Lecture 23: Metabolic Disorders Flashcards
How are most metabolic disorders inherited?
Autosomal recessive.
Exception: Fabry’s is X-linked.
What characterizes metabolic disorders?
- Absence or abnormality of an enzyme or its cofactor.
- Accumulation or deficiency in a specific metabolite.
What are the three primary products of carbohydrate metabolism?
- Glucose
- Galactose
- Fructose
What is sorbitol an alcohol of?
Fructose
Where is glycogen stored in the body?
- Liver
- Muscle
What do glycogen storage disorders result in?
Accumulation of glycogen in the tissues due to a defect in metabolism.
What is the typical clinical presentation of a GSD in the liver?
- Fasting hypoglycemia and ketosis that improves with eating.
- Possible hepatomegaly
What is the typical clinical presentation of a GSD in the muscles?
- Delayed growth in children
- Exercise intolerance
- Progressive weakness
What labs would we expect for a GSD pt?
- Fasting hypoglycemia
- Elevated LFTs and CPK
How do we generally manage a GSD?
- Avoid hypoglycemia
- Enzyme replacement for specific ones.
- Symptomatic therapy
What are the 3 subtypes of fructosemia?
- Deficiency of fructose 1,6-diphosphatase (FDPase)
- Deficiency of fructose 1,6-biphosphatase aldolase (Aldolase B/Hereditary fructose intolerance)
- Deficiency of fructokinase (Essential fructosuria)
What is the mechanism of FDPase deficiency and the result?
Mechanism: Conversion of Fructose 1,6-biphosphate to Fructose 6-phosphate.
Results in inadequate gluconeogenesis during periods of fasting.
How does a FDPase deficiency present clinically?
- Hypoglycemia symptoms
- Acidosis symptoms (buildup of lactate)
How do we manage FDPase deficiency?
- Avoid fructose
- Avoid fasting for too long
What is the effect of an aldolase B or fructose 1,6-biphosphatase aldolase deficiency?
Toxic accumulation of Fructose-1-phosphate in the Liver, Kidney and SI, causing cell death.
How does an Aldolase B deficiency present clinically?
Ingestion of fruit or sweetened cereal leads to…
- Severe abdominal pain
- Failure to thrive
- Jaundice and hepatomegaly
- Hypoglycemia
How do we diagnose and manage an aldolase B deficiency?
Genetic testing to diagnose.
Management includes complete avoidance of fructose and sucrose.
What is the most benign form of fructosemia?
Lack of fructokinase, aka essential fructosuria.
What is the pathophysiology of essential fructosuria?
Cannot convert fructose to anything, so you pee it out instead.
How do you manage essential fructosuria?
No management needed, as you will pee it out.
What causes galactosemia?
Autosomal recessive defect of chromosome 9p13.
What is galactosemia?
Toxic accumulation of galactose-related molecules due to an inability to metabolize it.
Where does galactose typically come from?
- Milk
- Baby formula
- Celery, kiwi, plum, avocado, and figs.
What 3 enzyme deficiencies result in galactosemia?
- Galactose-1-phosphate uridyl transferase (GALT), AKA Type 1 galactosemia, as it is the MC and severe.
- Galactokinase (GALK), Type 2.
- Galactose epimerase (GALE), Type 3.
How does Type 1, or classic galactosemia present clinically?
- Normal at birth.
- Within a few days of getting galactose, failure to thrive, vomiting, hepatomegaly, and jaundice can occur.
- Within 2 weeks, buildup of galactitol can cause cataracts.
What is galactitol?
Unmetabolized galactose.
What is the primary clinical finding in Type 2 or GALK galactosemia?
Cataract formation.
How does Type 3 or GALE galactosemia typically present clinically?
- Mild to classic galactosemia.
What lab value is elevated in a GALT deficiency? Decreased?
- RBC galactose-1-phosphate elevated.
- GALT enzyme activity depressed.
How do we manage galactosemia as a whole?
- Minimizing dietary milk.
- DC breastfeeding
- Use soy-based formulas
- Avoid dairy as they get older.
How do we manage galactosemia long-term?
- Annual ophthalmologic exam.
- CBC, LFTs, RBC galactose-1-phosphate
- Females: LH, FSH, and estradiol starting at age 10. (Females tend to rely on dairy)
What causes PKU?
Autosomal recessive mutation of chromosome 12.
What enzyme is someone with PKU deficient in? What is the function of that enzyme?
Phenylalanine hydroxylase (PAH), which converts phenylalanine to tyrosine
What does a buildup of phenylalanine in the brain result in?
Destruction of myelin covering individual nerve fibers.
Who is PKU MC in?
Caucasians and Native-Americans.
What is classic PKU?
Complete absence of PAH.
What kind of soda might contain phenylalanine?
Diet sodas
How does untreated PKU present clinically?
- Light hair and skin
- Neurologic dysfunction due to loss of myelin.
How do we diagnose PKU?
- Newborn screening
- Elevated serum phenylalanine
How do we manage PKU?
- Avoid foods with phenylalanine.
- Sapropterin to activate PAH to breakdown phenylalanine. (Kids/Adults)
- Pegvaliase to degrade phenylalanine. (ADULT ONLY)
What is maple syrup urine disease?
Autosomal recessive disorder with a deficiency in the enzyme that breaks down BCAAs.
What 3 BCAAs are affected by maple syrup urine disease? (MSUD)
- Leucine
- Isoleucine
- Valine
What specific enzyme is MSUD deficient in?
Branched-chain ketoacid dehyrogenase complex (BCKDC)
What does excess leucine and isoleucine do to the body?
- Excess leucine = neurological symptoms.
- Excess isoleucine = maple syrup odor in urine, like burnt caramel.
What are the two types of maple syrup urine disease? (MSUD)
- Classic MSUD: < 3% residual enzyme activity. (MC)
- Non-classic MSUD: 3-30% residual enzyme activity.
How does classic MSUD tend to present?
Symptoms within 48hrs to 2 weeks (delayed by breastfeeding.)
* Irritability
* Poor feeding
* Seizures
* Cerebral edema
* Death
How does non-classic MSUD tend to present?
Delayed onset until childhood, exacerbated by physical stress.
Variable symptoms (Like in classic MSUD)
How do we manage MSUD?
- Strict protein restriction using medical-grade formula/food.
- Trial of thiamine supplement for 4 weeks. (some subtypes respond)
A patient with MSUD demonstrates rapid buildup of leucine. What is the immediate intervention to rapidly lower their leucine?
Hemodialysis
A patient with MSUD has just underwent hemodialysis for elevated leucine. What are the next steps in their management?
- D/C protein intake for 24-48h
- IV glucose (inhibits protein catabolism)
- IV insulin if BG > 130 (enhances protein synthesis)
When is a liver transplant indicated for MSUD?
Last resort for classic MSUD.
10% of BCKDC is found in the liver.
What is homocystinuria?
Dysfunction of methionine formation , which results in a buildup of homocysteine.
What is the main enzyme deficiency that results in homocystinuria?
Cystathionine beta-synthase
What are the classic symptoms associated with homocystinuria?
- Failure to thrive
- Dislocated optic lenses and mental retardation (MC)
- Marfanoid habitus (very tall and thin)
- MSK deformity with osteoporosis
- Thromboembolic related symptoms.
What are the MSK deformities associated with homocystinuria?
- Pes excavatum (sternum sunken in)
- Pes carinatum (sternum protrudes out)
- Genu valgum (Knees bent inward, knock knees)
How do we assess for homocystinuria?
- Newborn screening (WV)
- Elevated homocysteine and methionine in plasma or urine.
How do we manage homocystinuria?
- Protein restriction
- Vit B6, B12, folate supplements (convert homocysteine to methionine)
- Betaine (convert homocysteine to methionine)
Methionine and homocysteine can be converted to one another.
Where are lysosomes formed?
Formed in the golgi body.
What are the 5 functions of lysosomes?
- Exocytosis
- Digest viruses and bacteria
- Autolysis
- Digest nutrients
- Cell membrane repair
What are the 5 lysosomal storage disorders and how are they classified?
Classified based on the material they store.
- Tay-sach’s disease
- Gaucher’s disease
- Fabry disease
- Niemann-pick disease
- Pompe disease
What are lysosomal storage disorders?
Abnormalities in the biosynthesis of a lysosome, resulting in impaired enzyme activation.
What is Tay-Sach’s disease?
Autosomal recessive, neurodegenerative disorder that comes from a mutation in hexosaminidase A (Hex A)
What is the function of Hex A? What is the result of its dysfunction?
- Breakdown of GM2 ganglioside (fatty substance)
- Dysfunction results in a buildup of this, resulting in neuronal destruction in the CNS.
What are the 3 subtypes of Tay-Sach’s?
- Infantile
- Juvenile
- Adult onset
What findings suggest infantile Tay-Sach’s?
- First sign: Exaggerated startle/Moro reflex
- Slowing of normal milestone development.
- Gross motor delay
- Seizures, vision loss, intellectual disability, etc
- Cherry-red spot on fundoscopy (HALLMARK SIGN), due to GM2 ganglioside buildup in retinal ganglion cells.
How do infants generally die from Tay-Sach’s?
Complications of pneumonia.
Life expectancy is 2-5 years only.
What is the Tay Sach’s mnemonic?
- Testing rec
- Autosomal recessive
- Young death (< 4)
- Spot in macula (cherry-red)
- Ashkenazi Jews
- CNS Degeneration
- Hex A deficiency
- Storage disease
How does Juvenile Tay Sach’s present?
- Symptoms present typically at 2-5y
- Hx of respiratory infections
- Slower loss of mental and motor function
- Progression to a state of unresponsiveness/unawareness for years prior to their death.
What is death in Juvenile Tay-Sach’s usually caused by?
Infectious causes
Life expectancy of 10-15 years.
How does adult-onset Tay Sach’s present?
- Clumsiness in childhood
- Progressive motor weakness
- Dysarthria
- Declining intelligence
- Increasing mental health issues
How is Tay-Sach’s screened for?
- Genetic testing
- Hex A/B Analysis, expecting low Hex A with normal/high Hex B.
How is Tay-Sach’s treated?
Supportive care only. No effective treatment exists.
What 3 ethnic groups are risk factors for Tay-Sach’s?
- Ashkenazi Jews
- French-Canadians
- Cajuns
What is Gaucher Disease a deficiency in?
Glucocerebrosidase (GCase), which breaks down its fatty chemical into glucose and ceramide (lipid/fat molecule)
When are glucocerebrosides released?
Cell degradation; they come from the membranes.
Where do glucocerebrosides accumulate? Effect?
Accumulation in Gaucher cells (macrophages), which then accumulate in the spleen, liver, bone marrow, and brain (Severe), causing chronic inflammation and fibrosis.
What ethnic group is MC for Gaucher disease?
Ashkenazi Jews
What are the 3 clinical subtypes of Gaucher Disease?
- G1 (MC): slow progression, primarily bone involvement, no CNS involvement.
- G2: early onset, aggressive, death by age 2. (grave by 2)
- G3: early onset, medium aggression, CNS involvement still.
What severe symptom is found in all Gaucher disease patients?
Bone crises.
* Localized excruciating pain
* Erythema
* Fever
* Leukocytosis
* Bone marrow infiltration by Gaucher cells, resulting in infarction.
What is the hallmark diagnostic tool for Gaucher disease?
Low beta-glucosidase leukocyte activity.
What confirms a diagnosis of Gaucher disease?
Genetic testing.
Also used to determine if someone is carrier.
What histology description of a macrophage would suggest Gaucher disease?
Wrinkled tissue paper appearance
How is Gaucher disease managed?
- Enzyme replacement therapy (ERT) with recombinant GCase (imiglucerase), but cannot relieve CNS symptoms.
- Substrate-reduction therapy (SRT) with eliglustat/miglustat, preventing the production of glucocerebrosides.
What is Fabry disease?
Alpha galactosidase A (GLA) deficiency, leading to accumulation of globotriaosylceramide (GL3), fatty substance in blood vessels.
What does a buildup of GL3 in Fabry disease result in?
Narrows blood vessels, leading to inadequate perfusion.
What are the MC organs affected in Fabry disease?
- Skin
- Kidneys
- Heart
- CNS
How is Fabry disease inherited?
X-linked recessive, so it is the only one more severe in males ):
What is a classic skin finding on Fabry disease?
Angiokeratomas
What are the classic findings associated with Fabry disease?
- Hypo/anhidrosis (prone to overheating)
- Corneal/len opacity
- Acroparesthesia (fingers and toes usually)
- Angiokeratomas
- Progressive, small vessel disease in kidney, heart, and brain.
What test is usually ordered to diagnose Fabry disease? What confirms it?
- Decreased GLA enzyme activity.
- Confirmed via genetic testing
How is Fabry disease managed?
- ERT (agalsidase beta)
- Chaperone therapy: migalastat (adult), which increases GLA activity to prevent GL3 builup. (Chaperone to the gala)
- Symptom control
- Stroke prevention (AC)
What is Niemann-pick disease? (NPD)
- Deficiency of acid sphingomyelinase (ASM)
- Accumulation of sphingomyelin in macrophages
- Result: cell death and organ malfunction
What description of macrophages under a microscope might suggest NPD?
“foam” cells with soap-suds appearance
What are the 3 subtypes of NPD?
- NPA (fastest onset, 2 year death)
- NPB (medium onset, adolescent death)
- NPC (medium onset, same as NPB + neurologic symptoms, death by aspiration pneumonia)
Describe the clinical manifestations of NPA.
- Rapid onset of 6 months post birth.
- Rapid and progressive CNS deterioration
- Death in 2 years.
Describe the clinical manifestations of NPB.
- Late childhood/adolescent onset
- Progressive HSM and cirrhosis as liver cells are replaced by macrophages.
- ILD (interstitial lung disease)
- Death in late adolescence/early adulthood dt lung/liver failure
CXR will show lung scarring.
Describe the clinical manifestations of NPC.
- Onset: middle-late childhood with normal early development.
- Liver, spleen, and/or lung (like NPB) + neurologic disease
- Death 2/2 to aspiration pneumonia
How is NPD screened for?
- Newborn screening (not WV)
- Genetic
How is NPD managed?
Supportive only.
What is Pompe disease?
- Deficiency in acid alfa-glucosidase (GAA)
- Accumulation of glycogen in lysosomes.
- Results in degradation of glycogenolysis and tissue destruction.
Also classified as a glycogen storage disease.
What are the 3 subtypes of Pompe disease?
- Classic infantile-onset
- Non-classic infantile onset
- Late onset
Describe the clinical presentation of classic infantile-onset Pompe disease.
- Onset: Within a few months of birth.
- Hypotonia
- Myocardiopathy
- HSM
- Death prior to 1y.
Describe the clinical presentation of non-classic infantile-onset Pompe disease.
- Onset: 12 months post birth
- Delayed motor skills
- Progressive muscle weakness => respiratory dysfunction
- Cardiomegaly with NO associated HF
- Death by early childhood.
Describe the clinical presentation of late-onset Pompe disease.
- Onset: late childhood or later.
- Low likelihood of cardiac involvement
- Slowly progressive muscle weakness
- Death usually due to respiratory failure later.
How is Pompe disease diagnosed?
- GAA enzyme levels decreased.
- Confirmed via genetic testing.
- Prenatal diagnosis can be done via DNA analysis, amniocentesis, or CV sampling.
How is Pompe disease managed?
- ERT: alglucosidase alfa (wary of antibody formation)
- Monitor for gradual weakness, fractures, dysphagia, and sleep apnea.
What 3 pathophysiologic processes result in hyperphosphatemia?
- Increased phosphate intake
- Decreased phosphate excretion (CKD MC)
- Shift of intracellular phosphate to extracellular space (rhabdo and tumor lysis)
What is the treatment for acute, severe, hyperphosphatemia?
- CKD present: Hemodialysis
- CKD not present: IV fluids
How does hyperphosphatemia typically present?
Similar to hypocalcemia since it is most likely also present.
For mild hyperphosphatemia, what is the treatment? Moderate/severe?
- Mild: dietary restrictions, avoiding dairy, meat, and beans.
- Mod/severe: phosphate binders (calcium acetate, lanthanum carbonate, sevelamer)
When is calcium acetate indicated and how does it work?
- Indicated for hyperphosphatemia for ESRD pts.
- MOA: Chelates phosphate in intestines to make calcium phosphate, which is then pooped out.
What drug does calcium acetate interact with?
Digitalis
How does lanthanum carbonate work?
Binds with phosphate to prevent GI absorption.
When is lanthanum carbonate not to be used?
Pregnancy, use the other 2 phosphate binders.
When might sevelamer be preferred over the other 2 phosphate binders? Why?
Patients that have electrolyte abnormalities.
It is a polymeric binder than does not affect any Ca, Bicarb, or aluminum concentrations.
If a patient is pregnant and prescribed sevelamer, what should they be counseled on?
Impairs absorption of fat-soluble vits and folic acid. May need additional supplementation
What are the typical underlying causes that result in hypophosphatemia due to inadequate intake?
- Intestinal malnutrition
- Vit D Deficiency
- Excessive use of antacids (Ca, Mg, Al)
What is the MC of increased phosphate excretion resulting in hypophosphatemia?
Hyperparathyroidism
What are the primary underlying causes of hypophosphatemia with extracellular shifts of phosphate?
- Insulin shifting phosphate in DKA or refeeding syndrome.
- Hungry bones syndrome
- Acute respiratory alkalosis
What level of phosphate is considered severely low? What symptoms might occur?
< 2mg/dL
- Weakness, bone pain, muscle pain, rhabdo
- HF
- Focal neurologic deficits, seizures, AMS
What is the treatment for hypophosphatemia?
- Treat underlying disorder
- 1-2g phosphate per day over 7-10 days.
- Mild: Increase dietary phosphate (meat, dairy, beans)
- Severe: Sodium or potassium phosphate supplements
When are phosphate supplements CI’d?
- Hyperphosphatemia
- Renal failure
- Hyperkalemia (> 4mg)
Where is 99% of Mg found?
Intracellular/bone
What is the normal range of Mg?
1.7-2.1 (very narrow)
What might cause decreased intake of magnesium?
- Alcohol abuse
- Extended parenteral nutrition
- A very bad diet
What syndrome results in intracellular shifts of Mg?
Hungry Bones syndrome
What is the MCC of hypomagnesemia?
GI loss (Vomiting)
How do I check magnesium?
Serum magnesium (Not part of BMP)
How does hypomagnesemia typically present?
Usually associated with hypokalemia or hypocalcemia.
Usually CV or CNS/PNS symptoms
How do we manage hypomagnesemia?
- Eat healthier
- IV magnesium if severe (keep > 1)
- Oral magnesium if mild/mod
- Also replace Ca and K
What is Paget’s disease?
- Excessive bone resorption
- Increased bone formation
What are the two bone cells involved in bone formation?
- Osteoclasts (crusher)
- Osteoblasts (builders)
Describe the bones of someone with Paget’s disease?
- Larger
- Weaker
- Vascularized
- Highly susceptible to fracture
Does not spread bone to bone.
What bones are MC affected in Paget’s disease?
Axial skeleton bones
What is the clinical presentation of Paget’s disease?
- Bone pain (MC)
- Osteoarthritis
- Bony deformity
- Excessive warmth due to excessive vascularity of bone
- Neurologic complications (Hearing loss MC)
How is bone pain often described?
- Dull
- Deep
- Aching
- Worse at night!
What serum labs are elevated in Paget’s disease?
- ALP
- Bone specific ALP (BSAP), which increases with osteoblast activity
What would an XRAY of someone with Paget’s disease show early on? Later on?
- Early: Lytic lesions
- Late: Lytic lesions and excessive bone formation (bowing)
What scan can I order to assess the extent of Paget’s disease?
Radionucleotide bone scan
Shows where Paget’s is active.
What referrals does someone with Paget’s disease need?
- Endocrinologist (Primary)
- Orthopedist
How do we manage Paget’s disease?
- Bisphosphonates (prevent osteoCLAST activity)
- NSAIDs (joint pain)
- Calcium and Vit D supplements
Alendronate, ibandronate, risedronate, zoledronic acid
