Thyroid Hormone Status in Sitosterolemia Is Modified by Ezetimibe.

OBJECTIVES: To assess the association between biomarkers of thyroid status and 5α-stanols in patients with sitosterolemia treated with ezetimibe (EZE). STUDY DESIGN: Eight patients with sitosterolemia (16-56 years of age) were studied during 14 weeks off EZE therapy and 14 weeks on EZE (10 mg/day). Serum thyroid biomarkers (free triiodothyronine [FT3], free thyroxine [FT4], FT3/FT4 ratio, thyroid-stimulating hormone), 5α-stanols (sitostanol and cholestanol), and cholestanol precursors (total cholesterol and its synthesis marker lathosterol, and 7α-hydroxy-4-cholesten-3-one cholestenol) were measured at baseline and during the 14 weeks off EZE and on EZE. RESULTS: EZE increased FT3/FT4 (10% ± 4%; P = .02). EZE reduced plasma and red blood cells sitostanol (-38% ± 6% and -20% ± 4%; all P < .05) and cholestanol (-18% ± 6% and -13% ± 3%; all P < .05). The change in plasma cholestanol level on EZE inversely correlated with the change in FT3/FT4 (r = -0.86; P = .01). EZE lowered total cholesterol (P < .0001) and did not affect 7α-hydroxy-4-cholesten-3-one cholestanol. EZE increased (P < .0001) lathosterol initially, but the level was not sustained, resulting in similar levels at week 14 off EZE and on EZE. CONCLUSION: In patients with STSL, 5α-stanols levels might be associated with thyroid function. EZE reduces circulating 5α-stanols while increasing FT3/FT4, implying increased conversion of T4 to T3, thus possibly improving thyroid hormone status. TRIAL REGISTRATION: ClinicalTrials.govNCT01584206.

Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia.

OBJECTIVE: To assess if ezetimibe (EZE), a sterol-absorption inhibitor, improves platelet (PLT) count and size relative to its effect on plasma plant sterol (PS) in patients with sitosterolemia (STSL). STUDY DESIGN: Patients with STSL (5 males, 3 females, 16-56 years of age) receiving EZE intervention as part of their routine care participated in this study. EZE was discontinued for 14 weeks (off) and then resumed for another 14 weeks (on). Hematology variables along with plasma and red blood cells (RBC) PS and total cholesterol (TC) levels were measured at the end of each phase. RESULTS: EZE increased PLT count (23% ± 9%) and decreased mean PLT volume (MPV; 10% ± 3%, all P < .05). In patients off EZE, PLT counts inversely correlated (r = -0.96 and r = -0.91, all P < .01) with plasma and RBC PS to TC ratio (PS/TC), and MPV positively correlated (r = 0.91, P = .03 and r = 0.93, P = .02) with plasma and RBC PS/TC. EZE reduced plasma and RBC sitosterol (-35% ± 4% and -28% ± 3%), total PS (-37% ± 4% and -28% ± 3%, all P < .0001) levels, and PS/TC (-27% ± 4% and -28% ± 4%, P < .01). CONCLUSIONS: EZE reduces plasma and RBC PS levels, while increasing PLT count and decreasing MPV, and thereby may reduce the risk for bleeding in STSL. Plasma PS levels and ABCG5/ABCG8 genes should be analyzed in patients with unexplained hematologic abnormalities.

Feeding impairments associated with plasma sterols in Smith-Lemli-Opitz syndrome.

OBJECTIVE: To quantitatively evaluate feeding impairment in children with Smith-Lemli-Opitz syndrome (SLOS) and to correlate feeding impairment with clinical and biochemical indices of disease severity. STUDY DESIGN: The study subjects were 26 children with SLOS ranging in age from 0.4 to 19 years. Clinical severity was measured using an existing scoring system. We created a tool to quantitatively evaluate feeding. Plasma sterol concentrations were measured, and statistical associations (correlations) with feeding scores were calculated. RESULTS: Oral hyposensitivity or hypersensitivity, adverse behaviors, and risk for dysphagia were seen in ∼65% of the children with SLOS. Thirteen of the 26 children experienced failure to thrive, and 10 children required gastrostomy. Plasma concentration of 7-dehydrocholesterol, as a measure of severity, was correlated with total feeding score and oral function subcategory score (P < .001) and less so with oral structure score, adverse behaviors, or dysphagia. Correlations with cholesterol concentrations were less statistically significant. A plasma 7-dehydrocholesterol concentration >0.24 mmol/L or cholesterol concentration <1.95 mmol/L was predictive of gastrostomy tube use. Feeding impairments may improve with age. CONCLUSION: Feeding impairment is common and complex in patients with SLOS. Our findings confirm that oral sensitivities, adverse feeding behaviors, and risk of oral phase dysphagia are amenable to quantitative evaluation and analysis. Feeding difficulties in children with SLOS are correlated with plasma sterol concentrations, suggesting a link between the biochemical severity of SLOS and feeding function. These findings expand the behavioral phenotype of SLOS and begin to provide insight into the biological causes of feeding difficulties.

Plasma plant sterol levels do not reflect cholesterol absorption in children with Smith-Lemli-Opitz syndrome.

OBJECTIVE: To test the hypothesis that there is a correlation between the ratio of plant sterols to cholesterol in plasma and dietary cholesterol absorption in children with Smith-Lemli-Opitz syndrome (SLOS), a cholesterol synthesis disorder. STUDY DESIGN: We obtained measurements of cholesterol absorption with a direct radioisotope cholesterol absorption method during 9 visits of children with SLOS. We measured plasma sterols in 22 children with SLOS and 16 control children, and we measured dietary intake of cholesterol and sitosterol (n=11 SLOS). RESULTS: The correlations of 2 plasma plant sterol ratios (sitosterol/cholesterol and campesterol/cholesterol) with direct cholesterol absorption measurement were poor (R= -0.33 and R= -0.25, respectively), significantly lower than the published correlation in adults (R=0.73; P< .02). CONCLUSIONS: Although the ratios of plant sterols to cholesterol in plasma has been used as a surrogate for cholesterol absorption in adults and children, these ratios may not accurately reflect cholesterol absorption in children with SLOS. These ratios should not be used as a surrogate for cholesterol absorption in children without further validation.

Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome.

OBJECTIVE: Smith-Lemli-Opitz syndrome (SLOS) results in multiple malformations, growth deficiency, and mental retardation. Cholesterol supplementation has been used for several years to treat symptoms of SLOS. We assessed the developmental progress of children and adolescents with SLOS over a 6-year period. STUDY DESIGN: Patients with SLOS (n=14) received continuous cholesterol supplementation as part of a longitudinal study. Assessment of their developmental progress in the areas of cognitive, motor, and adaptive skills occurred every 6 to 12 months. The progress of each subject over time and the progress of the group as a whole were analyzed by using a repeated-measures design and multiple t tests. RESULTS: Developmental quotients did not improve over time for children with SLOS receiving cholesterol. In addition, baseline cholesterol levels, rather than age when supplementation began or increase in cholesterol levels, best predicted developmental outcome. CONCLUSIONS: These results suggest that cholesterol supplementation in its current form does not improve the developmental progress of children and adolescents with SLOS.

Postmortem screening for fatty acid oxidation disorders by analysis of Guthrie cards with tandem mass spectrometry in sudden unexpected death in infancy.

A protocol was developed for the detection of fatty acid oxidation disorders (FOD) in cases of sudden unexpected death in infancy (SUDI). Tandem mass spectrometry blood acylcarnitine analysis of Guthrie card blood spots was performed. In the first 5 years, 1.2% of Oregon's 247 SUDI cases were identified with FOD, 2 with medium-chain acyl-CoA dehydrogenase deficiency, and one with very long-chain acyl-CoA dehydrogenase deficiency.

Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins.

OBJECTIVE: To increase awareness of congenital disorders of glycosylation (CDG), we report the features of patients with a variety of clinical presentations ranging from mild hypotonia and strabismus to severe neurologic impairment. STUDY DESIGN: Nine North American patients with CDG type I and different ethnic origins were studied. RESULTS: All patients had transferrin isoelectric focusing studies with a type 1 sialotransferrin pattern. Molecular analysis showed the previously described R141H, V231M, and T237M PMM2 mutations in four patients as well as 3 rare mutations (DeltaC389, L104V, and IVS1 -1 G-->A) in the PMM2 gene in two Asian patients. CONCLUSIONS: The clinical features of these patients with diverse ethnic backgrounds confirm the variable course of CDG type I. Screening for CDG should be considered in children with relatively mild neurologic impairment, especially if they have suggestive findings such as cerebellar hypoplasia and abnormal fat distribution.