GLYCOLIPID STORAGE DISEASES
These are hereditary disorders in which one or more tissues become engorged with specific lipids because of deficiencies of the lysosomal enzymes required for hydrolysis of one of the glycosidic bonds. The type of lipid and its tissue distribution have a characteristic pattern in each disorder.
In Gaucher disease (the most common disorder) and Niemann-Pick disease, major clinical manifestations result from macrophage accumulation of glucocerebroside and sphingomyelin, respectively, leading to their massive expansion in tissues.
Etiology and Pathogenesis
Glucocerebroside accumulates in macrophages because of a deficiency of β-glucocerebrosidase.
Inheritance is autosomal recessive, with high gene frequency among Ashkenazi Jews.
More than 100 different mutations have been reported, but the five mutations most common in Ashkenazi Jews account for more than 95% of mutations in that population.
The most common mutation in the Jewish population is 1226G (N370S). It usually gives rise to mild disease in the homozygous form.
Three types of Gaucher disease are recognized based on absence (type 1) or presence of neurological features (types 2 and 3) (see Table 37–1).
— Type 1 occurs in both children and adults, and is primarily caused by an accumulation of glucocerebroside-laden macrophages in liver, spleen, and marrow. Neurologic manifestations are rare and primarily affect the peripheral nervous system.
— Type 2 is exceedingly rare and is characterized by rapid neurologic deterioration and early death.
— Type 3, or juvenile Gaucher disease, is a subacute neuropathic disorder with later onset of symptoms and better prognosis than type 2.
Patients may be asymptomatic, or symptoms may range from minimal to severe:
— Chronic fatigue is common.
— Hemorrhage occurs after procedures.
— Splenic enlargement may cause positional symptoms. Hepatomegaly is usually asymptomatic.
— Skeletal lesions are often painful. “Erlenmeyer flask” deformity of the femur is common (Figure 37–1).
Table 37–1CHARACTERISTICS OF THE THREE TYPES OF GAUCHER DISEASE |Favorite Table|Download (.pdf) Table 37–1 CHARACTERISTICS OF THE THREE TYPES OF GAUCHER DISEASE
| ||TYPE 1 ||TYPE 2 ||TYPE 3 |
|Subtype ||Asymptomatic ||Symptomatic ||Neonatal ||Infantile ||3a ||3b ||3c |
|Common genotype ||N370S/N370S or two mild mutations ||N370S/other or two mild mutations ||Two null or recombinant mutations ||One null and one severe mutations ||None ||L444P/L444P ||D409H/D409H |
|Ethnic predilection ||Ashkenazi Jews ||Ashkenazi Jews ||None ||None ||None ||Norrbottnians, Asians, Arabs ||Palestinian Arabs, Japanese |
|Common presenting features ||None ||Hepatosplenomegaly, hypersplenism, bleeding, bone pains ||Hydrops fetalis; congenital ichthyosis ||SNGP, strabismus, opisthotonus, trismus ||SNGP; myoclonic seizures ||SNGP; hepatosplenomegaly growth retardation ||SNGP; cardiac valves’ calcifications |
|Central nervous system involvement ||None ||None ||Lethal ||Severe ||SNGP; slowly progressive neurologic deterioration ||SNGP; gradual cognitive deterioration ||SNGP; brachycephalus |
|Bone involvement ||None ||Mild to severe (variable) ||None ||None ||Mild ||Moderate to severe; kyphosis (gibbus) ||Minimal |
|Lung involvement ||None ||None to (rarely) severe ||Severe ||Severe ||Mild to moderate ||Moderate to severe ||Minimal |
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