GAUCHER'S DISEASE
DEFINITION:
A lysosomal storage disorder characterized by the accumulation of
lipid (glucosylceramide) primarily in peripheral tissues resulting
in 3 clinical variants.
EPIDEMIOLOGY:
- incidence: 1/600-2,500 (I); 1/50,000 (II and III)
- age of onset:
- risk factors:
- familial - autosomal recessive
- chrom. #: 1q21 (with a pseudogene)
- gene: glucocerebrosidase (beta-glucosidase)
- Ashkenazic Jews (I);
- Norrbottnain region of Sweden (III)
PATHOGENESIS:
- glucocerebrosidase (beta-glucosidase) catalyzes the removal
of glucose from glucosylceramide to form ceramide
- most common genetic disorder of Jews
- Gaucher's is the most prevalent of the lysosomal storage
disorders
2. History
1934 - Aghion
- glucosylceramide identified as the accummulating lipid
1965 - Patrick/Brady et al.
- glucocerebrosidase identified as the deficient enzyme
1983 - Barneveld et al.
- glucocerebrosidase assigned to chrom. #1
1985 - Choudary et al.
- genomic clone (11 exons, 10 introns)
1987 - Tsuji et al.
- single base mutation in neuronopathic type gene
3. Genetic Defect
- genetic defect(s) -> deficiency of glucocerebrosidase
activity-> accumulation of glucosylceramide primarily in
visceral tissues
- the CNS is more involved in Types II and III
- Gaucher cells may have a toxic effect on the tissues in
which they accumulate
- three clinical variants:
- Type I - Nonneuropathic Form
- Type II - Acute Infantile Neuropathic Form
- Type III - Subacute Neuropathic Form
CLINICAL FEATURES:
- 3 phenotypes based on clinical signs and symptoms and
prognostic predictors (rate of progression of neurologic
abnormalities)
- each type is a consequence of multiple genotypes
- most common form with variable age of onset
- variable systemic symptoms (see below)
- normal life expectancy (2% have a fulminant course)
- panethnic but increased frequency in Ashkenazic Jews
- by definition the CNS is spared
- painless, firm, does not rupture spontaneously
- most common symptom in all 3 types of Gaucher's
- may be 20x normal weight for age
- complications:
- pancytopenia, bleeding diathesis
- abdominal pain (from infarcts)
- mechanical interference with bowel, kidney,
diaphragm or circulation (high-output CHF)
2. Hepatomegaly
- usually asymptomatic but may be complicated by liver
failure with portal hypertension, cirrhosis, esophageal
varices bleeding occurs infrequently
2. Musculoskeletal
- bone pain
- bone marrow replacement
- anemia, leukopenia, thrombocytopenia
- femoral head necrosis
- pathologic fractures - femoral neck, long bones
- collapse of vertebral bodies with spinal cord
compression or thoracic kyphosis
- "bone crisis" (bone infarction)
- acute onset of severe localized pain and swelling with
fever
- usually resolves over 2-3 weeks but can last for
months
2. Minor Systemic Manifestations
- hypoxia (due to liver disease)
- restrictive lung disease (kyphoscoliosis)
2. Cardiovascular
- interstitial myocardial infiltration
- restrictive pericarditis
3. Renal
- proteinuria, glomerulonephropathy
4. Endocrine
- short stature, failure to thrive, growth hormone
deficiency
5. Skin
- yellow-brown pigmentation
6. Ophthalmologic
- horizontal saccadic abnormalities
- fundal abnormalities
7. Dental
Type II (Acute Infantile Neuropathic)
- average age of onset: 2-4 months
- may present with painless hepatosplenomegaly rapidly
followed by neurologic complications (see below)
- uniform in presentation
- no ethnic predilection
- nervous system involvement must be clearly established
before a diagnosis of type II is made
- trismus, strabismus, retroflexion of head (opisthotonus)
2. Later Manifestations
- progressive spasticity or spastic paraparesis
- hyperreflexia, positive Babinski, pathologic reflexes
2. Bulbar Dysfunction
- dysphagia
- difficulty in handling secretions
- death usually due to aspiration pneumonia or apnea
3. Others
- cranial nervey palsies
- ataxia, dementia, supranuclear ophthalmoplegia,
seizures
- death between 3-4 years of age
2. Major and Minor Systemic Manifestations
Type III (Subacute Neuropathic)
- age of presentation: late childhood/early adolescence
- clinical features of I plus some of the neurologic
complications of II although at an older age of onset and slower
rate of progression
- more heterogeneous in presentation than type II
INVESTIGATIONS:
- deficiency of glucocerebrosidase activity in leukocytes or
cultured skin fibroblasts
- prenatal
- deficiency of glucocerebrosidease activity in cultured
chorionic villi or amniocytes
- Gaucher cells on pathology
- PCR
2. Imaging Studies
- Erlenmeyer flask deformity of bones (cortical expansion of
distal bone), i.e., femur most affected
- pathologic fractures
2. Bone Crisis
- bone scans, CT, multiple blood cultures
3. Serum
- conjugated hyperbilirubinemia (jaundice)
4. Pathology
- hallmark of the disease
- tend to accumulate within the lysosomes of cells of the
reticuloendothelial system
- derivations:
- bone marrow - osteoclasts and macrophages
- liver - Kupffer cells
- lung - alveolar macrophages
- spleen - histiocytes
- also found in the thymus, Peyer's patches in the
intestines, pharyngeal tonsils, and CNS (types 2 and 3 only)
MANAGEMENT:
- only if complications - severe bleeding, high-output CHF,
severe mechanical obstruction, failure to thrive
- has no effect on the rate of progression of the disease
(if spleen acts to collect glucosylceramide, removal may
increase its deposition in other organs)
2. Liver Transplant
- only if complications of liver failure
3. Orthopedic
- supportive
- bone crisis - analgesics, adequate hydration and
oxygenation, bed rest
- hip replacement
2. Interventional Strategies
- exogenous injection of human placental glucocerebrosidase
modified to expose additional mannose residues to target
mannose receptors on macrophages
- clinical improvement with regression of organomegaly and
improvement in blood counts
- very expensive - ¼-3/4 of a million per year
2. Bone Marrow Transplantation
- rationale is that macrophages are progeny of hematopoietic
stem cells
- risk/benefit ratio too high in mild cases and too
dangerous in severe cases thus difficult to justify its use
- unknown if any neurologic benefits of BM transplantation
3. Gene Transfer
- introduction of glucocerebrosidase gene into autologous
hematopoietic stem cells and infusion of these cells into
patients
- introduction of gene into lymphoblasts that allows the
enzyme to be secreted and then taken up by cells with mannose
receptors
INTERNET LINKS:
|