Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants

Jones, Simon A.; Valayannopoulos, Vassili; Schneider, Eugene; Eckert, Stephen; Banikazemi, Maryam; Bialer, Martin G.; Cederbaum, Stephen D.; Chan, Alicia; Dhawan, Anil; Rocco, Maja Di; Domm, Jennifer; Enns, Gregory M.; Finegold, David N.; Gargus, J. Jay; Guardamagna, Ornella; Hendriksz, Christian J.; Mahmoud, Iman G.; Raiman, Julian; Selim, Laila; Whitley, Chester B.; Zaki, Osama K.; Quinn, Anthony G.

doi:10.1038/gim.2015.108

Cited by 79 publications

(98 citation statements)

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“…Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder that can present as a severe, infantile form also referred to as Wolman disease (OMIM #278000) [1]. Prior to the advent of enzyme replacement therapy (ERT) with a recombinant form of lipoprotein lipase, sebelipase alfa (Kanuma®), life expectancy was typically less than twelve months [2]. The only available treatment options (liver transplantation and hematopoietic stem cell transplant) were rarely successful in extending survival and were fraught with additional medical complications [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Early diagnosis of infantile-onset lysosomal acid lipase deficiency in the advent of available enzyme replacement therapy

Cohen¹,

Burfield²,

Valdez-Gonzalez³

et al. 2019

Orphanet J Rare Dis

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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. Electronic supplementary material The online version of this article (10.1186/s13023-019-1129-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Early diagnosis of infantile-onset lysosomal acid lipase deficiency in the advent of available enzyme replacement therapy

Cohen¹,

Burfield²,

Valdez-Gonzalez³

et al. 2019

Orphanet J Rare Dis

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“…Liver effects include hepatomegaly, liver dysfunction, and hepatic failure [1,4]. In contrast, infantile-onset LAL-D (historically called Wolman disease or LALD/Wolman phenotype), a very rare form of the disease, is the most rapidly progressive disease presentation, and is usually fatal within the rst 6 months of life [1,[6][7][8]. The predominant clinical features of infantile-onset LAL-D are early growth failure, severe hepatic disease-as evidenced by liver enlargement, elevation of transaminases, hyperbilirubinemia, coagulopathy, and hypoalbuminemiaand a macrophage activation syndrome, which are key contributors to early mortality [9][10][11].…”

mentioning

confidence: 99%

Long-Term Survival With Sebelipase Alfa Enzyme Replacement Therapy in Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency Final Results From 2 Open-Label Studies

Vijay

Brassier

Ghosh

et al. 2020

Preprint

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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 Survival of LAL-D Infants Treated With Sebelipase Alfa (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, and liver parameters, and was generally well tolerated, with an acceptable safety profile.

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“…This resulted in 47 known pathogenic variants from the literature being chosen. Table S3 lists these variants, as well as variants that were identified at later points in time from literature sources (Jones et al, ; Kim et al, ; Sjouke et al, ), and variants that were not amenable to plasmid‐based transfection due to being splicing mutations (Maciejko et al, ; Ruiz‐Andrés et al, ). All novel missense, frameshift or nonsense variants identified in patients participating in Sebelipase Alfa clinical studies ARISE (NCT0757184) and CL06 (NCT02112994) were selected. This resulted in seven more variants to be assayed.…”

Section: Methodsmentioning

confidence: 99%

“…In infants, disease progression occurs rapidly, presenting with a severe and life‐threatening manifestation; rapidly progressive LAL deficiency (RP‐LALD), historically referred to as Wolman disease, typically presents in the first year of life with diarrhea, failure to thrive, abdominal distension with massive hepatosplenomegaly, anemia, and rapidly progressive liver disease. Untreated infants have a median age at death of 3.7 months (Jones et al, ). A more variable presentation and the disease course are seen in children and adults.…”

Section: Introductionmentioning

confidence: 99%

Large‐scale functionalLIPAvariant characterization to improve birth prevalence estimates of lysosomal acid lipase deficiency

et al. 2019

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Lysosomal acid lipase (LAL) deficiency is an autosomal recessive disorder caused by LIPA gene mutations that disrupt LAL activity. We performed in vitro functional testing of 149 LIPA variants to increase the understanding of the variant effects on LAL deficiency and to improve disease prevalence estimates. Chosen variants had been reported in literature or population databases. Functional testing was done by plasmid transient transfection and LAL activity assessment. We assembled a set of 165 published LAL deficient patient genotypes to evaluate this assay's effectiveness to recapitulate genotype/phenotype relationships. Rapidly progressive LAL deficient patients showed negligible enzymatic activity (<1%), whereas patients with childhood/adult LAL deficiency typically have 1–7% average activity. We benchmarked six in silico variant effect prediction algorithms with these functional data. PolyPhen‐2 was shown to have a superior area under the receiver operating curve performance. We used functional data along with Genome Aggregation Database (gnomAD) allele frequencies to estimate LAL deficiency birth prevalence, yielding a range of 3.45–5.97 cases per million births in European‐ancestry populations. The low estimate only considers functionally assayed variants in gnomAD. The high estimate computes allele frequencies for variants absent in gnomAD, and uses in silico scores for unassayed variants. Prevalence estimates are lower than previously published, underscoring LAL deficiency's rarity.

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Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants

Cited by 79 publications

References 13 publications

Early diagnosis of infantile-onset lysosomal acid lipase deficiency in the advent of available enzyme replacement therapy

Early diagnosis of infantile-onset lysosomal acid lipase deficiency in the advent of available enzyme replacement therapy

Long-Term Survival With Sebelipase Alfa Enzyme Replacement Therapy in Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency Final Results From 2 Open-Label Studies

Large‐scale functionalLIPAvariant characterization to improve birth prevalence estimates of lysosomal acid lipase deficiency

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