Lysosomal acid lipase deficiency in Brazilian children: a case series / Deficiência de lipase ácida lisossomal em crianças brasileiras: casuística

Abstract Objective: To describe the demographic, clinical, laboratory and molecular characteristics of patients with lysosomal acid lipase deficiency. Methods: A retrospective review of the medical records of children with the disease. Results: Seven children with lysosomal acid lipase deficiency (5 male; 2 female); 6 were mixed race, and 1 was black. The mean ages at the first onset of symptoms and at diagnosis were 5.0 years (4 months to 9 years) and 6.9 years (3-10 years), respectively. Symptom manifestations at onset were: 3 patients had abdominal pain, one had bone/joint pain due to rickets, and 1 had chronic diarrhea and respiratory insufficiency due to interstitial pneumonitis. One was asymptomatic, and clinical suspicion arose due to hepatomegaly. Six patients had hepatomegaly, and none had splenomegaly. Two patients were siblings. Enzymatic assay and molecular analysis confirmed the diagnoses. Genetic analysis revealed a rare pathogenic variant (p.L89P) in three patients, described only once in medical literature and never described in Brazil. None of those patients were related to each other. Lysosomal acid lipase deficiency was previously described as an autosomal recessive disease, but three patients were heterozygous and undoubtedly had the disease (low enzyme activity, suggestive lab findings and clinical symptoms). Conclusion: This case series supports that lysosomal acid lipase deficiency can present with highly heterogeneous signs and symptoms among patients, but it should be considered in children presenting with gastrointestinal symptoms associated with dyslipidemia. We describe a rare variant in three non-related patients that may suggest a Brazilian genotype for lysosomal acid lipase deficiency.

Resumo: Objetivo: Descrever as características demográficas, clínicas, laboratoriais e moleculares de pacientes com deficiência de lipase ácida lisossomal. Métodos: Análise retrospectiva dos prontuários médicos de crianças com a deficiência de lipase ácida lisossomal. Resultados: Sete crianças com deficiência de lipase ácida lisossomal (5 M:2F); seis eram pardas e uma negra. As faixas etárias no início dos sintomas e no diagnóstico foram 5 anos (4 meses a 9 anos) e 6,9 anos (3 a 10 anos), respectivamente. As manifestações dos sintomas no início foram as que seguem: três pacientes apresentaram dor abdominal, um apresentou dor nos ossos/articulações devido a raquitismo e um apresentou diarreia crônica e insuficiência respiratória devido à pneumonite intersticial. Os outros não apresentaram sintomas e a suspeita clínica surgiu devido à hepatomegalia. Seis pacientes apresentaram hepatomegalia e um apresentou esplenomegalia. Dois pacientes eram irmãos. O ensaio enzimético e a análise molecular confirmaram os diagnósticos. A análise genética revelou uma variante patogênica rara (p.L89P) em três pacientes, descrita uma única vez na literatura médica e nunca descrita no Brasil. Nenhum desses pacientes tinha parentesco com os outros. A deficiência de lipase ácida lisossomal foi anteriormente descrita como uma doença recessiva autossômica, porém três pacientes eram heterozigotos e, sem dúvida, apresentaram a doença (atividade enzimática baixa, achados laboratoriais sugestivos e sintomas clínicos). Conclusão: Esta casuística afirma que a deficiência de lipase ácida lisossomal pode se manifestar com sinais e sintomas altamente heterogêneos entre os pacientes, porém deve ser considerada em crianças que apresentam sintomas gastrointestinais associados à dislipidemia. Descrevemos uma variante rara em três pacientes não relacionados que pode sugerir um genótipo brasileiro para deficiência de lipase ácida lisossomal.

Lysosomal acid lipase deficiency in Brazilian children: a case series.

OBJECTIVE: To describe the demographic, clinical, laboratory and molecular characteristics of patients with lysosomal acid lipase deficiency. METHODS: A retrospective review of the medical records of children with the disease. RESULTS: Seven children with lysosomal acid lipase deficiency (5 male; 2 female); 6 were mixed race, and 1 was black. The mean ages at the first onset of symptoms and at diagnosis were 5.0 years (4 months to 9 years) and 6.9 years (3-10 years), respectively. Symptom manifestations at onset were: 3 patients had abdominal pain, one had bone/joint pain due to rickets, and 1 had chronic diarrhea and respiratory insufficiency due to interstitial pneumonitis. One was asymptomatic, and clinical suspicion arose due to hepatomegaly. Six patients had hepatomegaly, and none had splenomegaly. Two patients were siblings. Enzymatic assay and molecular analysis confirmed the diagnoses. Genetic analysis revealed a rare pathogenic variant (p.L89P) in three patients, described only once in medical literature and never described in Brazil. None of those patients were related to each other. Lysosomal acid lipase deficiency was previously described as an autosomal recessive disease, but three patients were heterozygous and undoubtedly had the disease (low enzyme activity, suggestive lab findings and clinical symptoms). CONCLUSION: This case series supports that lysosomal acid lipase deficiency can present with highly heterogeneous signs and symptoms among patients, but it should be considered in children presenting with gastrointestinal symptoms associated with dyslipidemia. We describe a rare variant in three non-related patients that may suggest a Brazilian genotype for lysosomal acid lipase deficiency.

Experimental swainsonine poisoning in goats ingesting Ipomoea sericophylla and Ipomoea riedelii (Convolvulaceae)

Ipomoea sericophylla and Ipomoea riedelii cause a glycoprotein storage disease in goats. This paper reports the experimental poisoning in goats by dried I. sericophylla and I. riedelii containing 0.05 percent and 0.01 percent swainsonine, respectively. Three groups with four animals each were used. Group 1 received daily doses of 2g/kg body weight (bw) of dried I. sericophylla (150mg of swainsonine/kg). Goats from this group had clinical signs 36-38 days after the start of ingestion. Group 2 received dried I. riedelii daily doses of 2g/kg of I. riedelii (30mg of swainsonine/kg) for 70 days. No clinical signs were observed, therefore the swainsonine dose was increased to 60mg/kg for another 70 days. Goats from Group 2 had clinical signs 26-65 days after increase in swainsonine dose to 60mg/kg. Group 3 was used as control. In these experiments the minimum toxic dose was 60mg/kg which represents 0.0004 percent of the dry matter in goats ingesting 1.5 percent bw of the dry matter. For goats ingesting 2 percent-2.5 percent bw of dry matter this dose would be 0.00024 percent-0.0003 percent of the dry matter. After the end of the experiment two goats were euthanized and another six were observed for recovery of clinical signs. Four goats that continued to consume swainsonine containing plant for 39-89 days after the first clinical signs had non reversible signs, while two goats that ingested the plant for only 15 and 20 days after the first clinical signs recovered completely. These and previous results indicate that irreversible lesions due to neuronal loss occur in goats that continue to ingest the plants for about 30 days after the first clinical signs. Clinical signs and histological lesions were similar to those reported previously for goats poisoned by swainsonine containing plants. No significant alterations were found in packed cell volume, red and white blood cell counts, hemoglobin and mean corpuscular hemoglobin concentrations, mean...

Ipomoea sericophylla e Ipomoea riedelii causam uma doença de armazenamento de glicoproteínas em caprinos. Este trabalho relata a intoxicação experimental em caprinos por I. sericophylla e I. riedelii contendo 0,05 por cento e 0,01 por cento de swainsonina, respectivamente. Foram utilizados três grupos de quatro animais. O Grupo 1 recebeu doses diárias de 2g/kg peso vivo (pv) de I. sericophylla dessecada (150mg de swainsonina/kg). Os caprinos deste grupo apresentaram sinais clínicos 36-38 dias após o início da ingestão. O Grupo 2 ingeriu diariamente 2g/kg de I. riedelii dessecada (30mg de swainsonina/kg) por 70 dias. Como não foram observados sinais clínicos a dose de suainsonina foi aumentada para 60mg/kg por outros 70 dias. Os caprinos do Grupo 2 apresentaram sinais clínicos 26-65 dias após o aumento da dose de swainsonina para 60mg/kg. O Grupo 3 foi utilizado como controle. Neste experimento, a menor dose tóxica de swainsonina foi de 60mg/kg, que representa 0,0004 por cento da matéria seca, em caprinos ingerindo 1,5 por cento pv de matéria seca. Para caprinos ingerindo 2 por cento-2,5 por cento pv de matéria seca essa dose corresponderia a 0,00024 por cento-0,0003 por cento da matéria seca. Após o final do experimento dois caprinos foram eutanasiados e outros seis foram observados para conferir a recuperação dos sinais clínicos. Quatro caprinos que continuaram ingerindo as plantas contendo suainsonina por 39-89 dias após os primeiros sinais clínicos permaneceram com sinais clínicos irreversíveis, enquanto que dois caprinos que ingeriram as plantas por 15 e 20 dias após os primeiros sinais clínicos se recuperaram totalmente. Estes resultados e os de trabalhos anteriores sugerem que as lesões irreversíveis, devidas à perda neuronal, ocorrem quando os caprinos continuam ingerindo a planta por aproximadamente 30 dias após o início dos sinais clínicos. Os sinais clínicos e as lesões histológicas foram similares às descritas anteriormente...