A couple comes to the clinic for preconception counseling. They are offered genetic screening because they are of Ashkenazi Jewish descent. Test results show that both are carriers for a lysosomal enzyme deficiency disorder that results in decreased metabolic degradation of a phospholipid substrate to ceramide, which leads to a buildup of the phospholipid. They are counseled about the chance that their offspring will be affected by this disorder. The couple wants to know the clinical features of an affected child. Which of the following findings would be most consistent with this condition?

Question

A couple comes to the clinic for preconception counseling.  They are offered genetic screening because they are of Ashkenazi Jewish descent.  Test results show that both are carriers for a lysosomal enzyme deficiency disorder that results in decreased metabolic degradation of a phospholipid substrate to ceramide, which leads to a buildup of the phospholipid.  They are counseled about the chance that their offspring will be affected by this disorder.  The couple wants to know the clinical features of an affected child.  Which of the following findings would be most consistent with this condition?

Quizplus · Accepted Answer

11ec160b_36cc_df2b_9249_f35638a8a768_MD0001_00 Niemann-Pick disease is an autosomal recessive lysosomal storage disorder. It is caused by a deficiency of sphingomyelinase, the enzyme responsible for metabolizing sphingomyelin (a phospholipid) to ceramide. Excess sphingomyelin results in cells that appear enlarged, foamy, and vacuolated on electron microscopy. These lipid-laden foam cells accumulate in the liver (hepatomegaly), spleen (splenomegaly), and CNS (hypotonia, neurodegeneration). After a period of normal development, affected infants do not attain new skills and regress from previously acquired milestones (eg, sitting with support, head control, social smile). Accumulation of sphingomyelin in the retinal ganglion cells also leads to retinal opacification, which gives the appearance of a cherry-red macula. Disease is progressive, and death usually occurs by age 3. Niemann-Pick disease, like several other rare genetic disorders (eg, Tay-Sachs disease, Gaucher disease, Bloom syndrome), is more common in the Ashkenazi Jewish population than in the general population. The increased risk for rare and often life-threatening genetic mutations is attributed to the founder effect, or the loss of genetic variability within a group that historically conceived within their own community. An Ashkenazi Jewish couple should be offered genetic counseling and testing before they conceive a child. (Choices A and B) Hurler and Hunter syndromes are mucopolysaccharidoses characterized by the accumulation of heparan and dermatan sulfate, which are glycosaminoglycans (ie, polysaccharides, not phospholipids). Both disorders can cause dysostosis multiplex (eg, abnormally shaped bones, enlarged skull), coarse facial features, and cardiac dysfunction. Corneal clouding is unique to Hurler syndrome. (Choice C) Fabry disease is characterized by decreased metabolic degradation of globotriaosylceramide to glucocerebroside, not ceramide. Disease manifestations include neuropathic pain and angiokeratomas in adolescence and multiorgan (eg, renal, cerebrovascular, cardiac) involvement in adulthood. (Choice E) Small stature and infertility with a predisposition to malignancy and a classic sun-sensitive facial rash are typical signs of Bloom syndrome, an autosomal recessive disorder that leads to chromosomal instability, not phospholipid accumulation. Educational objective: Niemann-Pick disease is an autosomal recessive disorder that has a much higher incidence in the Ashkenazi Jewish population than in the general population. It is characterized by sphingomyelinase deficiency and sphingomyelin (phospholipid) accumulation, which cause neurologic regression, hepatosplenomegaly, and retinal opacification (ie, cherry-red macula).

A Couple Comes to the Clinic for Preconception Counseling