Detailed Phenotype

Natural History

• Lysosomal acid lipase deficiency (LAL-D), also called cholesteryl ester storage disease (CESD) and Wolman disease results from deficient lysosomal acid lipase (LAL) activity due to biallelic LIPA gene mutations (Fredrickson, 1963) (Young, 1970) (Anderson, 1991).
• Lysosomal acid lipase (LAL) function is hydrolysis of short and long chain fatty-acid triglycerides, and separation of cholesteryl esters into free fatty acids and cholesterol.
• Lysosomal acid lipase deficiency (LAL-D) is characterized by type IIB dyslipidemia, accelerated atherosclerosis, microvesicular steatosis leading to fibrosis, cirrhosis and premature demise.
• LAL-D has a variable course, from infantile lethal to survival into childhood or adulthood (Pagani, 1996).

Infantile Lethal LAL-D

• Age of Onset- Birth (or prenatally) to about 5 months of age (Eto, 1970).
• Infantile lethal LAL-D is characterized by marked abdominal distension, hepatosplenomegaly, steatorrhea, watery, yellow diarrhea, emesis, anemia, thrombocytopenia and failure to thrive. Some, but not all patients present with adrenal calcifications. Death occurs in the first year of life, often from inanition if untreated (Abramov, 1956) (Meyers, 1985)(Wolman, 1995).

​

Adrenal calcifications on abdominal radiograph, courtesy of Synageva Biopharma Corp.

• Adrenal calcifications are present in about 50% of infantile onset cases (Jones, 2014). Adrenal necrosis is also common and likely gives rise to the calcifications (Lough, 1970).
• LAL-D presents in the first weeks of life, or even prenatally with ascites or polyhydramnios visible on ultrasound.
• Some cases may appear normal at birth with onset in the first weeks or months of life or may present at birth with marked abdominal distention with or without organomegaly.
• In a series of 36 confirmed infantile lethal LAL-D patients, the median age at presentation was one month (0–6.0). The median age at diagnosis was 2.7 months of age (1.0 - 17.7), and the median age at death was 3.7 months (1.4 - 46.3) (Jones, 2014)(Reiner, 2014).

Clinical Characteristics

• Abdominal distension
• Failure to Thrive/ growth Failure
• Splenomegaly
• Hepatomegaly
• Emesis
• Steatorrhea
• Diarrhea
• Liver Fibrosis/Cirrrhosis
• Ascites
• Adrenal Calcifications (~50%)
• Adrenal Enlargement
• Adrenal Insufficiency
• Malabsorption
• Cachexia
• Massive lipid storage (triglycerides, cholesteryl esters) in spleen, adrenal glands, intestinal mucosa, liver and other tissues (Assman, 1975)
• Infants with infantile LAL-D disease are at high risk for respiratory infections, including pseudomonas aeruginaosa, staphylococcus and sepsis (Lowden, 1970)(Kathuria, 2012).

​

From Crocker, et al, 1965

Lab Abnormalities

• Low or absent lysosomal acid lipase activity is diagnostic.
• Anemia of less than 9 g/dL and/or thrombocytopenia can be severe, requiring packed red blood cell transfusions.
• microcytosis,
• hypochromia,
• Hemophagocytic lymphohistiocytosis
• elevated transaminases,
• hyperbilrubinemia,
• hypoalbuminemia,
• elevated LDL total serum cholesterol,
• decreased HDL cholesterol,
• high triglycerides,
• elevated serum cortisol.
• urine corticosteroid insufficiency on ACTH stimulation.
• Vacuolated cytoplasm with lipid–laden, foamy macrophages on bone marrow aspirate are typical.

​

Courtesy of Shome, 2001

Pathology

• Cholesteryl esters accumulate in multiple organ systems of patients with LAL deficiency.
• Cholesteryl ester accumulation was significantly increased in the spleen and lymph nodes in am infantile lethal LAL-D patient. In the liver, cholesteryl esters were 28 times normal  on autopsy (Sloan, 1972). Cholesteryl esters accumulate primarily in the Kupffer cells, as they are presumed to be released from the hepatic parenchyma and crystalized in the Kupffer cells (Lough, 1970).
• Triglyceride levels are elevated in the hepatic parenchyma.
• Triglyceride accumulation was 80 times that of a normal age-matched control in an LAL-D patient’s liver on autopsy, and 30 times greater than the control in the spleen (Eto, 1970)(Sloan, 1972).
• Lack of lysosomal enzyme activity in the enterocytes of the intestinal villi leads to triglyceride accumulation and blockage of the intestinal mucosa (Wolman, 1995).

Treatments

• HSCT- Although there are reports of three cases that survived following hematopoietic stem cell transplant, in a natural history study, 10 of 10 LAL-D disease patients did not survive, and many infants with LAL-D are too fragile to survive the chemo-ablation regimen (Krivit, 2000)(Stein, 2007)(Tolar, 2008)(Jones, 2014).
• Milk feeding, breast milk and triglyceride containing formulas should be discontinued at the time of diagnose, since these may increase lipid mediated gastrointestinal sequelae (Wolman, 1995).
• Parenteral hyperalimention that does not contain fatty acids may help decrease cachexia in some patients and help to stabilize patients prior to commencing enzyme replacement therapy (ERT).  ERT with sebelipase alfa is now commercially available.
• Sunflower oil, safflower oil, soy, canola, flax or cod liver oil applied cutaneously may alleviate some secondary essential fatty acid deficiency symptoms without increasing intestinal malabsorption, though the data are conflicting (Wolman, 1995).
• Five of six infantile onset patients in an ongoing phase II/III clinical trial for enzyme replacement therapy (ERT) with sebelipase alfa, (a recombinant version of lysosomal acid lipase) demonstrated improved weight gain, resolution of vomiting and diarrhea, decreased abdominal distension, reductions in hepatosplenomegaly and improved serum markers including AST, ALT and hemoglobin after 20 weeks.  One patient succumbed to LAL-D disease after only one infusion. Infusion associated reactions included fever and tachycardia, and three patients developed anti-drug antibodies but continue infusions at a dose of 3 mg/kg which has been well tolerated (Valayannopoulos, 2014).

LAL-D Attenuated Phenotype

LAL-D patients with residual lysosomal acid lipase activity frequently harbor at least one ESJM-1A>G mutation.

• ESJM-1 homozygotes’ symptom onset is as early 10 months of age, including gastrointestinal lipid laden histopathology and cholesteryl ester crystal accumulation. Compound heterozygotes for E8SJM-1 and another LIPA mutation may have onset from birth to early adulthood.
• Hepatomegaly from 4 cm to more than 10 cm below the costal margin is the most common presenting symptom.
• More than 80% of homozygous ESJM-1 patients reported were diagnosed before age six years. (Anderson, 1999) (Rassoul, 2001)(Bernstein, 2013).
• E8SJM-1 appears protective against the most severe LAL-D presentation, with all reported patients having childhood onset but surviving into adulthood (Anderson, 1999) (Michel, 1979). However, there is a paucity of long-term follow-up data.
• Although E8SJM-1 has never been reported in an infantile lethal LAL-D patient, considerable phenotypic overlap exists, including failure to thrive with weight and height below the 5th percentile, abdominal distention, chronic diarrhea, frequent respiratory infections, anemia, progressive liver disease and esophageal varices in E8SJM-1 homozygotes and compound heterozygotes.
• Despite the severe early childhood presentation, with the E8SJM-1 survival to adulthood is common.
• Life threatening dyslipidemia and liver disease may appear asymptomatic to the patient, despite laboratory and pathology abnormalities. Therefore, patients who do not experience pain may not present to medical attention.
• Silently progressive liver disease leading to fibrosis, portal hypertension and esophageal varices are life threatening complications.
• Several case reports describe patients who were not diagnosed until liver transplantation or autopsy (Sloan, 1972) (Dincsoy.1982) (Cagle, 1986)
• Premature atherosclerosis leads to early onset cerebrovascular and myocardial infarction (Michel, 1979) (Elleder, 1999).

Clinical Characteristics among LAL-D Patients with the E8SJM-1G>A Mutation

• Gastrointestinal lipid accumulation
• Hepatocellular microvesicular steatosis
• Liver fibrosis
• Hepatomegaly
• Splenomegaly
• Severe, acute and chronic diarrhea
• Malabsorption
• Abdominal pain
• Ascites
• Cachexia
• Failure to thrive
• Anemia
• Epistaxis
• Frequent hospitalizations for respiratory infections
• Portal hypertension with or without pulmonary vascular obstruction
• Coronary artery disease including atherosclerosis, cardiac arrhythmia, heart failure, aortic calcifications, aneurisms, myocardial infarction
• Stroke

Lab Abnormalities

• Deficient lysosomal acid lipase (LAL) enzyme activity
• Elevated AST
• Elevated ALT
• Elevated total serum cholesterol
• Elevated LDL cholesterol
• Elevated triglycerides
• Decreased HDL cholesterol
• Elevated chitotriosidase
• Anemia
• Thrombocytopenia
• Vacuolated lymphocytes/foam cells

Pathology

• Liver pathology is universal in cholesteryl ester storage disease patients.
• Striking orange-yellow buttery coloration on gross examination is described in several reports. Though characteristic, not all specimens appear yellow-orange (Du, 1998) (Anderson, 1999).
• Diffuse microvesicular steatosis is reported on all CESD liver biopsies.
• Massive lipid deposition of >500 times normal with pathognomonic, birefringent cholesteryl esters are typical in enlarged, vacuolated hepatocytes and Kupffer cells.
• Vacuolated parenchymal cells, portal inflammation, lipid and ceroid laden foamy macrophages are present in the sinusoids and portal tracts, with progression to trabecular architecture obliteration, fibrosis and cirrhosis.
• Duodenal lipid accumulation and foam cells, edema of small bowel mucosa, gallbladder enlargement and extrahepatic cholesteryl crystal accumulation are additional findings (Fredrickson, 1963) (Muntoni, 1995) (Levy R, 1992), (Ameis. 1995) (Drebber,2005) (Elleder, 1999).
• Electron microscopy is utilized to demonstrate the pathognomonic cholesteryl esters and clefts.
• Lysosomal immunostaining for LAMP1, LAMP2, LIMP2, or with a lysosomal luminal protein (cathepsin D) illustrated the localization the lipid accumulation to lysosomes without requiring ultrastructural demonstration of lysosomal lipid deposition (Hulkova, 2012).
• CESD associated cholesteryl ester accumulation results in increased endogenous cholesterol production. With insufficient LAL-D to hydrolize cholesteryl esters into free cholesterol, cholesteryl esters are trapped within the lysosomes. Therefore, inadequate delivery of free cholesterol to the cytosol results in upregulation of cholesterol synthesis by the liver cells (Hageman, 1984) (Ginsberg, 1987).

​

Pathognomonic, birefringent cholesteryl esters visible on electron microscopy

​

Fibrous bands with micronodular cirrhosis

​

Detailed Genotype

Genomic coordinates: Chr10: 89222511 (on Assembly GRCh38)

Gene Symbol: LIPA

Cytogenetic location: 10q23.31

Protein: Lysosomal Acid Lipase

Alternate names: lipase A, lysosomal acid, cholesterol esterase, cholesterol ester hydrolase, acid cholesteryl ester hydrolase.

The normal function of the LIPA gene product, lysosomal acid lipase (LAL) is hydrolysis of short and long chain fatty-acid triglycerides, and separation of cholesteryl esters into free fatty acids and cholesterol (Young, 1970).

LIPA Gene Mutations

LIPA gene mutation nomenclature varies, depending on the initiation sequence implemented. Many reported mutations have subsequently been redesignated by adding the 21 bases in the leader sequence.  For example, the LIPA mutation, p.G66V has been redesignated pG87V (Grabowski, 2012).

​

• >55 Genotyped patients with 106 known LIPA mutations

• (Only one mutation was identified in 4 LAL deficient patients. The second mutation may have been a gross deletion, or a non-coding mutation undetectable on sequencing).

• > 31 different mutations were reported.
• Several mutations are associated with in both infantile lethal LAL-D and a more attenuated phenotype when inherited in trans with a milder mutation.
• R65X, G87V, c.397_398delTC, W140X, L200P, and c.684delT have been identified in infantile lethal LAL-D patients and in patients who survive to adulthood (Fouchier, 2013).
• Several mutations have been identified in multile unrelated kindreds affected with LAL-D, including: R65X, c.397_398delTC, W140X, L200P, and c.684delT, Q85R, G342R, H295Y, E8SJM and G87V.
• The G87V mutation is a founder mutation in the Iranian Jewish and Bukharin Jewish populations, with an allele frequency of 1 in 64, and a carrier frequency of 1 in 32 individuals (Valles-Ayoub, 2011).
• Homozygosity for the G87V mutation results in infantile lethal LAL-D with death in the first year of life if untreated.
• Enzyme activity in the leukocytes of G87V homozygotes is less than 1%.

The Most Common LAL-D Mutation, E8SJM-1G>A

• E8SJM-1G>A (c.894G>A; p.delS275_Q298) is the most frequent mutation  – accounting for >60% of alleles 17 homozygotes, 29 compound heterozygotes
• E8SJM-1G>A  was identified exclusively in European, European American and Brazilian kindreds (Bernstein, 2013).

The LIPA gene E8SJM-1G>A is a splice junction mutation that results in a deletion of exon 8, encompassing 72 base pairs.

• E8SJM-1G>A produces ~ 3%- 8% of normal transcript, with ~4%-12% normal LAL activity
• The E8SJM-1G>A mutation is protective against the infantile lethal form of the LAL-D spectrum, even in trans with a null mutation, since it results in some normal transcript with sufficient residual enzyme activity of 4%-12%  (Klima, 1993) (Anderson, 1999).
• There are two other mutations, E8SJM +1 and E8SJM-3,  at the same acceptor site as E8SJM-1G>A that are completely deleterious, with no wild-type transcript, and are both associated with the severe infantile lethal LAL-D phenotype. (Grabowski, 2012).

​

Courtesy of Grabowski, et al 2012 in OMMBID.

Illustration of the 10 LIPA gene exons depicting the three E8SJM mutations, E8SJM+1 and E8SJM which result in complete loss of exon 8, whereas the common E8SJM-1 mutation results in alternate splicing, into two forms of the LAL protein, one with complete loss of exon 8 accounting for up to 97% with 3% to 8% of normal LAL enzyme including exon 8.

E8SJM-1 homozygotes reported all survived to adulthood, but not all compound heterozygotes.

Among 106 LIPA mutations detected in 55 patients (for four patients, only one mutation was identified, but the diagnosis was confirmed biochemically), the common E8SJM-1G>A allele accounted for 61% of mutant alleles, which included 17 patients who were E8SJM_1G>A homozygotes (Bernstein, 2013).

In another series with 19 genotyped LAL-D patients, only four patients were homozygous for E8SJM-1, three of whom were siblings. The vast majority were compound heterozygous for E8SJM-1 and another mutation, including deletions, complex rearrangements and truncating mutations The under-representation of E8SJM homozygotes, which has the highest carrier frequency, accounting for 61% to 84% of LAL-D associated alleles, raises the question of likely under-diagnosis of this genotype, possibly because of a more attenuated or silently progressive presentation. It is likely that some of these patients are dying prematurely and without a definitive diagnosis of LAL-D  (Burton, 2015b).

INHERITANCE

• LAL-D is autosomal  recessive.
• Mutation carriers are asymptomatic, but can pass on the mutation to their children.
• In autosomal recessive conditions, asymptomatic carriers can pass the mutation down from one generation to the next, until a carrier has a child with another mutation carrier, resulting in a one in four chance of having an affected child for each pregnancy.

Autosomal Recessive Inheritance

​

Prenatal Genetic Counseling

Prenatal testing and Preimplantation Genetic Diagnosis (PGD) are available.

Implications for family members

Disease Specific Counseling Considerations

• The LIPA G87V mutation, associated with infantile lethal LAL-D in homozygosity, is a founder mutation, with increased frequency in the Iranian Jewish Population that migrated to Los Angeles California and Great Neck, New York, and in the Bukharan Jewish immigrants in Israel, New York and other communities. Founder mutations arise when a small population that migrated from a larger one remains reproductively isolated (Valles-Ayoub, 2011).
• The carrier frequency of the LIPA G87V mutation is one in 32 among people of Iranian Jewish (Mizrahi) or Bukharan Jewish ancestry, but is very rare in the general population, with an estimated carrier frequency of about 1 in 300 individuals (Valles-Ayoub, 2011).
• Parents of an affected child are obligate carriers.
• If both members of a couple are carriers, there is a 25% chance for each pregnancy to be affected, a 50% chance for each pregnancy to be a carrier and a 25% chance for each pregnancy to be neither affected nor a carrier.
• In recessive conditions, mutation carriers are asymptomatic, but can pass on the mutation to the next generation.
• First-degree relatives of mutation carriers have a 50% chance of also being carriers.
• There is a 2 in 3 chance that unaffected siblings of an affected patient are carriers.
• The E8SJM-1 mutation is protective against the most severe, infantile lethal form of LAL-D, since it results in ~ 3%- 8% of normal transcript with some residual enzyme activity.
• Therefore, if both parents carry a mutation in the LIPA gene, as long as one parent’s mutation is E8SJM-1 or both, their pregnancies would not be at risk for the infantile lethal form of LAL-D. There would be a 1 in 4 (25%) chance for each pregnancy to be affected with LAL-D, and a 50% chance for each pregnancy to be an asymptomatic LIPA mutation carrier.
• If an affected LAL-D patient has children with a LIPA mutation carrier, there would be a 50% for each pregnancy to be affected.
• If the affected parent is an E8SJM-1 homozygote, there is a 50% of having a child with LAL-D if the other parent is a mutation carrier, but none of their children would be at risk for the severe infantile lethal (Wolman) form of LAL-D.
• LAL-D patients who are compound heterozygotes for E8SJM-1 and a deleterious mutation would have a 50% chance of having a child with LAL-D if their partner also carries a mutation. If the carrier parent’s mutation in not E8SJM-1 ,  there would be a 25% chance to have a child with the severe infantile lethal form of LAL-D, a 25% to have a child with the more attenuated CESD presentation and a 50% chance that each pregnancy would be an asymptomatic mutation carrier (Grabowski, 2012).
• When counseling patients of the protective nature of the E8SJM-1G>A mutation against the most severe infantile lethal form of LAL-D, it is essential to confirm that the mutation is in fact E8SJM-1G>A. Two other mutations, E8SJM +1 and E8SJM-3 at the same acceptor site as E8SJM-1G>A are deleterious, with no wild-type transcript, and are associated with the severe lethal lysosomal acid lipase deficiency phenotype.
• Consanguineous kindreds (often marriage between cousins), have an increased incidence of recessive conditions.

Pregnancy Considerations

• Prenatal carrier testing for the G87V mutation should be offered to all couples of Iranian Jewish or Bukharan Jewish ancestry.
• For couples of mixed ancestry, LIPA gene sequencing is necessary to rule out LAL-D in the parent who is not of Iranian Jewish or Bukharan ancestry.
• Prenatal testing for at-risk pregnancies can also be done by measuring the lysosomal acid lipase enzyme activity on chorionic villi or amniocytes.
• Prenatal testing is available via amniocentesis after 15 weeks of gestational age or via chorionic villus sampling (CVS) from week 10 to week 12 of gestation. Amniocentesis and CVS confer an estimated risk of miscarriage of about 1 in 300 procedures (Akolekar, 2015).
• If a diagnosis is not confirmed until after 24 weeks gestational age, termination of an affected fetus may not be feasible, since pregnancy termination is prohibited by law in most states after 24 weeks of gestational age.
• Preconception carrier testing is required in order to implement pre-implantation genetic diagnosis (PGD).
• Preimplantation Genetic Diagnosis (PGD) can test an embryo if the familial mutations have been identified, utilizing in vitro fertilization. One or two cells are removed from the pluripotent blastocyst to test for the mutations. Only unaffected embryos are implanted in the mother’s womb, almost eliminating the likelihood of having a child affected with the genetic condition test.

LAL-D Patient Information Handout

Diagnostic Testing Algorithm

Clinical Diagnosis

• Clinical suspicion for infantile LAL-D warrants immediate enzyme and molecular testing on dried blood spot card, which is commercially available through several diagnostic testing laboratories.
• Babies presenting with marked abdominal distension, hepatosplenomegaly, watery, yellow diarrhea, emesis, anemia, thrombocytopenia and failure to thrive in the first three months of life should be tested immediately.
• About 50% of infantile LAL-D patients present with bilateral adrenal calcifications.  LAL enzyme and Molecular LIPA testing is indicated for infants with bilateral adrenal calcifications.
• If bilateral adrenal calcifications are detected on third trimester prenatal ultrasound, prenatal testing may expedite diagnostic confirmation so that enzyme replacement therapy may be initiated as soon as possible after birth.
• Death in infantile lethal LAL-D occurs as early as the first weeks of life up to one year of age if untreated, so timely diagnosis is crucial.
• If mutations were previously identified in a family, lysosomal acid lipase enzyme analysis on leukocytes or fibroblasts should be done immediately to confirm the clinical diagnosis. Dried blood spot card testing for acid lipase enzyme activity and LIPA gene sequencing is commercially available through several diagnostic testing laboratories
• Type IIb dyslipidemia, consisting of elevated serum total cholesterol and LDL cholesterol and low HDL cholesterol with elevated transaminases should raise suspicion for LAL-D, especially in non-obese children and adults.
• Any patient with Type IIb dyslipidemia and microvesicular steatosis and/or micronodular cirrhosis is offered testing for LAL-D.
• Liver biopsy is not required for diagnostic purposes, since LAL-D can be diagnosed by a simple blood test.
• If liver biopsy is performed, the finding of pathognomonic birefringent cholesteryl ester crystals and clefts on ultrastructural or polarized light microscopy is diagnostic for lysosomal acid lipase deficiency.
• LAMP1, LAMP2, LIMP2, or lysosomal luminal protein (cathepsin D) immunostaining can reveal lipid accumulation localization to the lysosomes, which is suggestive of LAL-D (Hulkova, 2012).

Molecular and Enzyme Diagnosis

• Clinical suspicion including dyslipidemia and elevated serum transaminases warrants diagnostic enzyme and molecular genetic testing.
• Enzyme testing that reveals deficient lysosomal acid lipase is diagnostic for LAL-D.
• Molecular LIPA gene testing to identify the mutations is required for prenatal testing, PGD , for carrier testing of family members and is of prognostic value.
• For Iranian Jewish or Bukharan Jewish families, if there were no previously identified mutations in the family, targeted mutation analysis for the LIPA gene G87V mutation, in addition to enzyme lysosomal acid lipase enzyme analysis are to be done at the first suspicion of LAL-D. If the LAL enzyme test shows deficient enzyme activity, but two LIPA G87V mutations are not identified, sequencing and deletion studies may be informative.
• LIPA mutation analysis can be offered to patients of European ancestry to screen for the common E8SJM-1G>A  mutation, with reflex testing to full sequencing if no mutation is identified.
• If the family is of non-European ancestry, sequencing is required initially, since this mutation has been described only in Europeans and in two Brazilian kindreds (Pagani, 1998) (Du, 1998).
• If the lysosomal acid lipase enzyme activity is deficient in the affected range, but only one mutation or no mutations are identified on mutation analysis or full LIPA gene sequencing, deletion studies are indicated utilizing MLPA (Multiplex Ligation-dependent Probe Amplification), CGH, since large deletions or complex rearrangements may not be detected on sequencing.

Prenatal Testing

Carrier Testing of Parents of a Proband:

• Parents of an affected child are obligate carriers, and each has a 50% of passing down the mutation for each pregnancy. There is a 25% chance that both parents will pass down the mutation and for each pregnancy to be affected, so prenatal testing or preconception testing should be offered for these at risk couples.
• For all Iranian Jewish or Bukharan Jewish families who have concerns for reproductive purposes or diagnosis of at risk family members, LIPA gene G87V mutation analysis is indicated.
• If there is a family history of LAL-D, E8SJM-1G>A  mutation analysis or LIPA gene sequencing can be offered to determine parental carrier status
• Ideally carrier status for the couple should be identified before pregnancy so that Preimplantation Genetic Diagnosis (PGD) can be offered.
• If one or both parents harbor the E8SJM-1 mutation, they would not be at risk for a child with the infantile lethal form of LAL-D. There would be a 1 in 4 (25%)chance for each pregnancy to be affected with CESD, and a 1 in 2 (50%) chance for each pregnancy to be an asymptomatic LIPA mutation carrier.
• Although the E8SJM-1G>A mutation protects against the most severe infantile lethal form of LAL-D, it is essential to confirm that the mutation is in fact E8SJM-1G>A. Two other mutations, E8SJM +1G>A and E8SJM-3C>T at the same acceptor site as E8SJM-1G>A are completely deleterious, with no wild-type transcript, and are associated with the severe, infantile lethal LAL-D phenotype.
• If both parents are found to carry a mutation, prenatal testing can be offered via amniocentesis after 15 weeks of gestational age or via chorionic villus sampling (CVS) from week 10 to week 12 of gestation. Amniocentesis and CVS confer an estimated risk of miscarriage of about 1 in 200 to 1 in 300 procedures (Akolekar, 2015).
• For couples who are confirmed mutation carriers prior to conception, Preimplantation Genetic Diagnosis can test an embryo, utilizing in vitro fertilization. This is accomplished by removing one or two cells from the pluripotent blastocyst, and testing for the mutations. Only unaffected embryos are implanted in the mother’s womb.

Benefits and Limitations of Genetic Testing

• Mutation analysis confirms the diagnosis in infantile LAL-D caused by two copies of the G87V mutation. If a mutation other than G87V is responsible for LAL-D in the family, gene sequencing and/or deletion testing are required to determine the parental carrier status and to allow for PGD.
• To date, all known cases of infantile LAL-D in Iranian Jewish or Bukharan Jewish families were caused by G87V mutations in the LIPA gene.
• Couples of mixed Iranian Jewish or Bukharan Jewish families and other ethnic backgrounds can be tested for a panel of 5 known recurrent mutations, and then reflex to LIPA gene sequencing if negative. If the mutation panel and sequencing are negative, deletion studies may be offered.

 Diagnostic Testing Algorithm PDF version

​

*If the LAL enzyme activity is not deficient, and ultrastructural birefringent cholestryl ester accumulation was noted on pathology, or there is a high index of suspicion, an assay that is not specific to lysosomal acid lipase may have been used. Re-testing of LAL enzyme activity should be done by a laboratory utilizing using 4-methylumbelliferyl-palmitate, Lalistat 2 or another competitive acid lipase inhibitor.

** It is not requisite to wait for molecular testing results to begin enzyme replacement therapy (ERT). Genetic testing is of prognostic value and prenatal and carrier testing requires that the mutations in the proband are identified, but LAL enzyme deficiency is diagnostic. Molecular testing takes several weeks. In severe infantile LAL-D any delay in treatment may result in mortality.

***The common Mizrahi (Iranian and Bukharan) Jewish G87V mutation is sometimes called the G66V, depending on the starting place of the molecular probe used.

****Deletion studies such as MLPA (Multiplex Ligation-dependent Probe Amplification) or CGH (Comparative Genomic Hybridization) may identify mutations, such as deletions that would not be detectable using sequencing methods.

Differential Diagnosis

• Glycogen Storage disease type 1A (Von Gierke) presents in the first year of life with hepatomgaly, abdominal distesion, hyperlipidemia, diarrhea, hyperuricemia, reduced creatinine clearance, glomerulosclerosis, renal stones, gout, xanthoma, bleeding diathesis, and hyperglycemia glucose-6-phosphate deficiency (Chen, 1988).
• Autosomal Recessive Hypercholesterolemia- Presents with severe hypercholesterolemia, reduction in hepatic LDL uptake, coronary artery disease, xanthomas with normolipidemic parents and grandparents. Caused by mutations in ARH gene (Zuliani, 1999). (Garcia, 2001).
• Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)- Unless associated with metabolic syndrome, a well established, common cause of macrovesicular steatosis, LAL-D investigation is warranted (Begriche, 2011).
• Medium-chain and long-chain acyl CoA dehydrogenase deficiency, Reye’s syndrome and valproic acid poisoning may result in severe, mitochondrial beta-oxidation-mediated hepatotoxicity, which is one of the few other causes of microvesicular steatosis.  However, Reye’s syndrome has distinctive, mitochondrial enlargement that can be seen ultrastructurally. Microvesicular steatosis is uncommon in other metabolic causes of liver disease, and is a flag for LAL-D (Treem, 1986) (Saibara, 1994) (Begriche, 2011).
• Triptolide-induced liver injury, with a Chinese herb called lei gong teng, which is used in traditional Chinese medicine induces microvesicular steatosis, hyperlactacidemia and enhanced oxidant stress (Fu, 2011).
• Tangier disease is an autosomal recessive condition resulting from biallelic ATP-binding cassette 1 (ABCA1) gene mutations, characterized by deficient high density lipoprotein, with characteristic enlarged, orange-yellow tonsils, hepatosplenomegaly, hypocholesterolemia, chloromicrons, neurologic involvement and premature coronary artery disease. (Fredrickson, 1961) (Engel, 1967(Assmann, 1977).
• Lactose Intolerance- Postprandial emesis and steatorrhea may mimic milk protein intolerance (Meyers, 1985)(Drebber, 2005).
• Niemann-Pick C  (NPC) is a lysosomal storage disease, with defective cholesterol traficking, resulting in lipid accumulation, hepatosplenomegaly, and sea blue histiocytes on bone marrow aspirate. NPC has a variable age of onset, from infancy to adulthood, and may present with central nervous system involvement, including seizures and/or progressive dementia. (It is likely that an early report of Niemann Pick C with adrenal calcifications was in fact LAL-D, since adrenal calcifications do not occur in Niemann Pick, and there is phenotypic overlap. Foamy histiocytes, suggestive of macrophagic storage are common to late-onset Niemann-Pick disease type I and II and LAL-D (vom Dahl, 1999) (Grabowski, 2012) (Alexander, 1946)  (Brady, 1978)(Patterson, 2001).
• Myelodysplastic syndrome  Sea-blue histiocytosis in bone marrow smears is common in the myelodysplastic syndrome as well as storage diseases including LAL-D (vom Dahl, 1999).
• Gaucher disease is caused by deficient glucocerebrosidase activity from recessive GBA mutations. Type 2 Gaucher disease presents in early infancy with feeding difficulties, trismus, failure to thrive, hepatosplenomegaly, anemia, thrombocytopenia, lipid laden macrophages on bone marrow, opisthotonos and brains stem degeneration with death before 2 years of age. Types 1 and 3 Gaucher have significantly milder presentations, and may have a normal lifespan, but also present with hepatosplenomegaly, and chitotriosidase elevation. However, in untreated Gaucher disease, low cholesterol is often characteristic, as well as anemia, thrombocytopenia and progressive skeletal degenerative disease (vom Dahl, 1999).
• Type 2 Gaucher disease is caused by deficient glucocerebrosidase activity from recessive GBA mutations. Type 2 Gaucher disease presents in early infancy with feeding difficulties, trismus, failure to thrive, hepatosplenomegaly, anemia, thrombocytopenia, lipid laden macrophages on bone marrow, opisthotonos and brains stem degeneration with death before 2 years of age. Types 1 and 3 Gaucher have significantly milder presentations, and may have a normal lifespan (Kolodny, 1982).
• Familial hemophagocytic lymphohistiocytosis is an autosomal recessive immune disease with reduced NK cell function. Presentation is in infancy or childhood with hypertriglyceridemia, elevated LDL cholesterol, reduced HDL cholesterol, elevated ALT, hypofibrinogenemia, hepatosplenomegaly coagulation dysfunction, anemia, thrombocytopenia, increased risk of hmetalogic neoplasia, bulging fontanelle, and CNS involvement including seizures, ataxia, encephalitis, hemi/paraplegia, coma and death without HSCT. Familial hemophagocytic lymphohistiocytosis can be caused by biallelic mutations in one of five genes, including PRF1, encoding perforin on chromosome 10q22.1. (Dufourcq-Lagelouse, 1999) (Molleran, 2004).
• Infantile Liver Failure Syndrome presents from infancy to adulthood with steatosis, elevated transaminases, fibrosis, microcytic anemia, failure to thrive, renal tubulopathy, developmental delay and brain abnormalities on MRI. Recessive mutations in the Lars gene were identified through whole exome sequencing in one Irish consanguineous kindred (Casey, 2012), Mars mutations were described in one case of infantile liver failure with vomiting, failure to thrive, anemia, lactic acidosis, hypothyroidism, severe anemia, interstitial lung disease, steatosis on liver biopsy with cholestasis, lobular disarray, megakaryocytes on bone marrow and normal brain MRI (van Meel, E, 2013).  The pathophysiology is unknown, and causation cannot be established without further investigations.
• Bilateral adrenal calcifications, hypogonadism, and nephrotic syndrome and thrombocytopenia were reported in two cases in a consanguinous family of Arab ancestry. LIPA sequencing did not identify a mutation. Although testing for deletions, intronic splice variants and enzyme activity were not reported, nephrotic syndrome is not usually associated with LIPA gene dysfunction, though hypogonadism has been reported in lysosomal acid lipase deficiency (LAL-D). The etiology of disease in this kindred was not established, but presumed autosomal recessive because the patients were consanguineous (Schreyer-Shafir N, 2014).

Research and Clinical Trials

Clinical Trial in Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency

An Expanded Access Protocol for Sebelipase Alfa for Patients With Lysosomal Acid Lipase Deficiency

Lysosomal Acid Lipase (LAL) Deficiency Registry

National Lysosomal Acid Lipase Deficiency Study (LAL-D)

Biomarker For Wolman Disease - An International, Multicenter, Epidemiological Protocol

A Study to Identify and Characterize LAL-D Patients in High-risk Populations

Hypertriglyceridaemia - Cause and Effects

Additional Resources

Online Mendelian Inheritance in Man NCBI NIH Phenotype Information

Patient information from the NIH Genetics Home Reference Site

Gene Reviews by Erin P Hoffman, MS, CGC, Marci L Barr, ScM, Monica A Giovanni, MS, CGC, and Michael F Murray, MD.

LAL Deficiency Patient and Physician Information Site

Mount Sinai School of Medicine

Dr. Manisha Balwani

Department of Genetics and Genomic Sciences

One Gustave L. Levy Place, Box 1497

Mount Sinai School of Medicine

New York, NY 10029

Office: 212-241-0915

Fax: 212-426-9065

http://www.mountsinaifpa.org/patient-care/practices/genetics/programs-and-services

University of Minnesota

Dr. Chet Whitley

Genetics Clinic

Explorer Clinic

East Building, Twelfth Floor

2450 Riverside Ave.

Minneapolis, MN 55454

612-365-6777

http://www.uofmmedicalcenter.org/Clinics/AdultGeneticsClinic/index.htm

Cincinnati Children’s Hospital

Dr. T. Andrew Burrow

 Laurie Anne Bailey, LGC

Clinical Genetics and Medical Biochemical Genetics

STAR Center for Lysosomal Diseases

Department of Pediatrics

3333 Burnet Avenue,

Cincinnati, Ohio 45229-3026

Phone 513-636-4507

Fax 513-636-0124

Email laurie.bailey@cchmc.org

http://www.cincinnatichildrens.org/service/s/star/default

Northwestern Univeristy

Dr. Barbara Burton

Center for Genetic Medicine

225 East Chicago Avenue, Chicago, IL 60611

Phone:(312) 225-6120

http://www.cgm.northwestern.edu

Lucile Packard Children's Hospital at Stanford

Dr. Greg Enns

Pediatric Genetics

730 Welch Rd 2A

Palo Alto, CA94304

Tel: (650) 721-5804

Fax: (650) 498-4555

Children’s Hospital of Philadelphia

Dr. Can Ficicioglu

Metabolic Disease Program

34th St and Civic Center Blvd

Philadelphia, PA 19104

215-590-3376

Appointments and Referrals: 1-800-TRY-CHOP (1-800-879-2467)

http://www.chop.edu/doctors/ficicioglu-can#.VQHpqylLNW0

Women and Children‘s Hospital of Buffalo

Dr. Richard Erbe

Professor and Chief, Genetics

Department of Pediatrics

Division of Genetics

219 Bryant Street

Buffalo, NY 14222

Phone: (716) 878-7411

Fax: (716) 878-7405

Email: erbe@buffalo.edu

Children’s Hospital of Boston

Dr. Edward Neilan

Division of Genetics

300 Longwood Avenue

Fegan, 10th Floor

Boston, Massachusetts 02115

Contact: 617-355-6394

Fax: 617-730-0466

Praticien Hospitalier chez Hôpital Necker-Enfants Malades

Dr. Vassili Valayannopoulos

Unité fonctionnelle metabolism

Pôle Pédiatrie générale et multidisciplinaire - INSERM U781

CHU Paris - Hôpital Necker-Enfants Malades

149 rue de Sèvres

75743 PARIS

FRANCE

Phone  : 33 (0)1 44 49 48 52

Fax  : 33 (0)1 44 49 48 50

St Mary’s Hospital, CMFT

Dr. Simon Jones

Manchester Centre for Genomic Medicine,

Willink Biochemical Genetics Unit

University of Manchester, Manchester, UK

http://mangen.co.uk/ClinicalServices/WillinkClinical/WillinkLysosomalStorageDisease.php

http://mangen.co.uk/about-us/OurStaff/GeneticCounsellors.php

University of California, Irvine CHOC Children's

Dr. Jay Gargus

Genetics and Metabolism

1201 W. La Veta Ave.

Orange, CA 92868

Phone: 714-509-3919

Ain Shams University Hospital, Cairo, Egypt

Dr. Osama K. Zaki

Ain Shams University Hospitals, 3 Kamal Raslan St., Heliopolis, Cairo 11771, Egypt.

Tel.: +20 1005188879;

Fax: +20 226824170.

Addenbrooke's Hospital

Dr. Patrick Deegan

Addenbrooke's Lysosomal Disorders Unit

Box 135

Cambridge University Hospitals,

Hills Road,

Cambridge.

CB2 0QQ

Phone : 44 (0)1223 274 634

Fax : 44 (0)223 256 172:

UNITED KINGDOM

http://www.cuh.org.uk/addenbrookes/services/clinical/lysosomal/contacts.html

Federal University of Rio Grande do Sul (UFRGS)

Prof. Roberto Giugliani

Medical Genetics Service

Clinic Hospital of Porto Alegre

Rio Grande do Sul, Brazil

http://primeinc.org/faculty/biography/124/Roberto_Giugliani,_MD,_PhD,_MSc

Genetics Medical Service

Porto Alegre Clinics Hospital

Ramiro Barcelos Street, 2350 - POA / RS

Zip Code 90035-903 |

Phone (51) 33598011 / 0800510203

Preto, University of Sao Paulo

Dr. Charles Marques Lourenco

Neurogenetics Unit, Department of Medical Genetics, School of Medicine of Ribeirao

Av. Bandeirantes, 3900

Monte Alegre - Ribeirão Preto - SP - Brasil

CEP: 14049-900

Telefone: 55 (16) 3315-3102

Fax: 55 (16) 3315-0222

e-mail: secgen@fmrp.usp.br

Hospital Ángeles del Pedregal

Dr. Juana Ines Navarrete Martinez

Camino a Santa Teresa No. 1055 Consultorio 725 Colonia Fuentes del Pedregal Delegación Tlalpan Código Postal 14140 México, D.F.

Teléfonos: (01) 55 5652 8576 5568 2244 Celular: 55 3977 5576

Condition Specific Links

LAL Solace

www.laldaware.org

National Information Center for Metabolic Diseases (CLIMB),

www.climb.org.uk

Vaincres les Maladies Lysosomales,

www.vml-asso.org

National Organization for Rare Disorders (NORD)

www.rarediseases.org

Eurodis

www.eurodis.com

American Liver Foundation,

www.liverfoundation.org

Locate a Genetic Counselor

http://nsgc.org/p/cm/ld/fid=164

Selected References

Abramov, A., Schorr, S., and Wolman, M.1956. Generalized xanthomatosis with calcified adrenals. AMA J Dis Child 91:282-286. PMID: 13301142

Abello F, Guardamagna O, Baracco V, Bonardi R. The treatment of cholesteryl

storage disease (CESD) by ezetimibe monotherapy. Atheroscler Suppl

2010;11:28 P.55.

Afdhal NH. Fibroscan (transient elastography) for the measurement of liver fibrosis. Gastroenterol Hepatol (N Y). 2012 Sep;8(9):605-7. PMID: 23483859

Akolekar R, Beta J, Picciarelli G, Ogilvie C, D'Antonio F. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2015 Jan;45(1):16-26. Review PMID: 25042845

Alexander, W. 1946. Niemann-Pick disease: report of a case showing calcification in the adrenal glands. N Z Med J 45:43-45. PMID 21019394

Ameis D, Brockmann G, Knoblich R, Merkel M, Ostlund RE Jr, Yang JW, Coates PM, Cortner JA, Feinman SV, Greten H. A 5' splice-region mutation and a dinucleotide deletion in the lysosomal acid lipase gene in two patients with cholesteryl ester storage disease. J Lipid Res. 1995 Feb;36(2):241-50. PMID: 7751811

Anderson RA, Byrum RS, Coates PM, Sando GN. Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2718-22. PMID: 8146180

Anderson RA, Sando GN. Cloning and expression of cDNA encoding human lysosomal acid lipase/cholesteryl ester hydrolase. Similarities to gastric and lingual lipases. J Biol Chem. 1991 Nov 25;266(33):22479-84. PMID: 1718995

Arterburn JN, Lee WM, Wood RP, Shaw BW, Markin RS. Orthotopic liver

transplantation for cholesteryl ester storage disease. J Clin Gastroenterol

1991;13:482–485. PMID: 1918862

Ashkenazi E1, Kovalev Y, Zuckerman E. Evaluation and treatment of esophageal varices in the cirrhotic patient. Isr Med Assoc J. 2013 Feb;15(2):109-15. PMID: 23516775

Assmann G, and Seedorf U. Acid lipase deficiency: Wolman disease and cholesterol ester storage disease, in The metabolic and molecular basis of inherited disease, C.R. Scriver, et al., Editors. 1995, McGraw Hill Inc.: New York. p. 2563–2587.

Assmann G, Fredrickson DS, Sloan HR, Fales HM, Highet RJ. Accumulation of oxygenated steryl esters in Wolman's disease. J Lipid Res. 1975 Jan;16(1):28-38. PMID: 162929

Assmann, G., Smootz, E., Adler, K., Capurso, A., Oette, K. The lipoprotein abnormality in Tangier disease: quantitation of A apoproteins. J. Clin. Invest. 59: 565-575, 1977. PMID: 190272

Balwani M, Breen C, Enns GM, Deegan PB, Honzík T, Jones S, Kane JP, Malinova V, Sharma R, Stock EO, Valayannopoulos V, Wraith JE, Burg J, Eckert S, Schneider E, Quinn AG. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013 Sep;58(3):950-7. PMID: 23348766

Begriche K, Massart J, Robin MA, Borgne-Sanchez A, Fromenty B. Drug induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. J Hepatol 2011;54:773–794. PMID: 21145849

Ben-Haroush A, Yogev Y, Levit O, Hod M, Kaplan B. Isolated fetal ascites caused by Wolman disease. Ultrasound Obstet Gynecol. 2003 Mar;21(3):297-8 PMID: 12666227

Bernstein DL, Hülkova H, Bialer MG, Desnick RJ.Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013 Jun;58(6):1230-43. PMID: 23485521

Besley GT, Broadhead DM, Lawlor E, McCann SR, Dempsey JD, Drury MI, Crowe J.Cholesterol ester storage disease in an adult presenting with sea-blue histiocytosis. Clin Genet. 1984 Sep;26(3):195-203. PMID: 6478639

Brady, R. O. Sphingomyelin lipidosis: Niemann-Pick disease.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. : Metabolic Basis of Inherited Disease. New York: McGraw-Hill (pub.) (4th ed.) : 1978. Pp. 718-730.

Burton, B.K., Remy, W.T., and Rayman, L.1984. Cholesterol ester and triglyceride metabolism in intact fibroblasts from patients with Wolman's disease and cholesterol ester storage disease. Pediatr Res 18:1242-1245.PMID: 6522136

Burton BK1, Balwani M, Feillet F, Barić I, Burrow TA, Camarena Grande C, Coker M, Consuelo-Sánchez A, Deegan P, Di Rocco M, Enns GM, Erbe R, Ezgu F, Ficicioglu C, Furuya KN, Kane J, Laukaitis C, Mengel E, Neilan EG, Nightingale S, Peters H, Scarpa M, Schwab KO, Smolka V, Valayannopoulos V, Wood M, Goodman Z, Yang Y, Eckert S, Rojas-Caro S, Quinn AG. A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. N Engl J Med. 2015 Sep 10;373(11):1010-20. PMID: 26352813

Burton BK, Deegan PB, Enns GM, Guardamagna O, Horslen S, Hovingh GK, Lobritto SJ, Malinova V, McLin VA, Raiman J, Di Rocco M, Santra S, Sharma R, Sykut-Cegielska J, Whitley CB, Eckert S, Valayannopoulos V, Quinn AG. Clinical Features of Lysosomal Acid Lipase Deficiency. J Pediatr Gastroenterol Nutr. 2015b Dec;61(6):619-25. PMID: 26252914

Cagle PT, Ferry GD, Beaudet AL, Hawkins EP. Pulmonary hypertension in an

18-year-old girl with cholesteryl ester storage disease (CESD). Am J Med

Genet 1986;24:711–722. PMID: 3740103

Casey JP1, McGettigan P, Lynam-Lennon N, McDermott M, Regan R, Conroy J, Bourke B, O'Sullivan J, Crushell E, Lynch S, Ennis S Identification of a mutation in LARS as a novel cause of infantile hepatopathy. Mol Genet Metab. 2012 Jul;106(3):351-8. doi: 10.1016/j.ymgme.2012.04.017. PMID: 22607940

Chen YT1, Coleman RA, Scheinman JI, Kolbeck PC, Sidbury JB. Renal disease in type I glycogen storage disease. N Engl J Med. 1988 Jan 7;318(1):7-11. PMID: 3422104

Crocker, A.C., Vawter, G.F., Neuhauser, E.B., and Rosowsky, A.1965. Wolman's Disease: Three New Patients with a Recently Described Lipidosis. Pediatrics 35:627-640. PMID: 14269714

Crocker AC, Fisher JN, Filler RM. Nutritional support, including intravenous

alimentation, for the infant with Wolman’s disease. In: Volk BW, Aronson

SM, eds. Sphingolipids, Sphingolipidoses and Allied Disorders. New York, NY:

Plenum Press; 1972:661-670.

Dincsoy HP, Rolfes DB, McGraw CA, Schubert WK. Cholesterol ester storage

disease and mesenteric lipodystrophy. Am J Clin Pathol 1984;81:263–269. PMID: 6198903

Drebber U, Andersen M, Kasper HU, Lohse P, Stolte M, Dienes HP. Severe chronic diarrhea and weight loss in cholesteryl ester storage disease: a case report. World J Gastroenterol. 2005 Apr 21;11(15):2364-6 PMID: 15818756

Du H, Schiavi S, Wan N, Levine M, Witte DP, Grabowski GA. Reduction of atherosclerotic plaques by lysosomal acid lipase supplementation. Arterioscler Thromb Vasc Biol 2004; 24: 147-54. PMID: 14615393

Dufourcq-Lagelouse R Jabado N, Le Deist F, Stéphan JL, Souillet G, Bruin M, Vilmer E, Schneider M, Janka G, Fischer A, de Saint Basile G. Linkage of familial hemophagocytic lymphohistiocytosis to 10q21-22 and evidence for heterogeneity. Am J Hum Genet. 1999 Jan;64(1):172-9. PMID: 9915956

Edelstein RA, Filling-Katz MR, Pentchev P, Gal A, Chandra R, Shawker T,

et al. Cholesteryl ester storage disease: a patient with massive splenomegaly

and splenic abscess. Am J Gastroenterol 1988;83:687–692. PMID: 3376925

Elleder M, Poupĕtová H, Ledvinová J, Hyánek J, Zeman J, Sýkora J, Stozický F, Chlumská A, Lohse P. Lysosomal acid lipase deficiency. Overview of Czech patients. Cas Lek Cesk. 1999 Nov 29;138(23):719-24. PMID: 10746035

Engel, W. K., Dorman, J. D., Levy, R. I., Fredrickson, D. S. Neuropathy in Tangier disease. Alpha-lipoprotein deficiency manifesting as familial recurrent neuropathy and intestinal lipid storage. Arch. Neurol. 17: 1-9, 1967. PMID: 4165386

Eto Y, Kitagawa T. Wolman's disease with hypolipoproteinemia and acanthocytosis: clinical and biochemical observations. J Pediatr. 1970 Nov;77(5):862-7. PMID: 5504079

Fellgiebel A, Gartenschläger M, Wildberger K, Scheurich A, Desnick RJ, Sims K.

Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease.  Cerebrovasc Dis. 2014;38(6):448-56. PMID: 25502511

Fouchier SW, Defesche JC. Lysosomal acid lipase A and the hypercholesterolaemic phenotype. Curr Opin Lipidol. 2013 Aug;24(4):332-8. PMID: 23652569

Fredrickson, D. S., Altrocchi, P. H., Avioli, L. V., Goodman, D. S., Goodman, H. C. Tangier disease. Ann. Intern. Med. 55:1016-1031, 1961

Fredrickson DS. Newly recognized disorders of cholesterol metabolism. Ann

Intern Med 1963;58:718.

Fu Q1, Huang X, Shu B, Xue M, Zhang P, Wang T, Liu L, Jiang Z, Zhang L.

Inhibition of mitochondrial respiratory chain is involved in triptolide-induced liver injury. Fitoterapia. 2011 Dec;82(8):1241-8. PMID: 21907767

Garcia CK1, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.  Science. 2001 May 18;292(5520):1394-8. Epub 2001 Apr 26. PMID: 11326085

Ginsberg HN, Le NA, Short MP, Ramakrishnan R, Desnick RJ. Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein B synthesis. J Clin Invest 1987;80:1692–1697. PMID: 3680522

Grabowski GA, Charnas L, Du H. Lysosomal acid lipase deficiencies: the Wolman disease/cholesteryl ester storage disease spectrum. In: Scriver Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, editors. Metabolic and molecular bases of inherited disease – OMMBID. New York: McGraw-Hill; 2012, www.ommbid.com.

Gracey M, Burke V, Anderson CM.Medium chain triglycerides in paediatric practice. Arch Dis Child. 1970 Aug;45(242):445-52. PMID: 4918706

Hagemenas FC, Manaugh LC, Illingworth DR, Sundberg EE, Yatsu FM.

Cholesteryl ester hydrolase activity in mononuclear cells from patients with type II hypercholesterolemia. Atherosclerosis. 1984 Mar;50(3):335-44. PMID: 6712778

Haller W, Sharif K, Millar AJ, Brown RM, McKiernan PJ Gallbladder dysfunction in cholesterol ester storage disease. J Pediatr Gastroenterol Nutr. 2010 May;50(5):555-8. PMID: 19644392

Hoeg JM, Demosky SJ Jr, Pescovitz OH, Brewer HB Jr. Cholesteryl ester storage disease and Wolman disease: phenotypic variants of lysosomal acid cholesteryl ester hydrolase deficiency. Am J Hum Genet. 1984 Nov;36(6):1190-203. PMID: 6097111

Hoffman HN, Fredrickson DS. Tangier disease (familial high density lipoprotein deficiency). Clinical and genetic features in two adults. Am J Med. 1965 Oct;39(4):582-93. PMID: 5831900

Hůlková H, Elleder M. Distinctive histopathological features that support a diagnosis of cholesterol ester storage disease in liver biopsy specimens. Histopathology. 2012 Jun;60(7):1107-13. PMID: 22621222

Kaback M, Lopatequi J, Portuges AR, Quindipan C, Pariani M, Salimpour-Davidov N, Rimoin DL. Genetic screening in the Persian Jewish community: A pilot study. Genet Med. 2010 Oct;12(10):628-33. PMID: 20733503

Kale AS, Ferry GD, Hawkins EP. End-stage renal disease in a patient with

cholesteryl ester storage disease following successful liver transplantation

and cyclosporine immunosuppression. J Pediatr Gastroenterol Nutr

1995;20:95–97. PMID: 7884624

Kathuria R1, Poddar U, Ghosh J, Yachha SK, Gnanapriya V, Pandey R, Kaur A, Phadke S, Srivastava A. Intractable ascites as a manifestation of Wolman's disease: report of two sibs. Indian J Gastroenterol. 2012 Dec;31(6):343-5. PMID: 23007684

Kolodny EH, Ullman MD, Mankin HJ, Raghavan SS, Topol J, Sullivan JL. Phenotypic manifestations of Gaucher disease: clinical features in 48 biochemically verified type 1 patients and comment on type 2 patients. Prog Clin Biol Res. 1982;95:33-65. PMID: 6289358

Kolodny E, Fellgiebel A, Hilz MJ, Sims K, Caruso P, Phan TG, Politei J, Manara R, Burlina A . Cerebrovascular involvement in Fabry disease: current status of knowledge. Stroke. 2015 Jan;46(1):302-13. PMID: 25492902

Koo J. The Latest Information on Intracranial Atherosclerosis: Diagnosis and Treatment. Interv Neurol. 2015 Oct;4(1-2):48-50. PMID: 26600797

Krivit W, Peters C, Dusenbery K, Ben-Yoseph Y, Ramsay NK, Wagner JE, Anderson R. Wolman disease successfully treated by bone marrow transplantation. Bone Marrow Transplant. 2000 Sep;26(5):567-70. PMID:11019848

Landis CS, Ghabril M, Rustgi V, Di Bisceglie AM, Maliakkal B, Rockey DC, Vierling JM7, Bajaj J, Rowell R, Santoro M, Enriquez A, Jurek M, Mokhtarani M, Coakley DF9, Scharschmidt BF. PMID: 26781427

Prospective Multicenter Observational Study of Overt Hepatic Encephalopathy. Dig Dis Sci. 2016 Jan 19.

Leone L, Ippoliti PF, Antonicelli R. Use of simvastatin plus cholestyramine in

the treatment of lysosomal acid lipase deficiency. J Pediatr 1991;119:1008–1009.

PMID: 1801793

Leone L, Ippoliti PF, Antonicelli R, Balli F, Gridelli B. Treatment and liver

transplantation for cholesterol ester storage disease. J Pediatr 1995;127:509–510. PMID: 7658290

Levy R, Ostlund RE Jr, Schonfeld G, Wong P, Semenkovich CF. Cholesteryl ester storage disease: complex molecular effects of chronic lovastatin therapy. J Lipid Res. 1992 Jul;33(7):1005-15. PMID: 1431581

Lough, J., Fawcett, J., and Wiegensberg, B.1970. Wolman's disease. An electron microscopic, histochemical, and biochemical study. Arch Pathol 89:103-110. PMID: 5412920

Lowden JA, Barson AJ, Wentworth P. Wolman's disease: a microscopic and biochemical study showing accumulation of ceroid and esterified cholesterol. Can Med Assoc J. 1970 Feb 28;102(4):402-5. PMID: 5414926

Meyers, William F., et al. "The use of parenteral hyperalimentation and elemental formula feeding in the treatment of Wolman disease." Nutrition Research 5.4 (1985): 423-429.

Molleran Lee S, Villanueva J, Sumegi J, Zhang K, Kogawa K, Davis J, Filipovich AH. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet. 2004 Feb;41(2):137-44. PMID: 14757862

Muntoni S, Wiebusch H, Funke H, Ros E, Seedorf U, Assmann G. Homozygosity

for a splice junction mutation in exon 8 of the gene encoding lysosomal acid lipase in a Spanish kindred with cholesterol ester storage disease (CESD). Human Genet 1995;95:491–494. PMID: 7759067

Muntoni S, Wiebusch H, Jansen-Rust M, Rust S, Seedorf U, Schulte H, et al. Prevalence of cholesteryl ester storage disease. Arterioscler Thromb Vasc Biol 2007;27:1866–1868. PMID: 17634524

Pagani F, Zagato L, Merati G, Paone G, Gridelli B, Maier JA. A histidine to tyrosine replacement in lysosomal acid lipase causes cholesteryl ester storage disease. Human Mol Genet 1994;3:1605–1609. PMID: 7833918

Pagani F, Garcia R, Pariyarath R, Stuani C, Gridelli B, Paone G, et al.

Expression of lysosomal acid lipase mutants detected in three patients with

cholesteryl ester storage disease. Human Mol Genet 1996;5:1611–1617. PMID: 8894696

Pagani F, Pariyarath R, Garcia R, Stuani C, Burlina AB, Ruotolo G, et al. New

lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease. J Lipid Res 1998;39:1382–1388. PMID: 9684740

Patrick AD, Lake BD. Deficiency of an acid lipase in Wolman's disease. Nature. 1969 Jun 14;222(5198):1067-8. PMID: 5787090

Patterson, M. C., Vanier, M. T., Suzuki, K., Morris, J. A., Carstea, E., Neufeld, E. B., Blanchette-Mackie, J. E., Pentchev, P. G. Niemann-Pick disease type C: a lipid trafficking disorder.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. II. New York: McGraw-Hill (7th ed.) : 2001. Pp. 3611-3633

Pérez Rodríguez-Cuesta JM1, Suárez Tomás JI, Suárez Menéndez ME, Domínguez González J. Cholesterol ester storage disease in two siblings. An Esp Pediatr. 1990 Mar;32(3):249-52.PMID: 2346262

Pisciotta L, Fresa R, Bellocchio A, Pino E, Guido V, Cantafora A, Di Rocco M, Calandra S, Bertolini S. Cholesteryl Ester Storage Disease (CESD) due to novel mutations in the LIPA gene. Mol Genet Metab. 2009 Jun;97(2):143-8. PMID: 19307143

Rader DJ. Lysosomal Acid Lipase Deficiency--A New Therapy for a Genetic Lipid Disease.  N Engl J Med. 2015 Sep 10;373(11):1071-3. PMID: 26352819

Rassoul F, Richter V, Lohse P, Naumann A, Purschwitz K, Keller E.

Long-term administration of the HMG-CoA reductase inhibitor lovastatin in two patients with cholesteryl ester storage disease. Int J Clin Pharmacol Ther. 2001 May;39(5):199-204. PMID: 11380065

Reiner Ž, Guardamagna O, Nair D, Soran H, Hovingh K, Bertolini S, Jones S, Ćorić M, Calandra S, Hamilton J, Eagleton T, Ros E. Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014 Jul;235(1):21-30. PMID: 24792990

Ries S, Büchler C, Schindler G, Aslanidis C, Ameis D, Gasche C, Jung N, Schambach A, Fehringer P, Vanier MT, Belli DC, Greten H, Schmitz G. Different missense mutations in histidine-108 of lysosomal acid lipase cause cholesteryl ester storage disease in unrelated compound heterozygous and hemizygous individuals. Hum Mutat. 1998;12(1):44-51. PMID: 9633819

Saibara T, Himeno H, Ueda H, Onishi S, Yamamoto Y, Enzan H, et al. Acute hepatic failure with swollen mitochondria and microvesicular fatty degeneration of hepatocytes triggered by free radical initiator. Lab Invest 1994;70:517–524. PMID: 8176890

Saito S OK, Suzuki T, Sakuraba H. Structural bases of Wolman disease and cholesteryl ester storage disease. Mol Genet Metab 2012;105:244-248. PMID: 22138108

Schaub J, Janka GE, Christomanou H, Sandhoff K, Permanetter W, Hübner G, Meister P. Wolman's disease: clinical, biochemical and ultrastructural studies in an unusual case without striking adrenal calcification. Eur J Pediatr. 1980 Oct;135(1):45-53. PMID: 7449788

Schreyer-Shafir N, Sukenik-Halevy R, Tepper R, Arnon S, Litmanovitch I, Eliakim A, Pommeranz A, Ludman MD, Raas-Rothschild A. Prenatal bilateral adrenal calcifications, hypogonadism, and nephrotic syndrome: beyond Wolman disease. Prenat Diagn. 2014 Jun;34(6):608-11. doi: 10.1002/pd.4344. Epub 2014 Apr 27.  PMID: 24777844

Shome DK1, Al-Jishi E, Greally JF, Malik N, Zainaldeen HA, Das NS.

The Middle-East connection of Wolman Disease. Saudi Med J. 2002 May;23(5):597-601. PMID: 12070591

Sims K, Politei J, Banikazemi M, Lee P.Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry. Stroke. 2009 Mar;40(3):788-94. PMID: 19150871

Sloan HR, and Fredrickson DS: Enzyme deficiency in cholesteryl ester storage disease, J Clin Invest 51:1923, 1972. PMID: 5032533

Stein J, Garty BZ, Dror Y, Fenig E, Zeigler M, Yaniv I. Successful treatment of

Wolman disease by unrelated umbilical cord blood transplantation. Eur J

Pediatr 2007;166:663e6. PMID: 17033804

Tadiboyina VT, Liu DM, Miskie BA, Wang J, Hegele RA. Treatment of dyslipidemia

with lovastatin and ezetimibe in an adolescent with cholesterol ester

storage disease. Lipids Health Dis 2005;4:26.  PMID: 16255772

Taurisano R, Maiorana A, De Benedetti F, Dionisi-Vici C, Boldrini R, Deodato F. Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation. Eur J Pediatr. 2014 May 21. PMID: 24844354

Thelwall PE, Smith FE, Leavitt MC, Canty D, Hu W, Hollingsworth KG, Thoma C, Trenell MI, Taylor R, Rutkowski JV, Blamire AM, Quinn AG Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance. J Hepatol. 2013 Sep;59(3):543-9. PMID: 23624251

Tolar J, Petryk A, Khan K, Bjoraker KJ, Jessurun J, Dolan M, Kivisto T, Charnas L, Shapiro EG, Orchard PJ. Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease.Bone Marrow Transplant. 2009 Jan;43(1):21-7.  PMID: 18776925

Treem WR, Witzleben CA, Piccoli DA, Stanley CA, Hale DE, Coates PM, et al.

Medium-chain and long-chain acyl CoA dehydrogenase deficiency: clinical,

pathologic and ultrastructural differentiation from Reye’s syndrome. Hepatology 1986;6:1270–1278. PMID: 3793003

Tylki-Szymańska A, Jurecka A. Lysosomal acid lipase deficiency: wolman disease and cholesteryl ester storage disease. Prilozi. 2014;35(1):99-106. PMID: 24798600

Valayannopoulos, V., Plantaz, D., Vara, R., Eckert S., Tripuraneni, R,. Schneider, E., Quinn,  A., Le Quan Sang, KH., Brassier,A., Arnoux, J.,White, F., Breen, C., Jones, SA. Clinical effect of sebelipase alfa on survival and growth in infants with lysosomal acid lipase deficiency (Wolman disease). Mol Genet Metab 2014;111:S S108.

Valayannopoulos V, Malinova V, Honzík T, Balwani M, Breen C, Deegan PB, Enns GM, Jones SA, Kane JP, Stock EO, Tripuraneni R, Eckert S, Schneider E, Hamilton G1, Middleton MS, Sirlin C, Kessler B, Bourdon C, Boyadjiev SA, Sharma R, Twelves C, Whitley CB, Quinn AG. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol. 2014 Nov;61(5):1135-42. PMID: 24993530

Valles-Ayoub Y, Esfandiarifard S, No D, Sinai P, Khokher Z, Kohan M, Kahen T, Darvish D. Wolman disease (LIPA p.G87V) genotype frequency in people of Iranian-Jewish ancestry. Genet Test Mol Biomarkers. 2011 Jun;15(6):395-8. PMID: 21291321

Van Erum S, Gnat D, Finne C, Blum D, Vanhelleput C, Vamos E, Vertongen F.

Cholesteryl ester storage disease with secondary lecithin cholesterol acyl transferase deficiency. J Inherit Metab Dis. 1988;11 Suppl 2:146-8.  PMID: 3141694

van Meel E, Wegner DJ, Cliften P, Willing MC, White FV, Kornfeld S, Cole FS. Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype. BMC Med Genet. 2013 Oct 8;14:106. doi: 10.1186/1471-2350-14-106. PMID: 24103465

vom Dahl S, Harzer K, Rolfs A, Albrecht B, Niederau C, Vogt C, et al. Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase-1 exon 8 splice junction mutation. J Hepatol 1999;31:741–746. PMID: 10551400

Wolman M, Sterk Vv, Gatt S, Frenkel M. Primary Familial Xanthomatosis With Involvement And Calcification Of The Adrenals. Report Of Two More Cases In Siblings Of A Previously Described Infant. Pediatrics. 1961 Nov;28:742-57. PMID: 14008104

Wolman M. Wolman disease and its treatment. Clin Pediatr (Phila). 1995 Apr;34(4):207-12. Review. No abstract available. PMID: 7789014

Yatsu FM, Hagemenas FC, Manaugh LC, Galambos T. Cholesteryl ester hydrolase activity in human symptomatic atherosclerosis. Lipids. 1980 Dec;15(12):1019-22.

PMID: 7219070

Young EP, Patrick AD. Deficiency of acid esterase activity in Wolman’s disease. Arch Dis Child 1970;45:664–668. PMID: 5477680

Zimran A, Abrahamov A, Elstein D Children with type I Gaucher disease: growing into adulthood with and without enzyme therapy. Isr Med Assoc J. 2000 Feb;2(2):80-1. PMID: 10804921

Zschenker, O., Jung, N., Rethmeier, J., Trautwein, S., Hertel, S., Zeigler, M., and Ameis, D.2001. Characterization of lysosomal acid lipase mutations in the signal peptide and mature polypeptide region causing Wolman disease. J Lipid Res 42:1033-1040. PMID: 11441129

Zuliani, G., Arca, M., Signore, A., Bader, G., Fazio, S., Chianelli, M., Bellosta, S., Campagna, F., Montali, A., Maioli, M., Pacifico, A., Ricci, G., Fellin, R. Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 19: 802-809, 1999. PMID: 10073989