Lysosomal Acid Lipase Deficiency (Wolman Disease and CESD)

An autosomal recessive lysosomal storage disease caused by biallelic LIPA variants, with a continuous spectrum between the rapidly progressive infantile form (Wolman disease) and the childhood- or adult-onset form (cholesteryl ester storage disease, CESD).

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Founding description and historical overview

Wolman disease was described in 1956 by Abramov, Schorr and Wolman in Israel, under the title of generalised xanthomatosis with calcified adrenals: an infant with abdominal distension, hepatosplenomegaly, tissue accumulation of cholesterol and triglycerides and adrenal gland calcification, who died in the first months of life [2, 15]. In 1961, Wolman and colleagues reported two further siblings of the first patient with the same picture, establishing the familial nature of the disease and consistency of the phenotype: onset in the first weeks, progressive wasting and death before 3 months [2, 16]. Several cases published at that time as ‘Niemann-Pick disease with adrenal calcifications’ probably represent early Wolman disease cases, because bone marrow foamy histiocytes in the two diseases are similar under light microscopy [2].

The slowly progressive form was recognised independently. Fredrickson described it in 1963 in the United States and, in France, Lageron and colleagues named it ‘polycorie cholestérolique de l'adulte’ in 1967; Schiff and colleagues published familial hepatic cholesteryl ester storage disease in 1968, with hepatomegaly and hypercholesterolaemia in children and adults [2, 17]. In 1969, Patrick and Lake demonstrated acid lipase deficiency in the liver and spleen of Wolman disease patients [18], and in 1972 Burke and Schubert showed that hepatic acid lipase activity was also deficient in CESD [19]. The two entities were thus established to share the same enzyme deficiency despite a very different clinical course.

Prenatal diagnosis of Wolman disease was described in 1976 through measurement of enzyme activity in cultured amniocytes [2, 20]. The molecular phase began with cloning of lysosomal acid lipase complementary DNA by Anderson and Sando in 1991: a 2.6 kb transcript encoding a protein with 58 % identity to human gastric lipase [21]. This was followed by genomic organisation of the gene, with 10 exons [22], identification of the first variants in a Wolman disease patient [23] and description by Klima and colleagues in 1993 of the exon 8 splice variant in a 12-year-old boy with CESD, deleting 72 nucleotides from messenger RNA [24]. In 1996, Aslanidis and colleagues demonstrated that CESD and Wolman disease are distinguished by residual enzyme activity: the common CESD variant allows approximately 3 % of pre-messenger RNA to be correctly processed, whereas Wolman disease patients homozygous for an alteration at position +1 of the same donor site produce no normal transcript [25].

The therapeutic era began with sebelipase alfa, a recombinant human lysosomal acid lipase produced in the egg white of genetically modified chickens. The first human study, published in 2013, showed rapid decreases in aminotransferases and LDL cholesterol in adults with CESD [26]. In 2015, the phase 3 ARISE trial confirmed the effect in children and adults [27], and sebelipase alfa was authorised in the European Union (28 August 2015) and United States (8 December 2015) [13, 14].

1.2. Nomenclature and definition of the entities

Current nomenclature treats LAL-D as a single disease with a continuous severity spectrum rather than two distinct diseases. GeneReviews designates the two extremes as infantile-onset (formerly Wolman disease) and childhood- or adult-onset (formerly CESD) [1]. Orphanet retains the parent entity ORPHA:275761 and two clinical subtypes, Wolman disease (ORPHA:75233) and CESD (ORPHA:75234) [6–8]. OMIM assigns Wolman disease number 620151 and retains number 278000 for CESD [1]. GeneGuidance associates Wolman disease with numbers 278000 and ORPHA:75234, a mapping error; the correct designations are OMIM 620151 and ORPHA:75233 [1, 3, 7].

The infantile form is defined by symptom onset in the first 6 months of life, with rapid progression, absent enzyme activity or activity below 1 % of normal and death before 6 months without treatment [1, 5]. Regulatory labels use a similar operational definition, ‘patients with rapidly progressive LAL-D presenting within the first 6 months of life’, to distinguish dosing regimens [13, 14]. The childhood- or adult-onset form, referred to here as the late-onset form, presents after 6 months, with residual activity of 1 % to 12 % of normal and a course ranging from a child with hepatomegaly and dyslipidaemia to an adult diagnosed in the eighth decade [1, 5]. The terms Wolman and CESD remain in use in clinical literature, classifications and administrative codes, and this article uses them as synonyms for the two forms.

1.3. Nature of the available recommendations

There is no clinical practice guideline with formal evidence grading dedicated to LAL-D issued by a European or American scientific society; GeneGuidance and GeneReviews itself record this absence, and GeneReviews states that practices and dosing regimens vary between countries [1, 3]. Reference documents are expert consensus statements: the international consensus of Kohli and colleagues (2020) on baseline assessment and monitoring of children and adults, sponsored by Alexion, with all authors having company ties [10]; the Iberian practical recommendations of de las Heras and colleagues (2024), focused on the infantile form, with Spanish authors, one Portuguese author and the Spanish patient association, explicitly based on expert opinion and with several authors receiving Alexion/AstraZeneca fees [5]; the Gulf Cooperation Council panel recommendations (2025), without a formal Delphi method [12]; the Spanish transition consensus (2025) [28]; and the review of nutritional best practices in the infantile form (2026), funded by Alexion [29]. The article presents these recommendations with their level of evidence and highlights the differences between them.

2. Molecular Genetics and Pathophysiology

2.1. The LIPA gene and the enzyme

The LIPA gene is located at 10q23.31, has 10 exons distributed over approximately 36 kb, and the MANE Select reference transcript is NM_000235.4, encoding protein NP_000226.2 [1, 4, 5, 22]. Some sources, including ATLAS and the Iberian recommendations, give the historical location 10q23.2-q23.3, predating current mapping [2, 5]. The protein, termed lysosomal acid lipase or acid cholesteryl ester hydrolase (EC 3.1.1.13), is a glycoprotein acting at the acidic lysosomal pH; ATLAS describes it as a 46 kDa glycoprotein, and sebelipase alfa labelling describes the recombinant form as a monomer of approximately 55 kDa with six N-glycosylation sites and a sequence identical to the human enzyme [2, 13]. Electrophoresis separates acid lipase into isoenzymes A, B and C, and isoenzyme A is deficient in both forms of the disease [2]. Complementary DNA has 58 % identity to human gastric lipase and 57 % to rat lingual lipase, with three additional cysteines and two additional N-glycosylation sites [21].

The enzyme removes the fatty acid from cholesteryl esters contained in endocytosed low-density lipoproteins (LDL) and hydrolyses triglycerides and diglycerides, with a preference for acyl positions sn-1 and sn-3, releasing free cholesterol and fatty acids for cellular use [2, 3].

2.2. Molecular, cellular and tissue mechanism

Free cholesterol released in the lysosome is transferred to the endoplasmic reticulum, where it interacts with transcription factors suppressing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) activity, reducing cholesterol synthesis, and LDL receptor gene transcription, reducing LDL uptake [1]. In LAL-D, cholesteryl esters and triglycerides remain trapped in lysosomes; because free cholesterol fails to reach cellular sensors, the cell behaves as if cholesterol-deprived, increasing endogenous synthesis and LDL uptake [1, 3]. The overall result is lysosomal neutral lipid accumulation and dyslipidaemia with high LDL and low HDL cholesterol; the exact relationship with LDL receptor expression is not fully elucidated [1, 30]. This mechanism differs from tissue cholesterol deposition due to excess plasma lipoproteins, as in familial hypercholesterolaemia xanthomas, because the defect is intrinsic to intracellular lipid metabolism [31].

Lipids accumulate mainly in hepatocytes and macrophages of the liver, spleen, intestinal wall, adrenals, lymph nodes and vascular walls [2, 3]. In Wolman disease, liver and spleen triglycerides may reach 10 and 350 times normal values, and unusual oxygenated steryl esters, such as 7α-hydroxycholesterol esters, have been identified [2]. Lipid-laden macrophages become foam cells and produce inflammatory cytokines, explaining systemic inflammation, increased ferritin and lactate dehydrogenase (LDH), and progression to haemophagocytic lymphohistiocytosis (HLH) in the infantile form [1, 5]. In the adrenals, necrosis of cortical cells overloaded with hydrophobic lipids produces the characteristic calcifications [5]. In the intestine, infiltration of the lamina propria by foamy histiocytes causes malabsorption, and infiltration and fibrosis of mesenteric lymph nodes may cause intestinal obstruction [1, 2]. Because pathophysiology is mediated by bone marrow-derived monocytes and macrophages, isolated liver transplantation does not prevent graft recurrence [1, 32].

2.3. Inheritance pattern

LAL-D is autosomal recessive and results from biallelic loss-of-function LIPA variants [1]. Heterozygotes are asymptomatic and not at risk of disease [1]. Common LIPA variation is among genome-wide association loci for coronary artery disease, but these are common small-effect variants unrelated to Mendelian disease [33].

2.4. Variant spectrum and nomenclature

ClinVar records several hundred germline LIPA variants; the Iberian recommendations counted more than 600 variants, mostly of uncertain significance, and 127 classified pathogenic or likely pathogenic in March 2024, approximately 25 % associated with the infantile form, 50 % with the late-onset form and 25 % with both [5]; the Gulf panel counted 686 germline and 171 pathogenic or likely pathogenic variants in a later search [12]. ATLAS reports more than 40 loss-of-function variants; of the 19 variants then described in Wolman disease, 37 % were small deletions or insertions and 26 % nonsense variants, whereas half the 32 CESD variants were missense [2]. Large deletions are rare but have been described, including homozygous deletions encompassing LIPA and the neighbouring gene CH25H [1, 14].

The most frequent variant is NM_000235.4:c.894G>A, altering the last nucleotide of exon 8 without changing the encoded amino acid, p.(Gln298=), but causing exon 8 skipping and an in-frame deletion of 24 amino acids, p.(Ser275_Gln298del) [4, 5, 25]. Approximately 3 % to 5 % of the transcript is correctly processed, explaining residual activity and the late-onset phenotype [25, 34]. Historical literature uses several designations for this same variant: ‘E8SJM’ (exon 8 splice junction mutation), ‘E8SJM-1G>A’, ‘p.Q298Q’ and, in ATLAS, ‘G934A’, an old complementary DNA numbering that does not correspond to current nomenclature [2, 5]. The descriptions by Klima and Aslanidis refer to loss of ‘codons 254–277’, mature protein numbering that was not converted to NP_000226.2 and should be read as historical [24, 25]. For the same reason, old designations such as L179P, 634insT (Fs178), Tyr22X, Gly245 and the variants E8SJM+1G>A and E8SJM+3C>T, the latter described only in Wolman disease patients, remain here in their original form [2, 25].

Table sources: VariantValidator normalisation and ClinVar search [4, 35]; population context [12, 34, 36–40]. Two rows require caution. c.607G>A is classified in ClinVar as a variant of uncertain significance by a single submitter, although used as a causal variant in the Omani cohort described by the Gulf panel; and c.530C>T has no ClinVar record. In a laboratory report, neither should by itself establish the diagnosis without confirmation of enzyme activity, as GeneReviews stipulates for variants of uncertain significance [1, 12, 35].

2.5. Founder variants and population frequencies

The c.894G>A allele frequency was measured in 10,000 alleles from healthy New York individuals (African Americans, Asians, Caucasians, Hispanics and Ashkenazi Jews) and 6578 Dallas Heart Study alleles: it ranged from 0.0005 in Asians to 0.0017 in Caucasians and Hispanics, corresponding to a carrier frequency between 1/1000 and approximately 1/300, and no African American heterozygote was found [34]. In the Southern Californian Mizrahi Jewish population, screening of 549 individuals found an allele frequency of 1/52.2 and carrier frequency of 1/26.1 for c.260G>T p.(Gly87Val) [37]. In Spain, c.966+2T>G accounts for 75 % of infantile-form alleles and c.894G>A for 55 % of late-onset alleles, both on a common haplotype indicating a founder effect [36]. In Brazil, p.(Leu89Pro) was found in three unrelated children from São Paulo and, in homozygosity, in an adult diagnosed late, leading the authors to propose a Brazilian genotype [39, 40]. Prevalence figures derived from these frequencies are addressed in section 9.

2.6. Genotype–phenotype correlation, penetrance and expressivity

Broadly, null variants without residual activity cause the infantile form and variants with residual activity cause the late-onset form [1]. c.894G>A has never been found in patients with a Wolman phenotype, and CESD has been observed with c.894G>A in compound heterozygosity with variants causing Wolman disease in other patients, such as L179P [2]. In the review of 135 CESD patients, 61 % of variants identified in 55 genotyped patients were c.894G>A, with 18 homozygotes, and homozygotes typically had early onset and slow progression [41]. In the International LAL-D Registry, among 155 patients without the rapidly progressive form and with an available genotype, 40.0 % were homozygous for c.894G>A, 32.3 % compound heterozygous with c.894G>A, 16.8 % homozygous for other variants and 10.3 % compound heterozygous for other variants; c.894G>A homozygosity was associated with higher aminotransferases [42]. These data contradict the assertion that almost all CESD patients have at least one c.894G>A copy, found in ATLAS and Saudubray based on older series, since more than one quarter of registry patients lack it [2, 31, 42, 43].

Residual activity does not predict individual course. GeneReviews gives absent activity or activity of 1 % or less in the infantile form and 2 % to 11 % in the late-onset form, but manifestations vary considerably between patients with similar activities [1]. The Kohli consensus adds that severity varies within the same family and with the same genotype, and no clinical, enzymatic or genetic characteristic predicts long-term progression [10]. Enzyme assays in lysates also distinguish CESD from Wolman disease poorly, because the measured difference is small relative to the clinical difference [2]; a more specific dried blood spot substrate showed significantly lower activity in Wolman disease than CESD, with prognostic potential not yet validated [44]. Expressivity is highly variable, particularly in the late-onset form: patients diagnosed between the fifth and ninth decades may have only hepatomegaly or dyslipidaemia [10]. The sources consulted provide no formal penetrance estimate.

Variants eliminating the gene product are associated with greater risk of neutralising antibodies to enzyme replacement therapy. The European summary of product characteristics (SPC) describes three patients homozygous for a deletion encompassing LIPA and CH25H, with antibody inhibitory activity and suboptimal response, who improved with immunomodulation alone or combined with haematopoietic stem cell transplantation [14]. The Iberian recommendations compare this situation to Pompe disease patients without immunoreactive material and allow prophylactic immune tolerance induction as the authors' opinion [5].

2.7. Allelic disorders, modifiers and curation

No other Mendelian phenotype is known to be associated with germline LIPA variants [1]. A relevant laboratory modifier is the 24 bp CHIT1 duplication, frequent in the general population, which reduces or abolishes chitotriosidase activity and may make this biomarker falsely normal [5]. ClinGen has no actionability assertion for LIPA, either in adults or paediatrics, or dosage sensitivity curation [3].

3. Clinical Spectrum and Manifestations by System

3.1. Infantile form (Wolman disease): untreated natural history

The infantile form is a rapidly progressive storage disease. Symptoms begin in the first days to weeks of life, usually before 1 month: persistent vomiting, diarrhoea with steatorrhoea and abdominal distension worsening to severe hepatic dysfunction [1, 5]. In the classic ATLAS description, infants are normal for 2 to 7 weeks and then develop diarrhoea and vomiting, with watery green stools, initially interpreted as gastroenteritis; hepatosplenomegaly may be massive and was documented as early as the 4th day of life [2]. Abdominal distension may be so marked that it leads to laparotomy for suspected intestinal obstruction, when the yellow appearance of the liver and spleen suggests storage disease [2].

The natural history study of Jones and colleagues, comprising 35 infants (26 with early growth failure), underpins the trials' historical control cohort: median age at death was 3.7 months and probability of survival beyond 12 months was 0.114 (95 % CI 0.009–0.220); in the early growth failure subgroup, the median was 3.5 months and survival beyond 12 months 0.038 (0.000–0.112) [45]. The ten infants receiving haematopoietic stem cell transplantation, one combined with liver transplantation, survived longer, but with a median age at death of 8.6 months [45]. The Iberian recommendations cite a median age at death of 3.7 months with a range of 1.4 to 46.3 months and mortality approaching 100 % before 1 year without specific treatment [5]. In the VITAL trial historical cohort, none of the 21 untreated infants survived beyond 8 months [13, 14].

The frequency of manifestations in untreated infants, aggregated by GeneReviews from Witeck's scoping review and other series, is summarised in the following table; denominators are not given per item except for ferritin [1, 46].

Frequencies vary between sources: the Iberian recommendations estimate adrenal calcification in approximately 50 % of infants, below GeneReviews' 74 %, and Saudubray emphasises that its absence is associated with later diagnosis [5, 31]. The infantile lipid profile also varies: ATLAS describes low, normal or elevated plasma cholesterol and fasting hyperlipidaemic serum, and GeneReviews stresses that normal lipids do not exclude disease [1, 2].

Gastrointestinal and hepatic systems. Hepatic steatosis progresses rapidly to liver failure, the most frequent cause of death; lipid deposition in the intestinal wall thickens bowel loops and causes malabsorption, malnutrition and wasting [1]. On pathological examination, the liver is yellow, with periportal fibrosis invariably present at death and sometimes cirrhosis; the proximal small intestine is yellow, thickened and dilated, with foamy histiocytes and mucosal cells; colonic pneumatosis and intestinal ganglion cell infiltration have been described [2]. Mesenteric lymph nodes enlarge, fibrose and coalesce, especially when the infant receives unrestricted long-chain fat, and may cause intestinal obstruction [1, 5].

Haematological and immune systems. Anaemia appears early, usually evident by 6 weeks, worsens and may require transfusions; acanthocytosis has been described [2]. Peripheral blood lymphocytes and granulocytes show vacuoles, and bone marrow aspirate shows lipid-laden histiocytes, sometimes with erythrophagocytosis [2]. Lysosomal accumulation in macrophages triggers an inflammatory cascade: unexplained fever with elevated ferritin and LDH is a presenting sign that may progress to HLH [1]. Macrophage dysfunction has also been implicated in frequent abscesses or axillary lymphadenopathy after BCG (bacillus Calmette-Guérin) vaccination [1].

Nervous system. Psychomotor development appears delayed or deteriorating in untreated infants, but assessment is hampered by disease severity; neurological examination may be normal and electroencephalogram is usually normal [2]. Pathological examination documents neuronal and oligodendrocyte lipid storage, with deficient myelination [2]. In treated survivors, intellectual and neurological development is typically normal (see 3.2) [1].

Other systems. ATLAS describes low-density bones with a wide medullary cavity and thin cortex [2]. Saudubray includes Wolman disease among metabolic causes of hydrops fetalis and increased nuchal translucency, as well as neonatal and infantile liver failure and neonatal arrhythmias or conduction abnormalities [47–49].

3.2. Treated infantile form

With early diagnosis, sebelipase alfa and long-chain fat restriction, survival has substantially improved, with children reaching adolescence [1]. All infants with the infantile form have hepatic fibrosis; with treatment, liver function normalises within days to weeks, fibrosis does not progress and liver tests and lipid profile become normal [1]. In the pooled VITAL and LAL-CL08 trial analysis (19 infants), Kaplan-Meier survival was 79 % at 12 months and 68 % at 5 years, and survivors had normal psychomotor development [50]. In the French national cohort of five patients starting treatment at a median age of 1 month, with median follow-up of 7 years, all were alive, with normal growth and no special educational needs; one remained dependent on parenteral nutrition since acute gastroenteritis, and three had a transient neuromyopathic phenotype (steppage gait, waddling gait or muscle fatigue) with normal electromyography and strength [51].

Problems persist even with treatment: suboptimal growth, iron-deficiency anaemia and lipid accumulation in gastrointestinal mucosa, because enzyme replacement therapy is less effective in the gastrointestinal tract than the liver [1, 50, 51]. Adrenal calcification persists or becomes more evident [1]. Non-adherence to fat restriction causes recurrence of inflammatory symptoms, with increased ferritin and LDH, mesenteric lymphadenopathy and hepatic deterioration, regressing when diet is resumed [1, 5]. The course depends on early initiation: in a Manchester sibling pair, the sister treated at 4 months, already symptomatic, developed HLH, underwent bone marrow transplantation at 8 months and died at 13 months, whereas the brother treated immediately after birth was asymptomatic at 16 months, with weight, height and mid-upper arm circumference above the 95th centile and normal duodenal biopsies [52].

3.3. Late-onset form: presentation and natural history

The late-onset form is much more indolent. It may present at any age after 6 months; many patients are asymptomatic or have non-specific symptoms at diagnosis, and suspicion frequently arises from biochemical abnormalities [1, 5]. Organomegaly may be present for years before diagnosis, and patients diagnosed earlier in childhood tend to progress more rapidly [1, 2].

The most frequently used cohort data are as follows. The review of 135 published CESD patients found hepatomegaly in 99.3 % and splenomegaly in 74 %, elevated aminotransferases, high total cholesterol, LDL cholesterol and triglycerides and low HDL cholesterol in most; the 112 biopsied patients had characteristic histology and 17 progressed to liver failure with transplantation or death [41]. In Burton and colleagues' natural history study, with 48 confirmed patients (mean age at first abnormality 9.0 years and at diagnosis 15.2 years; 56 % younger than 20 years), alanine aminotransferase (ALT) exceeded the upper limit in 92 % of 499 measurements and aspartate aminotransferase (AST) in 59 % of 448; LDL cholesterol was elevated in 64 % despite lipid-lowering treatment in most, and HDL cholesterol low in 44 %; among the 31 biopsies (mean age 13 years), 87 % had steatosis and 52 % fibrosis, and six patients (13 %) underwent liver transplantation between 9 and 43.5 years [53]. The Kohli consensus summarises a longitudinal study of 48 patients with elevated ALT in 91.7 %, hepatomegaly in 87.5 %, elevated LDL cholesterol in 64.4 % and, among biopsied patients, steatosis in 87 % and fibrosis or cirrhosis in 64.5 %, with gastrointestinal symptoms in approximately 30 % [10]. In the International Registry, with 228 confirmed patients by May 2022 (61 % children, 92 % of European ancestry), median age at onset was 5.5 years and at diagnosis 10.5 years, with a median 3.3-year interval between onset and testing; suspicion arose from elevated ALT in 70 %, elevated AST in 67 % and hepatomegaly in 63 % [54].

GeneReviews aggregated late-onset frequencies from Witeck and the registry, as shown in the table; not all features were assessed in both sources [1].

Liver. Liver disease progresses from microvesicular steatosis to fibrosis, micronodular cirrhosis, portal hypertension with oesophageal varices and potentially fatal bleeding, and liver failure [1, 31, 41]. In the registry, among 118 biopsies, steatosis was exclusively microvesicular in 63 % and mixed in 23 %, and among 78 staged biopsies there was bridging fibrosis in 37 % and cirrhosis in 14 % [54]. At ARISE trial entry, all 32 biopsied patients had fibrosis and 31 % cirrhosis, between 4 and 21 years [14]. Splenomegaly results from portal hypertension or splenic infiltration by foamy macrophages and may cause anaemia and thrombocytopenia through hypersplenism [1, 5].

Hepatic malignancy. Hepatocellular carcinoma arises in advanced cirrhosis [1]. A Brazilian patient with cirrhosis at 43 years and LAL-D diagnosis at 53, never treated with sebelipase for financial reasons, developed hepatocellular carcinoma outside Milan criteria at 58 years, after missing three six-monthly surveillance ultrasound scans during the COVID-19 pandemic; the authors assembled three further published hepatic malignancies in untreated LAL-D (hepatocellular carcinoma in an 11-year-old girl, cholangiocarcinoma in a 51-year-old man and hepatocholangiocarcinoma in a 21-year-old man), without an established variant relationship [55]. In the International Registry, among 137 treated patients, one hepatocellular carcinoma occurred, classified as unrelated to the drug [42].

Gastrointestinal tract and nutrition. Intestinal lipid deposition causes diarrhoea, steatorrhoea and poor weight gain; iron-deficiency anaemia and fat-soluble vitamin deficiency may mimic coeliac disease [1]. Abdominal pain results from organomegaly, gaseous distension, mesenteric lymphadenopathy or intestinal obstruction [1]. Gallbladder dysfunction and cholesterol stones with severe hyperlipidaemia have been described [10, 31].

Cardiovascular system. Dyslipidaemia and atherosclerosis account for much late-onset morbidity: coronary disease, aneurysm and stroke [1]. The typical profile is high LDL cholesterol, low HDL cholesterol and normal or elevated triglycerides, corresponding to type IIb hyperlipoproteinaemia; xanthelasma may occur [2, 31]. Atherosclerosis has been described at 9 years [10]. In the French national database, eight of 26 late-onset patients had cardiovascular events (stroke, infarction, coronary disease, heart failure or cardiovascular surgery), all untreated with sebelipase and diagnosed as adults [56]. In some patients, total and LDL cholesterol are so high that the picture resembles autosomal recessive hypercholesterolaemia or severe familial hypercholesterolaemia [1, 57, 58].

Other systems. The Kohli consensus reports renal vascular lipid deposits [10]. ATLAS describes a patient with pulmonary hypertension who died at 18 years and a case with end-stage kidney failure after liver transplantation [2]. Cognitive development is normal in the late-onset form [1].

3.4. Intermediate phenotypes and intrafamilial variation

The spectrum is continuous. The Brazilian series of seven children from São Paulo includes patients with onset at 4 months and diagnosis at 3 years, another with rickets as the initial manifestation and another with chronic diarrhoea and interstitial pneumonitis with respiratory failure [39]. A Brazilian adult had symptoms from 4 months (recurrent diarrhoea, poor weight gain, hepatomegaly and dyslipidaemia), liver failure at 13 years, liver transplantation at 18 and diagnosis only at 24 years [40]. Severity varies even between siblings with the same genotype [10].

3.5. Adrenals: calcification and function, a difference between sources

Adrenal calcification is the radiological hallmark of the infantile form, and sources agree on its high frequency (74 % in GeneReviews, approximately 50 % in the Iberian recommendations) and rarity in the late-onset form (5 %) [1, 5]. They differ regarding function. GeneReviews 2026 states that calcification is not associated with adrenal dysfunction or insufficiency [1]. Saudubray lists adrenocortical insufficiency as rare and includes glucocorticoid and mineralocorticoid replacement in supportive treatment [31]. ATLAS reports a reduced response to adrenocorticotrophic hormone (ACTH) in older reports [2], and one of the two infants treated early in Philadelphia required treatment for partial adrenal insufficiency and hypothyroidism [59]. None of the consensus documents read recommends systematic adrenal function assessment; reading the sources together indicates that calcification alone does not justify hormone replacement, but adrenal insufficiency is documented in isolated cases and should be investigated with compatible clinical features; this reading is an interpretation of sources rather than a formal recommendation.

4. Clinical Recognition and Warning Signs

4.1. Infant: when to suspect

The infantile form should be considered in any infant with persistent vomiting, refractory diarrhoea or steatorrhoea, abdominal distension with hepatosplenomegaly and growth failure in the first weeks of life [1, 5]. Combining these signs with bilateral adrenal calcification, visible on plain radiography, ultrasound or computed tomography (CT), is strongly suggestive [2, 5]. Other supporting features are anaemia, thrombocytopenia or pancytopenia, unexplained fever with elevated ferritin, LDH and C-reactive protein, hypoalbuminaemia, hyperbilirubinaemia and coagulopathy, fat-soluble vitamin deficiency and a profile with high LDL cholesterol and triglycerides and low HDL cholesterol, which may also be normal [1]. A peripheral blood film showing vacuolated lymphocytes is a clue accessible in any laboratory and, with strong suspicion, justifies immediately initiating administrative procedures for drug access [2, 5]. A history of affected siblings or consanguinity strengthens suspicion, but its absence does not rule it out [1].

The most frequent initial misdiagnoses are gastroenteritis, cow's milk protein allergy, primary HLH and metabolic fatty liver disease [2, 29]. The two infants from Porto and Poland described by Santos Silva and colleagues were initially treated as HLH, progressed to cholestasis and liver failure, and only then, with vacuolated lymphocytes and adrenal calcifications, was LAL-D suspected; both died despite sebelipase, and the authors recommend considering disease in all infants with HLH [60]. In Australia, rapid whole-genome sequencing identified Wolman disease in two infants with HLH and enabled specific treatment [61]. Disease may also be detected prenatally through fetal adrenal calcification on ultrasound or non-immune hydrops fetalis [1, 47, 49].

4.2. Emergency signs

Once the infantile diagnosis is established or strongly suspected, the situation should be treated as a medical emergency; the Iberian recommendations call for sebelipase initiation ideally before 2 to 3 months, and GeneReviews recommends transfer to an inherited metabolic disease centre and immediate initiation of diet and enzyme replacement therapy [1, 5]. Signs of immediate severity include liver failure with coagulopathy, HLH, severe malnutrition with hypoalbuminaemia, transfusion-dependent anaemia and abdominal distension with signs of obstruction [1, 5, 12].

4.3. Child, adolescent and adult: settings for suspicion

In the late-onset form, suspicion should arise in four settings. The first is persistent unexplained aminotransferase elevation, with or without hepatomegaly or splenomegaly, particularly when ultrasound shows fatty liver in a child or adult without metabolic risk factors; excess weight does not exclude disease [1, 5]. The second is the lipid clinic: high LDL with low HDL cholesterol, especially with hepatic abnormalities, and any suspected familial hypercholesterolaemia without an identified LDLR, APOB or PCSK9 variant, especially with poor statin response [5, 10]. The third is fatty liver disease with microvesicular steatosis on biopsy, strongly suggesting lysosomal disease [5]. The fourth is advanced cryptogenic liver disease, including patients listed for transplantation without a defined aetiology [40].

Test yield in these settings is low and selection-dependent. In the Portuguese Familial Hypercholesterolaemia Study, LIPA sequencing in 492 patients with a clinical familial hypercholesterolaemia diagnosis without a causal variant and 258 individuals with dyslipidaemia or steatosis identified LAL-D in four children, all with clinical familial hypercholesterolaemia and overlooked mild hepatic dysfunction, and no adults [62]. In France, among 4174 at-risk patients tested by dried blood spot, 19 had very low activity (13 with CESD and 6 with Wolman disease), and the authors proposed a clinical–biological criteria grid to select whom to test [63]. In a São Paulo lipid clinic, only 21 of 2018 records (0.92 %) met testing criteria and the eight tested had normal activity [64]. In São Paulo, among 73 patients listed for liver transplantation for disease of unknown cause, one had LAL-D [40]. The Kohli consensus reports identification of cases by dried blood spot in cohorts with clinical familial hypercholesterolaemia, fatty liver disease, HLH and Gaucher disease [10]. Carter and colleagues' analysis concludes that LAL-D should be sought as second-line metabolic screening in fatty liver disease rather than universal screening [9].

The criteria used in the São Paulo lipid clinic exemplify operational selection: in adults, LDL cholesterol above 160 mg/dL, HDL cholesterol below 40 mg/dL in men or 50 mg/dL in women, and ALT or AST persistently above 1.5 times the upper limit, with ultrasound steatosis or microvesicular or mixed steatosis on biopsy, or suspected familial hypercholesterolaemia without a causal variant; below 18 years, hepatomegaly, LDL cholesterol above 130 mg/dL, HDL cholesterol below 40 mg/dL or aminotransferases above 1.5 times the upper limit, or fibrosis, cirrhosis or storage disease on biopsy [64]. The authors themselves consider the algorithm unvalidated [64].

4.4. Newborn screening

LAL-D can be diagnosed in dried blood spots and meets Wilson and Jungner screening criteria according to an expert review [29], and the argument in favour gained strength from the divergent courses of the Manchester siblings [52]. Newborn screening is not implemented in the United States [1]. LAL-D is included in three registered multidisease screening pilots: ScreenPlus (New York, 100,000 planned newborns), Early Check (North Carolina, 30,000) and Baby Detect, genomic screening for 126 diseases in Liège, Belgium, completed in 2025 with 6824 newborns, without LAL-D results published in the registry [65]. No published LAL-D results from these pilots were found, which does not mean none exist. The Gulf panel recommends newborn screening and national programmes for high-risk groups in highly consanguineous populations [12]. Siblings of an affected patient should be tested immediately after birth (see section 8) [10, 29].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

Diagnosis is established in a patient with suggestive findings when biallelic pathogenic or likely pathogenic LIPA variants are identified or deficient lysosomal acid lipase activity is demonstrated in peripheral blood leucocytes or dried blood spots [1]. GeneReviews follows the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) classification, in which pathogenic and likely pathogenic categories are synonymous for clinical purposes [1]. Two variants of uncertain significance, or one pathogenic and one of uncertain significance, neither establish nor exclude diagnosis, which in these cases rests on biochemical confirmation [1]. The Iberian recommendations go further: a patient with clinical suspicion and low enzyme activity should be diagnosed with LAL-D even if genetic testing is inconclusive [5].

5.2. Enzyme activity

Assay principle. Blood lysosomal acid lipase measurement is hampered by other lipases. The method of Hamilton and colleagues (2012) uses the substrate 4-methylumbelliferyl palmitate and inhibitor Lalistat 2: enzyme activity is the difference between total lipase activity and residual activity with the inhibitor, which reduces recombinant enzyme to 1 % activity at 1 µM and does not affect pancreatic lipase up to 10 µM [11]. ATLAS attributes this method to a 1970 reference, a citation error [2, 11]. Laboratory best practices include alternatives to mercury chloride as a stopping reagent, choice of excitation wavelength, quality control and expressing results as a percentage of the normal mean [66].

Reference values. Ranges are laboratory-specific and not interchangeable. In the original series, controls had 0.50 to 2.30 nmol/punch/h, CESD patients less than 0.03 and carriers intermediate values of 0.15 to 0.40 nmol/punch/h [11]. The Iberian recommendations cite a normal range of 0.59 to 2.40 nmol/punch/h [5]; the French at-risk screening study used a 0.12 nmol/punch/h cutoff, with patients below 0.05 [63]; and the São Paulo laboratory used reference values above 0.024 nmol/punch/h [64].

Sample choice. A dried blood spot is the fastest sample and is considered first-line in the Iberian recommendations [5]. GeneReviews considers leucocyte activity the confirmatory test and dried blood spots acceptable when correctly transported and stored; GeneGuidance emphasises that sample handling is part of the test [1, 3]. Activity can also be measured in hepatocytes and cultured fibroblasts [1, 2]. A positive dried blood spot result should be confirmed by a second sample, leucocyte or fibroblast activity or, ideally, LIPA sequencing [10]. With low activity, the Iberian recommendations direct exclusion of a preanalytical problem by measuring another reference lysosomal enzyme, such as β-galactosidase, before genetic testing [5].

Assay limitations. The Lalistat 2 assay distinguishes patients from controls but not the infantile from late-onset form, and residual activity level does not predict clinical course [1, 5]. A new substrate, a palmitic acid ester with 4-propyl-8-methyl-8-hydroxycoumarin, has greater than 98 % selectivity for the enzyme and enabled differentiation of Wolman disease from CESD in dried blood spots, with as yet unvalidated prognostic potential in newborn screening [5, 44]. An isolated normal result may be false-negative: in the family described in São Paulo, a woman with a previously normal test had activity of 0.00 nmol/punch/h on two repeats after a son's death, and her daughter died at 9 years with undetectable activity post mortem, while panel LIPA sequencing found no pathogenic variants; the authors note that testing took place under statin treatment and without leucocyte confirmation [64]. For the same reason, the Gulf panel recommends requesting genetic testing simultaneously rather than sequentially [12].

Carrier detection: a divergence. ATLAS states that heterozygosity is detectable by leucocyte or fibroblast assay, with approximately 50 % of normal activity, and that the Lalistat 2 method distinguishes carriers, and in Hamilton's original series the 15 carriers had intermediate values without overlap with controls [2, 11]. GeneReviews 2026, GeneGuidance and the Kohli consensus conclude that enzyme activity is not a suitable or reliable method for determining carrier status, because of overlap between carriers and non-carriers [1, 3, 10]. The more recent and broader position prevails: carrier status is determined by testing for the familial variants.

5.3. Genetic tests

LIPA sequencing detects more than 99 % of known pathogenic variants, and rare exon deletions or duplications require targeted analysis when only one variant or none is found [1]. This proportion of detectable variants is not the test's clinical sensitivity, which also depends on deep intronic and regulatory variants not covered by exome sequencing and panels; in these situations, the Iberian recommendations propose transcriptome or genome analysis [5]. GeneReviews describes two strategies: single-gene testing or a multigene panel including LIPA and differential diagnosis genes, or exome or genome sequencing when the phenotype is indistinguishable from other lipid storage diseases [1]. The primary hypercholesterolaemia panel recommended by a European Atherosclerosis Society panel includes LDLR, APOB, PCSK9, LDLRAP1, ABCG5, ABCG8 and LIPA [5]. When diagnosis is first suggested by variants in a panel, exome or genome, enzyme confirmation is recommended [1].

Apparent homozygosity requires caution: it may represent a deletion of one or more exons in the other allele undetected by sequencing, or uniparental isodisomy, and parental testing clarifies phase [1]. The Brazilian São Paulo series included three children with a single identified variant, low activity and a typical presentation, which should be read as an undetected second allele rather than dominant inheritance [39].

The report should state the gene, versioned transcript (NM_000235.4), HGVS (Human Genome Variation Society) nomenclature at DNA and protein levels, zygosity, ACMG/AMP class and, for c.894G>A, the splice effect beyond synonymous notation, because p.(Gln298=) alone may be misinterpreted as benign [4, 5]. Variants of uncertain significance are resolved by enzyme activity, parental segregation studies and, when possible, RNA studies [1, 5].

5.4. Biomarkers and imaging

There is no specific biomarker. Chitotriosidase and chemokine CCL18 (also termed PARC, pulmonary and activation-regulated chemokine) are elevated but non-specific, and chitotriosidase should be interpreted in light of CHIT1 genotype; the oxysterols 7-ketocholesterol and cholestane-3β,5α,6β-triol are elevated, as in acid sphingomyelinase deficiency and Niemann-Pick type C [5]. Ferritin and LDH are useful markers of inflammatory activity in the infantile form [1].

Magnetic resonance imaging (MRI) is the reference standard for quantifying hepatic fat, and ultrasound avoids sedation in children [5]. Transient and shear-wave elastography may underestimate LAL-D fibrosis because of massive lipid infiltration, serum fibrosis scores (NFS, NAFLD fibrosis score; FIB-4, fibrosis-4 index; FibroTest; ELF, enhanced liver fibrosis; FibroMeter) are not validated in the disease and FibroScan® is not validated in children [5, 10]. In the infantile form, CT is the best method to demonstrate adrenal calcifications, which follow gland contours; on ultrasound, they produce acoustic shadowing and may be missed on radiography with ascites [2].

5.5. Histology

Liver biopsy is unnecessary for infantile diagnosis [1]. In the late-onset form, GeneReviews allows it for diagnosis and staging, the Iberian recommendations consider it the reference standard for fibrosis with individualised use, and the Kohli consensus recommends it at baseline assessment in all patients, a real divergence between consensus documents [1, 5, 10]. The liver is yellow-orange; histology shows predominantly microvesicular steatosis, clear cytoplasm, fat-containing Kupffer cells, ceroid-laden macrophage aggregates in sinusoids and portal tracts, and micronodular cirrhosis [5, 10]. Birefringent cholesteryl ester crystals, or clefts left in processed tissue, are pathognomonic; birefringence disappears when the sample is heated to 50–60 °C and reappears on cooling [5, 41]. Immunohistochemistry for lysosomal markers cathepsin D, lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2) and lysosomal integral membrane protein 2 (LIMP2) distinguishes lysosomal from cytosolic fat [5, 31]. There is no dedicated staging system, and the Kohli consensus proposes using non-alcoholic steatohepatitis systems (NASH-CRN, NASH Clinical Research Network; Brunt; FLIP/SAF, steatosis, activity, fibrosis) [10]. Intestinal biopsy shows histiocytes with lipid vacuoles in the lamina propria, and Witeck's Brazilian review proposes intestinal biopsy at every upper gastrointestinal endoscopy in these patients [5, 46]. A known pitfall is glycogen storage disease type I, in which hepatic lipid quantity may lead the pathologist to suggest Wolman disease until normal acid lipase activity excludes diagnosis [67].

5.6. Practical algorithm

Algorithm sources: [1, 5, 10, 12].

5.7. Prenatal and preimplantation diagnosis

With familial variants identified, prenatal diagnosis may use chorionic villi or amniocentesis, and preimplantation genetic testing is possible [1, 10]. Historically, diagnosis used enzyme activity in cultured amniocytes [2, 20]. In a fetus without known risk, the infantile form may be incidentally detected through adrenal calcification on prenatal ultrasound or hydrops fetalis [1, 49].

6. Differential Diagnosis

6.1. Infantile form

The infantile differential includes diseases combining early liver failure, hepatosplenomegaly, cytopenias and inflammation. The table reproduces the GeneReviews differential [1], supplemented by the Iberian recommendations, Saudubray and ATLAS [2, 5, 47].

AR, autosomal recessive; AD, autosomal dominant.

Adrenal calcification has its own differential. In Wolman disease, calcifications are diffuse and stippled, follow the contours of enlarged glands and preserve their shape; in adrenal haemorrhage, the gland is reduced and calcification irregular; neuroblastoma, tuberculosis, congenital adrenal hyperplasia and Niemann-Pick disease also enter the differential [2, 68]. Gastrointestinally, initial presentation is confused with gastroenteritis, cow's milk protein allergy, pyloric stenosis or intestinal obstruction [2, 29]. Among storage diseases with hepatosplenomegaly and vacuolated lymphocytes, Saudubray lists GM1 gangliosidosis, sialidosis type II, mucolipidosis II, Niemann-Pick A, mucopolysaccharidosis VII, galactosialidosis and prosaposin deficiency, and notes that Pearson syndrome and some congenital disorders of glycosylation may present with hydrops and mimic storage disease [47]. High-performance liquid chromatography of tissue lipids was historically used to distinguish Wolman disease from Niemann-Pick and Gaucher disease [2]. Lymphocyte vacuoles also occur in infections, poisoning, tumours and other lysosomal diseases [5].

6.2. Late-onset form

Sources: [1, 5, 10, 31, 64].

The most important distinction, because of frequency, is from familial hypercholesterolaemia, affecting approximately 1 in 200 to 250 people [5]. Low HDL cholesterol and hepatic abnormalities are the most helpful features separating the two entities, because in familial hypercholesterolaemia HDL cholesterol is usually normal and there is no organomegaly [1, 10]. Resemblance may be misleading: the Danish case in section 10 met possible or probable familial hypercholesterolaemia criteria on four different scales [69], and in two Japanese women with late-onset LAL-D, Achilles tendon thickening on ultrasound met Japan Atherosclerosis Society familial hypercholesterolaemia criteria, although internal tendon structure was homogeneous without the hypoechoic areas or calcification typical of xanthomas [70]. ATLAS and Saudubray also describe type IIb hyperlipoproteinaemia and xanthelasma, placing familial combined hyperlipidaemia in the differential [2, 31]. Sources also remind readers to exclude secondary dyslipidaemia causes, such as hypothyroidism, obesity and metabolic syndrome [31].

With metabolic dysfunction-associated steatotic liver disease (MASLD), overlap is histological and in progression: both progress to fibrosis, cirrhosis and liver failure, but MASLD has predominantly macrovesicular steatosis and LAL-D mainly microvesicular steatosis [1, 5]. The Iberian recommendations propose including acid lipase activity in the exclusion workup for fatty liver disease, especially with microvesicular steatosis, and note that excess weight does not exclude LAL-D [5]. In childhood liver disease, Saudubray recommends first investigating Wilson disease (after 3 years), alpha-1-antitrypsin deficiency, cystic fibrosis, glycogen storage diseases, Wolman disease and hereditary fructose intolerance [47].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

There is no cure. Standard infantile treatment combines enzyme replacement therapy (ERT) with sebelipase alfa and dietary substrate reduction, that is, long-chain fat restriction; in the late-onset form, ERT is the only specific treatment and diet has an adjunctive role [1, 5]. In the infantile form, GeneReviews strongly recommends transfer to a specialist inherited metabolic disease centre with a metabolic physician, metabolic dietitian, paediatric gastroenterology and hepatology, haematology, genetics and social support, and informing the local hospital and treating paediatrician [1]. In the late-onset form, the Kohli consensus recommends an interdisciplinary team (hepatology or gastroenterology, lipidology, cardiology, genetics and nutrition) with a coordinating physician [10]. The European SPC requires supervision by a professional experienced in LAL-D, metabolic diseases or chronic liver disease, and emphasises that treatment should start as early as possible after diagnosis [14].

7.2. Sebelipase alfa: mechanism, formulation and administration

Sebelipase alfa (Kanuma®) is a recombinant human lysosomal acid lipase produced in the egg white of genetically modified chickens, with an amino acid sequence identical to the human enzyme and specific activity of 195 to 345 U/mg [13]. It binds cell surface receptors through its glycans and is internalised into lysosomes, where it hydrolyses cholesteryl esters and triglycerides; the Kohli consensus identifies mannose and mannose-6-phosphate receptors as delivery pathways [10, 13]. Pharmacokinetics are non-linear, with more-than-proportional exposure between 1 and 3 mg/kg, without accumulation; weight and body surface area are clearance covariates, whereas age, sex and enzyme maturation are not [13, 14]. The reported half-life differs between labels because it relies on different models: the United States label gives 5.4 to 6.6 minutes at week 22 on 1 mg/kg fortnightly, and the European SPC a population β half-life of 1.88 to 2.71 hours [13, 14].

The presentation is a single-dose vial containing 20 mg in 10 mL (2 mg/mL), with trisodium citrate dihydrate, citric acid monohydrate and human albumin (10 mg/mL) as excipients and 33 mg sodium per vial; it is stored at 2 to 8 °C [13, 14]. The number of vials is the total milligram dose divided by 20, rounded up to the next vial; the dose is diluted in 0.9 % sodium chloride to a final concentration of 0.1 to 1.5 mg/mL, according to the total volume in the following table, common to both labels [13, 14].

Intravenous infusion uses a low-protein-binding system and 0.2 µm in-line filter over at least 2 hours; it may be reduced to 1 hour in patients tolerating 1 mg/kg well, and should be prolonged with higher doses or after reactions [13, 14]. Diluted solution is used immediately or stored for up to 24 hours at 2 to 8 °C, without freezing or shaking; the European SPC also allows 12 hours below 25 °C [13, 14]. No renal or hepatic impairment adjustment is necessary; patients older than 65 years have not been studied and overweight patients have not been fully evaluated [13, 14].

7.3. Dosing by clinical form and jurisdiction

Sources: [13, 14, 71]. USA, United States of America; FDA, Food and Drug Administration; EU, European Union; ANVISA, Brazilian Health Regulatory Agency; IV, intravenous; LDL-C and HDL-C, LDL and HDL cholesterol.

In the infantile form, the Iberian recommendations advise a starting dose of 3 mg/kg/week with escalation to 5 mg/kg/week if response is suboptimal, and accept, off-label, 5 mg/kg twice weekly in very severe presentations (section 7.9) [5]. The Gulf panel adopts the European SPC doses and proposes escalation within the first three months when at least two criteria of suboptimal response are met: weight gain below 5 g/kg/day with a weight-for-length or length-for-age z-score below −2 according to the World Health Organization, albumin below 35 g/L, ALT above 2 times the upper limit of normal or continued transfusion requirement [12]. GeneReviews states that the approved United States dose is 1 mg/kg/week; that wording corresponds only to the starting dose, because the United States label has allowed escalation to 5 mg/kg/week since the amendment approved in 2021 [1, 13]. The Saudubray table, ‘1–5 mg/kg weekly in the infantile form and 1 mg/kg on alternate weeks in late-onset forms’, is consistent with the labels but omits escalation to 3 mg/kg fortnightly in late-onset forms [72].

7.4. Comparison of regulatory status

Sources: [13, 14, 71, 73, 74]. EMA, European Medicines Agency; EC, European Commission; BLA, biologics license application; CHMP, Committee for Medicinal Products for Human Use.

The medicine was approved in more than 30 countries in 2025 [42]. Actual access varies. In France, sebelipase alfa is not marketed for patients with symptomatic onset after 2 years, who receive it only in a trial or through individual compassionate access [56]. In Brazil, the medicine has marketing registration, but no assessment by the National Committee for Health Technology Incorporation into SUS (CONITEC) was found in the sources consulted, and the Campinas case was untreated for financial reasons [55, 71]. For Portugal, the sources consulted provide no reimbursement or hospital access data.

7.5. Hypersensitivity, anaphylaxis and anti-drug antibodies

Hypersensitivity reactions are the main adverse effect. In the United States label, 3 of 106 patients (3 %), all infants, had signs consistent with anaphylaxis, and 21 of 106 (20 %) signs consistent with or possibly related to hypersensitivity: 9 of 14 infants (64 %) and 12 of 92 patients aged 4 years or older (13 %), most during infusion or within the following 4 hours [13]. In the broader European SPC dataset, comprising 125 patients, severe anaphylaxis occurred in 5 (4 %), 3 of 19 infants (16 %) and 2 of 106 children and adults (2 %), up to 1 year after initiation, and at least one hypersensitivity reaction in 59 (47 %), 13 of 19 infants (68 %) and 46 of 106 children and adults (43 %) [14]. Figures differ because datasets and definitions are not the same.

Management includes temporarily interrupting infusion, reducing the rate and administering antihistamines, antipyretics or corticosteroids; pretreatment with antipyretics and antihistamines may prevent subsequent reactions, and trial patients were not routinely premedicated [13, 14]. Following a reaction, the Kohli consensus recommends testing anti-drug antibodies (ADA) and, if positive, neutralising antibodies, measuring serum tryptase 1 to 2 hours after the reaction and testing specific IgE, with referral to allergy and clinical immunology if positive [10]. Rapid desensitisation was successful in three patients, from infancy to adulthood, with immediate hypersensitivity [75]. GeneReviews recommends desensitisation protocols with serial dilutions and prolonged infusion times [1]. Because sebelipase is produced in egg white, patients with known egg allergy were excluded from trials [13, 14].

Immunogenicity differs between forms. In United States label data, approximately 8 % (9 of 106) of children and adults developed ADA, 2 with neutralising antibodies, compared with approximately 53 % (10 of 19) of infants, 9 with neutralising antibodies [13]. In the European SPC, ADA were transient and low-titre in children and adults and persistent in the 10 positive infants, with persistently high titres in 3 [14]. ARISE found no clear association between ADA and reduced efficacy [13]. In the infantile form, by contrast, ERT response was attenuated by ADA in three of five Manchester infants, and patients with complete LIPA deletion appear particularly exposed [5, 14, 76]. ADA testing is indicated with severe infusion reactions, lack or loss of effect and, according to GeneReviews, when ALT or AST exceed 3 times the upper limit or efficacy is uncertain (weight loss, increased stool frequency, rising ferritin and LDH); very few laboratories worldwide have validated methods for these antibodies [1, 14].

7.6. Other adverse effects

In the infantile VITAL trial, the most frequent adverse reactions were diarrhoea and vomiting (67 % each), fever and rhinitis (56 % each), anaemia (44 %), cough, nasopharyngitis and urticaria (33 % each) [13]. In ARISE, comparing sebelipase with placebo, headache occurred in 28 % versus 20 %, fever in 25 % versus 23 % and oropharyngeal pain in 17 % versus 3 % [13]. The European SPC adds dizziness, abdominal pain, fatigue, tachycardia, flushing, hypotension, dyspnoea and infusion-site reactions in children and adults, and a possible minor influence on driving [14]. Transient asymptomatic hyperlipidaemia is expected in weeks 2 to 4 after initiation through mobilisation of tissue deposits: in ARISE, LDL cholesterol increased in 81 % and triglycerides in 58 % of patients, falling below baseline within approximately 8 weeks [2, 13, 14]. Treatment interruption raises LDL cholesterol and ALT and lowers HDL cholesterol [13, 77]. There were no specific overdose signs up to 7.5 mg/kg/week and cytochrome P450-mediated interactions are not expected [14].

7.7. Clinical trials

Infant trials used a historical comparison cohort and non-randomised dose escalation, so the magnitude of survival effect lacks the robustness of a controlled trial, although the difference from historical mortality approaching 100 % is very large [45, 78]. Comparing VITAL with LAL-CL08 is not a randomised comparison: the Iberian recommendations attribute better LAL-CL08 survival (90 % at 12 months versus 67 % in VITAL), despite more severely affected patients, to higher starting and maximum doses and faster escalation, but this is an inference between trials with different populations and eras [5, 50]. In ARISE, the primary endpoint was ALT normalisation at 20 weeks, a surrogate marker; relative LDL cholesterol reduction should be read alongside the absolute value (mean ALT −57.9 U/L versus −6.7 U/L), and the United States label, expressing the between-arm difference (−22 %; 95 % CI −33 to −15), emphasises that relevance of these changes to liver disease progression has not been established [13, 14]. In paired ARISE biopsies, improvement in steatosis (10 of 16 versus 4 of 10) was not significant [14]. In the pooled LAL-CL02 and LAL-CL06 biopsy analysis, 31 of 36 patients (86.1 %) improved or did not progress in Ishak score at 12 months [14]. There are no trials with cardiovascular endpoints or transplantation or death endpoints in the late-onset form, and no published negative trials were identified.

7.8. Real-world and long-term data

In the International LAL-D Registry, among 53 treated patients with three consecutive annual measurements, ALT exceeded the upper limit in 96 % at baseline and normalised in 42 % after 1 year and 38 % after 3 years, with a median first-year reduction of 51.4 %; among 22 untreated patients, only 27 % had normal ALT at 3 years, without a consistent pattern [42]. In a study from the same registry with 144 treated patients without lipid-lowering drugs, the proportion with LDL cholesterol above 160 mg/dL fell from 78 % to 46 % after 1 year, and triglycerides above the upper limit from 63 % to 32 %, with sustained effect up to 3 years [82]. In the French national database (2007–2020), none of the 10 sebelipase-treated infants died, and the three deaths before 2 years occurred in untreated infants before drug availability [56]. A Canadian case documented histological regression from cirrhosis (Metavir F4) to stage 1 to 2 fibrosis after approximately 8 years of fortnightly treatment [83]. These data are observational, with selection of treated patients and loss to follow-up, and do not replace trials with clinical endpoints.

7.9. Intensified doses and immunomodulation in the infantile form (off-label)

The following regimens are not authorised and are described in small series. In three infants with severe Wolman disease, sebelipase 5 mg/kg twice weekly was well tolerated and effective; leucocyte enzyme activity and plasma oxysterols showed that activity is short-lived after each dose, with lipid reaccumulation at troughs even on this regimen [84]. The Iberian recommendations and GeneReviews accept 5 mg/kg/week or 5 mg/kg twice weekly in very severe presentations or with an inadequate response to 3 mg/kg/week, with reduction to 3 mg/kg/week when disease activity (aminotransferases, ferritin, LDH, weight, transfusion requirement) normalises [1, 5]. These sources do not define a maximum dose; the labels state that doses above 7.5 mg/kg per week have not been studied [14, 71]. A case review describes a newborn treated with 3 mg/kg twice weekly for the first 3 weeks and then 3 mg/kg weekly [29].

Severe systemic inflammation may require immunomodulation with bortezomib or rituximab, also off-label [1, 5]. In the Netherlands, an infant with Wolman disease received high-dose sebelipase, fat restriction and rituximab B-lymphocyte depletion as a bridge to early haematopoietic stem cell transplantation; at 32 months, the child was off ERT, disease-free, with 100 % peripheral blood donor chimerism [85]. This is a single case.

7.10. Diet in the infantile form

Dietary substrate reduction is an essential treatment component and starts at diagnosis [1]. There are no formal nutritional guidelines; the two reference sources are the Iberian recommendations and the 2026 best-practice review, both expert-based, differing on one point [5, 29].

Fat targets. GeneReviews gives total fat below 1 g/kg/day [1]. The 2026 review is more restrictive: lipids below 2 g/day up to 6 months and, with complementary feeding, a pragmatic target of 0.5 g/kg/day up to a maximum of 5 g/day; breast milk and standard infant formulas are contraindicated [29]. The GeneReviews treatment table contains unit errors: protein appears as ‘up to 4 mg/kg/day’ when the correct value is 4 g/kg/day, total fat as ‘<1 mg/g/day’ instead of <1 g/kg/day, and glucose as ‘12–25 mg/kg/day’, when the Iberian recommendations give 12 to 25 g/kg/day [1, 5].

Parenteral nutrition. Most symptomatic infants need parenteral nutrition at diagnosis, alone or combined with enteral nutrition [1, 29]. The Iberian recommendations propose low-lipid parenteral nutrition (up to 1 g/kg/day, with an emulsion containing medium-chain triglycerides, such as SMOFlipid®), protein 4 g/kg/day and glucose from 12 up to 25 g/kg/day, with glucose monitoring [5]. The 2026 review prefers avoiding lipids entirely initially, especially until ERT is established, using a mixed emulsion with medium-chain triglycerides up to 1 g/kg/day only if growth fails with maximal nitrogen and glucose, and avoiding proinflammatory soya-only emulsions; it specifies high sodium, 6 to 8 mmol/kg/day adjusted to urinary sodium [29].

Enteral nutrition. Transition uses a minimal-lipid elemental modular formula based on amino acids and monosaccharides. The Iberian recommendations' example for a 2-month-old infant weighing 3.5 kg is summarised in the table; the formula provides 300 kcal (85.7 kcal/kg) in 350 mL, with 18.7 % energy from protein, 69.1 % carbohydrate and 12.3 % fat [5].

The difference concerns medium-chain triglycerides: the Iberian recommendations include them from initiation (up to 1 g/kg/day), whereas the 2026 review adds them only if growth is not achieved after maximising carbohydrate and protein, with long-chain fat limited to essential fatty acid supplements [5, 29]. Enteral reintroduction starts with oral rehydration solution at 1 mL/kg/h, glucose polymer increases in approximately 1 % steps and complete transition from parenteral nutrition takes 1 to 6 months; a nasogastric tube is often necessary, but the vast majority of children achieve oral feeding [1, 5, 29]. Transition to intact protein with low-fat formula (for example Monogen® or Lipistart®) takes 4 to 6 weeks, or a single day in early-treated patients progressing well [5, 29]. Complementary feeding should not be delayed, and speech and language or occupational therapy helps with oral aversion; the carbohydrate-rich diet requires dental surveillance [29].

Supplements and monitoring. Deficiencies of vitamins A, D, E and K and anaemia are frequent at diagnosis; iron may need intravenous administration (GeneReviews refers to the intramuscular route) because enteral absorption is poor; essential fatty acids are supplemented, for example, with walnut oil or KeyOmega® [1, 29]. Mid-upper arm circumference is a better nutritional indicator than weight, which organomegaly confounds [29]. Diet is maintained long-term: in the 2026 review, poor adherence to lipid restriction between 5 and 8 years accompanied a fall in weight from the 25th to 3rd centile [29]. A patient's siblings should receive minimal-lipid formula from birth until their status is known [29].

7.11. Diet and lipid-lowering drugs in the late-onset form

GeneReviews considers fat restriction unindicated in the late-onset form, although some centres recommend it; the Iberian recommendations propose a low-lipid diet for substrate reduction without strict restriction; the transition consensus recommends a low-cholesterol, low-saturated-fat eating plan reviewed with a metabolic dietitian [1, 5, 28].

The role of lipid-lowering drugs is the greatest therapeutic divergence. GeneReviews includes statins, colestyramine and ezetimibe among supportive measures for hyperlipidaemia, with combination treatment if necessary [1]. The Kohli consensus states that lipid-lowering drugs do not treat pathophysiology or attenuate hepatic progression ‘and may even accelerate the course of disease’, and that no published data existed for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [10]. The Iberian recommendations consider statins controversial and unlikely to benefit, because HMG-CoA reductase inhibition increases hepatic LDL uptake and thus lysosomal burden; ezetimibe reduced hepatic volume, hepatic cholesterol and aminotransferases in deficient mice [5]. The Gulf panel states that statins and PCSK9 inhibitors accelerate hepatic progression, an assertion not demonstrated in a trial [12]. Conversely, a Turin centre treated five CESD patients with ezetimibe and observed LDL cholesterol and ALT improvement in four, without fibrosis progression, advocating lipid-lowering drugs first-line and ERT for non-response [86]. ATLAS considered statin use prudent but noted that many patients so treated progressed to transplantation or death [2, 41]. With ERT, lipid-lowering drugs generally become unnecessary, and improvement in atherogenic biomarkers is independent of them [5, 87]. No lipid-lowering drug has a specific LAL-D indication; available paediatric classes are described in Saudubray's dyslipidaemia chapter [31].

7.12. Haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation (HSCT) before ERT had very high morbidity and mortality: in Krivit's series, one patient died from pulmonary dysfunction and three others failed despite engraftment in two; two siblings died from graft failure and hepatic complications; isolated successful cases were published, including with unrelated umbilical cord blood [2, 88, 89]. Histological disease evidence may persist even after enzyme activity correction [90].

The current paradigm is multimodal therapy: ERT and diet to stabilise and nourish the patient, followed by HSCT. In Manchester, five infants were treated this way; in three, ERT response was attenuated by ADA and one had anaphylaxis; four were alive, with fewer gastrointestinal symptoms, greater fat tolerance and improved villous architecture, and one died after HSCT with active HLH; three had mixed chimerism [76]. The retrospective European Society for Blood and Marrow Transplantation (EBMT) inborn errors group analysis, cited by the Iberian recommendations, included 24 children with the infantile form: 5-year overall survival was 80 % (95 % CI 20–97) in the 5 with prior ERT versus 21 % (7–41) in the remainder (p = 0.03), and conditioning with fludarabine, treosulfan and thiotepa improved survival [5, 91]. Wide confidence intervals reflect sample size.

Described indications are HLH, poor ERT response due to ADA, progressive gastrointestinal mucosal lipid accumulation with malnutrition and growth failure, and difficult-to-manage infusion reactions [1]; the Gulf panel proposes considering HSCT for suboptimal ERT response with severe gastrointestinal symptoms [12]; the Manchester group proposes it for all patients with a well-matched donor [76]. GeneReviews considers more evidence necessary before HSCT can be regarded as definitive treatment, and there are no long-term combined-regimen data [1, 5].

7.13. Liver transplantation

Liver transplantation is indicated in end-stage liver failure but is not curative [1]. In the review of 18 transplanted patients, multisystem progression occurred in 11 (61 %) and death in 6 (33 %), with recurrent microvesicular steatosis, foamy macrophages and graft fibrosis [32]. Exceptions exist: a British boy transplanted at 9.5 years had normal growth, lipids and liver function without histological recurrence 8 years later [92]. The Kohli consensus recommends monitoring transplant recipients like other patients, with attention to vascular complications [10].

7.14. Supportive treatment and agents to avoid

In the infantile form, anaemia and thrombocytopenia are treated with packed red cell and platelet transfusions as indicated, and iron-deficiency anaemia refractory to oral iron with parenteral iron [1, 29]. HLH may require transfusions and anti-inflammatory treatment [5]. Intercurrent viral or catheter infections worsen gastrointestinal symptoms and may require nasogastric feeding [5]. Family support includes social work, care coordination and, when necessary, discussion of palliative care [1]. Saudubray includes electrolyte replacement, parenteral nutrition, liver disease formulas and vitamin and mineral supplementation in supportive care [31].

In the late-onset form, portal hypertension with oesophageal varices is treated according to standard practice, and non-selective beta-blockers reduce bleeding risk although they do not prevent varix formation [1]. Cardiovascular disease is managed by cardiology, controlling other risk factors [1]. The Kohli consensus recommends avoiding excessive alcohol with fibrosis and any alcohol with cirrhosis, stopping smoking, confirming hepatitis B vaccination and excluding coexisting liver disease (alcohol, hepatitis B and C, metabolic steatohepatitis); it adds that nothing indicates increased drug hepatotoxicity in LAL-D [10]. With thrombocytopenia, non-steroidal anti-inflammatory drugs should be avoided [1].

7.15. Pregnancy, lactation, perioperative care and transition

Pregnancy and lactation. Labels differ. The United States label states insufficient data and cites absence of embryo-fetal toxicity in rats and rabbits at exposures up to 164 and 526 times human exposure [13]. The European and Brazilian labels recommend avoiding sebelipase during pregnancy as a precaution [14, 71]. For breastfeeding, the United States label has no data and the European label calls for a decision between discontinuing breastfeeding or therapy [13, 14]. The Kohli consensus recommends referral to high-risk obstetrics and considering treatment discontinuation or modification [10]. No pregnancy series in women with LAL-D were found; in LAL-CL06, one patient left the study for pregnancy at week 64, without outcome data [14]. The decision is individual and should weigh liver disease severity and the effect of interruption, which increases LDL cholesterol and aminotransferases [13].

Perioperative care. The sources consulted contain no specific perioperative recommendations. Foreseeable risks arise from thrombocytopenia, coagulopathy and portal hypertension described in the preceding sections; in the infantile form, laparotomy for suspected obstruction and paracentesis caused severe complications [2, 78].

Transition. The 2025 Spanish consensus formulated 43 transition recommendations: a multidisciplinary team with metabolism, hepatology, nutrition, psychology and social work; a transition coordinator; joint paediatrician and adult physician consultation before transfer; transfer timing defined by patient readiness rather than a fixed age; education on the genetic nature of disease, ERT, cardiovascular risk, pregnancy and genetic counselling; competency checklists and teleconsultation; individual assessment of psychological support; and monitoring adherence to sebelipase and diet [28]. In a lysosomal disease survey, 80 % of patients knew they would be transferred, but half were informed only after 18 years [5]. The Kohli consensus also calls for a transition plan [10].

7.16. Developments over the last twelve months and research

Between October 2025 and October 2026, new evidence identified in the sources consulted was observational, regulatory, expert opinion and preclinical; no results from new interventional trials were found.

Outside this window but relevant to the research landscape are the 2025 registry aminotransferase study [42], the infantile prevalence re-estimate in Mizrahi Jews [37] and AAV8 gene therapy with a hepatocyte promoter developed by Genethon and Inserm, correcting lethality and lipid accumulation in mice [94]. An earlier AAVrh74 gene therapy was more effective in young adults than newborn mice, and the authors consider it better suited to the late-onset form [95]. A French project funded in 2024 is developing autologous haematopoietic stem cell editing with LIPA integration into the α-globin locus, at the preclinical stage [96]. There are also induced pluripotent stem cell-derived liver organoids described in an unreviewed preprint [97], and work on combined CH25H and LIPA deletion, also in preprint [98].

The University of California San Francisco phase 1 PEARL trial (NCT04532047) studies prenatal in utero ERT in several lysosomal diseases, including Wolman disease; it was recruiting in October 2026, with 10 planned participants and expected completion in 2032 [65]. The ClinicalTrials.gov search found no human gene therapy, novel ERT or other molecule trials for LAL-D, which does not exclude their existence in other registries [65].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

The parents of a patient are presumed heterozygous, and their molecular testing is recommended to confirm variant phase and enable reliable counselling [1]. If only one parent is a carrier, with parentage confirmed, the other allele's variant may have arisen de novo in the patient or in a parent with postzygotic germline mosaicism; apparent homozygosity may represent an undetected exon deletion or uniparental isodisomy [1]. In every pregnancy of a carrier couple, the risk is 25 % for an affected child, 50 % for an asymptomatic carrier and 25 % for an unaffected non-carrier [1]. A patient's children are obligate carriers unless the other parent is affected or a carrier, and the parents' siblings have a 50 % carrier probability [1]. Severity may differ between siblings with the same genotype, so one child's clinical form does not guarantee another's [10].

8.2. Sibling and cascade testing

All biological siblings of a patient should receive counselling and testing regardless of symptoms, because early treatment changes prognosis [1, 10]. With known familial variants, targeted molecular testing is performed; without them, enzyme activity is measured [1]. In the infantile form, siblings should be tested as early as possible after birth and fed minimal-lipid formula until the result is known [29]. The sibling treated from birth in the Manchester family is the strongest argument for this approach [52]. Testing minor siblings here has an immediate diagnostic and therapeutic purpose, distinguishing it from carrier status determination in minors, which the specific sources consulted do not address.

8.3. Carriers

Carrier status is determined by testing familial variants; enzyme activity is unsuitable despite ATLAS's contrary position (see 5.2) [1, 2, 10]. GeneReviews recommends offering testing to partners of known carriers and patients, particularly with shared ancestry [1]. In founder populations, the rationale changes: the Los Angeles study authors recommend prenatal carrier screening in Mizrahi Jewish ancestry, where 1 in 26 individuals carries p.(Gly87Val) [37, 38], and the Gulf panel recommends premarital screening in high-prevalence areas [12]. In the general population, carrier frequency is estimated at 1/421 [9], and the sources consulted do not propose population carrier screening outside founder and consanguineous settings.

8.4. Prenatal diagnosis and preimplantation genetic testing

With familial variants identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible; the Kohli consensus recommends informing parents of an affected child about these options [1, 10]. Ideally, counselling takes place before pregnancy and should be offered to affected, carrier or at-risk young adults [1]. GeneReviews recognises differences in perspective on these techniques and recommends DNA banking when molecular diagnosis is unconfirmed [1]. In a pregnancy without known risk, fetal adrenal calcification or hydrops may be the first sign [1, 49].

8.5. Counselling content

Counselling should explain recessive inheritance, variability between siblings, urgency of diagnosis in newborns of couples with an affected child, enzyme test limitations for carriers, reproductive options and, during transition to adulthood, reproductive risks and treatment during pregnancy [1, 5, 10, 28].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Prevalence estimates vary more than tenfold between sources because they measure different things: genetic prevalence calculated from allele frequencies, birth prevalence observed in diagnostic registries, or point prevalence. The table distinguishes them.

The gap between genetic prevalence and diagnosed patient numbers indicates underdiagnosis, especially of the late-onset form, confused with fatty liver disease and familial hypercholesterolaemia [5, 9, 34]. However, Carter's meta-analysis concludes that the disease is ultra-rare and the 1/40 000 estimate unsupported [9].

9.2. Founder populations and geography

In the Californian Mizrahi Jewish population, p.(Gly87Val) estimates differ by method. Jackson and colleagues' study of 1184 individuals of Middle Eastern ancestry (660 Mizrahi Jews) found 22 p.(Gly87Val) alleles (1.85 %), 20 in Mizrahi heterozygotes, and the authors write that LAL-D prevalence in this population is ‘1 in 900’ [38]. This value does not correspond to a Hardy-Weinberg disease prevalence calculated from the observed frequency, and GeneReviews and GeneGuidance reproduce it without explanation [1, 3]. Bernstein and colleagues' screening of 549 Mizrahi Jews, with a carrier frequency of 1/26.1, estimated the rapidly progressive infantile form in 1/2724.8 conceptions, approximately 35 % above prior estimates of 1/12 100 to 1/4200 [37]. This latter estimate rests on an explicit method and is preferred here.

In Spain, c.966+2T>G dominates infantile alleles and c.894G>A late-onset alleles [36]. In Gulf countries, consanguinity increases birth prevalence; Saudi Arabia has more infantile cases, Oman more late-onset cases and the United Arab Emirates a balanced distribution [12]. c.894G>A is rare in African and Asian populations [34]. In registries, most patients are of European ancestry (92 %), with limited data in other groups, including pharmacokinetic data [14, 42, 54].

9.3. Portugal and Brazil

In Portugal, the Portuguese Familial Hypercholesterolaemia Study at the National Institute of Health Doutor Ricardo Jorge identified LAL-D in four children with clinical familial hypercholesterolaemia among 750 individuals studied [62]. A Portuguese author from the same institute participated in the Iberian recommendations [5]. A Porto group, with Polish colleagues, described two infants with infantile disease presenting as secondary HLH who died despite sebelipase [60]. The sources consulted provide no prevalence or treatment access data for Portugal.

In Brazil, Witeck's scoping review assembled 206 paediatric patients from 30 countries [46]; the São Paulo series described seven children with predominant p.(Leu89Pro) [39]; an adult was diagnosed among 73 candidates for liver transplantation for disease of unknown cause [40]; the Federal University of São Paulo lipid clinic assessed targeted screening criteria [64]; and the Campinas case documented hepatocellular carcinoma after 15 untreated years for financial reasons [55]. Sebelipase has ANVISA registration [71].

9.4. Special populations

Patients older than 65 years were not studied in trials, and overweight patients have not been fully evaluated [13, 14]. In France, eight of 26 late-onset patients used antidepressants, an administrative finding suggesting psychological burden, recognised by the transition consensus in recommending individual assessment of psychological support [28, 56].

9.5. European reference networks, registries and patient organisations

In Europe, patients fall within MetabERN, the European reference network for inherited metabolic diseases (https://metab.ern-net.eu/), and ERN RARE-LIVER for rare liver diseases (https://rare-liver.eu/); the Iberian recommendations also involve ERN TransplantChild centres [5]. The prospective observational International LAL-D Registry (NCT01633489) collects data on both forms, treated or untreated, and is planned until 2029 [14, 65]. Patient organisations and information resources include the Spanish AELALD association (https://www.aelald.org/), co-author of Spanish consensus documents [5, 28], the United Kingdom MPS Society, supporting LAL-D patients (https://www.mpssociety.org.uk/), and resources listed by GeneReviews: LAL-D Aware, Metabolic Support UK, Liver UK, NORD (National Organization for Rare Disorders) and MedlinePlus and NINDS pages [1]. No specific Portuguese or Brazilian association was identified in the sources consulted.

10. Illustrative Clinical Case

10.1. Late-onset form with a familial hypercholesterolaemia phenotype

In 2026, Martinsen and colleagues from Aalborg and Aarhus, Denmark, published the case of a 13-year-old girl with right knee juvenile arthritis whose tests before starting methotrexate showed ALT 354 U/L (normal 10–45 U/L) and alkaline phosphatase 479 U/L (normal 45–115 U/L), without other symptoms [69]. Persistent abnormalities led to a lipid profile showing total cholesterol 9.3 mmol/L (approximately 360 mg/dL), LDL cholesterol 7.1 mmol/L (approximately 275 mg/dL) and triglycerides 2.7 mmol/L; haemoglobin, ferritin, thyrotropin, bilirubin, caeruloplasmin, alpha-1-antitrypsin, immunoglobulins, autoantibodies, erythrocyte sedimentation rate, C-reactive protein and viral serology were normal [69]. Ultrasound showed hepatomegaly, magnetic resonance cholangiopancreatography confirmed hepatosplenomegaly and excluded primary sclerosing cholangitis, and hepatic elastography measured 5.9 kPa, within normal limits [69]. Liver biopsy showed hepatocyte ballooning and clear cytoplasm, prompting suspected glycogen storage disease, without steatosis or autoimmune signs [69]. There was no xanthelasma, corneal arcus or xanthomas, parental LDL cholesterol was 2.4 mmol/L (father) and 3.3 mmol/L (mother), and there was no cardiovascular family history [69].

The familial hypercholesterolaemia panel (LDLR, APOB, PCSK9) was negative. Trio genome sequencing identified compound heterozygosity in LIPA for NM_000235.4:c.894G>A p.(Gln298=), inherited maternally, and NM_000235.4:c.419G>A p.(Trp140*), inherited paternally, both classified pathogenic; lysosomal acid lipase activity, measured subsequently, was undetectable [69]. The pedigree in Figure 1 shows the affected patient, heterozygous parents and siblings, a fraternal twin and a younger brother, not yet tested, with LDL cholesterol 2.1 mmol/L and normal ALT (Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC13289743/figure/ytag454-F1/) [69]. The authors applied familial hypercholesterolaemia scales: the patient met MEDPED (Make Early Diagnosis to Prevent Early Deaths) criteria, had a ‘possible’ diagnosis by Dutch Lipid Clinic Network and Simon Broome scales and ‘probable’ by the paediatric FH-PeDS scale (12 points), illustrating misdiagnosis risk [69].

Between June 2022 and January 2024, LDL cholesterol ranged from 4.9 to 7.1 mmol/L and ALT from 92 to 262 U/L. Initial treatment consisted of dietitian-guided dietary restriction and a statin while ERT was discussed; the authors identify high cost, fortnightly infusions in an asymptomatic adolescent and absence of guidelines on when to initiate as obstacles [69]. Over 21 months there was no fibrosis progression (elastography 5.9 kPa in January 2023 and 5.3 kPa in October 2024), and the plan is clinical assessment every 6 months, annual elastography and biopsy if necessary; at 17 years the patient remained without other symptoms [69]. The article's summary figure is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC13289743/figure/ytag454-F2/ [69].

The case illustrates four points. First, late-onset LAL-D may present as an isolated laboratory finding and meet familial hypercholesterolaemia criteria; HDL cholesterol was not reported, and the combination of very high LDL cholesterol with elevated aminotransferases and parents with normal lipids guided investigation [10, 69]. Second, biopsy without apparent steatosis, suggesting glycogen storage disease, shows that histology can mislead, just as glycogen storage disease can mimic LAL-D [67, 69]. Third, normal elastography is consistent with the warning that it may underestimate fibrosis in this disease [5]. Fourth, the authors started a statin despite reservations expressed by the Kohli and Iberian consensus documents; this is the report's management rather than a recommendation, and diverges from those consensus statements (see 7.11) [5, 10, 69]. According to the consensus recommendations, siblings should be tested regardless of symptoms [10].

10.2. Infantile form identified through adrenal calcifications

In 2026, Niño and colleagues from Bogotá described a 2-month-old girl with vomiting, postprandial distension, diarrhoea, poor weight gain, erythematous plaques in skin folds and hepatomegaly, initially treated as cow's milk protein allergy without improvement [68]. The article's laboratory table shows total cholesterol 297.4 mg/dL, LDL cholesterol 239 mg/dL, HDL cholesterol 8 mg/dL and triglycerides 251 mg/dL; the article text describes very low total and LDL cholesterol, contradicting its own table, and the tabulated values are followed here [68]. Ultrasound showed hepatosplenomegaly with steatosis and enlarged adrenals with echogenic foci and acoustic shadowing (Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC13002258/figure/FIG1/), and contrast CT showed stippled cortical calcifications preserving gland shape (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC13002258/figure/FIG2/) [68]. Acid lipase activity was below 0.03 per punch per hour (reference 0.37–2.30; the article prints the unit as mmol, probably instead of nmol), and genetics showed homozygosity for LIPA c.652C>T p.(Arg218Ter), without a transcript specified [68]. Sebelipase, at an unspecified dose, was accompanied by weight gain and resolution of vomiting [68]. The case shows the typical initial misdiagnosis pathway and the value of adrenal calcifications as an imaging clue, with the pattern distinguishing them from adrenal haemorrhage (see 6.1).

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Infantile form. Without treatment, disease is fatal in virtually all cases, with median age at death 3.7 months and probability of survival beyond 12 months 0.114 [45]. With sebelipase, 12-month survival was 67 % in VITAL and 90 % in LAL-CL08, and 5-year survival 68 % in the pooled analysis [14, 50, 78]. Of 19 children in the two trials, 6 died, none from a treatment-related cause, and 4 had received at most 4 doses, reinforcing the importance of early diagnosis and treatment [5]. Real-world cohorts starting treatment in the first month show 100 % survival with 1 to 10 years of follow-up, normal growth and schooling without special needs [51], and the infant treated from birth became asymptomatic [52]. Suboptimal growth, anaemia, intestinal lipid accumulation, immunogenicity and dependence on a highly restrictive diet remain limitations [1, 76]. Long-term data beyond adolescence do not yet exist [1].

Late-onset form. The course is unpredictable, ranging from subclinical forms to liver failure in the first decade [10, 41]. Without ERT, 13 % in Burton's series underwent liver transplantation [53], 17 of the 135 patients in Bernstein's review progressed to liver failure with transplantation or death [41] and, in the French database, cardiovascular events clustered in patients diagnosed in adulthood and untreated [56]. With ERT, ARISE showed no hepatic progression up to 5 years and most biopsies improved or stabilised [14, 79]. GeneReviews considers long-term efficacy for survival and complication prevention less clear than in the infantile form because of absent data beyond 5 years and hard clinical endpoints [1]. Patients diagnosed earlier in childhood tend to progress faster, but no clinical, enzymatic or genetic feature predicts individual course [2, 10].

11.2. Initial assessment

In the infantile form, initial assessment includes ALT, AST, albumin, gamma-glutamyltransferase (GGT), alkaline phosphatase, total and conjugated bilirubin, LDH, fat-soluble vitamins, essential fatty acids, magnesium, selenium and electrolytes; weight, length and mid-upper arm circumference; full blood count, ferritin and coagulation; and genetic counselling [1]. In the late-onset form, the Kohli consensus recommends LIPA sequencing, confirmation of hepatitis B vaccination, exclusion of coexisting liver disease, lipid profile (with directly measured LDL cholesterol if triglycerides exceed 400 mg/dL, that is, 4.52 mmol/L), hepatic assessment with elastography and steatosis quantification, baseline biopsy, kidney function, full blood count and coagulation and, in adults, echocardiography, carotid Doppler ultrasound with intima–media thickness and exercise testing when indicated [10]. GeneReviews adds upper gastrointestinal endoscopy for variceal screening in severe liver disease and cardiology referral for hyperlipidaemia [1].

11.3. Surveillance in the infantile form

11.4. Surveillance in the late-onset form

Intervals differ between documents, especially for clinical assessment, lipid profile, endoscopy and full blood count; none rests on comparative evidence, and optimal intervals for abdominal imaging and hepatocellular carcinoma surveillance are not established [1, 55]. ATLAS, predating consensus documents, proposed annual liver tests, chitotriosidase and lipid profile, periodic abdominal MRI and annual electrocardiogram and echocardiogram [2]. The Gulf panel proposes annual laboratory, cardiovascular, neurovascular, renal and haematological assessment, with optional follow-up biopsy [12]. The Danish case in section 10, without ERT, followed a six-monthly clinical assessment and annual elastography plan [69].

12. Summary and Final Considerations

Lysosomal acid lipase deficiency is an autosomal recessive LIPA disease in which deficient lysosomal hydrolysis of cholesteryl esters and triglycerides produces lipid storage in hepatocytes and macrophages and dyslipidaemia through dysregulated cholesterol synthesis and uptake. Disease forms a spectrum: at one extreme, the infantile form, or Wolman disease, with malabsorption, hepatosplenomegaly, adrenal calcification, systemic inflammation and death before 6 months without treatment; at the other, the late-onset form, or CESD, with hepatomegaly, elevated aminotransferases, microvesicular steatosis progressing to cirrhosis and high LDL with low HDL cholesterol and premature atherosclerosis.

Recognition depends on considering disease in settings where it is rare: the infant with vomiting, diarrhoea and distension treated as gastroenteritis, food allergy or HLH; the child or adult with unexplained elevated aminotransferases and fatty liver; and the patient with a familial hypercholesterolaemia phenotype without an identified variant, especially with low HDL cholesterol and hepatic abnormalities. Diagnosis rests on enzyme activity in dried blood spots or leucocytes and LIPA sequencing, requested simultaneously in the infantile form. Reference ranges are laboratory-specific, an isolated normal result may be false-negative, enzyme activity cannot identify carriers and the most frequent variant, c.894G>A, should be described by its splice effect rather than synonymous notation p.(Gln298=) alone.

Sebelipase alfa transformed the infantile form into a disease with prolonged survival, provided immediate treatment in a specialist centre with a highly fat-restricted diet and response-guided dose escalation. Labels differ in infant starting dose (1 mg/kg/week in the United States; 1 or 3 mg/kg/week in the European Union and Brazil), contraindication for anaphylaxis or egg allergy (present in Europe and Brazil, absent in the United States) and pregnancy, and the United States label has carried an anaphylaxis boxed warning since 2024. Intensified doses, immunomodulation and haematopoietic stem cell transplantation after stabilisation are off-label or limited-evidence options reserved for attenuated responses, especially antibody-mediated. In the late-onset form, sebelipase normalises aminotransferases in some patients, improves lipid profile and stabilises hepatic histology over 5 years, but there are no hard clinical endpoint trials, and lipid-lowering drugs remain controversial between consensus documents advising against them and centres using them first-line.

Available recommendations are expert consensus documents without formal grading and with declared conflicts of interest, differing on practical points: infant starting dose, medium-chain triglycerides in the initial formula, need for baseline liver biopsy, adrenal function and surveillance intervals. Treatment access is unequal, with documented French restrictions for the late-onset form and uncertain Brazilian and Portuguese access in the sources consulted. Testing siblings at birth, carrier screening in founder and consanguineous populations and newborn screening pilots are the strategies most likely to advance treatment timing, while gene therapy remains preclinical.

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