Malformation syndromes caused by disorders of cholesterol synthesis

Abstract

Cholesterol homeostasis is critical for normal growth and development. In addition to being a major membrane lipid, cholesterol has multiple biological functions. These roles include being a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development. After birth, most tissues can obtain cholesterol from either endogenous synthesis or exogenous dietary sources, but prior to birth, the human fetal tissues are dependent on endogenous synthesis. Due to the blood-brain barrier, brain tissue cannot utilize dietary or peripherally produced cholesterol. Generally, inborn errors of cholesterol synthesis lead to both a deficiency of cholesterol and increased levels of potentially bioactive or toxic precursor sterols. Over the past couple of decades, a number of human malformation syndromes have been shown to be due to inborn errors of cholesterol synthesis. Herein, we will review clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, HEM dysplasia, X-linked dominant chondrodysplasia punctata, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C-4 methyloxidase-like deficiency, and Antley-Bixler syndrome.

Fig. 1.

Presqualene cholesterol synthetic pathway. Cholesterol is synthesized from acetate in a series of enzymatic reactions. The biosynthetic pathway can be divided into two components. The presqualene cholesterol synthetic pathway is depicted in this figure. In addition to cholesterol, isoprenoid precursors are used to synthesize heme A, dolichol, and ubiquinone. Protein prenylation is a post-translational modification that involves the addition of either farnesyl or geranylgeranyl. Protein prenylation plays a role in localizing proteins to cellular membranes. Formation of squalene represents a commitment to sterol synthesis. Squalene undergoes cyclization to form lanosterol, the first sterol in the cholesterol synthetic pathway. PP: pyrophosphate.

Fig. 2.

Postsqualene cholesterol synthetic pathway. This figure depicts the postsqualene cholesterol synthetic pathway. Lanosterol is the first sterol formed after cyclization of squalene. Lanosterol is converted to cholesterol in a series of enzymatic reactions. Two major synthetic pathways exist, primarily distinguished by the timing of the reduction of the Δ24-bond in the aliphatic side chain by sterol Δ24-reductase. If reduction of the Δ24-bond occurs early, cholesterol is synthesized via the Kandutsch-Russel pathway (right side of the figure). This pathway appears to be favored in most tissues. In the Bloch pathway (left side of the figure) reduction of the Δ24-bond occurs as the last enzymatic step that converts desmosterol to cholesterol. Significant levels of desmosterol are found in the developing brain. The enzyme names and the corresponding genes are in italics (small and large type, respectively). *The C-4 demethylation complex consists of three proteins (NSHDL, sterol C-4 methyloxidase, and 3β-ketosterol reductase). Syndromes associated with defects at specific steps are indicated in red, bold type, genes in green, and enzymes in blue. HEM dysplasia and Antley-Bixler syndrome are in parentheses to indicate that they are not simply due to disruption of the corresponding enzymatic reaction. 7DHC is a precursor for both cholesterol and Vitamin D. In skin tissue photolysis of 7DHC in the skin leads to the formation of previtamin D3.

Fig. 3.

Common physical findings in SLOS. Facial appearance in severe (A), classical (B), and mild (C) cases of SLOS. Typical facial features include microcephaly, ptosis, midface hypoplasia, small upturned nose, and micrognathia. Cleft palate and submucosal clefts are frequently observed. Bifid uvula (D) are an observable manifestation of a submucosal cleft. Limb anomalies can include short proximally placed thumbs (E), postaxial polydactyly (E), or syndactyly of the second and third toes (F). Permission was obtained from guardians for the publication of these photographs.

Fig. 4.

Reduction of 7DHC. DHCR7 catalyzes the reduction of Δ7-bond in 7DHC to yield cholesterol. In SLOS there is a deficiency of DHCR7 activity that leads to the accumulation of 7DHC and its isomer 8DHC.

Fig. 5.

Oxysterol synthesis in SLOS. DHCR7 catalyzes the reduction of the Δ-7-bond in 7DHC to yield cholesterol in the final step of cholesterol synthesis. CYP27 normally functions to synthesize 27-hydroxycholesterol from cholesterol. 27-Hydroxy-7DHC and 27-hydroxy-8DHC have been identified in serum from SLOS patients. They likely arise due to CYP27 hydroxylation of 7DHC or 8DHC, respectively. 8DHC and the corresponding oxysterol are not depicted in this figure.

Fig. 6.

Phenotypic findings in CDPX2 and CHILD syndrome. Typical skin findings observed at birth in patients with CDPX2 include scaling and erythematous eruption in a linear or patchy distribution that follows the lines of Blaschko. This distinctive patterning is due to X-inactivation. B: Radiographs demonstrating epiphyseal stippling or chondrodysplasia punctata in a patient with CDPX2. Later hyperpigmentation at age 2 months following lines of Blaschko on the back (C) and scarring alopecia (D) in CDPX2. Unilateral, sharply demarcated, erythematous, ichthyosiform nevus, and ipsilateral limb reduction are characteristic findings in CHILD Syndrome (E and F). The photographs in this figure were originally published in reference (18) and reproduced with permission from Elsevier Ltd.

Fig. 7.

Sterol C-4 demethylation. The sterol C-4 demethylation complex consists of three enzymes that act in concert in the demethylation of 4,4-dimethylcholesta-8-en-3β-ol and 4,4-dimethylcholesta-8,24-dien-3β-ol (not shown). These enzymes include sterol C-4 methyl oxidase, NSDHL, and 3β-ketosterol reductase.

Fig. 8.

Sterol and steroid biochemical abnormalities in cytochrome P450 oxidoreductase deficiency. Cytochrome P450 oxidoreductase is an essential electron donor for P450 cytochrome containing enzymes involved in cholesterol and steroid synthesis. In cholesterol synthesis, deficient CYP51 activity leads to accumulation of lanosterol and dihydrolanosterol. In steroid hormone synthesis, impaired CYP17 and CYP21 activity leads to elevated pregnenolone, 17-OH progesterone, and other progesterone metabolites in combination with low androgen levels.