Practical Recommendations for the Diagnosis and Management of Lysosomal Acid Lipase Deficiency with a Focus on Wolman Disease
Javier de las HerasCarolina AlmohallaJavier Blasco‐AlonsoMafalda BourbonMaría L. CouceMaría José de Castro LópezMarcela de Jesús Vergara-JiménezDavid GilLuisa González‐DiéguezSilvia MeavillaAna Moreno‐ÁlvarezJosé Pastor-RosadoPaula Sánchez‐PintosIrene Serrano-GonzaloEduardo LópezPedro ValdivielsoRaquel YahyaouiJesús Quintero
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Abstract:
Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare lysosomal storage disease with two distinct phenotypes, an infantile-onset form (formerly Wolman disease) and a later-onset form (formerly cholesteryl ester storage disease). The objective of this narrative review is to examine the most important aspects of the diagnosis and treatment of LAL-D and to provide practical expert recommendations. The infantile-onset form occurs in the first weeks of life and is characterized by malnourishment and failure to thrive due to gastrointestinal impairment (vomiting, diarrhea, malabsorption), as well as systemic inflammation, hepatosplenomegaly, and adrenal calcifications. Mortality is close to 100% before one year of life in the absence of specific treatment. The later-onset form can be diagnosed in childhood or adulthood and is characterized by chronic liver injury and/or lipid profile alterations. When LAL-D is suspected, enzyme activity should be determined to confirm the diagnosis, with analysis from a dried blood spot sample being the quickest and most reliable method. In infantile-onset LAL-D, the initiation of enzyme replacement therapy (sebelipase α) and careful nutritional management with a low-lipid diet is very urgent, as prognosis is directly linked to the early initiation of specific treatment. In recent years, our knowledge of the management of LAL-D has increased considerably, with improvements regarding the initial enzyme replacement therapy dose and careful nutritional treatment with a low-lipid diet to decrease lipid deposition and systemic inflammation, leading to better outcomes. In this narrative review we offer a quick guide for the initial management of infantile-onset LAL-D.Keywords:
Hepatosplenomegaly
Failure to Thrive
A 27-year-old woman was admitted for further examination of thrombocytopenia. Symptoms were absent, but physical examination demonstrated hepatosplenomegaly without neurological abnormalities. Bone marrow examination revealed many Gaucher cells, and glucocerebrosidase activity from cultured skin fibroblasts was markedly reduced. A 1448C (L444P) mutation was detected on one allele of the glucocerebrosidase gene. Because magnetic resonance imaging (MRI) of the femora indicated severe infiltration of Gaucher cells into bone marrow, enzyme replacement therapy was initiated despite the absence of skeletal symptoms. Hematologic abnormalities, visceral and bone involvement have been improving. In cases of thrombocytopenia or hepatosplenomegaly, Gaucher's disease should be suspected.(Internal Medicine 40: 716-721, 2001)
Hepatosplenomegaly
Glucocerebroside
Gaucher's disease
Lysosomal storage disease
Asymptomatic carrier
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Niemann-Pick disease, types A and B, are lipid storage disorders caused by complete or partial deficiency of a lysosomal enzyme, acid sphingomyelinase. The disorders are inherited in an autosomal recessive pattern and result in the accumulation of sphingomyelin in various organs including the spleen, liver, lungs, bone marrow and brain. The infantile variant (type A) usually presents within the first year of life with failure to thrive, hepatomegaly and neurological symptoms, sometimes resulting in liver failure with ascites and jaundice. Most babies die at 2–3 years of age. In Niemann-Pick type B disease, the diagnosis is usually made early in childhood because of failure to thrive and the development of hepatosplenomegaly. Patients then develop progressive neurological symptoms and may have deteriorating pulmonary function because of foam cell infiltrates. Most patients die in childhood. An important clue to the diagnosis of Niemann-Pick disease, types A and B, is the presence of large foamy macrophages in the bone marrow or liver. In most patients, the diagnosis is confirmed by genetic tests for mutations in the SMPD1 gene or by the demonstration of low acid sphingomyelinase activity in peripheral blood white cells or in cultured fibroblasts. At present, there is no specific treatment for Niemann-Pick disease. The patient illustrated below was 15-month-old female who presented with a 4-month history of hepatosplenomegaly and failure to thrive. She was the product of a full-term normal pregnancy but her parents were consanguineous and a previous baby had died in the neonatal period. The parents described anorexia and recurrent pneumonia but no vomiting or diarrhea. The baby had a weight and height below the 5th percentile for age. Physical examination revealed marked hepatosplenomegaly but no ascites. Liver enzymes were abnormal with elevation of aspartate aminotransferase (311 u/l), alanine aminotransferase (251 u/l), gamma-glutamyltransferase (77 u/l) and alkaline phosphatase (724 u/l). She had a normal complete blood count, coagulation studies and serum albumin. A computed tomography scan of the chest revealed typical reticulonodular infiltrates in the upper lobes of both lungs (Figure 1). A percutaneous liver biopsy showed lipid-laden foam cells (Figure 2). The diagnosis of Niemann-Pick disease was confirmed by the demonstration of low acid sphingomyelinase activity in peripheral blood white cells. She is receiving symptomatic treatment only. Contributed by
Hepatosplenomegaly
Failure to Thrive
Niemann–Pick disease
Acid sphingomyelinase
Glucocerebroside
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Mucopolysaccharidosis type I (MPS I) is the hereditary disease characterized with alpha-L-iduronidase activity decrease and further accumulation of heparan and dermatan sulfate in lysosomes. MPS I is rare autosomal recessive disorder with incidence of 0.5–4 cases on 100.000 live-birth infants. Meantime there two approaches in MPS I treatment: hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). HSCT can be the best option for treatment of patients with severe MPS I (Hurler syndrome). Successful engraftment moderates such clinical signs as obstructive airway diseases, hepatosplenomegaly, cardiovascular system dysfunctions. HSCT prevents cognitive functions decline and other pathologic features of central nervous system. Presented clinical cases show various clinical courses according to age of diagnosis, ERT onset and HSCT implementation.
Hepatosplenomegaly
Hurler syndrome
Mucopolysaccharidosis
Mucopolysaccharidosis type I
Mucopolysaccharidosis I
Lysosomal storage disease
Hunter syndrome
Wiskott–Aldrich syndrome
Mucolipidosis
Hematopoietic stem cell
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Background: Gaucher disease is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, and neurological manifestation. Herein, we present a 3-year-old boy with type I Gaucher disease who had been treated with enzyme replacement therapy (ERT), and subsequently developed a focal Gaucheroma in the liver after 19 months of ERT.
Hepatosplenomegaly
Lysosomal storage disease
Liver enzyme
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Between October 1988 and October 1990 AIDS serodiagnostic tests and clinical examinations indicated that 129 15 day-5 year old children at the Central Hospital in Bulawayo Zimbabwe had symptomatic HIV infection (AIDS). 62% were less than 12 months old. Their mothers were also HIV positive There were slightly more males than females with AIDS (1.51:1). 74% of the children presented with pulmonary infiltrates. Other leading AIDS symptoms included lymphadenopathy (52%) hepatosplenomegaly (45%) oral candidiasis (43%) failure to thrive (42%) and skin rashes (25%). 51% of the children also had anemia. Children younger than 1 year old were more likely to have pulmonary infiltrates (82.5% vs. 59.2%; p = .0035) and hepatosplenomegaly (p = .0069) than children older than 1 year. On the other hand children older than 1 year were more likely to have lymphadenopathy (65.3% vs. 43.8%; p = .0174) and anemia (69.4% vs. 40%; p = .0011) and to fail to thrive (75.5% vs. 21.3%; p = .000001). These results indicated that all but 2 AIDS symptoms (oral candidiasis and skin rashes) were dependent on age in children in this area of Zimbabwe. Further they demonstrated that failure to thrive is not a common symptom of HIV infection in children younger than 1 year. Therefore health workers should not assume that children who do not fail to thrive but have other HIV related symptoms are not HIV seropositive. Even though further research is needed to verify these findings clinicians may begin considering them when suspecting HIV infection in children.
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Failure to Thrive
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We read with interest the paper by Elstein et al (2000), entitled 'Withdrawal of enzyme replacement therapy in Gaucher disease'. We report our experience of a patient with Gaucher disease who withdrew from enzyme replacement therapy (ERT) with imilglucerase for personal reasons. The patient was started on ERT at the age of 42 years when she presented with hepatosplenomegaly, mild anaemia [haematocrit (Ht) 33%, haemoglobin (Hb) 11·3 g/dl] and thrombocytopenia (75 × 109/l). She received imilglucerase for 18 months (60 U/kg every 2 weeks). A follow-up evaluation just before the withdrawal showed no hepatomegaly, a decrease in the spleen size and an increased Ht, Hb and platelet count (39·7%, 13·9 g/dl and 112 × 109/l respectively). After 3 months off the drug, she remained clinically stable and there were no significant differences in the pattern of bone pain, the size of the liver and spleen, or in haematological parameters. However, serum chitotriosidase activity was high (704 nmol/h/ml; normal values: 8·85–132 nmol/h/ml). Four months after ERT was resumed, serum levels of chitotriosidase activity decreased to 277 nmol/h/ml. These data are in agreement with the results presented by Czartoryska et al (2000), suggesting that, although serum chitotriosidase activity is a very sensitive marker of interruptions in ERT, it does not predict the clinical outcome. In agreement with Elstein et al (2000), we believe that adult patients with stable Gaucher disease may be withdrawn from ERT therapy for short periods of time.
Hepatosplenomegaly
Liver enzyme
Hematology
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Background
Gaucher disease is a rare genetic disorder, due to a deficiency of glucocerebrosidase activity. It is most often manifested by hepatosplenomegaly, haematological and biochemical disorder. First-line treatment is based on enzyme replacement therapy (ERT).Purpose
To evaluate the tolerance and effectiveness of ERT in children with type 1 Gaucher disease.Material and methods
We report the case of four patients with type 1 Gaucher disease treated with ERT (once every 15 days) at the neuro-metabolic diseases unit of our hospital. The evaluation was performed on the basis of primary effectiveness variables (haemoglobin concentration, platelet count, liver parameters) and the reporting of adverse events.Results
There were three girls and one boy, whose clinical signs were manifested by hepatosplenomegaly and haematological disorder in all patients. The ERT had generally been well tolerated and no adverse effects were identified.Conclusion
The ERT used by our patients has an acceptable tolerance profile as well as beneficial effects on the parameters related to the disease. These beneficial effects were demonstrated by the effectiveness variables that were kept stable or improved throughout the treatment in children with Gaucher disease.References and/or acknowledgements
Thanks to the paediatrics department for their support. No conflict of interest.Hepatosplenomegaly
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Failure to Thrive
Hepatosplenomegaly
Girl
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Hepatosplenomegaly
Girl
Gaucher's disease
Petechial rash
Chicken Pox
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Neimann-Pick disease (NPD) is an autosomal recessive lysosomal storage disorder caused by inherited deficiency of acid sphingomyelinase enzyme or its transport which leads to deposition of sphingomylin and cholesterol in the lysosomes of reticuloendothelial system. It is characterized by failure to thrive, hepatospleenomeagaly and neurodegenerative changes. There are four subgroups of neimann pick disease, type A, B, C and D. Here authors are reporting a case of 5 months old female child presenting with persistent jaundice since neonatal period, progressive abdominal distention and failure to thrive. On examination patient had significant abdominal distension with moderate hepatosplenomegaly. On laboratory evaluation child diagnosed to have NPD type C. This case emphasizes the need to keep NPD in differential diagnosis of children presenting with persistent neonatal jaundice, hepatosplenomegaly, failure to thrive.
Failure to Thrive
Hepatosplenomegaly
Abdominal distension
Niemann–Pick disease
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