This boy presents with findings of Tay-Sachs disease (TSD), which is caused by deficiency in hexosaminidase A leading to accumulation of GM2 ganglioside.
TSD is caused by a deficiency in the enzyme hexosaminidase A. Over time, GM2 ganglioside accumulates. Affected patients present with central nervous system degeneration, blindness, cherry red spot on macula, startle reflex, and death before age 4 years. The presentation is overall similar to Niemann-Pick’s disease, but without the hepatosplenomegaly characteristically seen in Niemann-Pick. The inheritance of TSD is autosomal recessive, and there is a substantially increased incidence in children of Ashkenazi-Jewish decent.
Irkham et al. discusses the genetic screening for several relatively common genetic disorders, including TSD. The authors recommend screening for parents of Ashkenazi-Jewish, Cajun, or French Canadian decent, as there is a substantially increased risk in all of these populations. The recommended screening tests includes checking serum hexosaminidase A levels in men and nonpregnant women, or checking WBC hexosaminidase A levels in pregnant women. In recent years, some centers have begun offering molecular genetic testing.
Chen et al. discuss ocular features of TSD in more detail. Several ocular findings are possible, including ganglioside accumulation in the cornea, retina, and optic nerve. Overall, the most common ocular findings in TSD are cherry-red spot on the macula, coupled with a pale optic disc. This finding occurs because of the contrast of the abnormal ganglion cells next to the fovea. In particular, the fovea lacks ganglion cells. When contrasted against the retinal ganglion cells, which are found in highest concentration in the macula and which contain accumulated gangliosides, the sharp contrast in color can been seen, resulting in the “cherry red spot.”
Illustration A shows a cherry red spot on the macula.
Incorrect answers:
Answer 1: Ceramide trihexoside accumulates in Fabry’s disease.
Answer 2: Galactocerebroside accumulates in Krabbe’s disease.
Answer 3: Sphingomyelin accumulates in Niemann-Pick disease.
Answer 5: Glucocerebroside accumulates in Gaucher’s disease.
This presentation combined the finding of tissue paper macrophages is consistent with a diagnosis of Gaucher’s disease. Gaucher’s disease is due to a defect in the enzyme ß-glucocerebrosidase.
Gaucher’s disease is an autosomal recessive lysosomal storage disorder caused by mutations to the ß-glucocerebrosidase gene. This gene is used in the metabolic pathway of sphingolipid breakdown and its removal causes accumulation of intermediate metabolites inside lysosomes. This biochemical deficiency leads to a variety of symptoms most notably including bruising, fractures, and hepatomegaly. The characteristic finding is the identification of tissue paper macrophages on peripheral blood smear. There are three types of this disorder with I being the most common and II being the most severe. This case presentation is consistent with type I Gaucher disease.
Raghuveer et al. discuss the classic presentations of childhood metabolic disorders. They claim that Gaucher’s disease is present in 1:60000 live births but that this ratio increases significantly to 1:900 in the Ashkenazi jewish population. The most common type of this disorder (type I) presents with hepatosplenomegaly, pancytopenia, and destructive bone disease. The more severe forms of this disease can also include seizures and neural degeneration. The symptoms can be alleviated with enzyme replacement in some cases.
Smid et al. studied the effects of substrate reduction therapy versus enzyme replacement therapy in the treatment of Gaucher disease. They found that enzyme replacement therapy and the precursor glycosphingolipid synthesis inhibitor eliglustat are effective in reducing markers of hepatic dysfunction. Miglustat was comparatively less effective.
Figure A shows tissue paper macrophages that are characteristic of Gaucher’s disease.
Incorrect Answers:
Answer 2: ß-galactocerebrosidase is deficient in Krabbe disease and presents with optic atrophy and developmental delay.
Answer 3: Hexosaminidase A is deficient in Tay-Sachs disease and presents with neurological degeneration and a cherry red spot on the macula.
Answer 4: Iduronate sulfatase is deficient in Hunter’s syndrome which presents with aggressive behavior.
Answer 5: Sphingomyelinase is deficient in Niemann-Pick disease which presents with failure to thrive and foamy macrophages.
Overview
- Function
- digest endosomal material
- via digestive enzymes
- glycosylases
- lipases
- proteases
- all are acid hydrolases which function at low pH
- via digestive enzymes
- found in all cells
- higher concentrations in phagocytic cells
- digest endosomal material
- Forms
- primary lysosomes
- newly formed from the trans-Golgi
- waiting to receive endocytosed material
- secondary lysosomes
- aka phagolysosome
- primary lysosomes
- formed when primary lysosomes fuse with endocytic vesicles
Lysosomal Storage Disease (by Deficient Enzymes)
- Sphingolipidoses
- β-galactocerebrosidase
- β-glucocerebrosidase
- deficient in Gaucher disease
- glucocerebroside accumulates in cells of phagocytic cells
- presentation
- three types
- type I
- most common
- hepatosplenomegaly
- aseptic necrosis of heads of long bones
- mild anemia
- possible to live a normal lifespan
- type II
- “infantile Gaucher”
- CNS involved
- death < 1 year
- type III
- “juvenile Gaucher”
- severity < type II
- type I
- three types
- deficient in Gaucher disease
- Arylsulfatase A
- deficient in metachromatic leukodystrophy
- cerebroside sulfate accumulates
- presentation
- demyelination in CNS and PNS
- resulting in ataxia and dementia
- demyelination in CNS and PNS
- inheritance
- AR
- deficient in metachromatic leukodystrophy
- Mucopolysaccharides
- XR
Other Lysosomal Disorders
- I (inclusion)-cell disease
- cause
- proteins marked for localization to lysosomes are post-translationally modified in the Golgi
- mannose residues are phosphorylated by N-acetylglucosamine-phosphotransferase enzyme
- defect in N-acetylglucosamine-phosphotransferase causes I-cell disease
- cells cannot degrade endocytosed material and inclusion bodies build up intracellularly
- proteins marked for localization to lysosomes are post-translationally modified in the Golgi
- presentation
- high plasma levels of lysosomal enzymes
- skeletal abnormalities
- restricted joint movement
- psychomotor retardation
- early death
- coarse facial features
- no treatment
- cause
- Chédiak–Higashi syndrome
- cause
- primary lysosomes of leukocytes cannot fuse with phagosomes
- due to inability of microtubles to polymerize
- also affects immune cell chemotaxis
- presentation
- ↑ infections
- especially S. aureus
- partial albinism
- peripheral neuropathy
- ↑ infections
- inheritance
- cause
- AR