Human pathology

cholesterol biogenesis diseases

defects of cholesterol biogenesis, anomalies of cholesterol biosynthesis, cholesterol biosynthesis disorders, inborn defects of cholesterol, cholesterol biosynthesis diseases, biosynthesis, inborn errors of cholesterol biosynthesis

Inborn defects of cholesterol biosynthesis are a group of metabolic disorders presenting with mental retardation and multiple congenital anomalies (MCA/MR syndromes).

Types

Smith-Lemli-Opitz syndrome (SLOS) (2.5-6%)
lathosterolosis
mevalonic aciduria
desmosterolosis
Conradi-Hunermann syndrome
Greenberg dysplasia
Pelger-Huet homozygosity syndrome.

Synopsis

progressive cholestasis
isolated hypertransaminasemia
mild hydropic degeneration of the hepatocytes
fetal hepatopathy
cholestasis

Physiopathology

Human disorders caused by inborn errors of cholesterol biosynthesis are characterized by dysmorphogenesis of multiple organs. This includes limb malformations that are observed at high frequency in some disorders, such as the Smith-Lemli-Opitz syndrome, indicating a pivotal role of cholesterol in limb morphogenesis.

Cholesterol can modulate the activity of the Hedgehog proteins, that act as morphogens to regulate the precise patterning of many embryonic structures, among which the developing limbs.

Animal models

In a rat model of cholesterol deficiency, treated with Triparanol, a distal inhibitor of cholesterol biosynthesis, patterning defects of the autopod at high frequency, including pre-axial syndactyly and post-axial polydactyly, are observed. These malformations originate from a modification of Sonic Hedgehog signaling in the limb bud at 13 days post-coitum, leading to a deficiency of the anterior part of the limb. This deficiency results in an imbalance of Indian Hedgehog expression in the forming cartilage, ultimately leading to reduced interdigital apoptosis and syndactyly. (12719383)

Human pathology

cholesterol biogenesis diseases

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