Ten-year enzyme replacement therapy in early childhood-onset lysosomal acid lipase deficiency: A case report

Abstract

BACKGROUND

Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lipid storage disorder caused by biallelic pathogenic variants in the LIPA gene. The clinical phenotype ranges from the rapidly progressive infantile form (Wolman disease), which usually results in death within the first year of life, to the childhood/adult-onset form, historically known as cholesteryl ester storage disease. Diagnosis of the later-onset form is often delayed owing to nonspecific clinical features, such as hepatomegaly, elevated transaminases, dyslipidemia resembling heterozygous familial hypercholesterolemia, and/or intestinal manifestations such as malabsorption.

CASE SUMMARY

A 21-month-old boy presented with abdominal swelling and fever. Physical examination and laboratory evaluation revealed short stature, hepatomegaly, dyslipidemia, and mildly elevated hepatic enzyme levels. Liver biopsy showed fibrosis, lobular inflammation, microvesicular steatosis, and portal inflammation. Lysosomal acid lipase enzyme activity was undetectable, and genetic analysis revealed a biallelic c.894G>A (p.Gln298=) pathogenic variant in the LIPA gene, confirming the diagnosis of LAL-D. The patient was initiated on enzyme replacement therapy with sebelipase alfa at 3 years and 11 months of age through a compassionate use access program. Over 10 years of follow-up, the patient showed clear clinical benefit, including normalization of liver enzymes, improvements in dyslipidemia, reduction in hepatomegaly and hepatic fat content, improvement in liver histopathology, and catch-up growth. No treatment-related adverse effects were observed.

CONCLUSION

This case highlights the long-term effectiveness and safety of sebelipase alfa initiated in early childhood and emphasizes the importance of early recognition and treatment of LAL-D to prevent irreversible organ damage and disease progression.

Key Words: Cholesteryl ester storage diseases; Wolman disease; Enzyme replacement treatment; Sebelipase alfa; Lysosomal acid lipase deficiency; Lysosomal storage disorders; Case report

Core Tip: Early diagnosis of lysosomal acid lipase deficiency (LAL-D) is challenging owing to its nonspecific clinical presentation. We report a rare case diagnosed before the age of 4 years, with long-term follow-up after early initiation of enzyme replacement therapy. Our patient showed marked improvements in growth, liver function, and histology over 10 years, with no treatment-related adverse events. This case highlights the importance of early recognition and timely treatment of LAL-D to optimize long-term outcomes in affected children.

INTRODUCTION

Lysosomal acid lipase (LAL) is an enzyme involved in lipid metabolism; it hydrolyzes cholesteryl esters and triglycerides to produce free fatty acids and cholesterol inside the cells. When the enzyme is deficient, intra-lysosomal cholesteryl ester and triglyceride substrates accumulate in the liver, spleen, gastrointestinal system, and vascular walls, causing progressive organ damage[1,2]. Biallelic pathogenic variants in the LIPA gene result in LAL deficiency (LAL-D), which is inherited in an autosomal recessive manner. True prevalence of LAL-D is unknown, but it is estimated to range between 1 in 40000 and 1 in 300000[3].

The clinical phenotype of LAL-D exists on a spectrum, with earlier onset generally associated with more severe disease. For clinical purposes, two forms are distinguished: A rapidly progressive infantile LAL-D (formerly known as Wolman disease) and a childhood/adult-onset form (formerly known as cholesteryl ester storage disease). The infantile form is characterized by failure to thrive, hepatosplenomegaly, portal hypertension, adrenal calcification, and systemic inflammation, and usually results in death within 6-12 months of birth. In contrast, childhood/adult-onset LAL-D presents with progressive hepatomegaly, elevated transaminases, dyslipidemia resembling heterozygous familial hypercholesterolemia, and/or gastrointestinal involvement, including malabsorption.

Diagnosis is established by measuring LAL enzyme activity in peripheral blood leukocytes or dried blood spots, the latter being a quick, reliable, and minimally invasive method, and is confirmed by genetic analysis. In leukocyte samples, residual enzyme activity is generally lower in infantile-onset LAL-D (≤ 5% of controls) compared to the childhood/adult-onset form (2%-11%)[4].

Historically, the management of LAL-D was limited to control of cholesterol levels through dietary modification and antihyperlipidemic agents, with the primary goal of preventing early atherosclerosis. However, the approval of enzyme replacement treatment (ERT) with sebelipase alfa by the European Medicines Agency and the United States Food and Drug Administration has significantly improved the survival and quality of life of affected patients[2,5].

CASE PRESENTATION

Chief complaints

A 21-month-old boy was hospitalized in the pediatric infectious diseases ward for the first time owing to abdominal swelling and elevated hepatic enzyme levels. He was initially suspected of having viral hepatitis.

History of present illness

There was no history of diarrhea, jaundice, fever, or bleeding. During follow-up, the patient’s organomegaly progressively increased and was accompanied by persistent elevation of transaminase levels. Subsequent laboratory evaluations revealed elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides, with decreased high-density lipoprotein cholesterol. Infectious causes, including viral hepatitis, malignancy, hematological disorders, and bile duct pathologies, were excluded. A liver biopsy was performed owing to the persistent hepatic dysfunction lasting more than 3 months.

History of past illness

The patient had no significant past medical history, and routine childhood vaccinations were up to date.

Personal and family history

The patient’s parents were first-degree cousins. There was no family history of similar illness, hepatic disease, or known genetic disorders. His mental and motor developmental milestones were appropriate for his age. The patient attends a public school and demonstrates age-appropriate academic performance.

Physical examination

On admission, the patient’s length was 78 cm (Z-score: -2.04) and weight was 10 kg (Z-score: -1.59). No jaundice, petechiae, or ecchymosis was observed. Cardiovascular and respiratory system evaluations were unremarkable. The liver was palpable 3 cm below the subcostal margin in the midclavicular line, with a soft and regular surface. Traube’s space was open. Neurological examination showed no abnormalities.

Laboratory examinations

Laboratory tests showed slight anemia (hemoglobin: 10.4 g/dL; normal range: 11.0-13.7 g/dL) and mildly elevated hepatic enzymes [alanine aminotransferase: 59 U/L (normal range: 0-40 U/L); aspartate aminotransferase: 62 U/L (normal range: 0-41 U/L)]. Complete blood count, serum albumin, bilirubin, and coagulation parameters were within normal ranges. No evidence of cholestasis was detected. LAL enzyme activity measurement was performed as a part of metabolic assessment, which was found to be 0 nmol/punch/h, and genetic testing revealed a homozygous c.894G>A pathogenic variant in the LIPA gene.

Imaging examinations

Abdominal ultrasonography revealed borderline hepatomegaly, while parenchymal echogenicity appeared normal. Magnetic resonance imaging showed hepatomegaly and hepatosteatosis (Figure 1). Initial liver biopsy revealed fibrosis, lobular inflammation, microvesicular fibrosis, portal inflammation, and clusters of ceroid-containing macrophages within the portal areas and lobules.

Figure 1  Magnetic resonance imaging of the upper abdomen indicated hepatomegaly and hepatosteatosis.

FINAL DIAGNOSIS

LAL-D, confirmed by absent LAL enzyme activity and a homozygous c.894G>A pathogenic variant in the LIPA gene.

TREATMENT

The patient was started on sebelipase alfa treatment, provided through Alexion’s managed access program, at a dose of 1 mg/kg every 2 weeks. A lipid-restricted diet was recommended; however, adherence was suboptimal. In addition to ERT, only omega-3 supplementation was administered. Owing to the patient’s age, antihyperlipidemic treatment was not initiated.

OUTCOME AND FOLLOW-UP

After 10 years of ERT, significant improvements were observed in the patient’s growth parameters, hepatomegaly, dyslipidemia, and liver biopsy findings. At the most recent evaluation, his length was 147 cm (Z-score: -1.04) and weight was 40 kg (Z-score: -0.83). Hepatic transaminase levels and blood lipid levels also improved significantly during ERT (Table 1). No treatment-related adverse effects were observed during follow-up.

Table 1 Hepatic function tests and lipid levels before and during enzyme replacement therapy.

Evaluation time	AST (9-43) U/L	ALT (4-45) U/L	TC (< 170) mg/dL	LDL-C (< 110) mg/dL	HDL-C (> 35) mg/dL	TG (< 130) mg/dL	GGT (6-26) U/L	ALP (150-420) U/L
Before treatment	59	82	264	193	29	168	28	320
Treatment week 52	46	43	222	160	47	69	-	221
Treatment week 104	55	71	222	173	36	62	13	315
Treatment week 156	31	30	227	166	43	89	11	280
Treatment week 208	32	34	340	271	50	93	16	371
Treatment week 260	51	46	297	211	62	118	-	406
Treatment week 312	28	26	202	126	58	87	-	-
Treatment week 364	33	33	236	130	56	64	-	337
Treatment week 416	38	34	187	129.4	44	68	13	263
Treatment week 468	28	28	177	92.4	55	76	13	-

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: γ-glutamyltransferase; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; TC: Total cholesterol; TG: Triglycerides.

Evaluation of liver and spleen size (expressed as multiples of normal) and lipid content by magnetic resonance imaging before treatment and at weeks 48 and 96 showed significant improvements (Table 2). Follow-up liver biopsies performed at weeks 52 and 104 revealed significant reductions in the Ishak fibrosis score[6], lobular inflammation, and portal inflammation (Table 3).

Table 2 Evaluation of liver and spleen size and lipid content by abdominal magnetic resonance imaging.

Parameter	Evaluation time	Absolute value (multiples of normal)	Change from baseline	% change from baseline
Hepatic volume	First visit	1.79
	Week 48	1.30	-0.48	-27.1
	Week 96	1.41	-0.37	-20.9
Hepatic lipid content	First visit	7.52
	Week 48	6.62	-0.9	-12.0
	Week 96	7.77	0.25	3.3
Splenic volume	First visit	2.24
	Week 48	2.73	0.49	21.9
	Week 96	2.16	-0.08	-3.7
Splenic lipid content	First visit	1.41
	Week 48	2.23	0.24	12.1
	Week 96	1.37	-0.62	-31.2

Table 3 Assessment of hepatic biopsy findings before and during enzyme replacement therapy.

Evaluation time	Ishak fibrosis score	Lobular inflammation	Macrovesicular steatosis	Microvesicular steatosis	Portal inflammation
Before treatment	3	2	0	4	3
Treatment week 52	2	1	1	2	1
Treatment week 104	1	1	0	4	2

DISCUSSION

LAL-D may present with variable clinical courses in each age group. Rapidly progressive, infantile-onset LAL-D, the most severe form of the disorder, typically manifests with hepatosplenomegaly, vomiting, diarrhea, and adrenal calcification, and progresses rapidly. In contrast, the childhood/adult-onset form often begins with milder signs, such as elevated hepatic aminotransferase levels, hepatosteatosis, and dyslipidemia, but may eventually progress to cirrhosis.

Owing to its acute clinical course, patients are more frequently diagnosed with LAL-D during the newborn period and early infancy. However, numerous cases have also been reported in adulthood. For example, a 29-year-old woman with a 7-year history of abdominal pain and intermittent diarrhea was diagnosed with LAL-D following the endoscopic detection of a duodenal xanthoma[7]. In another report, a 53-year-old patient with a normal body mass index underwent liver biopsy during the evaluation of unexplained hepatic cirrhosis in the setting of dyslipidemia, a family history of myocardial infarction and stroke, and intrahepatic calcifications identified on abdominal imaging[8]. The diagnosis of LAL-D was subsequently confirmed through genetic analysis following the histological detection of cholesteryl ester deposits.

The true prevalence of LAL-D is not well established, and epidemiological data from Türkiye remain limited. The number of reported cases remains low, partly because clinical findings in children between the newborn period and 4 years of age may be subtle, and LAL-D is usually not considered early in metabolic or non-metabolic differential diagnosis. In a case report from Mexico, the older of two siblings experienced intermittent diarrhea and constipation beginning at 2 months of age, followed by hepatosplenomegaly with liver function test abnormalities at 6 months; however, the child was not diagnosed with LAL-D until 9 years of age. As a result, the younger sibling underwent earlier evaluation (age of onset: 6 months) and was diagnosed at 4 years of age[9]. In another report from Türkiye, two siblings were diagnosed during infancy while being investigated for hepatic dysfunction, hepatomegaly, and dyslipidemia[10]. During treatment, their hepatic and adrenal functions were found to be normal; however, the duration of treatment was not specified.

Another reason for the low number of reported cases is that studies have demonstrated reduced dried blood spot LAL activity in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, clinical conditions characterized by hepatic lipid accumulation[11-13]. Therefore, some cases may remain unreported because they are actually LAL-D but have been misdiagnosed as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or cryptogenic liver cirrhosis.

Regarding the efficacy of ERT in patients diagnosed at an age comparable to our case, reports with follow-up extending beyond 2 years are lacking. Our patient was diagnosed after hospitalization for suspected viral hepatitis and subsequent assessment based on the findings of short stature, hepatomegaly, elevated liver transaminases, dyslipidemia, increased acid phosphatase levels, and confirmed liver biopsy findings. No evidence of vomiting, diarrhea, or adrenal calcification was observed, features that are commonly reported in the most severe manifestations of the disease. Similar cases have been reported where the clinical picture initially presents with hepatomegaly and hepatosteatosis in early childhood, with dyslipidemia and elevated hepatic transaminases appearing in late childhood or adolescence[14,15]. Liver biopsy findings suggestive of LAL-D may include micro- or macrovesicular steatosis and varying degrees of fibrosis[16].

In children and more than half of the adults diagnosed with LAL-D, the most commonly observed pathogenic variant in genotype analysis is the c.894G>A (E8SJM-1G>A, rs 116928232) splice-junction variant located on exon 8, which was also detected in our patient[17,18]. This variant causes in-frame deletion of exon 8 and produces a mutant enzyme with residual LAL activity[19]. In a study by Bernstein et al[20] examining 135 patients, individuals homozygous for the E8SJM variant were typically observed to have early disease onset but slow progression. Consistent with these observations, the disease onset in our patient was at 21 months of age; however, disease progression stabilized after initiation of ERT, with reversal of several clinical and biochemical abnormalities.

Before the introduction of ERT with sebelipase alfa, the primary goal of treatment in patients diagnosed outside the newborn period was improvement of dyslipidemia to prevent atherosclerosis and related complications. Management strategies included lipid-restricted diets and lipid-lowering agents such as statins and cholestyramine. Although these approaches were reported to improve dyslipidemia biochemically[21], persistent abnormalities were frequently reported, and the desired effects were not observed in liver biopsy samples[3,20-23].

Liver transplantation has also been used as a treatment option for LAL-D, particularly in some patients with end-stage hepatic failure or hepatic cancer. However, outcomes have been variable. Bernstein et al[24] reported that among 18 patients with LAL-D, disease progression with multisystem involvement continued in 61% of cases despite liver transplantation. Histologic evaluation demonstrated persistent lipid-laden macrophages in the liver, gastrointestinal tract, and bone marrow, attributed to the continuing deficiency of LAL enzyme activity in histiocytes of bone marrow origin and other tissues. Therefore, liver transplantation is not considered a curative treatment approach for LAL-D[17]. Although hematopoietic stem cell transplantation has been proposed to correct the metabolic defect, the potential benefits must be carefully weighed against the significant morbidity and mortality associated with the procedure[25].

Our patient started ERT with sebelipase alfa at 1 mg/kg every 2 weeks at 3 years and 11 months of age through a compassionate use early access program. No treatment-related adverse effects were observed during the 10-year treatment period. Dyslipidemia improved, and previously elevated hepatic transaminase levels returned to normal. In the second year of treatment, magnetic resonance imaging demonstrated reductions in hepatic and splenic size, along with a 12% decrease in hepatic lipid content and a 31% decrease in splenic lipid content. Liver biopsy also showed improvement in the second year. As liver biopsy is an invasive procedure, and the patient exhibited significant clinical improvement, further biopsies were not performed.

In the study by Burton et al[26], adult patients with LAL-D treated with sebelipase alfa demonstrated a four-fold greater reduction in hepatic lipid content and hepatic volume compared to those receiving placebo. Although not statistically significant, the reduction in hepatosteatosis was shown to be more frequent in the sebelipase alfa group than in the placebo group. Significant reductions in transaminases and other hepatic disease markers, as well as hepatic lipid content, suggest that sebelipase alfa may help reduce the risk of progression to fibrosis and cirrhosis. Consistent with these findings, sebelipase alfa, used as a recombinant ERT, has also been reported to decrease liver enzymes, total cholesterol, and triglycerides while increasing HDL levels in adult patients with rapidly progressive, infantile-onset LAL-D[23]. However, the duration of treatment outside the newborn period remains relatively short, typically spanning only 2-3 years. In comparison, our patient received ERT for 10 years, resulting not only in biochemical and imaging improvements but also in normalization of growth parameters, suggesting a positive impact of therapy on overall growth.

CONCLUSION

This case highlights the importance of considering LAL-D in the differential diagnosis of hepatomegaly, dyslipidemia, and persistent elevation of liver enzymes in early childhood. The long-term follow-up over 10 years demonstrates that early initiation of sebelipase alfa can lead to sustained clinical, biochemical, and histological improvement. These findings support the growing evidence that timely ERT may alter the natural course of LAL-D and prevent progressive liver disease.