poor diet and lifestyle
- genetics
- pregnancy
- being male
note patient will have pancreatitis likely if serum trigycide levels are > 1000
Symptoms/signs:
- cardiovascular/cerebrovascular disease signs
- Xanthomas
- corneal arcus (white/gray rings around the iris that doesnt affect vision)
- lab results show: increased TC, triglycerides, LDL and decreased HDL
Treatment:
- statins
- fish oil and fibrates supplements
Niemann-pick disease
Types A,B and C
Autosomal recessive Disorder that produces a deficency in acid sphingomyelinase (ASM) enzyme activity
- patients cannot break down sphingomyelin and therefore build up inside lysosomes and causes damage to brain/kidney/lungs/liver
- types A and B results in mutations in SMPD1 gene, this is NOT seen in type C
- type C results in mutations in NPC1/2 genes, this is NOT seen in types A and B
type A has high predisposition in ashkenazi Jews
Types:
1) Type A
- No ASM activity at all
- is the worst type with earlier onset and increased severity of symptoms
2) Type B
- reduced ASM activity
-
Signs/symptoms: All are type A unless noted
- “foam cells” in macrophages
- hepatosplenomegaly
- *hyporeflexia/ areflexia (ONLY SEEN IN A)
- jaundice
- dysphagia (ONLY SEEN IN A)
- Red macula in eye
- decreased central vision
- interstitial Lung disease w/ fibrosis (restrictive PFT)
- pancytopenia
- hypercholesterolemia
- sphingomyelin in blood
type B DOESNOT produce neurological symptoms
Treatment:
- supportive therapy and sleeping medications if needed
- No cure
Tay-Sachs Disease (TSD)
GM2 Gangliosidosis Type 1
Autosomal recessive Genetic mutation in chromsome 15 which results in a Deficiency of B-Hexosaminidase A.
- patients cant breakdown GM2-Ganglioside, resulting in accumulation in lysosomes
strong hereditary link to ashkenazi Jews, French Canadians and Amish populations
4 symptom onset’s:
1) infantile (3-6 months)
2) juvenile (2-5 years)
3) chronic (10-20 years)
4) late-onset (20-30 years)
Signs/symptoms: all are type 1-3 unless otherwise stated
- *hypotonia
- *hyperreflexia
- *seizures
- visual disturbances
- motor difficulties (type 4)
- Bipolar psychological symptoms (type 4)
- *cherry red spot on macula
Treatment:
- supportive care only (no cure)
Fabry disease
X-linked recessive with incomplete penetrance disorder that causes a mutation in the GLA gene
- produces a deficiency in the (a)-galactosidase A enzyme
- results in globotriaosylceramides and glycosphingolipid build up in lysosomes
because of incomplete penetrance, females and males are equally likely to get the disorder
Two forms:
1) classic (early onset)
- burning
- tingling/numbness
- neuropathic pain in hands/feet
- *decreased/no sweating
- angiokeratomas on the abdomen (dark red splotches)
- diarrhea and cramps
- corneal verticillata (brown/swirling shapes in the eye on a split lamp exam)
- cardiomegaly
2) nonclassic (late onset)
- GI pain
- kidney disease signs
- heart disease signs
Diagnosis (depends on sex of patients)
1) male:
- low amount of (a)-GAL A enzyme
2) female:
- requires genetic analysis, since (a)-GAL A enzyme levels are usually normal
Treatment:
- Migalastat
- synthetic enzyme therapy (Agalsidase-B)
- pacemakers
- renal transplant (serious only)
Metachromatic leukodystophy (MLD)
Autosomal recessive disorder which results in a Mutation in the ARSA or a PSAP gene which codes for arylsufatase-A enzyme and Saposin B cofactor respectively
- causes increased accumulation of cerebroside sulfatide in Schwann cells and oligodendrocytes due to inactivity of arylsulfatase-A enzyme
- causes demyelination of the nervous system slowly (CNS and PNS)
Types: (based on onset)
1) infantile
- 0-3 months
2) juvenile
- 4 yrs- 10 yrs
3) adult
- 16 yrs +
Symptoms/signs: (are in all three types unless stated)
- *metachromatic granules in nervous tissue samples
- peripheral neuropathy
- hypo/areflexia
- visual disturbances
- ataxia
- dysphagia
- behavioral disturbances
- irritability
- developmental delay (1)
- decreased focus/cognitive decline (2)
- memory loss/new onset psychiatric disorder (3)
- arylsulfatase enzyme A low levels in blood
- increased sulfatide in urine
- hyper-intensity of white matter on imaging
all three types lead to blindness, paralysis, dementia, psychosis and comaif left untreated
Treatment:
- supportive care (no cure)
Krabbe disease
Autosomal recessive disorder that results in a mutation in GALC gene
- results in a shortage of galactosylceramidase enzymes which break down galactocerebrosides and psychosine.
Signs/symptoms:
- presence of globoid cells (clear glial cells) in myelin
- seizures
- deafness
- blindness
- hypotonia
- general muscle weakness
- stiffness
- dysphagia
Treatment:
- avoid lipids
- physcial therapy
Adrenoleukodystrophy
Genetic disorder which results in a mutation of the ABCD1 gene
- causes a shortage of the adrenoleukodystrophy protein and produces excessive buildup of long chained fatty acids in cells And widespread nervous inflammation
Symptoms/signs
- feeding difficulties
- stiffness
- seizures
- deafness
- blindness
- muscle weakness
- decreased cortisol
- vomiting
- weight loss
- skin abnormalities (especially pigmentation)
Treatment:
- avoid lipids in diet
Hurler syndrome (MPS1)
Autosomal recessive disorder in the IDUA gene that causes a Deficiency of (a)-L-Iduronidase which prevent break down of heparan and dermatan sulfate sugars.
- causes a buildup of these sugars in the extracellular space as it gets worse.
Symptoms/signs
- flat nose bridge
- prominent forehead
- enlarged lips/tongue/gums
- corneal clouding
- prominent frontal bulging
- metacarpal irregularities
- short stature
- joint disease
- increased kyphosis
- hearing loss
- hydrocephalus
- Cardiomyopathies
- mucopolysacchrides in urine
- increased (a)-L-Idurnidase enzyme activity in leukocytes
Treatment: early the better
- bone transplant (only way to improve intellectual disabilities in severe form. It is NOT required in the attenuated form)
- (a)-L-Iduronidase replacement therapy
- treatment of symptoms
- physical and speech therapy
Hunter syndrome (MPS2)
X-linked recessive disorder which results in A deficiency in iduronate sulfatase enzyme which causes a build up of heparan and dermatan sulfate in the intercellular space as it gets worse
Symptoms/signs: (usually in infancy stage)
- hepatosplenomegaly
- abdominal hernias
- *recurrent ear infections
- prominent forehead
- flat nose bridge
- enlarged lips tongue and gums
- *ivory skin ridges “tiny pebbles”
- *ADHD/OCD symptoms
- *increased aggression
- *low iduronate sulfatase in blood
Treatment:
- bone marrow transplantation
- enzyme replacement therapy
- symptom treatment
What are the standard physical deformities in patients with MPS deficiencies?
Prominent forehead
Flat nose bridge
Enlarged lips/tongue and gums
Thickened heart valves
Obstructive lung disease
Short stature w/ stiff joints
Fetal alcohol syndrome (FAS)
Caused by maternal use of alcohol
- leading cause of intellectual disabilities in the US
Ethanol and acetaldehyde byproducts of alcohol metabolism are transferred across the placenta to the fetus
- fetus liver cannot metabolize these well, so accumulation occurs rapidly
Ethanol build up disrupts cell division and cell growth based usually the brain
Symptoms/signs
- seizures
- intellectual disability
- poor memory
- poor communication
- ataxia
- imbalance
- growth retardation
- microcephaly
- small palpebral fissures
- heart defects
Treatment:
- no cure
- symptomatic treatment only
