30 Inborn Errors of Cholesterol Biosynthesis Dorothea Haas, Richard I. Kelley

Dorothea Haas, Richard I. Kelley

30.1 Introduction

Defects of cholesterol biosynthesis comprise a heterogeneous group of disor- ders, most of which have only recently been described. With the exception of cholesterol supplementation in Smith-Lemli-Opitz syndrome, no therapeutic regimens have yet been proven effective.

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) are due to defects in mevalonate kinase, an enzyme located proximally in the pathway of cholesterol biosynthesis. Patients affected with these disorders present with recurrent febrile attacks and, in the case of classic MVA, often have malformations, neurological symptoms, and psychomotor retardation (Hoff- mann et al. 1993). Long-term administration of coenzyme Q10 together with vitamin C and E to treat an intrinsic deficiency in the synthesis of coenzyme Q10 and to treat a possible increased sensitivity to reactive oxygen species seems to stabilize the clinical course and improve somatic and psychomotor development (Haas et al. 2001; Prietsch et al. 2003). Dietary supplementation of cholesterol may reduce frequency and severity of febrile attacks in some mildly affected patients, but has further compromised more severely affected patients, similar to the apparent adverse effect of lovastatin in some patients (Hoffmann et al. 1993). In two patients (siblings) followed closely, intervention with corticosteroids was highly beneficial during clinical crises, with resolution of the crises within 24 h. The severity of attacks can also be reduced with the leukotriene receptor inhibitors montelukast and zafirlukast (R. I. Kelley, unpub- lished observations). Despite the apparent adverse effect of lovastatin in classic MVA, a recently completed study has shown a beneficial effect of simvastatin in HIDS (Simon et al. 2004).

The main characteristics of CHILD (congenital hemidysplasia, ichthyosi- form erythroderma, and limb deficiency) syndrome (König et al. 2000) and Conradi-Hünermann syndrome (Kelley et al. 1999) are skeletal defects, includ- ing, notably, chondrodysplasia punctata and ichthyosiform skin lesions. All re- ported cases of Greenberg dysplasia (also called hydrops-ectopic calcification-

“moth-eaten” skeletal dysplasia, HEM) have had nonimmune hydrops fetalis,

short limbs, abnormal severe chondro-osseous calcifications and have been

lethal prenatally. This autosomal recessive disorder is caused by a deficiency

322 Inborn Errors of Cholesterol Biosynthesis

of sterol- ∆

reductase encoded by the LBR gene (Waterham et al. 2003). LBR was first known to encode for the lamin B receptor. Missense mutations in this gene recently have been reported also to cause Pelger-Hu ¨ et anomaly, a disor- der characterized by abnormally shaped blood granulocytes (Hoffmann et al.

2002) with heterozygous LBR mutations and developmental delay, epilepsy, and skeletal abnormalities in some patients homozygous for specific LBR mu- tations. Antley-Bixler syndrome is a rare, multiple anomaly syndrome with limb anomalies, craniofacial dysmorphisms and, in some, ambiguous genitalia. In patients with ambiguous genitalia, Kelley et al. (2002) have found increased levels of lanosterol and dihydrolanosterol, suggesting a functional deficiency of lanosterol-14 α demethylase, a cytochrome P450 enzyme, encoded by CYP51.

Mutation analysis of CYP51, however, discloses no obvious pathogenic muta- tion. Instead, mutations in the POR gene encoding P450 oxidoreductase, the obligate electron donor for all cytochrome P450 enzymes, have been identified in patients with Antley-Bixler syndrome (Flück et al. 2004).

As a general rule, patients with defects in the more proximal steps in cholesterol biosynthesis have normal cholesterol serum levels. Furthermore, the pathology appears to be mostly if not exclusively embryonic, without ev- idence for most precursor sterols that their usually trivial levels are harmful beyond the embryonic period. Therefore, there are few indications for treat- ment of most of these conditions with cholesterol, unless the level of cholesterol is abnormally low and the level of the precursor sterols is elevated substan- tially more than usual. The principal exceptions among these disorders are the very rare male hemizygote for CDPX2, the occasional unfavorably lyonized CDPX2 heterozygote with hypocholesterolemia and severe skin disease, and patients with CHILD syndrome who have severe, persistent psoriasiform skin lesions.

Desmosterolosis and lathosterolosis are malformation syndromes involv- ing many different organ systems (FitzPatrick et al. 1998; Brunetti-Pierri et al.

2002). The total of four patients (two for each disorder) so far reported have clinical characteristics that overlap with SLOS, but serum cholesterol is normal or only marginally diminished in the two patients for whom serum data are available. There currently is no experience with treatment of lathosterolosis.

Theoretically, patients with lathosterolosis should require the same cholesterol

therapy used for SLOS if the cholesterol level is low and the level of lathosterol is

increased. However, unlike SLOS, lathosterolosis is characterized by clinically

significant lipid storage, possibly storage of cholesterol esters, which might be

aggravated by supplemental cholesterol. Only one patient with desmosterolosis

and a borderline low cholesterol level has been treated with cholesterol supple-

mentation (50 mg/kg per day. There was no clinical effect, but a mild reduction

in the plasma level of desmosterol was observed. Theoretically, the same criteria

for treatment of SLOS should apply to desmosterolosis, with a goal of achieving

a normal blood cholesterol level and a concomitant reduction in the level of

desmosterol.

Smith-Lemli-Opitz syndrome, caused by a deficiency of 7-dehydrocholesterol reductase (DHCR7), is characterized by an accumulation of 7- and 8-dehydro- cholesterol (7-DHC and 8-DHC), and, in 90% of patients, a lower-than-normal level of cholesterol in blood and all body tissues (Irons et al. 1993). SLOS has a highly variable phenotype, ranging from lethally affected infants with multi- ple organ and skeletal malformations to mildly affected patients with moderate mental retardation, mild dysmorphism, and a normal life expectancy. A large proportion of patients may require nasogastric tube feeding or gastrostomy to provide adequate caloric intake. However, it is important not to overfeed the children to archive a better growth. SLOS patients have a genetically determined short stature and, additionally, as a result of their muscle hypoplasia, their nor- mal, well-nourished weight during infancy typically is 1–2 standard deviations less than their length. Trying to achieve arbitrary and inappropriately high weight goals based on age or length alone only increases adipose tissue and thereby limits the availability of cholesterol to the organs.

Cholesterol supplementation results in improved growth and behavior in

most patients (Irons et al. 1997; Kelley and Hennekam 2000). Treatment with

supplements of bile acids has not been effective (Elias et al. 1997) except in

severely affected patients with cholestasis or when there is a clinically evident

deficiency of bile acids. Unfortunately, an effect of cholesterol supplementa-

tion on intrinsic cognitive abilities has been absent or minimal, most likely

because cholesterol cannot be transported across the blood-brain barrier and

because prenatal developmental insults cannot be reversed. Plasma sterol levels

often improve slowly over many months or years after initiation of cholesterol

supplementation. However, effects on behavior often are evident after only

several days of cholesterol treatment, possibly because of changes in levels of

adrenal steroids, many of which, unlike cholesterol, can cross the blood-brain

barrier. Treatment of mildly affected SLOS patients with simvastatin, an in-

hibitor of HMG-CoA reductase, causes a rapid fall of 7- and 8-DHC and a rise of

cholesterol (Jira et al. 2000), probably via augmentation of residual DHCR7 ac-

tivity, allowing more complete conversion of the abnormal sterols to cholesterol

(Wevers et al. 2003). Mental, motor, and social development as well as weight,

length, and head circumference reportedly improved in two patients who were

not pretreated with cholesterol. However, in several patients with satisfactory

improvement on cholesterol treatment, the addition of simvastatin had no mea-

surable clinical benefit at the same time that potentially serious side-effects of

simvastatin developed in some (Starck et al. 2002a; D. Haas, unpublished obser-

vations). Studies in a larger group of patients are needed to evaluate the use of

simvastatin. Simvastatin should not be used in severely affected patients (ratio

of (7-DHC + 8-DHC) to cholesterol is greater than 0.5) expected to have no or

minimal residual DHCR7 activity, because it might further lower cholesterol

levels, with severe side-effects (Starck et al. 2002b).

324 Inborn Errors of Cholesterol Biosynthesis

30.2 Nomenclature No. Disorder/

deficiency

Definition/comment Gene Gene

symbol

OMIM No.

30.1a Mevalonic aciduria

Mevalonate kinase deficiency, urinary mevalonate typically

>500 mmol/mol creat.

Mevalonate kinase MVK 251170

30.1b Hyper-IgD syndrome

Mevalonate kinase deficiency, urinary mevalonate typically

<100 mmol/mol creat.

Mevalonate kinase MVK 260920

30.2 Desmosterolosis 3 β -Hydroxysteroid- ∆

reductase deficiency

24-Dehydro- cholesterol reductase

DHCR24 602398

30.3 Antley-Bixler syndrome (lanosterolosis)

Lanosterol-14 α demethylase deficiency (secondary), skeletal dysplasia

Cytochrome P450 oxidoreductase

POR 207410

30.4a Greenberg dysplasia

Sterol- ∆

^reductase

deficiency, severe chon- drodysplasia punctata

Lamin B receptor LBR 215140

30.4b Pelger-Hu¨et anomaly

Sterol- ∆

^reductase

deficiency, mild skeletal anomalies, cognitive deficits (homozygous)

Lamin B receptor LBR 169400

30.5 CHILD syndrome

3 β -Hydroxysteroid dehydro- genase deficiency

NAD[P]H steroid dehydrogenase-like enzyme

NSDHL 308050

30.6 Conradi- H ¨unermann syndrome (X-linked dominant chon- drodysplasia punctata)

Sterol- ∆

^isomerase

deficiency

Emopamil-binding protein

EBP 302960

30.7 Lathosterolosis 3 β -Hydroxysteroid- ∆

desaturase deficiency

Sterol C5 desaturase SC5D 607330 30.8 Smith-Lemli-

Opitz syndrome

3 β -Hydroxysteroid- ∆

reductase deficiency

7-Dehydro-cholesterol reductase

DHCR7 270400

30.3 Treatment/Alternative Therapies/Experimental Trials

I

Disorders 30.2, 30.3, 30.4, 30.7 No treatment.

I

30.1 Mevalonate kinase deficiency 30.1a Mevalonic aciduria (MVA) 30.1b Hyper-IgD syndrome (HIDS)

No. Symbol Medication Dosage

(mg/kg per day

Doses per day

30.1a MVA Coenzyme Q10 5–10 3

Tocopherol 25 3

Ascorbic acid 50–60 2

Cholesterol 50–100 3

Alpha-lipoic acid 15 3

30.1b HIDS Coenzyme Q10 5–10 3

Simvastatin 0.5–1.0 2

a

Adult dosages based on body weight of 40–50 kg

Dangers/Pitfalls

1. Treatment with cholesterol may reduce the frequency and severity of febrile attacks in mildly affected patients but has further compro- mised severely affected patients, possibly by excessive downregulation of HMG-CoA reductase activity.

2. Intervention with HMG-CoA reductase inhibitors should not be at-

tempted in MVA. An experimental trial in two patients resulted in

clinical decompensation manifesting as elevated body temperature,

acute myopathic changes, highly elevated creatine kinase, and wors-

ened ataxia, diarrhea, and vomiting (Hoffmann et al. 1993).

326 Inborn Errors of Cholesterol Biosynthesis

I

Emergency Treatment

No. Symbol Age Medication Dosage (mg/d) Duration

30.1a MVA All ages Prednisone

2 mg / ^{kg per day Daily}

during crises

2–5 years Montelukast 4 mg Daily

Zafirlukast 10 mg during crises

6–14 years Montelukast 5 mg

Zafirlukast 10 mg

> 14 years Montelukast 10 mg

Zafirlukast 20 mg

30.1b HIDS All ages Prednisone

2 mg / ^{kg per day Daily}

during crises

2–5 years Montelukast 4 mg Daily

Zafirlukast 10 mg during crises

6–14 years Montelukast 5 mg

Zafirlukast 10 mg

> 14 years Montelukast 10 mg

Zafirlukast 20 mg

a

Because of the efficacy of leukotriene inhibitors, the use of steroids for treament of some inflammatory crises can be avoided

I

30.5 CHILD syndrome

Age Indication Medication Dosage (mg/d) Doses per day

0–10 years

Cholesterol < 120 mg / ^dl Cholesterol 50–150 mg / ^{kg per day 3}

Adults 500–1000 mg 3

All ages Active skin disease Cholesterol 500 mg 3

a

Normal serum cholesterol is 60 ± 15 mg / dl in the newborn period and rises to near adult level over the first 6–12 months

b

With feedings/meals

I

30.6 Conradi-Hünermann syndrome

Age Indication Medication Dosage (mg/d) Doses per day

0–10 years

Cholesterol < 120 mg / ^dl Cholesterol 50–150 mg / ^{kg per day 3}

Adults 500–1000 mg 3

All ages Active skin disease Cholesterol 500 mg 3

a

Normal serum cholesterol is 60 ± 15 mg / dl in the newborn period and rises to near adult level over the first 6–12 months.

b

With feedings/meals

I

30.8 Smith-Lemli-Opitz syndrome (SLOS) (7-DHC+8-DHC)

to cholesterol ratio

Age/indication Medication Dosage (mg/day) Doses per day

≤ 0.5 0–10 years Cholesterol 50–100 mg / ^{kg per day}

³

Adults 500–1000 mg

3

All ages Simvastatin 0.5–1 mg / ^{kg per day}

²

> 0.5 0–2 years Cholesterol 100–200 mg / ^{kg per day 3}

> 2 years 100–150 mg / ^{kg per day}

³

Cholestasis Ursodeoxycholate 15–25 mg / ^{kg per day 2–3}

a

Dosage for purified cholesterol powder. Cholesterol is more efficiently absorbed when given as egg yolk (cooked or, preferable in pasteurized, liquid form), in which form a dosage of 40 mg / kg per day, or 500 mg / day in adults, usually is sufficient

b

Therapy should be started with 0.5 mg / kg per day and increased to 1 mg / kg per day after 4 weeks when there is no increase in CK or transaminases

Dangers/Pitfalls

1. Hepatotoxic side-effects were reported in one patient with a ratio of (7+8-DHC) to cholesterol of > 1 under simvastatin treatment (Starck et al. 2002a, b).

2. A moderate and reversible increase in creatine kinase was reported in a patient with a (7+8-DHC) to cholesterol ratio of < 0.5 under simvastatin-treatment (Starck et al. 2002a, b).

I

Emergency Treatment

For acute illness, when enteral cholesterol supplementation cannot be con-

tinued, or under conditions of severe stress likely to deplete LDL cholesterol,

frozen plasma can be given as an emergency source of LDL cholesterol. Acute

respiratory distress syndrome (ARDS) appears to be a common if unpredictable

complication in severe SLOS, typically associated with lower respiratory-tract

infections and after anesthesia, and may be treated with frozen plasma and/or

surfactant.

328 Inborn Errors of Cholesterol Biosynthesis

No. Symbol Indication Medication Dosage

30.8a, 30.8b

SLOS Surgical interventions, acute illnesses when enteral cholesterol supplementation not possible

Frozen plasma 10 ml / ^{kg 1} × / ^{d or 2} × / ^d

ARDS Surfactant 50–100 mg / ^kg

Frozen plasma 10 ml / ^kg × 1 / ^day

or ×2 / ^day

Adrenal insufficiency Hydrocortisone 30 mg / ^m

per day depending on age NaCl 0.9%, glucose

10% 1:1 (v/v)

a

Depending on preparation

30.4 Follow-up/Monitoring

G

30.1a Mevalonic aciduria

Age Biochemical monitoring

Clinical monitoring

Opthalmological monitoring

Cranial MRI

Children 6 monthly 6 monthly Yearly Every 2 years

Adults Yearly Yearly Yearly

a

CK, cholesterol, coenzyme Q10, vitamin E, hepatic function, renal function

b

Body growth, general health. Detailed psychomotor and neurobehavioral examination and testing every 2 years until the age of 6, starting from the age of 24 months, e. g., with the Bayley Scales of Infant Development.

c

Cataracts as well as retinal dystrophy have been described in several patients (Prietsch et al. 2003). The diagnostic work-up should comprise a slit-lamp examination, funduscopy, and, in individual patients, ocular electrophysiology (ERG)

d

Until the age of 6 years

I

30.8 Smith-Lemli-Opitz syndrome

Age Biochemical monitoring

Clinical and developmental

monitoring

Infants 3 monthly Every 8 weeks

Children < 6 years 3 monthly 6 monthly

Children > 6 years 6 monthly 6 monthly

Adolescents/adults Yearly Yearly

a

Serum sterols, transaminases, albumin, total protein, Fe, ferritin, folate, vitamin B

. For severely affected children:

coagulation studies, assessment of adrenal function. Patients on simvastatin: CK, transaminases, and sterols 4 and 12 weeks after start of the treatment

b

Body growth, general health. Detailed psychomotor and neurobehavioral examination and testing every 2 years until the age of 6, starting from the age of 24 months, e. g., with the Bayley Scales of Infant Development. Autism assessment in patients with a developmental quotient (DQ) > 18 months

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EMG meeting, Paris, May

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