Biomedical Scientist, doctorate in Bioengineering. Determined to contribute to a world in which Healthcare and Innovation are accessible to everyone.
Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare pan-ethnic inherited autosomal recessive metabolic disorder with heterozygous carrier rate and disease prevalence at birth have been respectively estimated as 1:421 and 1:177,452.1 LAL-D is caused by pathogenic variant mutations in the LIPA gene and clinical manifestations display a wide phenotypic spectrum that may vary considerably between patients.2,3
Typical presenting features of LAL-D include dyslipidemia, hepatomegaly, splenomegaly, diarrhea, abdominal and epigastric pain, vomiting, anemia, malabsorption, cholestasis, steatorrhea, poor growth, gallbladder dysfunction, coronary heart disease, aneurysm, stroke, adrenal calcifications, and esophageal varices.2 Several of its most common symptoms, namely dyslipidemia, hepatomegaly and liver damage are also shared by other metabolic diseases, which often leads to misdiagnosis.2 Moreover, manifestations of milder or attenuated forms of LAL-D, collectively known as cholesteryl ester storage disease (CESD), are often only evident in late childhood or adulthood and, in the absence of previous family history, the diagnosis of LAL-D is frequently overlooked and delayed.3 As a result, the number of reported cases is lower than the estimated genetic prevalence.
Suspecting LAL-D is crucial to guarantee a timely diagnosis, adequate patient management, and disease monitoring. Therefore, raising awareness among clinicians and patients about the signs of the disease in specific clinical scenarios is fundamental to preventing the underdiagnosis of LAL-D and establishing its early differential diagnosis.
The Critical Role of Patient Education
Patient education is vital for several reasons. First, and perhaps foremost, taking into account that LAL-D is an autosomal recessive genetic disorder, it highlights the importance of genetic testing and counseling to identify carriers, diagnose patients, and establish a family pedigree.4,5
Second, patient education can help families recognize the signs and symptoms of the disease and seek medical attention sooner, providing the ground for a timely diagnosis and proper treatment. This is especially relevant in LAL-D as clinical manifestations may vary widely between patients.2,3 Although a cure for LAL-D is still lacking, an early treatment initiation is essential to help prevent and/or manage disease complications.
Third, patient education promotes patients’ understanding of their condition and available treatment options, nurturing their relationship with healthcare providers and caregivers, stimulating their confidence and reducing anxiety, fear, and stigma.
Last, but not least, patient education can also play an important role not only in raising awareness about the disease among families, friends, and society at large but also in disclosing available patient resources, such as support systems, networks, and programs that help patients navigate various aspects of living with LAL-D.
Finding a Specialist
Due to the multi-system nature of LAL-D, patients are advised to receive care and monitoring from an interdisciplinary team representing various relevant specialties, including a pediatrician (in case of children), a gastroenterologist or hepatologist, a lipidologist, a cardiologist, a geneticist, and a nutritionist.4 One member of the team preferably has experience with or special knowledge of LAL-D. As children age and approach adulthood, a plan should be established for the transition from pediatric to adult care. Additional special support for adult patients should be considered based on individual needs.
A comprehensive clinical evaluation is recommended every 3 months up to 1 year after diagnosis and annually thereafter.4
During pregnancy, patients should be referred to a high-risk obstetric specialist for management.4
Genetic counseling should provide information on the nature, mode of inheritance, and implications of LAL-D so that patients can make informed medical and personal decisions.
LAL-D is an autosomal recessive disorder.2,5 Thus, parents of a proband are obligate heterozygotes, carrying one LIPA pathogenic variant, and each biological sibling of carrier parents has a 25% chance of being affected, 50% chance being an asymptomatic carrier, and 25% chance of being unaffected and not a carrier.5 In the case of a LAL-D progenitor proband, the offspring are obligate heterozygotes.
The first step is to identify the disease-causing LIPA pathogenic variants in the family. Once this is done, carrier testing for at-risk relatives may be performed and family planning conducted. Genetic testing is advised for all biological siblings regardless of signs/symptoms, as disease severity and presentation may vary within families, even with the same genotype.4
Prenatal genetic testing (amniocentesis or chorionic villus sampling) is available for expectant parents who have had one or more children with LAL-D.4,5 Preimplantation genetic diagnosis is also possible.5
Banking DNA of affected individuals is possible and should be considered as testing methodologies and our understanding of LAL-D will improve in the future.5
Support and advocacy groups/programs are essential to improve the lives of children and families dealing with rare diseases. These usually develop patient-centered information and can direct patients to disease research, resources, services, and healthcare specialists.
LAL-D Aware (former LAL Solace) is a nonprofit voluntary organization that aims at building a strong community and ensuring an adequate support system is in place for LAL-D patients.6
The National Organization for Rare Disorders (NORD) provides assistance programs designed to help patients with financial assistance regarding diagnosis, treatment, traveling, and consultation.7
1. Carter A, Brackley SM, Gao J, Mann JP. The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD. J Hepatol. 2019;70(1):142-150. doi:10.1016/j.jhep.2018.09.028
2. Reiner Ž, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency – an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235(1):21-30. doi:https://doi.org/10.1016/j.atherosclerosis.2014.04.003
3. Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol. 2017;2(9):670-679. doi:10.1016/S2468-1253(17)30052-3
4. Kohli R, Ratziu V, Fiel MI, Waldmann E, Wilson DP, Balwani M. Initial assessment and ongoing monitoring of lysosomal acid lipase deficiency in children and adults: Consensus recommendations from an international collaborative working group. Mol Genet Metab. 2020;129(2):59-66. doi:10.1016/j.ymgme.2019.11.004
5. Hoffman EP, Barr ML, Giovanni MA, Murray MF. Lysosomal Acid Lipase Deficiency. 2015 Jul 30 [updated 2016 Sep 1]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021.
6. LAL-D aware. Accessed June 18, 2021.7. National organization for rare disorders. Accessed June 18, 2021.
Reviewed by Harshi Dhingra, MD, on 7/1/2021.