RESUMO
Lysosomal acid lipase (LAL) deficiency is an under-recognized lysosomal disease caused by deficient enzymatic activity of LAL. In this report we describe two affected female Mexican siblings with early hepatic complications. At two months of age, the first sibling presented with alternating episodes of diarrhea and constipation, and later with hepatomegaly, elevated transaminases, high levels of total and low-density lipoprotein cholesterol, and low levels of high-density lipoprotein. Portal hypertension and grade 2 esophageal varices were detected at four years of age. The second sibling presented with hepatomegaly, elevated transaminases and mildly elevated low-density lipoprotein and low high-density lipoprotein at six months of age. LAL activity was deficient in both patients. Sequencing of LIPA revealed two previously unreported heterozygous mutations in exon 4: c.253C>A and c.294C>G. These cases highlight the clinical continuum between the so-called Wolman disease and cholesteryl ester storage disease, and underscore that LAL deficiency represents a single disease with a degree of clinical heterogeneity.
Assuntos
Mutação , Irmãos , Esterol Esterase/deficiência , Esterol Esterase/genética , Doença de Wolman/genética , Biópsia , Criança , Pré-Escolar , Análise Mutacional de DNA , Progressão da Doença , Varizes Esofágicas e Gástricas/enzimologia , Varizes Esofágicas e Gástricas/genética , Esofagoscopia , Éxons , Fígado Gorduroso/enzimologia , Fígado Gorduroso/genética , Feminino , Predisposição Genética para Doença , Hepatomegalia/enzimologia , Hepatomegalia/genética , Heterozigoto , Humanos , Hipertensão Portal/enzimologia , Hipertensão Portal/genética , Imuno-Histoquímica , Lactente , Cirrose Hepática/enzimologia , Cirrose Hepática/genética , México , Linhagem , Fenótipo , Irmãos/etnologia , Fatores de Tempo , Ultrassonografia Doppler em Cores , Doença de Wolman/complicações , Doença de Wolman/diagnóstico , Doença de Wolman/enzimologia , Doença de Wolman/etnologia , Doença de WolmanRESUMO
Niemann-Pick type C disease (NPC) is a rare lysosomal disease with a protean presentation, ranging from a fatal neonatal course with visceromegaly to an adult presentation with only neurological or psychiatric symptomatology. In this report we describe the genetic and clinical characteristics of 3 Mexican patients from different families with juvenile presentation of NPC. Clinical examination, imaging of central nervous and gastrointestinal system, and EEG were performed. Genetic studies include sequencing and deletion/duplication analysis of NPC1 and NPC2 genes. All patients presented with cognitive impairment, ataxia, and supranuclear vertical gaze palsy; one case had gelastic cataplexy. Also they developed epilepsy and cortical atrophy and two patients had thinning of corpus callosum. The 3 patients were compound heterozygotes for NPC1 sequence variants, including 5 missense and 1 nonsense mutations: p.P1007A and p.F1087L in Case 1; p.Q921P and p.G992R in Case 2; and p.R348∗ and p.V1165M in case 3. Mexican patients with juvenile NPC presented with a variable clinical phenotype and compound heterozygosity. This suggests a relative high frequency of mutation carriers as it is reported for European population. Consequently, clinicians should consider NPC as a diagnosis possibility in any adolescent or young adult patient with juvenile dementia and/or ataxia, even in absence of gelastic cataplexy and supranuclear vertical gaze palsy.
