Inborn Errors- Glycolipids Flashcards
What are lysosomes?
The garbage (or recycling) centers in cells that are acidic, contain ~50 hydrolase enzymes, that break down macromolecules into smaller components.
Lysosomal Storage Disease
Occur when a lysosomal enzyme (usually) is deficient/missing resulting in substrate(s) accumulation (storage) in various organs.
Lysosomal Storage Disease Inheritance
The majority of LSDs are inherited in an autosomal recessive fashion. Three exceptions that are inherited in X-linked fashion are: Fabry disease (alpha-galactosidase) Hunter syndrome (iduronate-2-sulfatase) Damon Disease (Lysosome associated Membrane Protein 2)
General picture of lysosomal storage disease presentation
In general LSDs are progressive diseases that present less acutely than many other metabolic conditions.
Therapy options for lysosomal storage diseases
Supportive Surgery Bone marrow transplant ENZYME REPLACEMENT Substrate inhibition Chaperone therapy
A 25 year-old woman with a history of hepatosplenomegaly with eventual splenectomy, bone and joint pain, and a liver biopsy that showed wrinkled-looking cells (‘or foamy macrophages’) with accumulations of glucosylceramides. The most likely diagnosis is
Gaucher’s
Mucopolysaccharidoses are inherited storage diseases caused by
defects in the degradation of proteoglycans
Infant dies after cardiomegaly and progressive weakness. What disease do you suspect? And what’s the enzyme defect?
Pompe
Alpha-glucosidase
A 3-year-old girl is seen in clinic for frequent otitis media infections, and a history of developmental delay. On exam, she has severe growth retardation, corneal opacities, hepatosplenomegaly, and coarse facial features. What’s the disease?
Hurler
A 47-year-old man is seen in clinic for a 5-year history of a hearing defect, moderate intellectual disability, and valvular heart disease. The eye examination reveals a clear cornea. The defective enzyme is found to be iduronate sulphate sulfatase. The most likely diagnosis is:
Hunter Disease (remember x-linked)
A 7-month old male infant is brought to medical attention because of progressive loss of motor and developmental skills and the recent onset of seizures. On examination you note poor visual tracking, mild muscle hypertonicity, an increased startle reflex. Ophthalmologic examination shows bilateral cherry red-spots.
What’s the disease and what’s the enzyme?
Tay-Sachs
Beta-hexosaminidase
A 25 year-old woman presents to clinic complaining of muscle weakness and pain. She tells you that she has noted progressive decline of exercise capacity for the past six years. She continues to try and exercise and reports that she has great difficulty at the beginning of her aerobics class, but if she rests for 10-20 minutes she often gets a ‘second wind’ and can then rejoin her class. She competed in a 5K run last year and had significant myalgias after the race as well as particularly dark urine for two days after the race. An important complication of this disorder is:
Renal failure
This is McArdle’s disease
An 18 year-old man complains of a multi-year history of recurrent painful episodes involving his palms and the soles of his feet. He also has a history of irritable bowel syndrome and has been hospitalized twice for heat-intolerance this past summer. His past medical history is remarkable for two clavicular fractures, myopia, and one hospitalization for pneumonia. Which test is most likely to reveal his diagnosis?
Alpha-galactosidase activity in leukocytes
this is Fabry’s disease
Gaucher Type I
Most common lysosomal storage disease
AR
Adult Onset
Presentation: fatigue, bone pain, enlarging abdomen, anemia
Deficient enzyme: Beta glucosidase (a.ka. Glucocerebrosidase)
Treatment: enzyme replacement therapy, oral substrate inhibition
Key features: Hepatosplenomegaly, anemia, thrombocytopenia, looks like ‘lymphoma’ (big spleen/anemia) but isn’t
Tay Sachs
AR lysosomal storage disease
Infantile or early, early childhood
Presentation: BLINDNESS, seizures, mental/motor deterioration CHERRY RED SPOTS, increased startle reflex, normal liver/spleen
Enzyme deficiency: Beta-hexosaminidase A
Treatment: supportive
Form 1st aid: Tay-SaX lacks heXosaminidase
Fabry
X-linked!!! Lysosomal storage disease
Pre-Teen/Teen with neurological findings or
Adult with renal failure of
Older adult with LVH or stroke
acroparethesias (pain in palms or soles), angiokeratomas,
Renal failure, Left ventricular hypertrophy/stroke
enzyme deficiency: Alpha-galactosidase
Treatment: agalsidase beta
Pompe disease
AR glycogen storage disease
Infantile: present at 3-6 months; dead at 1 year (w/o Rx)
Childhood: not likely tested on
Adult: slowly progressive muscle weakness
Findings: Elevated CK; no cherry red spot; normal liver/spleen; glycogen on muscle biopsy, cardiomegaly
Presentation:
Infant with muscle weakness, high CK, and LVH on ECG
Adult with sleep apnea and trouble climbing stairs
Deficient enzyme: Alpha-glucosidase
Treatment: Alglucosidase alfa
From 1st Aid: Pompe trashes the Pump
Hunter
X-linked recessive mucopolysaccharidoses
Childhood
Presentation: Coarse facies, airway disease, ear infections, hoarse voice, Hepatosplenomegaly, short stature,
NO CORNEAL CLOUDING
Deficient enzyme: Iduronate sulfatase
Treatment: Idursulfase
From 1st aid: Hunters see clearly (no corneal clouding) and aggressively aim for the x (x-linked)
Hurler
Mucopolysaccharidoses
Similar to Hunter but GIRLS can be affected and YES CORNEAL CLOUDING
AR
Childhood
Presentation: Coarse facies, airway disease, ear infections, hoarse voice, + corneal clouding, hearing loss, Hepatosplenomegaly, short stature,
Enzyme: Alpha iduronidase
Treatment: laronidase
Niemann Pick Disease
AR lysosomal storage disease
Major hepatosplenomegaly, xanthomas in skin, cherry red spot, SUPRANUCLEAR PALSY (vertical gaze palsy), corneal opacities, anemia, coronary artery dz
Enzyme deficiency: Sphingomyelinase
From 1st aid: No man picks (Niemann-Pick) his nose with his sphinger (sphingomyelinase)
McArdle Disease
AR glycogen storage disease
Muscle cramping after exercise; myogolbuinuria (coffee colored urine after exercise)
Enzyme deficiency: glycogen phosphorylase
From 1st aid: McArdle=Muscle
Fix card
Fix card
