Open access peer-reviewed chapter

Human Cholesterol Biosynthesis Defects

Written By

Erin Anderson and David Coman

Submitted: January 24th, 2019 Reviewed: May 30th, 2019 Published: June 24th, 2019

DOI: 10.5772/intechopen.87150

Chapter metrics overview

896 Chapter Downloads

View Full Metrics


Cholesterol plays an essential role in normal embryogenesis and perturbations in its de novo synthesis are responsible for organ malformations in the cholesterol biosynthesis defects. Ten distinct inherited disorders have been linked to different enzyme defects in the isoprenoid/cholesterol biosynthetic pathway: mevalonic aciduria, hyperimmunoglobulinemia syndrome, squalene synthase deficiency, lanosterol synthase deficiency, hydrops-ectopic calcification-moth-eaten (Greenberg) skeletal dysplasia, X-linked dominant chondrodysplasia punctata, congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome, lathosterolosis, Smith-Lemli-Opitz syndrome and desmosterolosis. These Mendelian disorders are clinically heterogeneous with protean manifestations reflecting the important role of cholesterol, and its intermediary metabolites, in embryogenesis and development. Key clinical features commonly represented by the cholesterol biosynthesis defects include structural brain malformations, axial skeletal developmental anomalies and genital and cardiac malformations. The aetiology of the underlying pathophysiology is unclear and multifactorial but may be due to lowered cholesterol and/or the elevated, teratogenic levels of the intermediate sterol precursors. Herein, we will review clinical, biochemical and molecular aspects of the known human cholesterol biosynthesis defects.


  • cholesterol biosynthesis defects
  • mevalonate
  • squalene
  • skeletal dysplasia
  • chondrodysplasia
  • Smith-Lemli-Opitz

1. Introduction

Cholesterol is essential for normal cellular function. All nucleated cells can synthesise cholesterol from acetyl-CoA in the isoprenoid biosynthesis pathway via enzymatic reactions that are localised to the endoplasmic reticulum. Isoprenoids function in a variety of important cellular processes, including cell growth and differentiation, protein glycosylation, as precursors of oxysterols, steroid hormones and bile, in mitochondrial electron transport and signal transduction pathways, especially that of the hedgehog pathway [1, 2, 3]. Cholesterol biosynthesis is divided into two major pathways: pre-squalene cholesterol synthesis and post-squalene cholesterol synthesis. Pre-squalene cholesterol synthesis contributes to both sterol and isoprenoid synthesis, whereas post-squalene cholesterol synthesis is a committed pathway to sterol and vitamin D synthesis [3].

Isoprenoid biosynthesis (Figure 1) begins with the C2 compound acetyl-CoA, which, via six subsequent enzyme reactions, is converted into isopentenyl-pyrophosphate, the basic C5 isoprene unit used for synthesis of all subsequent isoprenoids [3]. The first committed step to the production of sterol isoprenoids is C30 squalene (composed of 6 isoprene units) which, after cyclisation, is converted into C30 lanosterol (4,4,14-α-trimethyl-cholesta-8(9),24-dien-3β-ol) [4]. Following this transformation, cholesterol can be synthesised via one of two independent routes; the Bloch pathway [5] or the Kandutsch-Russell pathway [6]. Both pathways utilise the same enzymes, but in different orders in a tissue-dependent manner, leading to the formation of different intermediates [7]. C27 cholesterol is subsequently produced from lanosterol via a series of at least eight different enzyme reactions, including one demethylation at C14, two demethylations at C4, one isomerisation of the D8 [9] double bond to D7, three reductions of the D24, D14 and D7 double bonds and one desaturation between C-5 and C-6 [3].

Figure 1.

Schematic representation of the human cholesterol biosynthesis pathway. HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; P, phosphate; PP, pyrophosphate; 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.

Currently, 10 Mendelian disorders of cholesterol biosynthesis have been characterised, all with complex multisystem clinical phenotypes, supporting the importance of cholesterol in embryogenesis and development (see Figure 1 and Table 1). Currently, the only reported defects in the pre-squalene pathway are the mevalonate kinase deficiency allelic conditions of mevalonic aciduria (MA, OMIM 610377) and hyper IgD syndrome (HIDS, OMIM 260960), squalene synthase deficiency (SQSD, OMIM 618156) and lanosterol synthase deficiency (LSS, OMIM 600909). Six Mendelian diseases in the post-squalene pathway have been reported: hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM, OMIM 215140), congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome (CHILD, OMIM 308050), chondrodysplasia punctate 2 (CDPX2, OMIM 302960), lathosterolosis (OMIM 607330), Smith-Lemli-Opitz syndrome (SLOS, OMIM 270440) and desmosterolosis (OMIM 602398). Improved understanding of molecular mechanisms associated with intracellular trafficking of cholesterol and regulation of key rate limiting steps in cholesterol synthesis (e.g. via the ubiquitin proteasome system) has generated opportunities for identification of other novel Mendelian defects associated with cholesterol homeostasis [8, 9].

SyndromeOMIMChromosome locationGeneEnzymeKey featuresInheritance
MA61037712q24.11MVKMevalonate kinaseAutoinflammatory flares, dysmorphia, DD, psychomotor retardation and hepatosplenomegalyAR
HIDS26096012q24.11MVKMevalonate kinaseRecurrent cyclical fevers and abdominal painAR
SQSD6181568p23.1FDFT1Squalene synthaseDysmorphia, DD, male genital malformations, brain malformations, seizures and abnormal urine organic acidsAR
LSS60090921q22.3LSSLanosterol synthaseCongenital cataracts and hypotrichosisAR
HEM skeletal dysplasia2151401q42.12LBR3β-hydroxysteroid-sterol Δ14-reductaseNon-immune hydrops fetalis, stippling and erroneous calcification and dwarfismAR
CHILD308050Xq28NSDHLSterol C4-demethylase aka 3β-hydroxysteroid dehydrogenaseUnilateral ichthyosis, male-lethal, ipsilateral limb reductionXLD
CDPX2302960Xp11.22–23EBP3β-hydroxysteroid-Δ87-sterol isomeraseRhizomelia, calcific stippling cataractsXLD
Lathosterolosis60733011q23.3-q24.1SC5DL3β-hydroxysteroid-Δ5-desaturaseMicrocephaly, cataracts, poly and syndactyly, DD, IIAR
SLOS27040011q13.4DHCR77-dehydrocholesterol reductase2–3 syndactyly, cleft palate, II, typical craniofacial stigmataAR
Desmosterolosis6023981p32.3DHCR2424-dehydrocholesterol reductaseSLOS-like dysmorphia, CHD, microcephaly, DD, IIAR

Table 1.

Known human defects of cholesterol biosynthesis.

Modulating flux through the cholesterol biosynthesis pathway has been of interest for many years as a pharmacological treatment option for hypercholesterolemia. The statin family of drugs inhibit HMG-CoA reductase, the rate limiting step in the pre-squalene pathway, and similar efforts have focused on inhibitors of squalene synthase as this enzyme is the first committed step in cholesterol biosynthesis. Animal and human models of squalene synthase inhibitors generated a complex array of farnesol-derived metabolites [10, 11, 12], the recognition of which was instrumental in describing SQSD, a newly described pre-squalene cholesterol biosynthesis defect [4]. That pathogenesis of the cholesterol biosynthesis defects is complex, reflective of the multisystem nature of the clinical phenotypes.


2. Disorders of the pre-squalene cholesterol pathway

2.1 Mevalonate kinase deficiency

Mevalonate kinase phosphorylates mevalonate, the product of the reduction of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA), which is important in cholesterol biosynthesis and for farnesylation and isoprenylation of proteins [13]. Mevalonate kinase deficiency (MKD) is a recessively inherited autoinflammatory disorder in the isoprenoid biosynthetic pathway with a spectrum of manifestations, including the well-defined allelic clinical phenotypes of HIDS and MA [14], both of which were identified in the mid-1980s [15, 16].

Mevalonate kinase is essential for the biosynthesis of non-sterol isoprenoids, which mediate protein prenylation. MKD is caused by mutations in the MKD gene which encodes mevalonate kinase, with the degree of residual enzyme activity largely determining disease severity. MKD leads to perturbations in the mevalonate pathway of cholesterol synthesis with episodes of hyperinflammation [17]. MKD is now viewed as a phenotypic continuum based on the degree of enzyme deficiency, with MA the most severe phenotype and HIDS the mild end of the spectrum [18].

MKD is characterised by autoinflammatory flares with fever, abdominal pain, mucoid and cutaneous lesions and arthralgias [14]. The more severely affected patients with MA classically have developmental delay, dysmorphism, psychomotor retardation, hepatosplenomegaly and ocular abnormalities [14]. During attacks, patients with MKD have increased levels of acute-phase proteins including C-reactive protein and cytokines such as TNF-α, IL-6 and interferon-γ [19, 20]. The MA phenotype characteristically presents in the first few months of life, with antenatal presentations linked with a high rate of stillbirth [21]. Commonly reported dysmorphic features include frontal bossing, hypertelorism, long eyelashes and triangular-shaped facies, as well as failure to thrive, developmental delay, ataxia, seizures, myopathies and autoinflammatory attacks [21, 22]. MA is a multisystem phenotype with gastrointestinal manifestations including cholestasis and liver dysfunction [23], and ocular findings including recurrent conjunctivitis, cataracts and uveitis [24].

The HIDS phenotype typically presents with recurrent (four-to-six weekly) self-limited bouts of multisystem inflammation characterised by fever, abdominal pain, adenopathy, rash and arthralgia [14]. As these are common symptoms of many childhood infectious illnesses, the diagnosis of HIDS is often delayed for many years. HIDS episodes usually last 3–7 days, occurring in a cyclical fashion or induced by a provocative physiological stress such as illness, injury or vaccination. Acute abdominal pain may be the most marked and debilitating feature of systemic inflammation and can mimic a ‘surgical acute abdomen’ [24]. A long-term follow-up study of 103 HIDS patients revealed that the frequency of the attacks decreases over time, but 50% of patients greater than 20 years of age still experience six or more attacks per year, impacting on the quality of life [24].

The epidemiology of MKD is largely unknown. At least 300 people are documented worldwide, the majority with HIDS, although this is likely to be underdiagnosed as recurrent fevers in childhood are a common occurrence. The highest documented prevalence is in the Netherlands, with an estimated 1:200,000 affected nationwide, consequent to a high carrier rate which is estimated at 1:65 [24, 25].

Elevations in IgD in MKD are inconsistent and can be normal in up to 20% of cases [24]. Serum amyloidosis is a long-term sequela of prolonged inflammatory activation, with elevations in serum amyloid A noted in approximately 3% of HIDS patients [24]. Urinary excretion of mevalonic acid can persist in MA and maybe present in some HIDS patients during febrile attacks [21]. The diagnosis is confirmed by identifying pathogenic mutations in the MVK gene; currently more than 120 sequence variants in this gene have been reported in association with MKD [26], most of which are missense mutations that impair mevalonate kinase stability [27]. Some genotype-phenotype correlations exist: MVK variants located in the core of the protein (affecting folding and stability) are highly associated with the more severe MA phenotype [25, 28, 29]. In contrast, other variants such as the C-terminal V377I substitution typically manifest as the HIDS phenotype and are rarely associated with MA [25].

Although the precise pathogenesis of MKD remains unclear, increasing evidence suggests that deficiency in protein prenylation leads to innate immune activation and systemic hyperinflammation, which has assisted in the development of cytokine-directed biologic therapy. Corticosteroids induce a complete response in 24% of HIDS patients [30]. Biologics targeting IL-1, including anakinra and canakinumab, and TNF-α blocking agents such as etanercept and adalimumab, have been used with varying success [30]. Some cases that have failed to respond to anakinra have demonstrated a successful reduction in symptoms with tocilizumab, a monoclonal antibody targeted against the IL-6 receptor [31]. One patient with MKD, treated with alendronate for steroid-induced osteoporosis, subsequently achieved complete remission [32]. Alendronate inhibits farnesol-pyrophosphate synthase. For refractory cases of MA phenotype, the last consideration for therapy includes liver transplantation or haematopoietic stem cell transplantation [14].

Blockade of the mevalonate pathway with the HMG-CoA reductase inhibitors reduces both mevalonic acid levels and residual isoprenoid production and but can trigger disease flares [22]. The inflammatory hyper-responsiveness in MKD appears to be due to lack of isoprenoid products and not accumulation of mevalonic acid. This appears to be due to the need for geranylgeranylation rather than other mevalonate pathway products, such as cholesterol biosynthesis, in mediating the hypersecretion of IL-1β [27]. The use of statins in this disease process has therefore largely been abandoned [30]. Mvk+/− mice do have some features of immune dysfunction, including increased serum IgD and TNF-α levels, as well as increased expression of activation markers on T-lymphocytes and macrophages [33].

2.2 Squalene synthase deficiency

Squalene synthase deficiency (SQSD) is a recently identified pre-squalene defect to have been characterised. In 2018, three patients were reported with this novel cholesterol biosynthesis defect [4]. Salient clinical features include facial dysmorphism, dry skin with photosensitivity, generalised tonic-clonic seizures, structural brain malformations, cortical visual impairment, profound global developmental delay and genital malformations in the two males [4].

Gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy profiles yielded a consistent and complex pattern of abnormal metabolites including accumulation of methylsuccinic acid, mevalonate lactone, mesaconic acid, 3-methyladipic acid, saturated and unsaturated branched-chain dicarboxylic acids and glucuronides derived from farnesol [4]. A similar metabolite profile has previously been observed in the urine of animal models and humans treated with pharmacological inhibitors of squalene synthase, as well as in animals loaded with farnesol [10, 11, 12]. This urine metabolic profile is specific to and thus diagnostic of SQSD. Plasma total farnesol levels (the sum of free farnesol and farnesyl-pyrophosphate) in affected individuals were, however, significantly increased (1.5–3.9 mmol/L; reference <0.12) while plasma squalene levels were reduced or normal (0.17–0.93 mmol/L, reference 0.36–1.04).

A range of pathogenic FDFT1 molecular variants have been described in the three SQSD patients identified thus far (a sibship and an unrelated patient) [4]. The sibship was compound heterozygous for a maternally-inherited 120 kb deletion, resulting in loss of exons 6–10 of FDFT1 and the entire coding sequence of the neighbouring CTSB gene (encoding cathepsin B (OMIM 116810)); and a paternally inherited variant c.88024_88023delinsAG, which created a novel splice acceptor site. The unrelated patient was homozygous for a novel 16-bp intronic deletion. Functional characterisation of the variants demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis and/or uptake in steady state [4].

Fdft1-null mice demonstrate embryonic lethality at day 12.5 in conjunction with growth restriction and neurodevelopmental disorders [34]. The fact that the FDFT1 variants in the human SQSD cases are compatible with life may be explained by the fact that all individuals have some form of residual FDFT1 activity, either resulting from the diminished levels of correctly-spliced enzyme or by functional compensation for disrupted regulation [4].

2.3 Lanosterol synthase deficiency

In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclisation of (S)-2,3-oxidosqualene into lanosterol. Pathogenic mutations in the LSS gene have recently been reported in a spectrum of clinical phenotypes including congenital cataracts in three families [35], hypotrichosis simplex (HS) in three families [36] and a more severe neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome in six unrelated families [37]. HS (OMIM 618275) is a rare form of hereditary alopecia characterised by childhood onset of diffuse and progressive scalp and body hair loss [36]. APMR syndrome (OMIM 203650) is a rare disorder with autosomal recessive transmission. A recent report identified 11 individuals from seven unrelated families affected with alopecia, male genital abnormalities, variable MRI abnormalities and neurological symptoms [37]. In this cohort, total alopecia was universal with other common dermatological manifestations including ichthyosis and erythroderma. Neurological manifestations included significant developmental delay, microcephaly, epilepsy and hypomyelination [37].

Sterol profiling in lanosterol synthase deficiency cases has not identified any specific abnormalities, thus supporting the previously proposed hypothesis of an alternative cholesterol pathway [36]. LSS variants identified to date include truncating, missense and splicing variants. LSS has also been associated with congenital cataracts in rat [38]. Mice homozygous for the Lsstm1b(KOMP)Wtsi allele demonstrate variable lethality, from embryonic day 9.5 to postnatal prior to weaning [39].


3. Disorders of the post-squalene cholesterol pathway

3.1 Hydrops-ectopic calcification-moth-eaten skeletal dysplasia

Most proximal in the post-squalene pathway is hydrops-ectopic calcification-moth-eaten (HEM) skeletal dysplasia, or Greenberg dysplasia. This very rare and severe autosomal recessive disorder was first described in 1988 [40] with only 11 examples identified in the literature to date. All but one of these have been lethal in utero, with the remaining case dying at 2 days of age [41]. HEM skeletal dysplasia is characterised by significant non-immune hydrops fetalis, erroneous chondro-osseous calcification of vertebrae, ribs, pelvis, larynx and trachea as well as a diagnostic mottled ‘moth-eaten’ appearance of long bones on radiography [42, 43, 44]. Further skeletal abnormalities can include rhizomelic and mesomelic shortening of the limbs, platyspondyly, decreased skull ossification and distal dysmorphisms such as absent phalanges or postaxial polydactyly [42, 43, 44, 45]. Non-skeletal congenital malformations include pulmonary hypoplasia, intestinal malrotation, cystic hygroma and excessive extramedullary haematopoiesis [45, 46]. Histology shows significant bone and cartilage disorganisation [43, 45].

HEM skeletal dysplasia was first suggested as an inborn error of cholesterol biosynthesis by Kelley et al. [47] with identification of increased levels of 4,4-dimethylcholesta-8 [9],14-dien-3β-ol and 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol in cultured fibroblasts, indicating a deficiency of sterol ∆14-reductase. This enzyme converts these sterols to 4,4-dimethylcholesta-8(9)-en-3β-ol and 4,4-dimethylcholesta-8(9),24-dien-3β-ol, respectively. This point on the cholesterol biosynthesis pathway is unique with sterol ∆14-reductase activity by both the lamin B receptor (LBR) and a second enzyme DHCR14 (TM7FS2), although functional redundancy is disputed [48, 49]. It was originally thought that the more prominent role in sterol biosynthesis was that of DHCR14 compared to the lamin B receptor. However, it has more recently been demonstrated that it is a deficiency in the lamin B receptor due to mutations in LBR at 1q42.12 that is causative for HEM skeletal dysplasia [50, 51] and that it is the LBR, not DHCR14, that is required for cholesterol biosynthesis [48, 52].

The involvement of LBR has raised contention as to whether HEM skeletal dysplasia should be classified as a laminopathy rather than as an error of cholesterol synthesis [49]; however, it is appropriate to recognise that mutations in LBR can cause different disorders in different contexts. The type of mutation (missense, nonsense or splice-site), the functional location of each mutation in the LBR gene and the residual protein activity affect the clinical outcome of this disorder [53, 54]. The LBR protein has both a nuclear domain involved in anchoring chromatin to the nuclear membrane, and a transmembrane domain with sterol ∆14-reductase activity critical for cholesterol synthesis [48], the latter primarily where mutations causing HEM dysplasia are located [50]. Some mutations found in LBR in HEM dysplasia patients have been identified in the heterozygous state in the relatively benign autosomal dominant condition of Pelger-Huët anomaly in which granulocytes have bilobed nuclei but patients are otherwise clinically normal. These two conditions may represent different allele patterns of the same disorder for some mutations [53, 55]. The less common homozygous Pelger-Huët is clinically more severe with round or ovoid granulocyte nuclei and some cases with mild skeletal abnormalities [56, 57]. This highlights the role of the lamin B receptor sterol reductase function as essential in prenatal development but also the phenotypic continuum that can occur for various allele combinations of the LBR gene.

Species variation with respect to the role of the LBR can make mouse model outcomes difficult to elucidate. Studies of mutations in both LBR and DHCR14/TM7FS2 have been investigated in ichthyosis (ic) mice with contrasting conclusions, including those highlighted above and as reviewed by Herman and Kratz [58].

3.2 Congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome is a rare X-linked dominant disorder of cholesterol biosynthesis, with fewer than 100 cases discussed in the literature [58]. The earliest identification of the condition is thought to be in 1903 [59], through the proposal of the syndromic acronym in 1980 [60]. CHILD syndrome is nearly always male-lethal although perhaps two males with this syndrome have been identified, one with a 46, XY karyotype, postulated to have survived due to a postzygotic mutation [61]. The distinguishing hallmark of the condition is that of unilateral skin lesions with ipsilateral limb defects [60, 62, 63]. The characteristic yellow, scaly plaques are usually present at birth or emerge in the first few months of life and while there may be some resolution over time, they often remain for life [60]. These markings may follow the lines of Blaschko, but more commonly, there is a striking delineation at the midline with the lesions showing a unique lateralisation pattern [62]. This has been proposed to be due to interactions between X-inactivation and the organisation of left-right axis symmetry in the developing embryo [60]. The lateralisation of these lesions and their persistence is a distinguishing feature of CHILD syndrome compared to differentials such as CDPX2, a similar but distinct inborn error of cholesterol biosynthesis [64].

CHILD syndrome demonstrates complete limb aplasia, severe phocomelia or severe hypoplasia on the same side of the body as ichthyosiform lesions [60]. Infant radiography may show epiphyseal stippling such as that seen in CDPX2, as well as milder skeletal malformations such as scoliosis, hypo or hemi-plastic vertebrae, distal digit shortening, syndactyly or polydactyly [65]. Non-skeletal manifestations include alopecia, verruciform xanthoma, dystrophic nails and congenital malformations on the affected side that can involve the heart, kidneys and CNS [60, 65]. Intelligence may be normal or slightly reduced. Despite the severity of these symptoms, mild cases of CHILD syndrome with no skeletal and/or cutaneous involvement have been identified through molecular analysis [66].

Molecular investigation has identified various mutations in the NSDHL (NADH steroid dehydrogenase-like) gene as causative for CHILD syndrome [67]. NSHDL is located at Xq28 and encodes 3β-hydroxysteroid dehydrogenase, part of a three-part enzyme complex. This C4 demethylation complex acts on the sterol ring in the post-squalene pathway, converting 4,4-dimethylcholesta-8(9),24-dien-3β-ol to zymosterol and 4,4-diemthylcholesta-8(9)-en-3β-ol to cholesta-8(9)-en-3β-ol. Mutations are most often loss-of-function [68]. Cholesterol and sterol levels are normal and so a diagnosis requires clinical and molecular assessment. Various NSDHL mutations have been studied in the allelic ‘bare patches’ (Bpa) and ‘striated’ (Str) murine models [69]. These have given insights into facets of CHILD syndrome and cholesterol synthesis disorders in general, for example, the roles of the maternal placenta [70] and Hedgehog signalling pathways [71] in disease presentation.

Treatment options for CHILD syndrome have generally focused on topical management of skin lesions with symptomatic remedies such as emollients or with pathogenesis-based therapies generally involving combinations of cholesterol and a cholesterol synthesis-inhibitor [72, 73], the latter with some efficacy.

3.3 X-linked dominant chondrodysplasia punctata 2

X-linked dominant chondrodysplasia punctata 2 (CDPX2), or Conradi-Hünermann-Happle syndrome, is estimated to have an incidence of 1/400,000 and, similarly to CHILD syndrome, is almost entirely male-lethal. The CDPX2 phenotype, like the other cholesterol biosynthesis disorders, is heavily based on the skeletal and cutaneous domains, and there can be significant variability even within family lines [74, 75, 76] with generational anticipation [74]. Severe manifestations can result in neonatal or infant death with considerable skeletal and internal abnormalities, while mild cases may be nearly asymptomatic. This range of phenotypic variability is likely due to the combination of somatic and/or gonadal mosaicism and X-inactivation patterns [76]. Occasional male patients are identified with CDPX2, usually due to somatic mosaicism [77, 78] with one case of 46,XXY [79]. Gonadal mosaicism is possible which is relevant for recurrence risk [80].

Widespread epiphyseal stippling is seen on infant radiographs, often including not just the long bones but the trachea and vertebrae as well [81, 82, 83]. Additional skeletal stigmata include short stature and scoliosis (which can be congenital), clubfoot, joint contractures, and postaxial polydactyly [74, 77, 83]. Cutaneous manifestations include skin with patches of scaly hypo or hyper-pigmentation, which usually follows the lines of Blaschko. The initial skin scaling and erythroderma present at birth usually fades over the first few months of life, leaving follicular atrophoderma, pigmentation and alopecia, although ichthyosis can persist [8485]. The pattern and then resolution of skin scaling as well as its histological profile is a differentiating diagnostic feature for CDPX2 compared to CHILD syndrome. Diagnosis of CDPX2 in adulthood can be difficult due to the childhood resolution of the characteristic skin lesions and epiphyseal stippling [86]; however, a combination of cutaneous manifestations, asymmetric limb reduction and cataracts (found in 65% of patients) is a good suggestion of this condition for further investigation [86]. CDPX2 presents with characteristic facial features including frontal bossing, midface hypoplasia and flat nasal bridge [74, 81]. The condition is also associated with microphthalmia or microcornea, congenital heart disease, renal abnormalities including hypoplasia and hydronephrosis and sensorineural hearing loss [87]. Cognition is usually normal [87].

CDPX2 is caused by mutations in the EBP (emopamil binding protein) gene [88, 89] located at Xp11.23 and encoding a Δ87-sterol isomerase. This enzyme functions downstream of the C4-demethylation complex affected in CHILD syndrome and converts zymosterol and cholesta-8(9)-en-3β-ol to cholesta-7,24-dien-3β-ol and lathosterol, respectively. There is a phenotypic correlation with enzyme function with lethality of homozygous females and clinically affected heterozygous females; however, there is no clear genotype-phenotype correlation, presumably due to X-inactivation patterns [74, 76]. Surviving males with CDPX2 are almost always due to mosaic postzygotic mutations as a hemizygous male genotype is lethal in utero. CDPX2 mutations (including deletions, insertions, nonsense, missense and splice-site) of EBP have been identified as both de novo and inherited mutations and are found throughout the entire length of the gene [74].

While there is no clear CDPX2 genotype-phenotype correlation, there is a distinct association between genotype and CDPX2 sterol profile [74], and plasma sterol assay is a highly specific indicator for an EBP mutation [83]. Plasma shows increased 8-dehydrocholesterol and 8(9)cholesterol levels, with the ratios compared to cholesterol increased 0.71–0.80% [74]. Plasma cholesterol is usually normal. Treatment and surveillance are symptomatic, and studies in these areas have been advanced by the ‘tattered’ (Td) mouse which shares both phenotypic and molecular similarities with human CDPX2 [89].

3.4 Lathosterolosis

Lathosterolosis (OMIM 607330) results from impaired 3-hydroxysteroid-5-desaturase (SC5D) activity [90]. In the Kandutsch-Russel synthetic pathway, SC5D catalyses the conversion of lathosterol to 7-dehydrocholesterol (7DHC) in the enzymatic step immediately preceding the defect in SLOS, whereas in the Bloch pathway of cholesterol synthesis, SC5D catalyses the conversion of cholesta-7,24-dienol to 7-dehydrodesmosterol [90].

To date, deleterious missense mutations of SC5D have been reported in six patients from three families [91, 92, 93, 94, 95]. The clinical features include microcephaly, facial dysmorphism, bitemporal narrowing, ptosis, cataracts, anteverted nares, micrognathia, postaxial polydactyly, syndactyly, ambiguous genitalia, non-neuronal mucolipidosis, global developmental delay, intellectual impairment, hepatic cirrhosis, and early lethality [91, 92, 93, 94, 95]). One surviving patient who developed end-stage hepatic failure and received a liver transplantation had improvement of lathosterolosis symptoms [96]. Another patient had a milder clinical phenotype of microcephaly and learning defects with cataracts [91] highlighting the possible under-diagnosis of the syndrome without plasma sterol analysis.

Plasma cholesterol levels are normal with accumulation of lathosterol in plasma and in cultured fibroblasts, and lamellar inclusions within cellular lysosomes [95]. Sc5d−/− pups are stillborn and demonstrate craniofacial malformations including cleft palate and limb defects such as postaxial polydactyly [94].

3.5 Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS) is the prototypical inborn error of cholesterol biosynthesis first described in 1964 [97]. It is by far the most common disorder in this group, with an incidence of approximately 1/40,000 although this can range from 1/70,000 to 1/10,000 depending on the population in question [98]. The carrier frequency can range from approximately 1:100 in North American Caucasians to 1:50–1:30 in various Central European populations [99]. While these carrier rates would imply a far greater incidence than is clinically observed, there is thought to be a level of misdiagnosis or non-diagnosis in mildly-affected patients, and in utero prenatal demise is estimated to affect 42–88% of conceptuses [100], mostly in the first trimester [98, 101].

SLOS has a broad range of phenotypic variabilities: mild cases can comprise minor physical abnormalities and behavioural or learning difficulties through a wide spectrum to a severe phenotype comprising major and life-limiting congenital abnormalities. Cognition can range from near-normal [102] to profound intellectual impairment, and on MRI, up to 96% of SLOS patients have a structural brain abnormality [103]. There is a correlation of atypical sterol profiles with both intellectual impairment and brain malformations, particularly abnormalities of the septum pellucidum and corpus callosum [103]. CNS myelination is normal despite its high proportion of cholesterol content and the mostly in situ synthesis of cholesterol in the CNS [104]. As well as intellectual impairment, patients are often diagnosed with language delays or impairment, autistic spectrum disorder and sleep disturbances, and can engage in self-harm. Global developmental delay, hypotonia and failure to thrive are common [105, 106, 107]. The most common physical manifestation reported with SLOS is that of 2,3 toe syndactyly, and a combination of this with other structural or cognitive symptoms should suggest a possible SLOS diagnosis for investigation [108]. Limb anomalies are common, including polydactyly, short proximal thumbs and a single palmar crease [105, 106, 107]. Other structural malformations that can occur include microcephaly, cleft palate, bifid uvula and characteristic facies with micrognathia, ptosis and broad nasal tip with anteverted nares [105, 106, 107]. This facial dysmorphia can be less recognisable in older patients [107]. Congenital abnormalities can also affect the heart and lungs, gastrointestinal tract and genitalia [105, 106, 107]. Patients with SLOS often have severe ultraviolet photosensitivity [109].

The final steps of the post-squalene cholesterol biosynthesis pathway are conversion of 7-dehydrodesmosterol to desmosterol and 7-dehydrocholesterol (7-DHC) to cholesterol. The latter is catalysed by the 3β-hydroxysteroid-Δ7-reductase (or 7-dehydrocholesterol reductase, DHCR7) enzyme, encoded by the DHCR7 gene at 11q13.4. Increased levels of 7-DHC and decreased levels of cholesterol led to SLOS being identified as a disorder of sterol biosynthesis in 1993 [110, 111]. This altered plasma profile is a useful diagnostic tool for SLOS, and there is evidence of a relationship between serum sterols and disease severity [112, 113].

Over 100 mutations in DHCR7 have been identified in SLOS [114] with no clear genotype-phenotype correlations [115, 116], although some mutations are associated with more mild phenotypes due to some residual enzyme activity [117]. There is a significant correlation between SLOS patient phenotype and maternal genotype for ApoE and ABCA1 [118, 119]. These correlations are positive for amelioration of SLOS symptomatology and pathogenesis and with the potential for therapeutic mediation [120].

As well as being the precursor to cholesterol, 7-DHC is also the precursor to vitamin D with exposure of cutaneous 7-DHC to ultraviolet B and subsequent synthesis to vitamin D by the liver and kidney. Increased levels of circulating vitamin D are seen in patients with SLOS [121], despite their increased photosensitivity and ensuing limited sun exposure. One of the primary theories for a possible heterozygous advantage of DHCR7 mutations is that of protection against vitamin D deficiency [105], particularly given the greater carrier rate seen in populations of northern Europe [98, 99].

A prenatal diagnosis can be obtained via molecular or biochemical analysis (e.g. of amniotic fluid sterols [122]); however, non-invasive techniques can also identify pregnancies requiring SLOS investigation. Measurement of a low maternal serum unconjugated estriol (uE3), particularly when combined with abnormal sonography results, can be utilised for prenatal screening although this can yield false positive results and uE3 levels can also be predictive for other disorders [101]. Baseline screening for a SLOS-affected pregnancy is also possible non-invasively via serial measurement of steroids such as pregnanetriol in maternal urine [123, 124]. Abnormal plasma sterol ratios in unaffected heterozygotes [125] mean that carrier status may be determined prior to pregnancy for increased reproductive options.

Current treatment protocols for SLOS usually involve endogenous cholesterol supplementation with or without adjunct therapies such as simvastatin [126]. There is broad anecdotal evidence throughout the literature as to the positive benefit of cholesterol supplementation for patient growth, overall health (including improved photosensitivity and response to infection) and behaviour, as well as measurable changes towards typical plasma sterols [127, 128, 129]. These improvements have been reported following initiation of cholesterol treatment in both children and adults [130], although with greater rate of improvement with earlier intervention [131]. Limitations to the efficacy of cholesterol treatment certainly exist, such as cholesterol’s inability to cross the blood-brain barrier in any practical quantity (which makes the apparent behavioural improvements reported interesting). The real value of cholesterol supplementation is yet to be definitively determined as trials of increased dietary cholesterol both with and without placebo controls have yielded very mixed results [132, 133, 134]. Antioxidant [135, 136] and virus vector [137] therapies have also been explored as an avenue for improved patient outcomes for SLOS and other disorders of cholesterol synthesis. Both mouse and rat models of null and hypomorphic alleles in DHCR7 have been useful homologues for characterisation and investigation of human SLOS [138, 139].

3.6 Desmosterolosis

Desmosterolosis (OMIM 602398) is currently the final inborn error of cholesterol biosynthesis and is caused by defective enzymatic function of 3-hydroxysterol-delta 24-reductase (DHCR24). This reaction causes the reduction of the C-24 bond in the aliphatic side chain of cholesterol [140]. Reduction of the C-24 bond catalysed by DHCR24 can occur at different times in the cholesterol synthetic pathway: this step occurs early in the Kandutsch-Russel cholesterol synthetic pathway [6] but is the penultimate step in the Bloch pathway of cholesterol synthesis [5].

While first described in 1998, the molecular mechanisms of desmosterolosis were not characterised until 2001 [140, 141]. To date, only nine cases have been reported and clinical features include SLOS-like dysmorphism, thick alveolar ridges, gingival nodules, cleft palate, short limbs, severe congenital heart defect, atherosclerosis, arthrogryposis, ambiguous genitalia, microcephaly, agenesis of the corpus callosum, global developmental delay and intellectual impairment [141, 142, 143, 144, 145, 146, 147]. The diagnosis of desmosterolosis is made by demonstrating elevated levels of desmosterol by GC-MS analysis, with serum cholesterol levels usually normal [141, 142]. Reported DHCR24 pathogenic mutations thus far have all been missense mutations.

A targeted mouse model for desmosterolosis has been generated, and Dhcr24−/− mice are viable with some postnatal growth retardation and infertility [148]. Pharmacological inhibitors of DHCR24 have been developed for studies in rat models [135, 149, 150]. Treatment of pregnant rats with these inhibitors of sterol-D24-reductase is teratogenic and produces cataracts, CNS abnormalities, genitourinary and skeletal anomalies [149, 150, 151].


4. Cholesterol biosynthesis genes in other Mendelian diseases

Inherited defects in genes encoding cholesterol biosynthetic enzymes or regulators of cholesterol homeostasis create severe clinical phenotypes as discussed above and highlighted in Table 1. The central nervous system is highly susceptible to perturbations in cholesterol biosynthesis, with manifestations including structural brain malformations, defects in myelin structures and, in some cases, profound developmental delay. While the cholesterol biosynthesis defects are genetically distinct individual disorders, their characterisation has demonstrated interrelation between human disease processes. This underscores the importance of cholesterol in normal cellular function and opens the possibility of novel therapies for Mendelian disorders associated with cholesterol synthesis, transport and regulation. Lessons learnt from abrogation of the cholesterol biosynthesis pathway, either by deliberate pharmacological manipulation or via inherited Mendelian diseases, serve to provide vital information amongst a raft of seemingly unrelated human disease such as inflammatory bowel disease (IBD), the cholesterol trafficking disorders Niemann-Pick disease type C (NPC, OMIM 257220) and Tangier disease (TD, OMIM 205400) and neurodegenerative diseases such as Alzheimer’s disease (OMIM 104300).

NPC is an autosomal recessive lysosomal storage disorder of cholesterol trafficking due to mutations in the NPC1 and NPC2 genes [152]. NPC1 encodes a 13-transmembrane-spanning protein in late endosomes/lysosomes, while NPC2 encodes a soluble lysosomal cholesterol-binding protein [153]. This is a devastating disease characterised by a relentless neurodegenerative disease course that is usually fatal in the second decade of life, although a subset of patients will die in infancy consequent to hepatic or pulmonary failure [152]. Free cholesterol is stored in the late endosome/lysosome with minimal escape of cholesterol from the acidic compartment to the endoplasmic reticulum. NPC leads to a block in trafficking/fusion essential for the functioning of the endosomal/lysosomal system, causing the secondary storage of cholesterol, glycosphingolipids and sphingomyelin [154]. It is likely that cholesterol accumulation is a secondary storage metabolite in NPC [154].

TD has been reported in approximately 100 patients and is caused by mutations in the gene encoding ABCA1 [155, 156]. Patients have minimal circulating HDL and accumulate cholesterol, leading to the formation of foam cells and the development of cardiovascular disease, orange-coloured tonsils, enlarged spleen, liver and lymph nodes and peripheral neuropathy. The membrane-associated protein ABCA1 regulates cellular cholesterol and phospholipid homeostasis by functioning as a cholesterol efflux pump [157]. Tangier disease patients have structurally abnormal late endocytic vesicles, which are also observed in the cells of patients with NPC disease [158]. There exists a link between ABCA1 expression and function with the NPC pathway [158159]. NPC disease is characterised at the cellular level by storage of glycosphingolipids, fatty acids, cholesterol, sphingomyelin and sphingosine. NPC cells also have low levels of calcium in the late endosome/lysosome. These cellular hallmarks were also identified in TD patients, suggesting that the loss of function of ABCA1 inhibits the NPC pathway through an unknown mechanism. A recent serendipitous clinical observation has provided a further link between TD and the NPC pathway: an adult patient thought to have NPC1 was treated with miglustat and demonstrated measurable clinical improvements in neurological and haematological parameters. TD was ultimately diagnosed when the molecular investigations for NPC were negative [160].

SLOS cellular pathophysiology should theoretically be correctable with cholesterol replacement therapy, as this should bypass the enzymatic defect in the conversion of 7DHC to cholesterol. However, when SLOS patient fibroblasts are cultured in a lipid-depleted medium to induce de novo cholesterol synthesis, cells exhibit a significant cholesterol trafficking defect leading to the accumulation of unesterified cholesterol in the late endosome/lysosome, which mimics the fate of LDL-derived cholesterol in NPC cells [161]. This proposes a possible mechanistic convergence between these very different inborn errors of metabolism. 7DHC could be interfering with the function of NPC1 and NPC2 by inhibition, akin to the U18666A drug that induces NPC cellular phenotypes [162]. In SLOS patient fibroblasts, accumulation of 7DHC led to the accumulation of metabolic indicators of NPC, that is, the lysosomal storage of cholesterol, sphingomyelin and multiple glycosphingolipids [163]. Elevated sphingosine levels in SLOS patient cerebrospinal fluid have been described. This serendipitous discovery of a link between the NPC pathway, two cholesterol trafficking disorders and the prototypic cholesterol biosynthesis defect SLOS will prove important in delineating the pathogenesis of these diseases and the development of novel therapies. Miglustat is an iminosugar drug that inhibits glucosylceramide synthase, the enzyme that catalyses the first step in glycosphingolipid biosynthesis, and it is in use as a substrate reduction therapy for a number of lysosomal storage defects including NPC [164]. The finding that SLOS and TD involve secondary inhibition of the NPC pathway suggests that miglustat could be a novel therapy for SLOS and TD.

The recently described SQSD exhibits a characteristic sterol pattern dominated by farnesol-derived dicarboxylic acids secondary to accumulation of farnesol-PP proximal to the enzymatic block. The role of these metabolites in the pathogenesis of this rare disease remains to be determined but is of interest as farnesol and its products exhibit a wide variety of biological activities including 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 Alzheimer’s disease [166].

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

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 of the cholesterol biosynthesis defects.


5. Conclusion

Inborn errors of cholesterol metabolism have provided many fundamental 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 currently lack effective treatments.

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, X-linked dominant.



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


Conflict of interest

The authors have no COI to declare.


  1. 1. Cooper MK, Wassif CA, Krakowiak PA, Taipale J, Gong R, Kelley RI, et al. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nature Genetics. 2003;33(4):508-513
  2. 2. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343(6257):425
  3. 3. Waterham HR. Defects of cholesterol biosynthesis. FEBS Letters. 2006;580(23):5442-5449
  4. 4. Coman D, Vissers LELM, Riley LG, Kwint MP, Hauck R, Koster J, et al. Squalene synthase deficiency: Clinical, biochemical and molecular characterisation of a defect in cholesterol biosynthesis. American Journal of Human Genetics. 2018;103(1):125-130
  5. 5. Bloch K. The biological synthesis of cholesterol. Science. 1965;150(3962):19-28
  6. 6. Kandutsch AA, Russell AE. Preputial gland tumor sterols. The Journal of Biological Chemistry. 1960;235(8):2256-2261
  7. 7. Mitsche MA, McDonald JG, Hobbs HH, Cohen JC. Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways. eLife. 2015;4:e07999
  8. 8. Ikonen E, Jansen M. Cellular sterol trafficking and metabolism: Spotlight on structure. Current Opinion in Cell Biology. 2008;20(4):371-377
  9. 9. Sharpe LJ, Cook ECL, Zelcer N, Brown AJ. The UPS and downs of cholesterol homeostasis. Trends in Biochemical Sciences. 2014;39(11):527-535
  10. 10. Bostedor RG, Karkas JD, Arison BH, Bansal VS, Vaidya S, Germershausen JI, et al. Farnesol-derived dicarboxylic acids in the urine of animals treated with zaragozic acid A or with farnesol. The Journal of Biological Chemistry. 1997;272(14):9197-9203
  11. 11. Jemal M, Ouyang Z. Gas chromatography-mass spectrometric method for quantitative determination in human urine of dicarboxylic (dioic) acids produced in the body as a consequence of cholesterol biosynthesis inhibition. Journal of Chromatography. B, Biomedical Sciences and Applications. 1998;709(2):233-241
  12. 12. Vaidya S, Bostedor R, Kurtz MM, Bergstrom JD, Bansal VS. Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase Inhibitor zaragozic acid A. Archives of Biochemistry and Biophysics. 1998;355(1):84-92
  13. 13. van der Meer JWM, Simon A. The challenge of autoinflammatory syndromes: With an emphasis on hyper-IgD syndrome. Rheumatology. 2016;55(suppl 2):ii23-ii29
  14. 14. Favier L, Schulert G. Mevalonate kinase deficiency: Current perspectives. The Application of Clinical Genetics. 2016;9:101-110
  15. 15. Berger R, Smit GPA, Schierbeek H, Bijsterveld K, le Coultre R. Mevalonic aciduria: An inborn error of cholesterol biosynthesis? Clinica Chimica Acta. 1985;152(1-2):219-222
  16. 16. van der Meer JW, Vossen JM, Radl J, van Nieuwkoop JA, Meyer CJ, Lobatto S, et al. Hyperimmunoglobulinaemia D and periodic fever: A new syndrome. Lancet (London, England). 1984;1(8386):1087-1090
  17. 17. Frenkel J, Rijkers GT, Mandey SHL, Buurman SWM, Houten SM, Wanders RJA, et al. Lack of isoprenoid products raises ex vivo interleukin-1? Secretion in hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis and Rheumatism. 2002;46(10):2794-2803
  18. 18. Simon A, Kremer HPH, Wevers RA, Scheffer H, de Jong JG, van der Meer JWM, et al. CME Mevalonate kinase deficiency. Neurology. 2004;62:994-997
  19. 19. Drenth PH, van Deuren M. Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood. 1995;85(12):3586-3593
  20. 20. Drenth JPH, Powell RJ, Brown NS, Meer JWMVD. Interferon-γ and urine neopterin in attacks of the hyperimmunoglobulinaemia D and periodic fever syndrome. European Journal of Clinical Investigation. 1995;25(9):683-686
  21. 21. Haas D, Hoffmann GF. Mevalonate kinase deficiencies: From mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet Journal of Rare Diseases. 2006;1(1):13
  22. 22. Hoffmann F, Charpentier C, Mayatepek E, Mancini J, Leichsenring M, Gibson KM, et al. Clinical and biochemical phenotype in 11 patients with mevalonic aciduria. Pediatrics. 1993;91(5):915-921
  23. 23. Hinson DD, Rogers ZR, Hoffmann GF, Schachtele M, Fingerhut R, Kohlschutter A, et al. Hematological abnormalities and cholestatic liver disease in two patients with mevalonate kinase deficiency. American Journal of Medical Genetics. 1998;78:408-412
  24. 24. van der Hilst JCH, Bodar EJ, Barron KS, Frenkel J, Drenth JPH, van der Meer JWM, et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008;87(6):301-310
  25. 25. Houten SM, van Woerden CS, Wijburg FA, Wanders RJA, Waterham HR. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with hyper-IgD and periodic fever syndrome in the Netherlands. European Journal of Human Genetics. 2003;11(2):196-200
  26. 26. Galeotti C, Georgin-Lavialle S, Sarrabay G, Touitou I, Koné-Paut I. Mevalonate kinase deficiency in 2016. La Revue de Médecine Interne. 2018;39(4):265-270
  27. 27. Mandey SHL, Schneiders MS, Koster J, Waterham HR. Mutational spectrum and genotype–phenotype correlations in mevalonate kinase deficiency. Human Mutation. 2006;27(8):796-802
  28. 28. Cuisset L, Drenth JPH, Simon A, Vincent MF, van der Velde Visser S, van der Meer JWM, et al. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. European Journal of Human Genetics. 2001;9(4):260-266
  29. 29. Houten SM, Koster J, Romeijn G-J, Frenkel J, Di Rocco M, Caruso U, et al. Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome. European Journal of Human Genetics. 2001;9(4):253-259
  30. 30. ter Haar NM, Jeyaratnam J, Lachmann HJ, Simon A, Brogan PA, Doglio M, et al. The phenotype and genotype of mevalonate kinase deficiency: A series of 114 cases from the Eurofever Registry: Phenotype and genotype of MKD. Arthritis & Rhematology. 2016;68(11):2795-2805
  31. 31. Shendi HM, Devlin LA, Edgar JD. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. JCR: Journal of Clinical Rheumatology. 2014;20(2):103-105
  32. 32. Cantarini L, Vitale A, Magnotti F, Lucherini O, Caso F, Frediani B, et al. Weekly oral alendronate in mevalonate kinase deficiency. Orphanet Journal of Rare Diseases. 2013;8(1):196
  33. 33. Hager EJ, Tse HM, Piganelli JD, Gupta M, Baetscher M, Tse TE, et al. Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome. Journal of Inherited Metabolic Disease. 2007;30(6):888-895
  34. 34. Tozawa R, Ishibashi S, Osuga J, Yagyu H, Oka T, Chen Z, et al. Embryonic lethality and defective neural tube closure in mice lacking squalene synthase. The Journal of Biological Chemistry. 1999;274(43):30843-30848
  35. 35. Chen X, Liu L. Congenital cataract with LSS gene mutations: A new case report. Journal of Pediatric Endocrinology & Metabolism. 2017;30(11):1231-1235
  36. 36. Romano M-T, Tafazzoli A, Mattern M, Sivalingam S, Wolf S, Rupp A, et al. Bi-allelic mutations in LSS, encoding lanosterol synthase, cause autosomal-recessive hypotrichosis simplex. American Journal of Human Genetics. 2018;103(5):777-785
  37. 37. Besnard T, Sloboda N, Goldenberg A, Küry S, Cogné B, Breheret F, et al. Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome. Genetics in Medicine. [published online ahead of print 6 February 2019]. DOI:10.1038/s41436-019-0445-x
  38. 38. Mori M, Li G, Abe I, Nakayama J, Guo Z, Sawashita J, et al. Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat. The Journal of Clinical Investigation. 2006;116(2):395-404
  39. 39. The International Mouse Phenotyping Consortium, Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, et al. High-throughput discovery of novel developmental phenotypes. Nature. 2016;537(7621):508-514
  40. 40. Greenberg CR, Rimoin DL, Gruber HE, DeSa DJB, Reed M, Lachman RS, et al. A new autosomal recessive lethal chondrodystrophy with congenital hydrops. American Journal of Medical Genetics. 1988;29(3):623-632
  41. 41. Lubala TK, Lubala N, Munkana AN, Nyenga AM, Mutombo AM. Greenberg skeletal dysplasia: First reported case in the Democratic Republic of Congo. The Pan African Medical Journal. 2013;14:55
  42. 42. Chitayat D, Gruber H, Mullen BJ, Pauzner D, Costa T, Lachman R, et al. Hydrops-ectopic calcification-moth-eaten skeletal dysplasia (Greenberg dysplasia): Prenatal diagnosis and further delineation of a rare genetic disorder. American Journal of Medical Genetics. 1993;47(2):272-277
  43. 43. Konstantinidou A, Karadimas C, Waterham HR, Superti-Furga A, Kaminopetros P, Grigoriadou M, et al. Pathologic, radiographic and molecular findings in three fetuses diagnosed with HEM/Greenberg skeletal dysplasia. Prenatal Diagnosis. 2008;28(4):309-312
  44. 44. Madazli R, Aksoy F, Ocak V, Atasü T. Detailed ultrasonographic findings in Greenberg dysplasia. Prenatal Diagnosis. 2001;21(1):65-67
  45. 45. Trajkovski Z, Vrcakovski M, Saveski J, Gucev ZS. Greenberg dysplasia (hydrops-ectopic calcification-moth-eaten skeletal dysplasia): Prenatal ultrasound diagnosis and review of literature. American Journal of Medical Genetics. 2002;111(4):415-419
  46. 46. Horn L-C, Faber R, Meiner A, Piskazeck U, Spranger J. Greenberg dysplasia: First reported case with additional non-skeletal malformations and without consanguinity. Prenatal Diagnosis. 2000;20(12):1008-1011
  47. 47. Kelley RI, Kratz LE, Wilcox WG. Abnormal metabolism of 14-dehydrosterols in hydrops-ectopic calcification-moth-eaten skeletal dysplasia: Evidence for new defect of cholesterol biosynthesis. Proceedings of the Greenwood Genetic Center. 2000;20:116
  48. 48. Tsai P-L, Zhao C, Turner E, Schlieker C. The Lamin B receptor is essential for cholesterol synthesis and perturbed by disease-causing mutations. eLife. 2016;5:e16011
  49. 49. Wassif CA, Brownson KE, Sterner AL, Forlino A, Zerfas PM, Wilson WK, et al. HEM dysplasia and ichthyosis are likely laminopathies and not due to 3b-hydroxysterol D14-reductase deficiency. Human Molecular Genetics. 2007;16(10):1176-1187
  50. 50. Turner EM, Schlieker C. Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism. Rare Diseases. 2016;4(1):e1241363
  51. 51. Waterham HR, Koster J, Mooyer P, van Noort G, Kelley RI, Wilcox WR, et al. Autosomal recessive HEM/Greenberg skeletal dysplasia Is caused by 3β-hydroxysterol Δ14-reductase deficiency due to mutations in the lamin B receptor gene. American Journal of Human Genetics. 2003;72:1013-1017
  52. 52. Bennati AM, Schiavoni G, Franken S, Piobbico D, Fazia MAD, Caruso D, et al. Disruption of the gene encoding 3β-hydroxysterol Δ14-reductase (Tm7sf2) in mice does not impair cholesterol biosynthesis. The FEBS Journal. 2008;275(20):5034-5047
  53. 53. Clayton P, Fischer B, Mann A, Mansour S, Rossier E, Veen M, et al. Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein. Nucleus. 2010;1(4):354-366
  54. 54. Hoffmann K, Dreger CK, Olins AL, Olins DE, Shultz LD, Lucke B, et al. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly). Nature Genetics. 2002;31(4):410-414
  55. 55. Oosterwijk JC. Congenital abnormalities reported in Pelger-Huët homozygosity as compared to Greenberg/HEM dysplasia: Highly variable expression of allelic phenotypes. Journal of Medical Genetics. 2003;40(12):937-941
  56. 56. Borovik L, Modaff P, Waterham HR, Krentz AD, Pauli RM. Pelger-huet anomaly and a mild skeletal phenotype secondary to mutations in LBR. American Journal of Medical Genetics. Part A. 2013;161(8):2066-2073
  57. 57. Thompson E, Abdalla E, Superti-Furga A, McAlister W, Kratz L, Unger S, et al. Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes. Bone. 2019;120:354-363
  58. 58. Herman GE, Kratz L. Disorders of sterol synthesis: Beyond Smith-Lemli-Opitz syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 2012;160C(4):301-321
  59. 59. Bittar M, Happle R. CHILD syndrome. Journal of the American Academy of Dermatology. 2004;50(2):34-37
  60. 60. Happle R, Koch H, Lenz W. The CHILD syndrome: Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. European Journal of Pediatrics. 1980;134(1):27-33
  61. 61. Happle R, Effendy I, Megahed M, Orlow SJ, Kiister W. CHILD syndrome in a boy. American Journal of Medical Genetics. 1996;62:192-194
  62. 62. Happle R, Mittag H, Kuster W. The CHILD nevus: A distinct skin disorder. Dermatology. 1995;191(3):210-216
  63. 63. Hummel M, Cunningham D, Mullett CJ, Kelley RI, Herman GE. Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene. American Journal of Medical Genetics. 2003;122A(3):246-251
  64. 64. Herman G. X-Linked dominant disorders of cholesterol biosynthesis in man and mouse. Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids. 2000;1529(1-3):357-373
  65. 65. Avgerinou G, Asvesti A, Katsambas A, Nikolaou V, Christofidou E, Grzeschik K, et al. CHILD syndrome: The NSDHL gene and its role in CHILD syndrome, a rare hereditary disorder: CHILD syndrome. Journal of the European Academy of Dermatology and Venereology. 2009;24(6):733-736
  66. 66. Bittar M, Happle R, Grzeschik K-H, Leveleki L, Hertl M, Bornholdt D, et al. CHILD syndrome in 3 generations: The importance of mild or minimal skin lesions. Archives of Dermatology. 2006;142(3):348-351
  67. 67. König A, Happle R, Bornholdt D, Engel H, Grzeschik K-H. Mutations in the NSDHL gene, encoding a 3β-hydroxysteroid dehydrogenase, cause CHILD syndrome. American Journal of Medical Genetics. 2000;90:339-346
  68. 68. Bornholdt D. Mutational spectrum of NSDHL in CHILD syndrome. Journal of Medical Genetics. 2005;42(2):e17-e17
  69. 69. Liu XY, Dangel AW, Kelley RI, Zhao W, Denny P, Botcherby M, et al. The gene mutated in bare patches and striated mice encodes a novel 3β-hydroxysteroid dehydrogenase. Nature Genetics. 1999;22(2):182-187
  70. 70. Caldas H, Cunningham D, Wang X, Jiang F, Humphries L, Kelley RI, et al. Placental defects are associated with male lethality in bare patches and striated embryos deficient in the NAD(P)H Steroid Dehydrogenase-like (NSDHL) Enzyme. Molecular Genetics and Metabolism. 2005;84(1):48-60
  71. 71. Cunningham D, DeBarber AE, Bir N, Binkley L, Merkens LS, Steiner RD, et al. Analysis of hedgehog signaling in cerebellar granule cell precursors in a conditional Nshdl allele demonstrates an essential role for cholesterol in postnatal CNS development. Human Molecular Genetics. 2015;24(10):2808-2825
  72. 72. Bergqvist C, Abdallah B, Hasbani D-J, Abbas O, Kibbi AG, Hamie L, et al. CHILD syndrome: A modified pathogenesis-targeted therapeutic approach. American Journal of Medical Genetics. Part A. 2018;176(3):733-738
  73. 73. Paller AS, van Steensel MAM, Rodriguez-Martín M, Sorrell J, Heath C, Crumrine D, et al. Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. The Journal of Investigative Dermatology. 2011;131(11):2242-2248
  74. 74. Cañueto J, Girós M, Ciria S, Pi-Castán G, Artigas M, García-Dorado J, et al. Clinical, molecular and biochemical characterization of nine Spanish families with Conradi-Hünermann-Happle syndrome: New insights into X-linked dominant chondrodysplasia punctata with a comprehensive review of the literature. The British Journal of Dermatology. 2012;166(4):830-838
  75. 75. Pacault M, Vincent M, Besnard T, Kannengiesser C, Bénéteau C, Barbarot S, et al. New splicing pathogenic variant in EBP causing extreme familial variability of Conradi-Hünermann-Happle Syndrome. European Journal of Human Genetics. 2018;26(12):1784
  76. 76. Has C, Bruckner-Tuderman L, Traupe H, Seedorf U, Kannenberg F, Folkers E, et al. Gas chromatography-mass spectrometry and molecular genetic studies in families with the Conradi-Hünermann-Happle syndrome. The Journal of Investigative Dermatology. 2002;118(5):851-858
  77. 77. Aughton DJ, Kelley RI, Metzenberg A, Pureza V, Pauli RM. X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male. American Journal of Medical Genetics. Part A. 2003;116A(3):255-260
  78. 78. Milunsky JM, Maher TA, Metzenberg AB. Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X-linked dominant Conradi-Hunermann-Happle syndrome and a mutation in EBP. American Journal of Medical Genetics. Part A. 2003;116A(3):249-254
  79. 79. Sutphen R, Amar MJ, Kousseff BG, Toomey KE. XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome). American Journal of Medical Genetics. 1995;57(3):489-492
  80. 80. Traupe H, Has C. The Conradi-Hünermann-Happle syndrome is caused by mutations in the gene that encodes a 8-7 sterol isomerase and is biochemically related to the CHILD syndrome. European Journal of Dermatology. 2000;10(6):425-428
  81. 81. Hellenbroich Y, Grzeschik K-H, Krapp M, Jarutat T, Lehrmann-Petersen C, Buiting K, et al. Reduced penetrance in a family with X-linked dominant chondrodysplasia punctata. European Journal of Medical Genetics. 2007;50(5):392-398
  82. 82. Pazzaglia UE, Zarattini G, Donzelli C, Benetti A, Bondioni MP, Groli C. The nature of cartilage stippling in chrondrodysplasia punctata: Histopathological study of Conradi-Hunermann-Happle syndrome. Fetal and Pediatric Pathology. 2008;27(2):71-81
  83. 83. Herman GE, Kelley RI, Pureza V, Smith D, Kopacz K, Pitt J, et al. Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome). Genetics in Medicine. 2002;4(6):434-438
  84. 84. Kelley RI, Herman GE. Inborn errors of sterol biosynthesis. Annual Review of Genomics and Human Genetics. 2001;2(1):299-341
  85. 85. Happle R. X-linked dominant chondrodysplasia punctata. Human Genetics. 1979;53:65-73
  86. 86. Posey JE, Burrage LC, Campeau PM, Lu JT, Eble TN, Kratz L, et al. Adult presentation of X-linked Conradi-Hünermann-Happle syndrome. American Journal of Medical Genetics. Part A. 2015;167(6):1309-1314
  87. 87. Dempsey M, Tan C, Herman GE. Chondrodysplasia punctata 2, X-linked. In: Adam MP, Ardinger HH, Pagon RA, editors. Gene Reviews. Seattle (WA): University of Washington; 2011
  88. 88. Braverman N, Lin P, Moebius FF, Obie C, Moser A, Glossmann H, et al. Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome. Nature Genetics. 1999;22(3):291-294
  89. 89. Derry JM, Gormally E, Means GD, Zhao W, Meindl A, Kelley RI, et al. Mutations in a delta-8-delta-7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. Nature Genetics. 1999;22(3):286-290
  90. 90. Porter FD, Herman GE. Malformation syndromes caused by disorders of cholesterol synthesis. Journal of Lipid Research. 2011;52(1):6-34
  91. 91. Anderson R, Rust S, Ashworth J, Clayton-Smith J, Taylor RL, Clayton PT, et al. Lathosterolosis: A relatively mild case with cataracts and learning difficulties. In: Morava E, Baumgartner M, Patterson M, Rahman S, Zschocke J, Peters V, editors. JIMD Reports. Berlin, Heidelberg: Springer Berlin Heidelberg; 2018. pp. 79-84
  92. 92. Brunetti-Pierri N, Corso G, Rossi M, Ferrari P, Balli F, Rivasi F, et al. Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3β-hydroxysteroid Δ5-desaturase. American Journal of Human Genetics. 2002;7:952-958
  93. 93. Ho ACC, Fung CW, Siu TS, Ma OCK, Lam CW, Tam S, et al. Lathosterolosis: A disorder of cholesterol biosynthesis resembling Smith-Lemli-Opitz syndrome. JIMD Reports. 2013;12:129-134
  94. 94. Krakowiak PA. Lathosterolosis: An inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Human Molecular Genetics. 2003;12(13):1631-1641
  95. 95. Rossi M, D’Armiento M, Parisi I, Ferrari P, Hall CM, Cervasio M, et al. Clinical phenotype of lathosterolosis. American Journal of Medical Genetics. Part A. 2007;143A(20):2371-2381
  96. 96. Calvo PL, Brunati A, Spada M, Romagnoli R, Corso G, Parenti G, et al. Liver transplantation in defects of cholesterol biosynthesis: The case of lathosterolosis. American Journal of Transplantation. 2014;14(4):960-965
  97. 97. Smith DW, Lemli L, Opitz JM. A newly recognized syndrome of multiple congenital anomalies. The Journal of Pediatrics. 1964;64(2):210-217
  98. 98. Nowaczyk MJM, Waye JS, Douketis JD. DHCR7 mutation carrier rates and prevalence of the RSH/Smith-Lemli-Opitz syndrome: Where are the patients? American Journal of Medical Genetics. Part A. 2006;140A(19):2057-2062
  99. 99. Cross JL, Iben J, Simpson C, Thurm A, Swedo S, Tierney E, et al. Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets. Clinical Genetics. 2015;87(6):570-575
  100. 100. Lazarin GA, Haque IS, Evans EA, Goldberg JD. Smith-Lemli-Opitz syndrome carrier frequency and estimates of in utero mortality rates. Prenatal Diagnosis. 2017;37(4):350-355
  101. 101. Schoen E. Maternal serum unconjugated estriol as a predictor for Smith-Lemli-Opitz syndrome and other fetal conditions. Obstetrics and Gynecology. 2003;102(1):167-172
  102. 102. Eroglu Y, Nguyen-Driver M, Steiner RD, Merkens L, Merkens M, Roullet J-B, et al. Normal IQ is possible in Smith-Lemli-Opitz syndrome. American Journal of Medical Genetics. Part A. 2017;173(8):2097-2100
  103. 103. Lee RWY, Conley SK, Gropman A, Porter FD, Baker EH. Brain magnetic resonance imaging findings in Smith-Lemli-Opitz syndrome. American Journal of Medical Genetics. Part A. 2013;161(10):2407-2419
  104. 104. Jurevics H, Morell P. Cholesterol for synthesis of myelin is made locally, not imported into brain. Journal of Neurochemistry. 1995;64(2):895-901
  105. 105. Kelley RI, Hennekam RCM. The Smith-Lemli-Opitz syndrome. Journal of Medical Genetics. 2000;37(5):321-335
  106. 106. Nowaczyk MJM, Irons MB. Smith-Lemli-Opitz syndrome: Phenotype, natural history, and epidemiology. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 2012;160C(4):250-262
  107. 107. Ryan AK, Bartlett K, Clayton P, Eaton S, Mills L, Donnai D, et al. Smith-Lemli-Opitz syndrome: A variable clinical and biochemical phenotype. Journal of Medical Genetics. 1998;35(7):558-565
  108. 108. Porter FD. Smith-Lemli-Opitz syndrome: Pathogenesis, diagnosis and management. European Journal of Human Genetics. 2008;16(5):535-541
  109. 109. Charman R, Tyrrell P, Arlett K, et al. Photosensitivity associated with the Smith-Lemli-Opitz syndrome. The British Journal of Dermatology. 1998;138(5):885-888
  110. 110. Irons M, Roy Elias E, Salen G, Tint GS, Batta Ashok K. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. The Lancet. 1993;341(8857):1414
  111. 111. Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Optiz syndrome. The New England Journal of Medicine. 1994;330(2):107-113
  112. 112. Donoghue SE, Pitt JJ, Boneh A, White SM. Smith-Lemli-Opitz syndrome: Clinical and biochemical correlates. Journal of Pediatric Endocrinology & Metabolism. 2018;31(4):451-459
  113. 113. Oláh AV, Szabó GP, Varga J, Balogh L, Csábi G, Csákváry V, et al. Relation between biomarkers and clinical severity in patients with Smith-Lemli-Opitz syndrome. European Journal of Pediatrics. 2013;172(5):623-630
  114. 114. Correa-Cerro LS, Porter FD. 3β-Hydroxysterol Δ7-reductase and the Smith-Lemli-Opitz syndrome. Molecular Genetics and Metabolism. 2005;84(2):112-126
  115. 115. Ciara E, Nowaczyk MJM, Witsch-Baumgartner M, Malunowicz E, Popowska E, Jezela-Stanek A, et al. DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome. Clinical Genetics. 2004;66(6):517-524
  116. 116. Yu H, Lee M-H, Starck L, Elias ER, Irons M, Salen G, et al. Spectrum of ∆7-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Human Molecular Genetics. 2000;9(9):1385-1391
  117. 117. Wassif CA, Krakowiak PA, Wright BS, Gewandter JS, Sterner AL, Javitt N, et al. Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith-Lemli-Opitz syndrome fibroblasts. Molecular Genetics and Metabolism. 2005;85(2):96-107
  118. 118. Lanthaler B, Steichen-Gersdorf E, Kollerits B, Zschocke J, Witsch-Baumgartner M. Maternal ABCA1 genotype is associated with severity of Smith-Lemli-Opitz syndrome and with viability of patients homozygous for null mutations. European Journal of Human Genetics. 2013;21(3):286-293
  119. 119. Witsch-Baumgartner M, Gruber M, Kraft HG, Rossi M, Clayton P, Giros M, et al. Maternal apo E genotype is a modifier of the Smith-Lemli-Opitz syndrome. Journal of Medical Genetics. 2004;41(8):577-584
  120. 120. Lindegaard ML, Wassif CA, Vaisman B, Amar M, Wasmuth EV, Shamburek R, et al. Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome. Human Molecular Genetics. 2008;17(23):3806-3813
  121. 121. Movassaghi M, Bianconi S, Feinn R, Wassif CA, Porter FD. Vitamin D levels in Smith-Lemli-Opitz syndrome. American Journal of Medical Genetics. Part A. 2017;173(10):2577-2583
  122. 122. Tint GS, Abuelo D, Till M, Cordier MP, Batta AK, Shefer S, et al. Fetal Smith-Lemli-Opitz syndrome can be detected accurately and reliably by measuring amniotic fluid dehydrocholesterols. Prenatal Diagnosis. 1998;18(7):651-658
  123. 123. Jezela-Stanek A, Małunowicz EM, Ciara E, Popowska E, Goryluk-Kozakiewicz B, Spodar K, et al. Maternal urinary steroid profiles in prenatal diagnosis of Smith-Lemli-Opitz syndrome: First patient series comparing biochemical and molecular studies. Clinical Genetics. 2006;69(1):77-85
  124. 124. Shackleton CHL, Marcos J, Palomaki GE, Craig WY, Kelley RI, Kratz LE, et al. Dehydrosteroid measurements in maternal urine or serum for the prenatal diagnosis of Smith-Lemli-Opitz syndrome (SLOS). American Journal of Medical Genetics. Part A. 2007;143A(18):2129-2136
  125. 125. McGaughran J, Donnai D, Clayton P, Mills K. Diagnosis of Smith-Lemli-Opitz syndrome. The New England Journal of Medicine. 1994;330(23):1685-1686
  126. 126. Jira PE, Wevers RA, de Jong J, Rubio-Gozalbo E, Janssen-Zijlstra FSM, van Heyst AFJ, et al. Simvastatin: A new therapeutic approach for Smith-Lemli-Opitz syndrome. Journal of Lipid Research. 2000;41(8):1339-1346
  127. 127. Azurdia RM, Anstey AV, Rhodes LE. Cholesterol supplementation objectively reduces photosensitivity in the Smith-Lemli-Opitz syndrome. The British Journal of Dermatology. 2001;144(1):143-145
  128. 128. Steiner RD, Linck LM, Flavell DP, Lin DS, Connor WE. Sterol balance in the Smith-Lemli-Opitz syndrome: Reduction in whole body cholesterol synthesis and normal bile acid production. Journal of Lipid Research. 2000;41(9):1437-1447
  129. 129. Svoboda MD, Christie JM, Eroglu Y, Freeman KA, Steiner RD. Treatment of Smith-Lemli-Opitz syndrome and other sterol disorders. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 2012;160C:285-294
  130. 130. Pauli RM, Williams MS, Josephson KD, Tint GS. Smith-Lemli-Opitz syndrome: Thirty-year follow-up of “S” of “RSH” syndrome. American Journal of Medical Genetics. 1997;68(3):260-262
  131. 131. Elias ER, Irons MB, Hurley AD, Tint GS, Salen G. Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS). American Journal of Medical Genetics. 1997;68(3):305-310
  132. 132. Sikora DM, Ruggiero M, Petit-Kekel K, Merkens LS, Connor WE, Steiner RD. Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome. The Journal of Pediatrics. 2004;144(6):783-791
  133. 133. Tierney E, Conley SK, Goodwin H, Porter FD. Analysis of short-term behavioral effects of dietary cholesterol supplementation in Smith-Lemli-Opitz syndrome. American Journal of Medical Genetics. Part A. 2010;152A(1):91-95
  134. 134. Wassif CA, Kratz L, Sparks SE, Wheeler C, Bianconi S, Gropman A, et al. A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. Genetics in Medicine. 2017;19(3):297-305
  135. 135. Fliesler SJ. Antioxidants: The missing key to improved therapeutic intervention in Smith-Lemli-Opitz syndrome? Hereditary Genetics: Current Research. 2013;2(2):119
  136. 136. Korade Z, Xu L, Harrison FE, Ahsen R, Hart SE, Folkes OM, et al. Antioxidant supplementation ameliorates molecular deficits in Smith-Lemli-Opitz syndrome. Biological Psychiatry. 2014;75(3):215-222
  137. 137. Pasta S, Akhile O, Tabron D, Ting F, Shackleton C, Watson G. Delivery of the 7-dehydrocholesterol reductase gene to the central nervous system using adeno-associated virus vector in a mouse model of Smith-Lemli-Opitz Syndrome. Molecular Genetics and Metabolism Reports. 2015;4:92-98
  138. 138. Correa-Cerro LS, Wassif CA, Kratz L, Miller GF, Munasinghe JP, Grinberg A, et al. Development and characterization of a hypomorphic Smith-Lemli-Opitz syndrome mouse model and efficacy of simvastatin therapy. Human Molecular Genetics. 2006;15(6):839-851
  139. 139. Dehart DB, Lanoue L, Tint GS, Sulik KK. Pathogenesis of malformations in a rodent model for Smith-Lemli-Opitz syndrome. American Journal of Medical Genetics. 1997;68(3):328-337
  140. 140. Waterham HR, Koster J, Romeijn GJ, Hennekam RCM, Vreken P, Andersson HC, et al. Mutations in the 3β-hydroxysterol Δ24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. American Journal of Human Genetics. 2001;69:685-694
  141. 141. Fitzpatrick DR, Keeling JW, Evans MJ, Kan AE, Bell JE, Porteous MEM, et al. Clinical phenotype of desmosterolosis. American Journal of Medical Genetics. 1998;75:145-152
  142. 142. Andersson HC, Kratz L, Kelley R. Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay. American Journal of Medical Genetics. 2002;113(4):315-319
  143. 143. Clayton P, Mills K, Keeling J, FitzPatrick D. Desmosterolosis: A new inborn error of cholesterol biosynthesis. The Lancet. 1996;348(9024):404
  144. 144. Dias C, Rupps R, Millar B, Choi K, Marra M, Demos M, et al. Desmosterolosis: An illustration of diagnostic ambiguity of cholesterol synthesis disorders. Orphanet Journal of Rare Diseases. 2014;9(1):94
  145. 145. Rohanizadegan M, Sacharow S. Desmosterolosis presenting with multiple congenital anomalies. European Journal of Medical Genetics. 2018;61(3):152-156
  146. 146. Schaaf CP, Koster J, Katsonis P, Kratz L, Shchelochkov OA, Scaglia F, et al. Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature. American Journal of Medical Genetics. Part A. 2011;155(7):1597-1604
  147. 147. Zolotushko J, Flusser H, Markus B, Shelef I, Langer Y, Heverin M, et al. The desmosterolosis phenotype: Spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter. European Journal of Human Genetics. 2011;19(9):942-946
  148. 148. Wechsler A. Generation of viable cholesterol-free mice. Science. 2003;302(5653):2087-2087
  149. 149. Cenedella RJ. Cholesterol synthesis inhibitor U18666A and the role of sterol metabolism and trafficking in numerous pathophysiological processes. Lipids. 2009;44(6):477-487
  150. 150. Roux C. Teratogenic action of triparanol in animals. Archives Françaises de Pédiatrie. 1964;21:451-464
  151. 151. Gofflot F, Hars C, Illien F, Chevy F, Wolf C, Picard JJ, et al. Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: Implications of Hedgehog signaling. Human Molecular Genetics. 2003;12(10):1187-1198
  152. 152. Vanier MT. Niemann-Pick disease type C. Orphanet Journal of Rare Diseases. 2010;5(16):18
  153. 153. Xu Z, Farver W, Kodukula S, Storch J. Regulation of sterol transport between membranes and NPC2. Biochemistry. 2008;47(42):11134-11143
  154. 154. Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nature Medicine. 2008;14(11):1247-1255
  155. 155. Fredrickson DS. The inheritance of high density lipoprotein deficiency (Tangier disease). The Journal of Clinical Investigation. 1964;43(2):228-236
  156. 156. Puntoni M, Sbrana F, Bigazzi F, Sampietro T. Tangier disease: Epidemiology, pathophysiology and management. American Journal of Cardiovascular Drugs. 2012;12(5):303-311
  157. 157. Sahoo D, Trischuk TC, Chan T, Drover VAB, Ho S, Chimini G, et al. ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from murine hepatocytes. Journal of Lipid Research. 2004;45(6):1122-1131
  158. 158. Boadu E, Francis GA. The role of vesicular transport in ABCA1-dependent lipid efflux and its connection with NPC pathways. Journal of Molecular Medicine. 2006;84(4):266-275
  159. 159. Boadu E, Nelson RC, Francis GA. ABCA1-dependent mobilization of lysosomal cholesterol requires functional Niemann-Pick C2 but not Niemann-Pick C1 protein. Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology. 2012;1821(3):396-404
  160. 160. Sechi A, Dardis A, Zampieri S, Rabacchi C, Zanoni P, Calandra S, et al. Effects of miglustat treatment in a patient affected by an atypical form of Tangier disease. Orphanet Journal of Rare Diseases. 2014;9(1):143
  161. 161. Wassif CA, Vied D, Tsokos M, Connor WE, Steiner RD, Porter FD. Cholesterol storage defect in RSH/Smith-Lemli-Opitz syndrome fibroblasts. Molecular Genetics and Metabolism. 2002;75(4):325-334
  162. 162. Liscum L, Ruggiero RM, Faust JR. The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts. The Journal of Cell Biology. 1989;108(5):1625-1636
  163. 163. Platt FM, Wassif C, Colaco A, Dardis A, Lloyd-Evans E, Bembi B, et al. Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease. Annual Review of Genomics and Human Genetics. 2014;15(1):173-194
  164. 164. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: A randomised controlled study. Lancet Neurology. 2007;6(9):765-772
  165. 165. Joo JH, Jetten AM. Molecular mechanisms involved in farnesol-induced apoptosis. Cancer Letters. 2010;287(2):123-135
  166. 166. Hottman DA, Li L. Protein prenylation and synaptic plasticity: Implications for Alzheimer’s disease. Molecular Neurobiology. 2014;50(1):177-185
  167. 167. Bianco AM. Genetics of inflammatory bowel disease from multifactorial to monogenic forms. World Journal of Gastroenterology. 2015;21(43):12296
  168. 168. Bianco AM, Girardelli M, Vozzi D, Crovella S, Kleiner G, Marcuzzi A. Mevalonate kinase deficiency and IBD: Shared genetic background. Gut. 2014;63(8):1367-1368
  169. 169. Levy M, Arion A, Berrebi D, Cuisset L, Jeanne-Pasquier C, Bader-Meunier B, et al. Severe early-onset colitis revealing mevalonate kinase deficiency. Pediatrics. 2013;132(3):e779-e783
  170. 170. Rakheja D, Boriack RL. Precholesterol sterols accumulate in lipid rafts of patients with Smith-Lemli-Opitz syndrome and X-linked dominant chondrodysplasia punctata. Pediatric and Developmental Pathology. 2008;11(2):128-132
  171. 171. Frisso G, Gelzo M, Procopio E, Sica C, Lenza MP, Dello Russo A, et al. A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization. Molecular Genetics and Metabolism. 2017;121(4):329-335
  172. 172. He M, Kratz LE, Michel JJ, Vallejo AN, Ferris L, Kelley RI, et al. Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay. The Journal of Clinical Investigation. 2011;121(3):976-984

Written By

Erin Anderson and David Coman

Submitted: January 24th, 2019 Reviewed: May 30th, 2019 Published: June 24th, 2019