72 Gaucher Disease and Related Lysosomal Storage Disease

Question 1

GAUCHER DISEASE

Result of a hereditary mutation in the GBA gene leading to dysfunction of a lysosomal enzyme

Answer 1

β-glucocerebrosidase

Resulting in an accumulation of glucocerebroside

Inheritance is autosomal recessive, with high gene frequency among Ashkenazi Jews.

Question 2

Among those of Ashkenazi Jewish origin, the predominant mutation is

Answer 2

N370S

Accounts for approximately 75% of mutant alleles

Question 3

The second most common mutation is ___________, which when homozygous accounts for most patients with neuronopathic disease and is the most prevalent mutation in Asians, Arabs, and Norrbottnians.

Answer 3

L444P

Question 4

Types of Gaucher disease

Occurs in both children and adults and is primarily caused by an accumulation of glucocerebroside-laden macrophages in the liver, spleen, and marrow.

Neurologic manifestations are rare and primarily affect the peripheral nervous system.

Answer 4

Type 1

Question 5

Types of Gaucher disease

Rare and is characterized by rapid neurologic deterioration and early death

Answer 5

Type 2

Question 6

Types of Gaucher disease

Subacute neuropathic disorder with later onset of symptoms
and better prognosis than type 2

Answer 6

Type 3, or juvenile Gaucher disease

Question 7

Radiogrophic finding of deformity of the femur

Answer 7

“Erlenmeyer flask” deformity

Skeletal lesions are often painful

Question 8

Characteristics of Gaucher cells

Answer 8

Small, eccentrically placed nuclei and cytoplasm with characteristic crinkles or striations

The cytoplasm stains with the periodic acid–Schiff (PAS) technique

Question 9

Biomarker that is more sensitive and specific

Answer 9

Lyso-Gb1 (glucosyl-sphingosine)

Other one is chitotriosidase

Question 10

The diagnosis of Gaucher disease should be considered in:

Answer 10

• (1) any patient who presents with unexplained splenomegaly, thrombocytopenia, frequent nosebleeds, anemia, or acute or chronic bone pain;
• (2) children with short stature for their age; and
• (3) a patient with nontraumatic avascular necrosis of a large joint at any age, especially if it is associated with any of the other features

Definitive diagnosis requires a reduced enzymatic activity of β-glucocerebrosidase in leukocytes supported by an elevated biomarker, combined with mutation analysis at the DNA level (best performed by wholegene sequencing).

Question 11

TRUE OR FALSE

Marrow aspiration is indicated only when other hematologic diseases must be considered.

Answer 11

TRUE

Marrow aspiration is indicated only when other hematologic diseases must be considered.

Question 12

Treatment for Gaucher’s Disease

Answer 12

Enzyme replacement therapies (ERTs)
* Imiglucerase
* Velaglucerase
* Taliglucerase

• Responses (reduction in fatigue, decrease in liver and spleen size, and improved blood counts) usually occur within 6 months.
• Skeletal improvement may not be evident until after 2 to 3 years of therapy.
• The enzyme does not cross the blood–brain barrier and hence does not affect neuronopathic features.

Question 13

In patients who are not suitable for ERT, substrate reduction therapy (SRT) with________________ may be considered.

Answer 13

Oral eliglustat or miglustat

Question 14

There is an increased incidence of malignancies in patients, particularly hematologic malignancy:

Answer 14

Multiple myeloma

Question 15

NIEMANN-PICK DISEASE

A group of disorders that results from the accumulation of

Answer 15

Sphingomyelin

It is autosomal recessive.

Question 16

SUBTYPE OF NIEMANN-PICK DISEASE

A consequence of acid sphingomyelinase (ASM) deficiency and are an infantile disease and a disease with later onset, respectively.

Answer 16

Types A and B disease

They are now referred to as ASM deficiency.

Type A: presents in infancy with poor growth and neurologic manifestations

Type B: presents with hepatosplenomegaly in the first decade of life but in mild cases not until adulthood. Neurologic findings are usually absent, but pulmonary involvement is common

Question 17

SUBTYPE OF NIEMANN-PICK DISEASE

Not a result of sphingomyelinase deficiency but rather of mutations in a gene designated NPC1 or NPC2, which is involved in cholesterol and glycolipid transport

Characterized by neonatal jaundice and dementia, ataxia, and psychiatric symptoms in later life

Answer 17

Type C disease

Question 18

The predominant lipid accumulating in tissues

Types A and B:
Type C:

Answer 18

Types A and B: sphingomyelin
Type C: unesterified cholesterol and several glycolipids

Question 19

Histologic featiure of Niemann-Pick disease

Answer 19

Large histiocytes containing small lipid droplets (foam cells) or sea-blue histiocytes