Abnormal sterol metabolism in holoprosencephaly: studies in cultured lymphoblasts.
BACKGROUND
Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans. The aetiology is heterogeneous and remains unexplained in approximately 75% of patients.


OBJECTIVE
To examine cholesterol biosynthesis in lymphoblastoid cell lines of 228 patients with HPE, since perturbations of cholesterol homeostasis are an important model system to study HPE pathogenesis in animals.


METHODS
An in vitro loading test that clearly identifies abnormal increase of C27 sterols in lymphoblast-derived cells was developed using [2-(14)C] acetate as substrate.


RESULTS
22 (9.6%) HPE cell lines had abnormal sterol pattern in the in vitro loading test. In one previously reported patient, Smith-Lemli-Opitz syndrome was diagnosed, whereas others also had clearly reduced cholesterol biosynthesis of uncertain cause. The mean (SD) cholesterol levels were 57% (15.3%) and 82% (4.7%) of total sterols in these cell lines and controls, respectively. The pattern of accumulating sterols was different from known defects of cholesterol biosynthesis. In six patients with abnormal lymphoblast cholesterol metabolism, additional mutations in genes known to be associated with HPE or chromosomal abnormalities were observed.


CONCLUSIONS
Impaired cholesterol biosynthesis may be a contributing factor in the cause of HPE and should be considered in the evaluation of causes of HPE, even if mutations in HPE-associated genes have already been found.
Haas
D
D
Division of Inborn Metabolic Diseases, University Hospital for Pediatric and Adolescent Medicine, Heidelberg, Germany. dorothea.haas@med.uni-heidelberg.de
Morgenthaler
J
J
Lacbawan
F
F
Long
B
B
Runz
H
H
Garbade
S F
SF
Zschocke
J
J
Kelley
R I
RI
Okun
J G
JG
Hoffmann
G F
GF
Muenke
M
M
D000085:Acetates / Q000378:metabolism; D000328:Adult; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002675:Child, Preschool; D002784:Cholesterol / Q000096:biosynthesis; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D016142:Holoprosencephaly / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D009930:Organic Chemicals / Q000378:metabolism; D012015:Reference Standards; D012997:Solvents / Q000378:metabolism; D013261:Sterols / Q000302:isolation & purification / Q000378:metabolism*
D000085:Acetates; D002250:Carbon Radioisotopes; D009930:Organic Chemicals; D012997:Solvents; D013261:Sterols; D002784:Cholesterol