Lipid Storage Diseases

Question 1

Gaucher Type I - Etiology and Presentation

Answer 1

Autosomal recessive deficiency of beta-glucosidase with accumulation of glucocerebroside in liver, spleen, bone marrow

Presents in adulthood with hepatosplenomegaly, anemia, thrombocytopenia, bone pain; NO CNS involvement

Question 2

Gaucher Type II

Answer 2

Autosomal recessive deficiency of beta-glucosidase with accumulation of glucocerebroside in CNS, liver, spleen, bone marrow

Presents in infancy (2-4 months) with CNS involvement, hepatosplenomegaly, anemia, thrombocytopenia

Fatal without treatment; enzymatic replacement therapy exists

Question 3

Tay Sachs Type I

Answer 3

Autosomal recessive deficiency of beta-hexosaminidase A

Presents in infancy with CNS involvement - blindness, seizures, mental and motor deterioration; classic finding is cherry red spot of retina

Fatal
1/3,000 incidence among Ashkenazi Jews

Question 4

Fabry Disease

Answer 4

X-linked deficiency of alpha galactosidase

Presents earlier in males than females with acroparesthesias (pain in palms and soles), proteinuria, angiokeratomas, renal failure; death occurs in males by age 40 if untreated but enzymatic replacement therapy exists

Question 5

Pompe Disease

Answer 5

Autosomal recessive deficiency of alpha-glucosidase

Presents in infancy with profound muscle weakness and hypertrophic cardiomyopathy; alternatively may present in adults with gradual, proximal muscle weakness and respiratory failure (sleep apnea)

Labs show elevated CK, glycogen on muscle biopsy

Infantile form is fatal without treatment but enzymatic replacement therapy exists

Question 6

Hunter Disease

Answer 6

X-linked deficiency of Iduronate sulfatase

Presents in boy children with coarse facies, short stature, airway disease (hoarseness, frequent URIs), and cognitive disability; NO corneal clouding

Severely affected boys will die without treatment but enzymatic replacement therapy exists; females do not have clinical disease

Question 7

Hurler Disease

Answer 7

Autosomal recessive disease of alpha iduronidase

Presents like Hunter, but girls are affected also with coarse facies, airway disease, skeletal deformities, + corneal clouding

Severely affected children will die without treatment, but enzymatic replacement therapy exists

Question 8

McArdle Disease

Answer 8

Autosomal recessive deficiency of glycogen phosphorylase

Presents with muscle weakness and cramping after exercise, myoglobinuria after exercise; liver enzymes and cognition are normal

Question 9

Which glycolipid disorders are X-linked?

Answer 9

Fabry disease (alpha-galactosidase) 
Hunter Syndrome (Iduronate-2-sulfatase)

Question 10

How are hydrolases targeted to the lysosome?

Answer 10

Hydrolases express mannose-6-phosphates which interact with M6P receptors on the lysosome

Question 11

What phenotypic features are associated with LSDs?

Answer 11

Macrocephaly 
Cognitive regression
Corneal clouding 
Cherry red spot 
Macroglossia
Hepatosplenomegaly
Proteinuria 
Dysostosis multiplex
Joint stiffness

Question 12

Dysostosis Multiplex

Answer 12

Abnormal bony structure on X-ray including vertebral ‘beaking,’ broad bases of metacarpals and phalanges, scoliosis

Question 13

Cherry Red spot

Answer 13

Retinal finding, most commonly associated with Tay Sachs disease

Question 14

Therapeutic options for LSDs

Answer 14

Enzyme replacement - improves degradation
Substrate inhibition - prevents accumulation
Chaperone therapy - stabilizes damaged enzyme

Question 15

Gaucher Type I - Diagnosis and Treatment

Answer 15

Labs: Anemia, thrombocytopenia
Imaging: ‘Erlenmeyer Flask Sign’ of distal femur
Histology: ‘Gaucher cells’ show enlarged lysosomes filled with glucocerebroside (‘crumpled tissue paper’ appearance)

Treatment: Imiglucerase (enzyme replacement therapy)