Wolman Disease: Diagnosis by Leucocyte Acid Lipase Estimation
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《美国医学杂志》
Department of Pediatrics, Seth G.S. Medical College & K.E.M. Hospital, Parel, Mumbai, India
Abstract
Wolman disease is a rare fatal autosomal recessive disorder caused by absence of acid lipase enzyme leading to accumulation of cholesterol ester. Hepatosplenomegaly is a constant feature and occurs as early as fourth day of life. Progressive mental deterioration may occur after few weeks of onset of symptoms. Adrenal calcification seen on X-ray abdomen, USG or CT scan is the hallmark of Wolman disease. For the first time in Indian literature, the authors report a case of Wolman disease that was confirmed by acid lipase enzyme estimation.
Keywords: Wolman disease; Acid lipase enzyme
Wolman disease is a rare fatal autosomal recessive disorder caused by absence of acid lipase enzyme leading to accumulation of cholesterol ester due to point mutation of 10q24-q25 chromosome. 51 cases have been reported in the literature. Only 5 cases have been reported in Indian literature[1],[2] of which one case was diagnosed antenatally on the basis of adrenal calcification seen on ultrasonography.[2] However, for the first time in Indian literature, we report a case of w0 olman disease which was confirmed by acid lipase enzyme estimation.
Case report
A three-month-old male child born of non-consanguinity with no similar history in earlier four siblings, presented with progressive abdominal distention noted since the age of one month accompanied with few episodes of intermittent loose motions and vomiting since age of 2 months. Examination revealed abdominal distention with sharp edged, irregular surface, firm hepatomegaly of 6 cms (span 9 cms) and a firm splenomegaly of 5 cms. Rest of the system was normal except for hypotonia. Investigations revealed hemoglobin of 8.9 gm %, SGOT-97 U/L, SGPT-92 U/L, serum triglycerides-140 mg % and cholestrol-124 mg %. Ultrasonography and liver scan confirmed hepatosplenomegaly. CT scan of the abdomen showed hepasplenomegaly and bilateral symmetrically enlarged adrenal glands with calcification of the right adrenal gland. Liver biopsy revealed extensive fatty change with PAS positive material which was digested by diastase without evidence of cholestasis or cirrhosis. The estimation of acid lipase enzyme showed zero level in the patient while a similarly processed age control sample showed enzyme levels of 0.279 nanomols/hour/mg protein. a0 bout 10 cc of patient's blood collected in EDTA bulb was centrifuged to separate the white blood cells. The white blood cell extract was further lysed by 0.1 % triton-X-100. The lysate (0.2 mg/ml suspension) was then incubated with equal volume of p-nitro-phenyl-laurate buffer for 18 hours at 37° C at a pH of 4.5. After incubation the enzyme activity was read by a spectrophotometer at 465 nm wavelength. An age matched control sample was similarly processed to compare the enzyme activity.
Discussion
In 1956, Wolman et al described the clinical picture of this disease in an infant.[3] Patrick and Lake in 1969 demonstrated the deficiency of acid lipase for the first time.[4] Onset of the disease is usually seen in the first few weeks of life with marked abdominal distention.[5] Hepatosplenomegaly is a constant feature and occurs as early as fourth day of life.[5] Progressive mental deterioration may occur after few weeks of onset of symptoms.[3],[5],[6] Persistent vomiting and loose stools leading to malabsorption and failure to thrive may be present.[3],[6] Investigations reveal anemia, deranged liver function, plasma lipids in the lower range of normal[5] as seen in our case. Bone marrow reveals lipid laden histiocytes or foam cells which may be seen in other reticulo-endothelial organs.[7] Adrenal calcification seen on X-ray abdomen, USG or CT scan is the hallmark of w0 olman disease.[3],[6] The levels of acid lipase enzyme are absent or markedly reduced.[4],[8] The method for acid lipase estimation was described by Beaudet AL et al[9] which was followed by us as mentioned.
No specific treatment is available for Wolman disease, which has a progressive downhill course eventually leading to death by 3 to 6 months. Drug like lovastatin (which reduces cholesterol, triglycerides, LDL cholesterol) and simvastatin with cholestyramine has been tried.[5] Bone marrow transplant and liver transplant may be tried.[10] Replacement of the missing enzyme is a future possibility. Prenatal diagnosis by chrionic villus biopsy and amniocentesis can be tried.[11]
References
1. Uniyal KJ, Colaco MP, Bharath NS, Pradhan MR, Murthy AK. Wolman's disease. Indian p0 ediatr 1995; 32: 232-235.
2. Swamy PM, Mallikarjuna HB, Shantala CC, Prashanth S, Maiya PP, Dandekar C. Wolman's disease. Indian J p0 ediatr 1997; 64: 561-563.
3. a0 bramov A, Schorr S, William S, Wolman M. Generalized xanthomatosis with calcified adrenals. Am J Dis Child 1956; 91: 282-286.
4. Patrick AD, Lake BD. Deficiency of an acid lipase in Wolman's disease. Nature 1969; 222: 1067-1068.
5. Assmann G, Seedorf Udo. Acid Lipase deficiency: Wolman disease and cholesterol ester storage disease. i0 n Scriver CR, Beaudet AL, Sly WS. Valle D, eds. t0 he Metabolic and Molecular Bases of Inherited Disease. McGraw h0 ill i0 nc., New York; 1998; 2563-2587.
6. Wolman M, Sherk VV, Datts, Frenkea M. Primary familial xanthomatosis with calcified adrenals -Report of two more siblings of a described case. Pediatrics 1961; 28: 742-746.
7. Marshall WC, Ockenden BG, Fosbrooke AS, Cumings JN. Wolman disease. A rare lipidosis with adrenal calcification. Arch Dis Child 1969; 44: 331-341.
8. Lough J, Fawcett J, Weigensberg B. Wolman's disease. An electron microscopic, histochemical, and biochemical study. Arch p0 atho 1970; 89: 103-110.
9. Beaudet AL, Lipson MH, Ferry GD, Nichols BL Jr. Acid lipase in cultured fibroblasts: cholesterol ester storage disease. J l0 ab c0 lin m0 ed 1974; 84(1): 54-61.
10. Krivit W, Freese D, Chan KW, Kulkarni R. Wolman's disease: a review of treatment with bone marrow transplantation and considerations for the future. Bone m0 arrow t0 ransplant 1992; 10(suppl 1): 97-101.
11. Bona G, Gallina MR, Dolfin G, Iavarone A, Perona A, Zaffaroni M. Prenatal diagnosis of heterozygosis in a pregnancy at risk for Wolman's disease at the 8th week of gestation. p0 anminerva Med 1989; 31: 180-182.(Surve Talib Y, Muranjan M)
Abstract
Wolman disease is a rare fatal autosomal recessive disorder caused by absence of acid lipase enzyme leading to accumulation of cholesterol ester. Hepatosplenomegaly is a constant feature and occurs as early as fourth day of life. Progressive mental deterioration may occur after few weeks of onset of symptoms. Adrenal calcification seen on X-ray abdomen, USG or CT scan is the hallmark of Wolman disease. For the first time in Indian literature, the authors report a case of Wolman disease that was confirmed by acid lipase enzyme estimation.
Keywords: Wolman disease; Acid lipase enzyme
Wolman disease is a rare fatal autosomal recessive disorder caused by absence of acid lipase enzyme leading to accumulation of cholesterol ester due to point mutation of 10q24-q25 chromosome. 51 cases have been reported in the literature. Only 5 cases have been reported in Indian literature[1],[2] of which one case was diagnosed antenatally on the basis of adrenal calcification seen on ultrasonography.[2] However, for the first time in Indian literature, we report a case of w0 olman disease which was confirmed by acid lipase enzyme estimation.
Case report
A three-month-old male child born of non-consanguinity with no similar history in earlier four siblings, presented with progressive abdominal distention noted since the age of one month accompanied with few episodes of intermittent loose motions and vomiting since age of 2 months. Examination revealed abdominal distention with sharp edged, irregular surface, firm hepatomegaly of 6 cms (span 9 cms) and a firm splenomegaly of 5 cms. Rest of the system was normal except for hypotonia. Investigations revealed hemoglobin of 8.9 gm %, SGOT-97 U/L, SGPT-92 U/L, serum triglycerides-140 mg % and cholestrol-124 mg %. Ultrasonography and liver scan confirmed hepatosplenomegaly. CT scan of the abdomen showed hepasplenomegaly and bilateral symmetrically enlarged adrenal glands with calcification of the right adrenal gland. Liver biopsy revealed extensive fatty change with PAS positive material which was digested by diastase without evidence of cholestasis or cirrhosis. The estimation of acid lipase enzyme showed zero level in the patient while a similarly processed age control sample showed enzyme levels of 0.279 nanomols/hour/mg protein. a0 bout 10 cc of patient's blood collected in EDTA bulb was centrifuged to separate the white blood cells. The white blood cell extract was further lysed by 0.1 % triton-X-100. The lysate (0.2 mg/ml suspension) was then incubated with equal volume of p-nitro-phenyl-laurate buffer for 18 hours at 37° C at a pH of 4.5. After incubation the enzyme activity was read by a spectrophotometer at 465 nm wavelength. An age matched control sample was similarly processed to compare the enzyme activity.
Discussion
In 1956, Wolman et al described the clinical picture of this disease in an infant.[3] Patrick and Lake in 1969 demonstrated the deficiency of acid lipase for the first time.[4] Onset of the disease is usually seen in the first few weeks of life with marked abdominal distention.[5] Hepatosplenomegaly is a constant feature and occurs as early as fourth day of life.[5] Progressive mental deterioration may occur after few weeks of onset of symptoms.[3],[5],[6] Persistent vomiting and loose stools leading to malabsorption and failure to thrive may be present.[3],[6] Investigations reveal anemia, deranged liver function, plasma lipids in the lower range of normal[5] as seen in our case. Bone marrow reveals lipid laden histiocytes or foam cells which may be seen in other reticulo-endothelial organs.[7] Adrenal calcification seen on X-ray abdomen, USG or CT scan is the hallmark of w0 olman disease.[3],[6] The levels of acid lipase enzyme are absent or markedly reduced.[4],[8] The method for acid lipase estimation was described by Beaudet AL et al[9] which was followed by us as mentioned.
No specific treatment is available for Wolman disease, which has a progressive downhill course eventually leading to death by 3 to 6 months. Drug like lovastatin (which reduces cholesterol, triglycerides, LDL cholesterol) and simvastatin with cholestyramine has been tried.[5] Bone marrow transplant and liver transplant may be tried.[10] Replacement of the missing enzyme is a future possibility. Prenatal diagnosis by chrionic villus biopsy and amniocentesis can be tried.[11]
References
1. Uniyal KJ, Colaco MP, Bharath NS, Pradhan MR, Murthy AK. Wolman's disease. Indian p0 ediatr 1995; 32: 232-235.
2. Swamy PM, Mallikarjuna HB, Shantala CC, Prashanth S, Maiya PP, Dandekar C. Wolman's disease. Indian J p0 ediatr 1997; 64: 561-563.
3. a0 bramov A, Schorr S, William S, Wolman M. Generalized xanthomatosis with calcified adrenals. Am J Dis Child 1956; 91: 282-286.
4. Patrick AD, Lake BD. Deficiency of an acid lipase in Wolman's disease. Nature 1969; 222: 1067-1068.
5. Assmann G, Seedorf Udo. Acid Lipase deficiency: Wolman disease and cholesterol ester storage disease. i0 n Scriver CR, Beaudet AL, Sly WS. Valle D, eds. t0 he Metabolic and Molecular Bases of Inherited Disease. McGraw h0 ill i0 nc., New York; 1998; 2563-2587.
6. Wolman M, Sherk VV, Datts, Frenkea M. Primary familial xanthomatosis with calcified adrenals -Report of two more siblings of a described case. Pediatrics 1961; 28: 742-746.
7. Marshall WC, Ockenden BG, Fosbrooke AS, Cumings JN. Wolman disease. A rare lipidosis with adrenal calcification. Arch Dis Child 1969; 44: 331-341.
8. Lough J, Fawcett J, Weigensberg B. Wolman's disease. An electron microscopic, histochemical, and biochemical study. Arch p0 atho 1970; 89: 103-110.
9. Beaudet AL, Lipson MH, Ferry GD, Nichols BL Jr. Acid lipase in cultured fibroblasts: cholesterol ester storage disease. J l0 ab c0 lin m0 ed 1974; 84(1): 54-61.
10. Krivit W, Freese D, Chan KW, Kulkarni R. Wolman's disease: a review of treatment with bone marrow transplantation and considerations for the future. Bone m0 arrow t0 ransplant 1992; 10(suppl 1): 97-101.
11. Bona G, Gallina MR, Dolfin G, Iavarone A, Perona A, Zaffaroni M. Prenatal diagnosis of heterozygosis in a pregnancy at risk for Wolman's disease at the 8th week of gestation. p0 anminerva Med 1989; 31: 180-182.(Surve Talib Y, Muranjan M)