Clinical phenotype of lathosterolosis

Abstract

Lathosterolosis (LS) is a defect of cholesterol biosynthesis due to the deficiency of the enzyme sterol-C5-desaturase. Only two patients have been described to date, both presenting with multiple malformations, mental retardation, and liver involvement. In addition in one of them pathological examination revealed mucolipidosis-like inclusions on optic microscopy analysis, and peculiar lysosomal lamellar bodies on electron microscopy analysis. This study is focused on a better characterization of the clinical phenotype of LS. We describe a further case in a fetus, sibling of the first patient reported, presenting with neural tube defect, craniofacial and limb anomalies, and prenatal liver involvement. The fetal phenotype suggests the possible occurrence of significant intrafamilial variability in LS, and expands the phenotypic spectrum of the disease. Histological examination of autopsy samples from the fetus and skin fibroblasts from the living sibling suggested that the mucolipidosis-like picture previously reported is not a constant feature of LS, being possibly associated with the most severe biochemical defects, but confirmed the ultrastructural finding of lamellar inclusions. The LS phenotype appears to be characterized by the distinctive association of a recognizable pattern of congenital anomalies, involving axial and appendicular skeleton, liver, central nervous and urogenital systems, and lysosomal storage. This condition partially overlaps with other defects of sterol metabolism, suggesting intriguing pathogenic links among these conditions.

Lathosterolosis: A Disorder of Cholesterol Biosynthesis Resembling Smith-Lemli-Opitz Syndrome

“…The bilateral small dot cataract with no visual significance could also be a manifestation of the disease. Except the stillborn, the other two lathosterolosis patients also had either unilateral or bilateral cataract (Rossi et al 2007;Krakowiak et al 2003). Furthermore, hereditary factor could not be completely ruled out as the patient's father also had bilateral small dot opacity without any visual significance.…”

“…It might already be present before commencement of treatment. Liver diseases were also reported in the other two lathosterolosis patients (Brunetti-Pierri et al 2002;Rossi et al 2005Rossi et al , 2007Krakowiak et al 2003). Although there are some adult studies suggesting cataract as an adverse effect of statin (Hippisley-Cox and Coupland 2010), the causal relationship between cataract and statin use has not been fully established.…”

“…The second case was reported initially as apparent Smith-Lemli-Opitz syndrome by Parnes in 1990(Parnes et al 1990), but was subsequently diagnosed to have lathosterolosis by postmortem examination by Krakowiak et al in 2003(Krakowiak et al 2003. The third case was reported by Rossi in 2007 who followed up on the first case reported by Brunetti-Pierri and described her affected sibling who was a stillborn (Rossi et al 2007). Our patient contributed to the fourth reported case of lathosterolosis in the literature.…”

“…To our knowledge, our patient is the first lathosterolosis patient receiving a therapeutic trial of simvastatin. This drug was started at a low dose (0.2 mg/kg/day) and was Each sterol is given in percent of total sterols Table 3 Comparison of clinical features of reported lathosterolosis cases Case 1 (Fetus) (Rossi et al 2007) Case 2 (Brunetti-Pierri et al 2002) (Rossi et al 2007) Case 3 (Krakowiak et al 2003) (Parnes et al 1990) Case gradually stepped up to 1 mg/kg/day. The level of lathosterol successfully decreased from 81.6 mmol/L to 15.1 mmol/L within 4 weeks time (normal level: <18 umol/L) and remained at a relatively low level afterwards.…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…Parents were not consanguineous; however, both were of French Canadian ancestry. The mucolipidosis observed in the case reported by Parnes was not observed in the two Italian siblings; however, lamellar lysosomal inclusions could be induced in cultured fi broblasts from both families ( 209,210 ). Krakowiak et al ( 209 ) disrupted Sc5d to produce a lathosterolosis mouse model.…”