Maple syrup urine disease
Jan. 08, 2023
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
The etiology of lysosomal acid lipase deficiency, which is known as Wolman disease in its most severe form and historically as cholesteryl storage disease in its milder form is the deficient activity of acid lipase (E.C. 188.8.131.52), a hydrolase that cleaves cholesteryl esters and triglycerides under acid conditions, with an autosomal recessive mode of inheritance. It has been referred to as lysosomal acid lipase, acid lipase, or acid esterase. The abnormal accumulation of cholesteryl esters and triglycerides is the biological basis of lysosomal acid lipase deficiency. Due to apparently complete absence of enzyme activity in the most severe form, Wolman disease, the accumulation in that disorder is more severe and affects a larger variety of tissues, whereas the slight residual enzyme activity in the milder cholesteryl ester storage disease offers some protection. The incidence of both conditions can be diminished by genetic counseling, familial carrier testing, and preimplantation genetic diagnostics. The demonstration of deficient acid lipase activity or molecular diagnosis can serve as the definitive diagnostic tests. Intravenous enzyme replacement therapy has emerged as a therapeutic option with some success.
• Wolman disease was first described in Iranian-Jewish children. It is the infantile form of autosomal recessive lysosomal acid lipase deficiency.
• Characteristically, Wolman disease presents in early infancy with diarrhea, massive hepatosplenomegaly, failure to thrive, and calcification of adrenal glands.
• Without treatment, hepatic failure followed by death occurs within the first year of life.
• Milder lysosomal acid lipase deficiency, historically described as cholesteryl ester storage disease, is characterized by hepatic steatosis and dyslipidemia.
• Enzyme replacement therapy has emerged as a therapeutic option.
In 1956, Abramov and colleagues described an infant with abdominal distension, hepatosplenomegaly, and massive calcification of the adrenal gland who died at 3 months of age (01). In 1961, Wolman and colleagues reported the same clinical findings in two siblings of the first patient and also demonstrated that the accumulated lipids consisted mainly of cholesterol esters and triglycerides (76). The name "Wolman disease" was introduced by Crocker and colleagues in 1965 (21). In 1969, Patrick and Lake demonstrated a deficient activity of a lysosomal acid lipase catalyzing the hydrolysis of cholesterol ester and triglycerides in the liver and spleen of patients with Wolman disease (57), and this led to diagnostic assays in cultured fibroblasts (20) and lymphocytes (18). Anderson and Sando cloned human lysosomal acid lipase in 1991 (04). The crystal structure has been described (61).
Defective activity of lysosomal acid lipase is also a feature in cholesteryl ester storage disease (09), a somewhat milder disorder characterized by hepatomegaly and hyperlipoproteinemia that is compatible with survival to the second decade or adulthood. It is now clear that Wolman disease and cholesteryl ester storage disease are allelic and describe a continuum of lysosomal acid lipase deficiency. A variety of mutations in the gene that encode lysosomal acid lipase have been reported for both disorders (02; 55; 54; 48; 07).
In 2015, a phase 3 trial of sebelipase alfa, a recombinant human enzyme replacement therapy, demonstrated that this therapeutic option could result in reduction of several measures of disease severity in children and adults (15). This drug has since been approved for use both in Europe and by the FDA in the United States (56).
•Wolman is the severe form and cholesteryl ester storage disease is the milder form of lysosomal acid lipase deficiency.
•Adrenal calcifications are a characteristic radiological finding.
The most severe form of lysosomal acid lipase deficiency, Wolman disease has a striking and consistent clinical presentation. The disease has its clinical onset in the first few weeks of life, with persistent vomiting and abdominal distension as the most frequent initial symptoms. Increasing vomiting, diarrhea, abdominal distension associated with hepatosplenomegaly, anemia, and inanition are the predominant abnormalities. Calcification of the adrenal glands is a characteristic radiological finding (78). Primary adrenal insufficiency in children is an uncommon but potentially lethal condition. In a study that included 55 girls and 48 boys with primary adrenal insufficiency who attended one hospital department between September 1981 and September 2001, Wolman disease was diagnosed in three patients in two different consanguineous families (58). Wolman disease should also be considered if fetal hepatomegaly or bilateral adrenal echogenicity suggestive of diffuse calcification are noted on prenatal ultrasound examination (12).
Without treatment, death usually occurs by the age of 3 to 6 months, but it has been as protracted as 14 months (08). Ben-Haroush and colleagues report a case of isolated fetal ascites diagnosed at 32 weeks’ gestation, with negative work-up for immune and nonimmune hydrops fetalis and congenital infections and malformations (10). After delivery, the diagnosis of Wolman disease was established. This suggests that Wolman disease should be considered in cases of isolated fetal ascites.
Cholesteryl ester storage disease has a much more variable phenotype (43). The principal and sometimes only sign, hepatomegaly, may be evident at birth or in early childhood, but may be delayed until the second decade or occasionally until adulthood (26; 43). The resultant loss of lysosomal acid lipase-derived free cholesterol leads to hypercholesterolemia in patients with cholesteryl ester storage disease, as well as premature atherosclerosis. Other clinical findings are xanthelasma and splenomegaly, which occur in about one third of the patients. Liver failure and jaundice occur occasionally. Radiologically demonstrable adrenal calcification is absent in most patients but has been reported occasionally. Drebber and colleagues describe the first case in the literature with diarrhea as a putative symptom of cholesteryl ester storage disease in adult patients. Histopathologic changes in the liver tissue and DNA sequence analysis confirmed the diagnosis of cholesteryl ester storage disease due to homozygosity for the most common cholesteryl ester storage disease mutation, a G934A splice site defect encoded by exon 8 of the lysosomal acid lipase gene (24). Bindu and colleagues describe two patients with hitherto unreported ptosis and external ophthalmoplegia associated with cholesteryl ester storage disease (11). Kathuria and colleagues report two siblings with Wolman disease presenting with intractable ascites, requiring therapeutic paracentesis, albumin infusion, and diuretics to control tense ascites. Although intractable ascites is rare in Wolman disease, it should be considered in the differential diagnosis of infantile ascites (40). There is a strong association between Wolman disease and bilateral adrenal calciﬁcations. Schreyer-Shafir and colleagues report on prenatal and postnatal findings of two fetuses with bilateral adrenal calcifications, increased nuchal translucency, increased nuchal fold, micropenis, hypogonadism, and congenital nephritic syndrome, which they consider as a new clinical entity, probably of autosomal recessive inheritance (64).
In untreated Wolman disease, death usually occurs by 3 to 6 months of age. One patient survived to 14 months (47). Treatment with sebelipase alfa has been shown to reduce hepatomegaly and normalize transaminase levels as well as improve dyslipidemia in lysosomal acid lipase deficiency (LAL-D). In Wolman disease, enzyme replacement is correlated with longer survival than the natural history (27).
Patients with cholesteryl ester storage disease survive to the second decade or later. Two patients with a benign variant were diagnosed at 43 and 56 years of age (26). Death is due to complications of liver disease, obstructive pulmonary vascular disease (35), and anemia. Although premature arteriosclerosis is known to occur on pathological study, clinically evident coronary or cardiovascular disease has not been reported (08). However, a case series of 14 patients did demonstrate increased common carotid artery mean intima-media thickness of about the 95th percentile in several patients (59).
Hemophagocytic lymphohistiocytosis is a life-threatening condition that may be genetically determined or secondary to infections, malignancies, immune deficiencies, and rheumatologic disorders. It has been anecdotally described in three patients with Wolman disease. Taurisano and colleagues reported a patient with Wolman disease with clear-cut clinical, biochemical, and histological features indicative of hemophagocytic lymphohistiocytosis (69). They discussed the role of cholesteryl ester–induced inflammasome activation in macrophages, suggesting that Wolman disease can cause secondary hemophagocytic lymphohistiocytosis.
Wolman disease. Pregnancy and delivery were unremarkable and birth weight was 3600 g (62). The baby was less active than normal. After 2 months the clinical condition deteriorated and a dilated abdomen was noted. When taken into the hospital at 3 months, the clinical condition was poor and hepatosplenomegaly and increased bleeding tendency were observed. X-ray examinations revealed calcified adrenal glands on both sides. The spleen was increased in size. Vacuolated monocytic cells were present in the blood smear, and the bone marrow showed an infiltration of histiocytic cells with pale foamy cytoplasm. The child was severely anemic. Acid lipase activity in leukocytes was 70 units compared to 800±240 in controls and 335 and 324 in the father and mother, respectively. Inanition progressed and the child died at 4.5 months.
Cholesteryl ester storage disease. A 2-year-old girl was noted to have hepatosplenomegaly during hospitalization due to measles (09). Although she remained generally well until 7 years of age, her height and weight had fallen progressively to or below the third percentile. Occult blood was found in the stool and she had a chronic iron deficiency anemia. She was readmitted to a hospital at 8 years of age. The abdomen was protuberant, with the liver 10 cm below the right costal margin and the spleen 8 cm below the left. Hemoglobin was 10.5 g/dL and hematocrit 35%. Radiographs of the abdomen revealed bilateral adrenal calcification. The bone marrow contained isolated large histiocytes scattered irregularly among the hematopoietic cells. A liver biopsy had similar cells in greater number. Bands of dense connective tissue extended from the portal areas into the lobules forming large and small nodules of different sizes. Many large foam cells occupied the portal areas and were also present in the lamina propria of the duodenum. Leukocyte acid lipase activity was 0.88 nmol/min per mg protein compared to 14.33 in controls and 5.49 and 6.00 in the father and mother, respectively. At a follow-up at 13 years of age, the height and weight had fallen further below the third percentile. Epistaxis was frequent, stool specimens were positive for occult blood, and chronic iron deficiency anemia required therapy. Two sisters with the same illness had died at 7 and 9 years with similar illness complicated by hepatic portal cirrhosis, epicarditis, myocarditis, and renal failure.
The etiology of Wolman disease and of cholesteryl storage disease is the deficient activity of acid lipase (E.C. 184.108.40.206), a hydrolase that cleaves cholesteryl esters and triglycerides under acid conditions. It has been referred to as lysosomal acid lipase, acid lipase, or acid esterase. It has been purified from many sources (30). It has a molecular weight of 41 kd. The purified enzyme hydrolyzes trioleyl glycerol, dioleoylglycerol, mono-oleoylglycerol, as well as cholesteryl oleate. The gene that encodes this enzyme has been mapped to chromosome 10q23.2-q23.3 (03). The gene structure includes 10 exons dispersed over 45 kilobases (06). Mutations in this gene have been demonstrated in both Wolman disease and in cholesteryl ester disease. Anderson and Sando reported a patient with Wolman disease with two mutations: a T-insertion after position 634, which resulted in a stop codon, and a leucine-to-proline substitution at amino acid 179 (04). Pagani and colleagues reported a tyrosine to histidine at codon 274 in a patient with cholesteryl ester storage disease and subsequently identified four other mutations in this disease, namely a proline 181 leucine transition, a leucine 273 serine transition, an A to G 3' splice site substitution that caused skipping of exon 7, and a 5' splice site mutation (G to A) that led to skipping of exon 8 (55; 54). The mutation in a rat model of Wolman disease has been identified (49).
It is now clear that Wolman disease and cholesteryl ester storage disease are allelic. They are distinguished by the degree of reduction of acid lipase activity. Aslanidis studied two patients, one with Wolman disease and the other with cholesteryl ester storage disease, who both had splice site mutations leading to a skipping of exon 8 (07). In the patient with the milder cholesteryl ester storage disease, 3% of the genes were spliced correctly, resulting in 3% of normal enzyme activity, whereas in the patient with Wolman disease the defect was total, resulting in the absence of enzyme activity (07).
The abnormal accumulation of cholesteryl esters and triglycerides is the biological basis of both Wolman disease and cholesteryl ester storage disease. Due to apparently complete absence of enzyme activity in Wolman disease, the accumulation in that disorder is more severe and affects a larger variety of tissues, whereas the slight residual enzyme activity in cholesteryl ester storage disease offers some protection. The enzyme plays an important role in the cellular processing of plasma lipoproteins and contributes to the homeostatic control of lipoprotein levels in blood and to prevention of cellular lipid overloading (08). The enzyme is involved in the cellular degradation of plasma low-density lipoprotein (14). The acid lipase deficiency, thus, causes a severe disturbance in regulatory mechanisms of cholesterol metabolism. The inability to release free cholesterol results in an elevated synthesis of endogenous cholesterol, upregulation of low-density lipoprotein receptor gene expression, and increased production of apo-B containing lipoproteins (63). Fitoussi and colleagues have postulated that the adrenal calcification is secondary to the toxic effects of mildly oxidized low-density lipoprotein (28). The transport into the cell of this substance is down-regulated poorly in Wolman disease (28).
In Wolman disease the liver is enlarged to twice normal weight, the hepatic and Kupffer cells are enlarged and vacuolated, and there is marked portal and periportal fibrosis and sometimes frank cirrhosis. The spleen is grossly enlarged. The adrenal glands are grossly and symmetrically enlarged and may each weigh 13 g compared to a normal weight of 5 g. Swollen and lipid-laden cells are most prominent in the inner zone fasciculata and the entire zona reticularis (46). The small intestine is thickened and dilated. The lamina propria and mucosa are infiltrated with foamy histiocytes. Studies of the digestive and absorptive functions in the jejunum of a 1-month-old infant with Wolman disease indicated that the absorptive defect was so severe that it virtually excluded the absorption of any form of enteral nutrition (42).
In the brain, foamy histiocytes and sudanophilic droplets are found in the leptomeninges (21), capillaries of the gray matter (76), choroid plexus, microglia, and Purkinje cells. The white matter may show a sudanophilic leukodystrophy (33). Characteristic lipid inclusions are also present in Schwann cells, oligodendrocytes, astrocytes (16), and in the ganglion cells of the plexuses of Auerbach and Meissner (39). In cholesteryl ester storage disease the liver is enlarged with lipid droplets and variable amounts of periportal fibrosis, which in some patients progresses to micronodular cirrhosis with esophageal varices. The adrenal glands are not grossly involved. Foam cells are present in the interstitium of the lung and renal glomeruli. The nervous system is not involved. Three of four autopsied patients have shown anatomic evidence of accelerated arteriosclerosis (08).
Wolman disease and cholesteryl ester storage disease are rare disorders with an autosomal recessive mode of inheritance. There is an increased incidence of consanguinity. The original Israeli patients were reported by Wolman (19,610 were Jews of Iraqi and Iranian origin). Other patients have been reported from North America, Western Europe, Pakistan, China, and Japan (08). An Italian and Greek cohort has been described as well (59). Consanguinity has not been documented in cholesteryl ester storage disease, but remains a risk factor due to its recessive inheritance. Based on their analysis of 162DNA specimens of Iranian-Jewish origin by automated sequencing, Valles-Ayoub and colleagues reported an estimated risk of Wolman disease incidence as high as 1 in 4200 newborns of Iranian-Jewish couples (73). Studies looking at a selected cohort of individuals with familial hypercholesterolemia in the United Kingdom demonstrated a carrier rate of approximately 1 in 221 (05).
The worldwide occurrence is estimated at 1 in 175,000 based on metanalysis of existing studies and databases (17).
The incidence of Wolman disease and cholesteryl storage disease can be diminished by genetic counseling. Heterozygotes can be identified by assay of acid lipase activity in leukocytes (77) or by mutation analysis in families in which the DNA abnormality has been defined in the proband. Prenatal diagnosis has been accomplished by measurement of acid lipase activity in cultured amniotic fluid cells (19).
The combination of failure to thrive, bilateral adrenal calcification associated with hepatosplenomegaly, and gastrointestinal symptoms is pathognomonic of Wolman disease. Hepatosplenomegaly and failure to thrive are also seen in Niemann-Pick disease, but adrenal calcification is not a feature of that disease. X-linked adrenoleukodystrophy does not manifest during the neonatal period and is often associated with melanoderma and frank adrenal insufficiency, which is generally not observed in Wolman disease, and the liver and spleen are not enlarged. Neonatal adrenoleukodystrophy and infantile Refsum disease also show failure to thrive and the liver and spleen may be enlarged. These patients often are dysmorphic and have severe neonatal seizures; adrenal calcification is not a feature. Adrenal calcification may also be observed in adrenal teratomas, neuroblastoma, ganglioneuroma, and pheochromocytoma, but these conditions are not associated with hepatosplenomegaly.
Cholesteryl ester storage disease may be confused with glycogen storage disease, Niemann-Pick disease type B, mucopolysaccharidoses, and GM1 gangliosidosis and precise diagnosis depends on enzymatic assays or molecular testing. Congenital biliary cirrhosis can usually be distinguished because patients with cholesteryl ester storage disease are rarely jaundiced until the late stage of the disease.
Cirrhosis, liver fibrosis, gall bladder dysfunction, dyslipidemia, and malabsorption of fat soluble vitamins are common associated complications in those who survive.
The demonstration of deficient lysosomal acid lipase activity is the definitive diagnostic test. The activity of this enzyme is measured in freshly prepared extracts of leukocytes or cultured skin fibroblasts. The most frequently used substrates are [1-14C]trioleyl glycerol or cholesteryl-[1-14C] oleate (20). Artificial compounds such as nitrophenyl laurate (09), methylumbelliferyl oleate (66), triphenylaminolauric acid (51), and pyrenemethyl laurate for a fluorescence-based determination have been reported (52). The natural substrates are more specific (08). More recently deficient enzyme can be identified in dried blood spots; however, confirmation should be done in leukocytes or fibroblasts or by genetic sequencing demonstrating mutations in the LIPA gene (43).
Wolman disease should be considered in any neonate with bilateral adrenal calcification, which often delineates the outline of both glands, especially if there is a family history of consanguinity or early neonatal deaths (75). Wolman feels that this finding is pathognomonic for Wolman disease and for its milder form, cholesterol ester storage disease (75). Boldrini and colleagues describe the histological and ultrastructural aspects disclosed by intestinal or liver biopsy in three cases of Wolman disease and in two cases of cholesteryl ester storage disease, emphasizing the role of morphological findings in pointing the diagnosis toward a metabolic storage disease (13). Liver section typically shows microsteatosis and macrosteatosis and cholesterol crystals in hepatocyte cytoplasm, consistent with Wolman disease. Diffuse bowel thickening with dilatation, because of infiltration of the lamina propria by foamy histiocytes, is a well-established feature of Wolman disease (53). These changes predominate in the jejunum and the ileum, the internal layers indistinguishable from the submucosa. Infiltration of the lamina propria by foamy histiocytes results in malabsorption, bowel dilatation, bowel-wall thickening, and ulceration. Nchimi and colleagues further showed the correlation between ultrasound and pathology findings; the infiltrated lamina propria became hyperechoic and indistinguishable from the adjacent submucosa (50). Shome and colleagues report a case of Wolman disease with a few atypical features such as lack of adrenal calcification and unusual morphology of vacuolated marrow macrophages (65). Prenatal diagnosis is possible by measuring acid esterase activity in cultured embryonic cells (37), or through molecular testing when a familial mutation is known. Iavarone and associates have further confirmed this finding, though mutational analysis of LIPA, the gene coding for lysosomal acid lipase, may provide a more rapid diagnosis (02).
Desai and colleagues demonstrated deficient lysosomal acid lipase activity in cultured amniocytes from an at-risk fetus prenatally (23). The affected 17-week fetus revealed massive lysosomal cholesterol and lipid accumulation in the fetal hepatocytes, adrenal cells, and syncytiotrophoblasts. The adrenal glands revealed extensive necrosis suggesting that this might precede the calcification observed in these patients.
Lohse and colleagues have elucidated the genetic defects in 15 unrelated patients with cholesteryl ester storage disease (45). Seven were homozygotes for the prevalent human lysosomal acid lipase (hLAL) exon 8 splice junction mutation that results in incomplete exon skipping, whereas eight probands were compound heterozygotes for E8SJM and a rare mutation on the second chromosome. Combined with the reported data in the literature, their results demonstrate that compound heterozygosity for a mutation causing Wolman disease is common among patients with cholesteryl ester storage disease.
Whole gene or exon scale deletions have not been reported in the literature in association with Wolman disease. With a history of a previously affected individual in the family, electron microscopic examination of chorionic villus samples might allow prenatal diagnosis of storage diseases including Wolman disease (29). Molecular testing of chorionic villus samples or amniocytes is possible in families where the causative mutations are known.
To diagnose the deficiency of lysosomal acid lipase in Wolman disease, Hamilton and colleagues described a new method for its measurement in dried blood spots using Lalistat 2, a specific inhibitor of lysosomal acid lipase (34).
Huang and colleagues, using enzymatic and molecular analysis, report a case of Wolman disease in a Chinese infant, with a novel mutation of LIPA gene. The patient was homozygote for a novel insert mutation allele c.318 ins T, p. Phe106fsX4 in exon 4 on LIPA gene. Both parents were carriers of the mutation (36).
Nearly all untreated patients with Wolman disease have died during the first 6 months of life due to a combination of malabsorption of orally administered food and liver disease. More specific therapy would require parenteral nutrition and some means to provide the normal enzyme or other means to reduce the accumulation of cholesteryl esters and triglycerides. Adrenal function would also need to be assessed and replacement therapy provided if required. Enzyme replacement therapy is approved by the FDA and in Europe, and has prolonged survival and diminished symptoms when the disease is recognized and therapy started early in infancy.
Initial work up for all with lysosomal acid lipase deficiency following confirmation includes a comprehensive clinical examination, lipid biomarkers (eg, triglyceride levels, total cholesterol, HDL-C, non-HDL-C, and calculated LDL-C), ALT, AST, alkaline phosphatase, GGT, BUN, serum creatinine, CBC with differential, PT and INR (43).
Lipid biomarkers, hepatic tests (ie, ALT, AST, GGT, and alkaline phosphatase), BUN, and serum creatinine should be checked every 3 months up to 1 year and then every 6 to 12 months thereafter. CBC with differential, PT, and INR can be followed annually as can liver imaging. Cardiac evaluation is more important for the milder phenotypes, and timing is dependent on age since screening for premature atherosclerotic burden (43).
Krivit and colleagues have performed bone marrow transplantation in two patients and, as expected, corrected the lysosomal acid lipase deficiency in leukocytes, but did not otherwise alter the course of the disease (44). The rationale behind bone marrow transplantation is that a reconstituted hematopoietic system from a healthy, matched donor will contain stem cells that can produce the missing enzyme or enzymes.
The first report of a successful unrelated HLA-mismatched umbilical cord blood-derived stem cell cord blood transplant in a patient with Wolman disease resulted in restoration of normal acid lipase levels before the onset of permanent end-organ damage (67). Four years after transplantation, the patient is thriving and has normal levels of acid lipase in peripheral blood cells. The authors claim that umbilical cord stem cell transplantation can restore acid lipase levels in Wolman disease, and if performed early, can cure the disease.
In spite of the gloomy prognosis, Tietge and colleagues have reported phenotypic correction of lipoid storage and growth arrest in Wolman disease after gene transfer of lysosomal acid lipase into affected fibroblasts (70).
The therapy of cholesteryl ester storage disease includes the management of liver disease and its complications, and of epistaxis and gastrointestinal bleeding (09). Administration of the HMG-CoA reductase inhibitor lovastatin in a dosage of 20 mg twice daily resulted in a significant reduction of plasma cholesterol, triglycerides, and low-density lipoprotein cholesterol (31). Such therapy may also have a beneficial effect on liver and adrenal function. The combined administration of simvastatin (0.28 mg/kg each evening) and cholestyramine (0.22 g/kg twice a day) plus a low-cholesteryl diet and administration of vitamins A, D, E, and K had similar favorable effects on plasma lipoproteins in another patient (08). Assman and Seedorf reported that a patient who had chronic liver failure due to cholesteryl ester storage disease had a liver transplant and was said to be well 2 years later (41; 08). Adrenal function should be investigated and treatment initiated if basal or ACTH-stimulated cortisol is abnormal.
Du and colleagues demonstrate the feasibility of using plant-expressed, recombinant hLAL for the enzyme therapy of human Wolman disease/cholesteryl ester storage disease with general implications for other lysosomal storage diseases (25). Tolar and colleagues describe four cases of Wolman disease treated with stem cell transplant (71). Associated relatively high mortality rate (two out of four) was attributed to sinusoidal obstruction syndrome, multi-organ failure, and sepsis in the first case and hepatic failure and sepsis in the second case. Presently, there are no proven strategies to accelerate the differentiation and engraftment of donor-derived macrophages in a stem cell transplant recipient (32).
Based on their experience with hematopoietic cell transplantation of four patients with Wolman disease, Tolar and colleagues conclude that Wolman disease can be treated with hematopoietic cell transplantation with success, and that with early diagnosis and timely referral to a transplant center, hepatic and cognitive function can be preserved (71).
Sun and colleagues studied the effects of intravenous investigational enzyme therapy on survival and efficacy in Lipa knockout, lal-/- mice with advanced disease using recombinant human lysosomal acid lipase (rhLAL) (68). In the study, rhLAL extended the lifespan of lal-/- mice in a dose-dependent manner. Enzyme therapy in high doses resulted in a significant improvement in organ size (liver, spleen, and small intestine) and tissue histology as well as significant decreases in cholesterol and triglyceride in all treated groups. In the treated livers and spleens, cholesterol and triglyceride levels were reduced to below treatment initiation levels indicating a reversal of disease manifestations, even in advanced disease, with diminished liver fibrosis and macrophage proliferation. Their results suggest that lysosomal acid lipase deficiency can be improved biochemically and histopathologically by various dosages of enzyme therapy, even in advanced disease. Valayannopoulos and colleagues reported that long-term dosing with sebelipase alfa in patients with lysosomal acid lipase deficiency is well-tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile, and reduction in the hepatic fat fraction (72).
A phase 3 trial of sebelipase alpha, a recombinant human enzyme replacement therapy, demonstrated that this therapeutic option could result in reduction of several measures of disease severity in children and adults (15). This drug has since been approved for use both in Europe and by the FDA in the United States.
Enzyme replacement therapy can be initiated as soon as a diagnosis is confirmed and has been shown to affect disease course. Jones and colleagues performed an open-label multicenter dose-escalation study of sebelipase alfa (38). The study included children who were symptomatic prior to 6 months of life with growth failure. Out of the nine enrolled infants, six survived past 1 year, and five were still alive at the 2-year follow-up with improved growth and liver function. A long-term follow-up study of French patients found that of five patients with Wolman disease treated early with enzyme replacement, all had normalized growth and improved gastrointestinal symptoms, with most able to have entirely enteral nutrition support (none requiring long term parenteral nutrition), as well as 100% survival at the time of publication (22).
Multi-modal therapy combining hematopoietic stem cell transplant, enzyme replacement therapy with sebelipase alfa, and dietary restriction has been reported in patients who developed anti-drug antibodies leading to diminished effect of enzyme replacement therapy (60). Four of five patients treated this way survived, with reported improved outcomes compared to when the patients were on enzyme replacement therapy alone.
A decrease in biomarkers for atherosclerosis risk in patients treated with sebelipase alfa irrespective of their use of lipid lowering medications was identified (74).
Pregnancy is not relevant to patients with Wolman disease because of their early death.
We are not aware of reports of pregnancy in patients with cholesteryl ester storage disease, but this may well have occurred. Management of pregnancy would require observation and appropriate therapy in regard to liver function, anemia, and bleeding; administration of fat soluble vitamins; and assessment of adrenal function.
For patients with Wolman disease, anesthesia requires great caution because of their greatly impaired capacity to absorb food, inanition, liver disease, and possible adrenal insufficiency and autonomic nervous system dysfunction.
For patients with cholesteryl ester storage disease, anesthesia requires evaluation of liver function, anemia and abnormal bleeding tendency, possible pulmonary dysfunction, and adrenal insufficiency.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Kimberly A Chapman MD PhD
Dr. Chapman of George Washington University and Children’s National Rare Disease Institute has no relevant financial relationships to disclose.See Profile
Christina Grant MD PhD
Dr. Grant of Children’s National Hospital received a consulting fee from Amicus Therapeutics and honorariums from Sanofi Genzyme for serving on an advisory committee.See Profile
Seth I Berger MD PhD
Dr. Berger of Children’s National Health System has no relevant financial relationships to disclose.See Profile
AHM M Huq MD PhD
Dr. Huq of Wayne State University has no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.
Childhood Degenerative & Metabolic Disorders
Jan. 08, 2023
Childhood Degenerative & Metabolic Disorders
Jan. 08, 2023
Childhood Degenerative & Metabolic Disorders
Jan. 01, 2023
Childhood Degenerative & Metabolic Disorders
Jan. 01, 2023
Childhood Degenerative & Metabolic Disorders
Dec. 29, 2022
Childhood Degenerative & Metabolic Disorders
Dec. 22, 2022
Dec. 20, 2022
Dec. 18, 2022