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Detailed information of SANDHOFF DISEASE
SANDHOFF DISEASE
DEFINITION:
A lysosomal storage disorder characterized by the accumulation of
lipids (GM2 gangliosides, globosides) in the central nervous system
(CNS) and peripheral tissues resulting in 2 clinical variants.
EPIDEMIOLOGY:
- incidence: ?
- age of onset:
- infancy (Type I); 3-10 years (Type II)
- risk factors:
- familial - autosomal recessive
- chrom.#: 5q13
- gene: beta-hexosaminidase (beta-chain)
- M = F
PATHOGENESIS:
- there are two isoenzymes of beta-hexosaminidase:
- A - a heterodimer composed of an alpha-chain & a beta-chain
- B - a homodimer composed of two beta-chains
- a defect in the beta-chain will therefore affect the
activity of both isoenzymes
- a defect in the beta-hexosaminidase A isoenzyme (due to
either an alpha- or beta-chain defect) will present like Tay
Sachs Disease with the accumulation of GM2 gangliosides in the
CNS
- a defect in the beta-hexosaminidase B isoenzyme (due to a
beta-chain defect) prevents the degradation of globoside
resulting in the accumulation of globoside in the visceral
tissues (liver, reticuloendothelial system, vascular
endothelium)
- thus, a person with a beta-chain defect will present like
Tay Sachs Disease with peripheral tissue involvement
2. Genetic Defect
- genetic defect -> decreased expression of the beta-chain ->
deficiency of beta-hexosaminidase A+B isoenzyme activities ->
accumulation of GM2 gangliosides and globosides in the CNS and
peripheral tissues, respectively
- two clinical variants:
CLINICAL FEATURES:
- same as in Tay Sachs Disease
- normal development up to 3-6 months of age
- onset of developmental delay followed by rapid
regression by the end of the first year of life
- progressive hypotonia with motor weakness
- poor head control
- failure to turn over, crawl, or sit
- assumes a frog-like position
- eventually becomes hypertonic with exaggerated
reflexes
2. Social/Behavioural
- decreasing eye contact and focussing
- interacts very little with the environment eventually
becoming unresponsive to exogenous stimuli reaching a
vegetative state
2. Others
- initially an exaggerated startle response to sharp
sounds eventually becoming unattentive and unresponsive
2. Seizures
- common begin after the first year of life and vary in
type and frequency
3. Macrocephaly
- commonly by 1.5-2 years of life due to a reactive
cerebral gliosis
2. Ophthalmologic Manifestations
- cherry red spot of the macula (prominent macular fovea
centralis)
- progressive visual inattention with blindness by the 2nd
year of life
3. Visceral Manifestations
2. Type 2 (Juvenile Form)
- slurred speech (dysarthria)
- progressive psychomotor retardation
- progressive ataxia
- progressive hypertonia with increased spasticity
- progressive loss of intellectual function
2. Ophthalmologic Manifestations
3. Visceral Manifestations
INVESTIGATIONS:
- deficiency of beta-hexaminidase B activity in leukocytes and
cultured skin fibroblasts
- prenatal:
- deficiency of enzyme activity in cultured chorionic villi
and amniocytes
2. Imaging Studies
- progressive atrophy of the grey and white matter
2. Skeletal X-Rays
3. EEG
- paroxysmal discharges initially with decreasing activity as
the disease progresses
4. Pathology
- multiple membrane-bound laminated structures found within
the cytoplasm of ganglion cells by electron microscopy
2. Bone Marrow
MANAGEMENT:
- no treatment for underlying disorder
- multidisciplinary approach:
- Paediatrics, Neurology, Ophthalmology, Orthopedics, etc.
- genetic counselling
2. Prognosis
- Type I - relentless progression with death by 4 years of age
- Type II - relentless progression with death by 10-15 years
of age
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Pediatric Database - SANDHOFF DISEASE
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