Question 1

What is the RareMedEd website about?

Accepted Answer

RareMedEd is a resource to help aid healthcare professionals in recognizing and diagnosing certain rare diseases. We offer a robust library of resources - including in-depth videos, interactive modules, and real-world case studies.

Question 2

Who is Mirum Pharmaceuticals?

Accepted Answer

Our mission is to put patients first by addressing urgent unmet needs and filling therapeutic gaps. Through continued research and clinical evaluation, we aim to transform lives impacted by rare conditions.

Question 3

What is CTX?

Accepted Answer

Cerebrotendinous xanthomatosis is a rare, autosomal recessive metabolic disorder caused by biallelic variants in the CYP27A1 gene encoding sterol 27-hydroxylase. Although production of primary bile acids is impaired in CTX, the rate of bile acid synthesis is increased. This results in toxic accumulation of bile acid pathway intermediates and derived metabolites such as cholestanol and bile alcohols. Cholestanol is the key driver of symptomatic burden and disease progression.

Question 4

What are the incidence and prevalence rates for CTX?

Accepted Answer

CTX is rare, with less than 600 cases reported globally. CTX prevalence estimates were highest in Asians (1:44,407-93,084) and lowest in the Finnish population (1:3,388,767). Intermediate estimates were found in Europeans, Americans, and Africans/African Americans (1:70,795-233,597). Retrospective cohort studies suggest a substantial diagnostic delay of 15 to 25 years for CTX patients. While several hundred cases have been reported, the number of undiagnosed/misdiagnosed cases is unknown.

Question 5

What are the main clinical symptoms in CTX?

Accepted Answer

CTX is a multisystemic disorder which causes a distinct array of hallmark manifestations with variability of onset and severity. Symptoms, such as early-onset chronic diarrhea, bilateral cataracts, tendon xanthomas, and progressive neurologic deterioration, can be seen in many CTX patients. However, not all patients present with all the hallmark symptoms, and other patients may present with less frequently described symptoms such as infantile cholestasis or earlier onset of osteoporosis and coronary artery disease. Due to the heterogeneous nature of the condition, patients with CTX may present to many different specialists. Age at diagnosis and early treatment initiation are considered to have the biggest impact on outcomes.

Question 6

What causes CTX?

Accepted Answer

CTX is caused by biallelic pathogenic variants in the CYP27A1 gene. The CYP27A1 gene on chromosome 2q encodes for the mitochondrial enzyme sterol 27-hydroxylase which catalyzes the first step in the acidic pathway for cholesterol elimination via conversion to bile acids in the liver. Pathogenic variants in CYP27A1 result in impaired or nonfunctional sterol 27-hydroxylase activity, resulting in an absence, or significant reduction of, primary endogenous bile acids, both cholic acid (CA) and chenodeoxycholic acid (CDCA). Additionally, lack of CDCA leads to impaired negative feedback regulation, resulting in the upregulation of 7-alpha-hydroxycholesterol and its metabolites. These metabolites, such as cholestanol and bile alcohols, are elevated in the serum and urine, and deposition of cholestanol mainly in the neurological and systemic systems (brain, lenses of the eye, and tendons) lead to the characteristic clinical manifestations of CTX. These biochemical abnormalities have the ability to drive accumulation of cholestanol in various tissues within the body resulting in neurological and systemic manifestations. Through 2024, 158 pathogenic variants in CYP27A1 have been identified worldwide, and the most common variant change is the amino acid arginine to the amino acid cysteine at position 362 in the protein. Genotype-phenotype correlations have not been fully elucidated in CTX, and disease manifestations vary even in patients with the same genotype.

Question 7

How is CTX diagnosed?

Accepted Answer

Diagnosing CTX as early as possible is a vital first step toward arresting the natural course of the disease and preventing serious intellectual and physical disability. Currently, the mean age at diagnosis in CTX is 35.5 years (plus or minus 11.8). Currently, no standard guidelines exist for the diagnosis, treatment, and management of CTX. In a 2021 modified Delphi story, an expert panel reached consensus regarding CTX diagnosis: Unexplained prolonged neonatal jaundice should raise suspicion for CTX. Presence of biallelic CYP27A1 pathogenic variants is the indicator of greatest diagnostic value. Typical CTX patients have elevated serum cholestanol levels, which should be considered an appropriate secondary means for investigating a diagnosis. However, in some atypical cases, patients exhibit normal cholestanol levels and additional biomarkers can be used to confirm diagnosis. Dried blood spot testing should facilitate detection in newborns.

Question 8

What is the suggested CTX diagnostic criteria?

Accepted Answer

While these are not formal diagnostic criteria, the following recommendations for CTX diagnosis have been suggested/published. The current recommendations in place emphasize the importance of early diagnosis: A. Major CTX symptoms include: Tendon xanthoma, progressive neurological dysfunction or intellectual disability, idiopathic juvenile cataracts, juvenile coronary artery disease, chronic unexplained diarrhea, juvenile osteoporosis, and prolonged neonatal cholestasis. B. Biochemical findings: Elevated serum cholestanol level (elevated cholestanol and/or urine bile alcohols). C. Genetic testing: Pathogenic variants in CYP27A1 gene (homozygosity or compound heterozygosity). D. Differential diagnoses: Increased serum cholestanol level due to the following diseases should be excluded: familial hypercholesterolemia, sitosterolemia, obstructive biliary tract disease, and hypothyroidism. Diagnostic category: Definite: At least one of symptom in A and B+C+D. Probable: At least one of symptom in A and B+D. Possible: At least one of symptom in A and B.

Question 9

What are the typical laboratory findings for CTX?

Accepted Answer

Typically laboratory findings for CTX are: High plasma cholestanol concentration (greater than or equal to 5-10x normal), Normal-to-low plasma cholesterol concentration, Elevated urine bile alcohol concentration, Decreased CDCA levels, Increased apolipoprotein B in CSF.

Question 10

What is SLOS?

Accepted Answer

Smith-Lemli-Opitz syndrome is an autosomal recessive inborn error of cholesterol biosynthesis and neurodevelopmental disability. It is caused by biallelic pathogenic variants in the 3-beta-hydroxysteroid-Delta-7-reductase (DHCR7) gene which results in increased levels of toxic 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC) and a decreased production of cholesterol and primary bile acids (including chenodeoxycholic acid and cholic acid). Primary bile acids are needed to break down fats and fat-soluble vitamins to support growth and development and to absorb cholesterol.

Question 11

What are the incidence and prevalence rates for SLOS?

Accepted Answer

SLOS affects about 1 in 10,000 to 70,000 newborns, but this is likely an underestimation, given the fatality of severely affected cases and nondiagnosis of mild cases. SLOS affects males and females equally and is more common in individuals of European descent and less common in those of Asian or African ancestry.

Question 12

What causes SLOS?

Accepted Answer

SLOS is a genetic disorder caused by biallelic pathogenic variants in DHCR7 (HGNC:2860), encoding 7-dehydrocholesterol reductase (DHCR7), the enzyme responsible for the last step in cholesterol biosynthesis. Reduced DHCR7 enzymatic activity contributes to SLOS pathogenesis at multiple levels - biochemical, physical, neurocognitive, and behavioral. DHCR7 deficiency in SLOS results in accumulation of the cholesterol precursor, 7-DHC, which may alter vitamin D synthesis and interference with normal fetal development. Additionally, a DHCR7 deficiency may lead to decreased levels of cholesterol and deficiencies in steroid hormones, bile acids, and oxysterols. The intricate connections between these factors make clinical course prediction a challenge as manifestations and severity vary dramatically from patient to patient.

Question 13

What is the clinical presentation of SLOS?

Accepted Answer

SLOS is a multisystem condition with considerable variation in severity and features. It is characterized by multiple congenital malformations and neurocognitive deficits and behavioral disorders. Patients with SLOS may experience cholesterol deficiency, feeding problems, growth problems or delays, and cognitive/behavioral changes.

Question 14

What are the main clinical symptoms in SLOS?

Accepted Answer

The most frequently occurring feature is syndactyly of the second and third toes (ie, 'webbed toes') which occurs in more than 99% of patients. Additionally, growth restriction and developmental delays are very common clinical manifestations in SLOS patients. Patients often have a growth restriction of approximately 2 standard deviations (SDs) below the Centers for Disease Control (CDC) age-adjusted norms. Mildly affected individuals may exhibit only subtle features, including syndactyly of the second and third toes, subtle facial characteristics, hypotonia, and mild to no intellectual disability. Severely affected individuals may have more overt and widespread clinically severe manifestations, including prenatal and postnatal growth restriction, microcephaly, moderate to severe intellectual disability, ambiguous genitalia, lethal cardiac and/or brain malformations, cleft palate, and multisystemic failure.

Question 15

What are the laboratory findings in SLOS?

Accepted Answer

Laboratory findings for SLOS include: Low or low-normal plasma cholesterol concentrations (a normal cholesterol level does not exclude SLOS), Accumulation of cholesterol precursors and derivatives such as precursors including 7-DHC and its isomer 8-DHC and oxidized derivatives include oxysterols.

Question 16

What is the suggested SLOS diagnostic criteria?

Accepted Answer

There are no guidelines to establish a clinical diagnosis of SLOS. However, a diagnosis of SLOS is typically based on: Clinical features such as: 2-3 toe syndactyly, growth restriction, feeding difficulty, intellectual disability, behavioral changes/autistic traits, microcephaly, hypotonia, and cleft palate. Biochemical testing of sterols (plasma/serum cholesterol, 7-DHC, 8-DHC). Genetic testing (biallelic pathogenic DHCR7 variants). Targeted gene panels (single gene testing or multiple gene panels). Patients with SLOS may be misdiagnosed or remain undiagnosed until later in childhood or adulthood, especially those with milder forms of the condition.

Question 17

What is the role of genetics and genetic testing in SLOS?

Accepted Answer

SLOS is an autosomal recessively inherited condition. Changes in the same gene can cause different symptoms, depending on variant type. Biallelic variants in DHCR7 that lead to a premature stop codon and termination of the protein formation often result in prenatal lethality, whereas biallelic missense variants and other variant types generally allow for live births. DHCR7 gene is located on chromosome 11q12-13 and encodes for DHCR7. Over 150 different SLOS-inducing variants in DHCR7 have been identified and the most common variant is IVS8-1G>C (28%). Establishing a genotype-phenotype correlation in SLOS is challenging due to the large number of individual variants and the variable expressivity of the condition.

Frequently Asked Questions (FAQ)

General

Cerebrotendinous Xanthomatosis (CTX)

Smith-Lemli-Opitz Syndrome (SLOS)