Wolman病临床及LIPA基因突变1例

目的探讨Wolman病的临床特点及分子诊断的意义。方法对1例符合Wolman病临床表现的患儿进行白细胞溶酶体酸性脂酶LIPA基因测序,分析其突变的类型。结果约5月龄女婴,发现"皮肤黄染10余天,加重伴发热3d"入院。查体见肝脾显著肿大,黄疸。实验室检查提示贫血,肝功能衰竭,高三酰甘油血症;X线胸腹片和腹部增强CT均提示特征性双侧肾上腺增大和广泛钙化。骨髓涂片可见海蓝色泡沫状组织细胞,PAS染色提示脂质沉积。DNA测序显示,LIPA基因编码区第7外显子上发生c.796G>T,p.G266*的纯合无义突变,导致266位甘氨酸(GGA)突变为终止密码(TGA)(p.G266*),致溶酶体酸性脂酶缺失。结论 Wolman病婴儿期起病,以显著肝脾肿大、特征性双侧肾上腺增大和广泛钙化、高三酰甘油血症为特征,相应的酶学分析和LIPA基因检测均可确诊Wolman病。

Wolman Disease in Bulgarian Patients: Selective Genetic Screening in Two Presumable Endemic Regions

Wolman disease is a rare autosomal recessive disorder caused by mutations in the LIPA gene (10q23.31). The LIPA gene encodes lysosomal acid lipase (LAL), which plays a key role in hydrolysis of the cholesteryl esters and triglycerides. Two unrelated families from Bulgaria were referred for genetic testing with clinical diagnosis Wolman disease. Sanger sequencing of all coding exons and exon-intron boundaries of the LIPA gene was performed. The index patients were found to be homozygous for two different mutations in the LIPA gene: a missense mutation, c.260G > T, p.Gly87Val, which affects the enzyme active site and a splice-site change, c.822+1G > A, which most probably destroys the enzyme polypeptide chain. These two completely different types of mutations along the LIPA gene resulted in a very similar phenotype involving liver, kidney, gastrointestinal, muscle and blood disturbances. As consanguinity is not typical for the Bulgarian population, a possible explanation of the homozygosity could be presence of endemic regions for given mutations. To check this hypothesis, selective screening for these mutations was performed in two presumable endemic regions in Bulgaria. Altogether, 100 newborns were screened for p.Gly87Val mutation and the detected carrier frequency was about 1% (1/100), while in the group of 100 newborns screened for the c.822 + 1G > A mutation the detected carrier frequency was 2% (2/100). The results indicate a high recurrence risk of Wolman disease in these particular Bulgarian regions of about 1:10000. These findings are from crucial importance for the inhabitants of the corresponding parts of Bulgaria. They may benefit from early genetic testing and adequate genetic counselling during family planning.

Wolman病一例分析及LIPA基因新突变

目的探讨Wolman病的临床特点、酶学及分子诊断。方法对1例临床高度疑似Wolman病患儿进行白细胞溶酶体酸性酯酶测定及LIPA基因PCR扩增及PCR产物直接测序研究，回顾分析其临床、影像学及病理学特点。结果生后16d男婴，因呕吐、腹胀、体重不增、肝脾肿大10d，疑似肠梗阻行剖腹探查术。腹部x线片及CT显示双侧肾上腺钙化。术中发现肝、脾、淋巴结肿大，其表面有黄色沉积物，小肠肿胀、僵硬。肝脏及淋巴结活检显示大量泡沫样细胞浸润。血清壳三糖苷酶572．78nmol／（ml·h）[正常0-50nmol／（ml·h）]，白细胞溶酶体酸性酯酶3．5nmol／（mg·h）[正常参考范围35．5-105．8nmol／（mg·h）]，LIPA基因突变分析发现第4外显子上c．318insT，P．Phel06fsX4纯合插入新突变，父母均为该突变携带者。结论Wolman病以生后早期出现呕吐、腹胀、生长障碍、肝脾肿大及双侧肾上腺钙化为临床特点，腹部x线平片可见肾上腺钙化，白细胞溶酶体酸性酯酶缺乏，LIPA基因第4外显子上检出c．318insT，P．Phel06fsX4突变。

Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?

Lysosomal acid lipase(LAL)plays a key role in intracellular lipid metabolism.Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage,as observed in two recessive autosomal genetic diseases,Wolman disease and Cholesterol ester storage disease.Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency.By contrast,few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene.In the last few years,a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease(NAFLD),suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease.Patients with NAFLD show a significant,progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis.Among cirrhosis of different etiologies,those with cryptogenic cirrhosis show the most significant reductions of LAL activity.These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD.Moreover,the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting.

Natural history and management of liver dysfunction in lysosomal storage disorders

Lysosomal storage disorders(LSD)are a rare group of genetic disorders.The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage[Gaucher disease(GD)and Niemann-Pick disease]and lysosomal acid lipase deficiency[cholesteryl ester storage disease and Wolman disease(WD)].These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension.Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders.Dyslipidemia causes micronodular cirrhosis in lipid storage disorders.These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults.GD,Niemann-Pick type C,and WD also cause neonatal cholestasis and infantile liver failure.Genotype and liver phenotype correlation is variable in these conditions.Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease.The diagnosis of all LSD is based on enzymatic activity,tissue histology,and genetic testing.Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome.Those that progress invariably require liver transplantation with variable outcomes.The prognosis of Niemann-Pick type C and WD is universally poor.Enzyme replacement therapy has a promising role in cholesteryl ester storage disease.This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.

Novel LIPA mutations in Mexican siblings with lysosomal acid lipase deficiency

Lysosomal acid lipase(LAL) deficiency is an underrecognized lysosomal disease caused by deficient enzymatic activity of LAL.In this report we describe two affected female Mexican siblings with early hepatic complications.At two months of age,the first sibling presented with alternating episodes of diarrhea and constipation,and later with hepatomegaly,elevated transaminases,high levels of total and low-density lipoprotein cholesterol,and low levels of highdensity lipoprotein.Portal hypertension and grade 2 esophageal varices were detected at four years of age.The second sibling presented with hepatomegaly,elevated transaminases and mildly elevated lowdensity lipoprotein and low high-density lipoprotein at six months of age.LAL activity was deficient in both patients.Sequencing of LIPA revealed two previously unreported heterozygous mutations in exon 4:c.253C>A and c.294C>G.These cases highlight the clinical continuum between the so-called Wolman disease and cholesteryl ester storage disease,and underscore that LAL deficiency represents a single disease with a degree of clinical heterogeneity.

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