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This phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, which causes cirrhosis and severe dyslipidemia, showed that enzyme replacement lessened multiple disease-related hepatic and lipid abnormalities. Lysosomal acid lipase deficiency (Online Mendelian Inheritance in Man number, 278000) 1 is an autosomal recessive storage disease that is caused by mutations in the LIPA gene. 2 In infants, progression of the disease (historically known as Wolman’s disease) is very rapid, with death typically occurring by 6 months of age. 2 In older patients, progression of the disease (historically known as cholesteryl ester storage disease) leads to cirrhosis and other complications in childhood or later in life. 3 Common features in infants, children, and adults include elevated serum aminotransferase levels, dyslipidemia, hepatomegaly, liver fibrosis, and cirrhosis. 3 – 5 Awareness of the disease is low, . . .

Background Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age. Results Nine patients were enrolled; median age at baseline was 3.0 months (range 1.1–5.8 months). Sixty-seven percent (exact 95% CI 30%–93%) of sebelipase alfa–treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%–16%) for a historical control group ( n  = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious. Conclusion Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency Trial registration Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.

Background Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, presents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age. In clinical trials, enzyme replacement therapy (ERT) with sebelipase alfa led to improved survival, growth and biological parameters in WD patients followed up to 5 years. Long-term follow-up and health-related quality of life (HRQoL) evaluation are lacking. Results We performed a nationwide, retrospective study of sebelipase alfa in WD patients. Five patients with abolished LAL activity and bi-allelic LIPA mutations were included with a median follow-up of 7 years (1–10). ERT was initiated at a median age of 1 month (0–4). Infusion tolerance was excellent on the long-term with only one patient requiring systematic pre-medication. Cholestyramine, fat-soluble vitamin supplements and a specific diet (high in medium-chain triglycerides and low in long-chain fatty acids) were prescribed. Liver function tests, plasma lipid profiles, fat-soluble vitamin levels and growth parameters improved. Three patients transiently exhibited a neuromyopathic phenotype (footdrop gait, waddling walk or muscle fatigue) but electromyography and muscle strength testing were normal. At last follow-up, all patients were alive with normal growth parameters and a satisfactory HRQoL, no patient had special education needs, and one patient required parenteral nutrition since an acute gastroenteritis. Conclusions Early ERT initiation allowed 100% survival with positive outcomes. Very long-term follow-up and hematopoietic stem cell transplantation while on ERT should be evaluated to strengthen the benefits of sebelipase alfa.

There are more than 50 different lysosomal storage diseases, genetic disorders characterized by lysosomal accumulation of substrate. 1 Phenotypes vary widely, depending on the specific cell types affected. Enzyme-replacement therapy has been transformational in the treatment of some lysosomal storage diseases 2 ; however, enzyme-replacement therapy is currently approved and commercially available for only 7 lysosomal storage diseases. The principle of enzyme-replacement therapy is that after administration of a recombinant enzyme, it is taken up by target cells and directed to lysosomes, where it can hydrolyze its substrate. 2 In Gaucher’s disease, the recombinant enzyme is taken up by target macrophages by means . . .

Wolman’s disease, a severe form of lysosomal acid lipase deficiency, leads to pathologic lipid accumulation in the liver and gut that, without treatment, is fatal in infancy. Although continued enzyme-replacement therapy (ERT) in combination with dietary fat restriction prolongs life, its therapeutic effect may wane over time. Allogeneic hematopoietic stem-cell transplantation (HSCT) offers a more definitive solution but carries a high risk of death. Here we describe an infant with Wolman’s disease who received high-dose ERT, together with dietary fat restriction and rituximab-based B-cell depletion, as a bridge to early HSCT. At 32 months, the infant was independent of ERT and disease-free, with 100% donor chimerism in the peripheral blood. An infant with Wolman’s disease, diagnosed in utero, received enzyme-replacement therapy, a fat-restricted diet, and rituximab-based B-cell depletion as a bridge to early hematopoietic stem-cell transplantation.

Correspondence to Dr Paul Manka, Department for Gastroenterology and Hepatology, University Hospital Essen, Essen 45122, Germany; paul.manka@uk-essen.de Clinical presentation Here we report a case of a 68-year-old woman who presented to our centre for further evaluation of elevated liver function tests (LFTs). In the following years, she complied with a strict Mediterranean diet and intensified physical activity with an initial body mass index of 29.4 kg/m2. Numerous specialists from different areas missed the diagnosis even though liver histology was performed. [...]if lifestyle change measures do not show any effects and if medical history of relatives is suspicious, LAL-D should be considered even in older patients.

Lysosomal acid lipase (LAL) is a necessary enzyme for the hydrolysis of both triglycerides (TGs) and cholesteryl esters (CEs) in the lysosome. Deficiency of this enzyme encoded by the lipase A (LIPA) gene leads to LAL deficiency (LAL-D). A severe disease subtype of LAL-D is known as Wolman disease (WD), present with diarrhea, hepatosplenomegaly, and adrenal calcification. Untreated patients do not survive more than a year. The aim of this study was to assess the clinical and molecular characterizations of WD patients in Egypt. A total of seven patients (from five unrelated Egyptian families) were screened by targeted next-generation sequencing (NGS), and the co-segregation of causative variants was analyzed using Sanger sequencing. Furthermore, multiple in silico analyses were performed to assess the pathogenicity of the candidate variants. Overall, we identified three diseases causing variants harbored in the LIPA gene. One of these variants is a novel missense variant (NM_000235.4: c.1122 T > G; p. His374Gln), which was classified as a likely pathogenic variant. All variants were predicted to be disease causing using in silico analyses. Our findings expand the spectrum of variants involved in WD which may help to investigate phenotype-genotype correlation and assist genetic counseling. To the best of our knowledge, this is the first clinico-genetic study carried out on Egyptian patients affected with WD.

Background If symptomatic in infants, the autosomal recessive disease lysosomal acid lipase deficiency (LAL-D; sometimes called Wolman disease or LAL-D/Wolman phenotype) is characterized by complete loss of LAL enzyme activity. This very rare, rapidly progressive form of LAL-D results in severe manifestations leading to failure to thrive and death, usually by 6 months of age. We report results from 2 open-label studies of enzyme replacement therapy with sebelipase alfa, a recombinant human LAL, in infants with LAL-D: the phase 2/3 Sur v ival of LAL-D I nfants T reated With Sebelipase Al fa (VITAL) study (NCT01371825) and a phase 2 dose-escalation study (LAL-CL08 [CL08]; NCT02193867). In both, infants received once-weekly intravenous infusions of sebelipase alfa. Results The analysis population contained 19 patients (9 in VITAL; 10 in CL08). Kaplan–Meier estimates of survival to 12 months and 5 years of age were 79% and 68%, respectively, in the combined population, and the median age of surviving patients was 5.2 years in VITAL and 3.2 years in CL08. In both studies, median weight-for-age, length-for-age, and mid-upper arm circumference-for-age z scores increased from baseline to end of study. Decreases in median liver and spleen volume over time were noted in both studies. Short-term transfusion-free hemoglobin normalization was achieved by 100% of patients eligible for assessment in VITAL, in an estimated median (95% confidence interval [CI]) time of 4.6 (0.3–16.6) months. In CL08, short-term transfusion-free hemoglobin normalization was achieved by 70% of patients eligible for assessment, in an estimated median (95% CI) time of 5.5 (3.7–19.6) months. No patient discontinued treatment because of treatment-emergent adverse events. Most infusion-associated reactions (94% in VITAL and 88% in CL08) were mild or moderate in severity. Conclusions The findings of these 2 studies of infants with rapidly progressive LAL-D demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival with normal psychomotor development, improved growth, hematologic parameters, and liver parameters, and was generally well tolerated, with an acceptable safety profile. Plain Language Summary • Lysosomal acid lipase deficiency (LAL-D) is a rare, inherited disease in which fatty material (cholesterol and triglycerides) becomes trapped in cells throughout the body, causing organ damage. • Infants can experience a particularly aggressive form of this disease where the functioning of the liver and intestine is impaired, thus leading to an enlarged abdomen and failure to grow and thrive. • If left untreated, LAL-D in infants leads to death, usually by 6 months of age. • This publication reports the results from 2 studies involving 19 infants with rapidly progressive LAL-D; infants received once-weekly intravenous infusions of sebelipase alfa for up to 3 or 5 years, depending on the study. • Results show that with sebelipase alfa treatment, the likelihood of an infant with LAL-D surviving to 12 months of age is 79% and the likelihood of surviving to 5 years of age is 68%. • Throughout both studies, treatment with sebelipase alfa was associated with (1) improvements in growth (weight, length/height, and arm circumference), (2) improvements in liver function, and (3) a decrease in liver and spleen size. • All patients experienced 1 or more adverse events (unwanted side effects), most of which were mild or moderate in severity; no patient stopped receiving treatment because of these events.

Background Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder that can present as a severe, infantile form also known as Wolman disease. We sought to determine the outcomes and clinical needs of infants diagnosed with LAL-D, treated with enzyme replacement therapy (ERT). Methods A chart review was conducted on two infantile-onset LAL-D patients to determine clinical outcomes based on laboratory results, abdominal imaging, growth and dietary records, cardiology, endocrinology, ophthalmology, hematology, and neurocognitive evaluations. Results Two patients, both diagnosed and treated before 6 months old, demonstrated clinical improvement following weekly ERT. They required dosage increases to optimize growth and symptomatology. Both received a formula low in long chain triglycerides and high in medium chain triglycerides, an intervention that allowed significant catch-up growth. Patient 1 required treatment for partial adrenal insufficiency and hypothyroidism. Both patients demonstrated reduction in liver and spleen size and varying degrees of improved liver function. Neither experienced serious adverse reactions to ERT. Conclusion ERT has led to longer and healthier survival of affected infants. It is imperative that dietary interventions and systemic clinical care become integral to the management. Continued evidence of survival and clinical improvement in this population, coupled with available mass spectrometry enzyme assay from dried blood spots, raises the question of this rare and possibly underdiagnosed disorder’s candidacy for newborn screening.

Background Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy. Methods A chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy. Results Two patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme. Conclusion Enzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.