**Acknowledgements**

*Apolipoproteins, Triglycerides and Cholesterol*

as a feature of MVK deficiency [14, 168, 169].

of the cholesterol biosynthesis defects.

currently lack effective treatments.

**5. Conclusion**

Alzheimer's disease [166].

cell growth inhibition, induction of apoptosis and regulation of bile acid secretion [165]. Evidence is emerging that dysregulation of the mevalonate pathway may be involved in the progression of neurodegeneration in disorders such as

Inflammatory bowel disease (IBD) comprises a spectrum of phenotypes from Crohn's disease to ulcerative colitis. IBD usually occurs in young adults; however, onset in infancy and childhood are described. IBD occurs both in isolation and in monogenic syndromes with early-onset autoinflammation including the *NOD2*, *ATG16L1*, *IL23R*, *IL10R*, *IL10* and *XIAP* genes which have previously been correlated with IBD both in multifactorial and in Mendelian models [167]. MVK mutations may perhaps then synergistically augment the risk of developing IBD, especially as severe neonatal onset colitis responsive to anakinra has been reported

Recent studies have implicated the accumulation of pre-cholesterol sterols and the replacement of cholesterol with some of these sterols in lipid rafts as playing a key role in the underlying pathophysiology of cholesterol synthesis defects [170]. The meiosis-activating sterols were the first group of cholesterol biogenesis intermediates that were found to have important extrahepatic functions in mammals. Mutations in sterol-C4-methyl oxidase-like gene (*SC4MOL*) are causative for a rare autosomal recessive syndrome associated with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly and developmental delay [171, 172]. This gene encodes a sterol-C4-methyl oxidase (SMO) which catalyses demethylation of C4-methylsterols in the cholesterol synthesis pathway [172]. C4-methylsterols are meiosis-activating sterols, and further work is required to understand the role of these novel biomolecules in the pathogenesis

Inborn errors of cholesterol metabolism have provided many fundamental

MA, mevalonic aciduria; HIDS, hyper IgD syndrome; SQSD, squalene synthase deficiency; LSS, lanosterol synthase deficiency; HEM, hydrops-ectopic calcification-moth-eaten; CHILD, congenital hemidysplasia with ichthyosiform erythroderma and limb defects; CDPX2, X-linked chondrodysplasia punctate 2; SLOS, Smith-Lemli-Opitz syndrome; DD, developmental delay; II, intellectual impairment; CHD, congenital heart defect; AR, autosomal recessive; XLD,

insights into normal cholesterol homeostasis and cell biology over several decades. These disorders have been viewed as discrete diseases with their own unique genetic, biochemical and cellular consequences that in turn cause the clinical spectrum of symptoms associated with each disease. There remain specific pre-squalene enzymatic defects to be characterised and many unanswered questions regarding the pathogenesis of the cholesterol biosynthesis defects. What has been surprising is that at least three cholesterol-related disorders (SLOS, NPC and TD) all share a common pathological inhibition of the NPC pathway. The precise mechanism that inhibits this pathway in SLOS and TD remains to be fully elucidated, but these findings are suggestive of novel therapeutic approaches to treating SLOS and TD using drugs that modify the cell biology of NPC such as miglustat. Whether other human diseases also involve NPC pathway dysfunction remains to be determined. Current investigation of this question may pave the way for novel approaches to therapy for diseases that

**144**

X-linked dominant.

The authors thank Kevin Milo for proof reading and insightful comments in the manuscript preparation.
