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Inheritance

1

Autosomal recessive HP:0000007

Autosomal recessive inheritance

Show evidence (2 references)

PMID:33204591 SUPPORT Human Clinical

"Lathosterolosis is a rare autosomal recessive disorder of cholesterol biosynthesis."

States the inheritance pattern.

PMID:38060690 SUPPORT Human Clinical

"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier"

The GeneReviews Genetic Counseling transmission risks, which the inheritance mode alone does not give.

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Mechanistic Hypotheses

2

Cholesterol deficiency drives the malformation arm

lath_cholesterol_deficit_drives_malformation CANONICAL

The malformations follow from insufficient cholesterol for hedgehog morphogen modification. The Sc5d-null mouse supports this over the alternative directly, reporting that the defects appear to result from decreased cholesterol rather than increased lathosterol.

Pathograph links

Cholesterol Deficiency -> Impaired Hedgehog Signalling DIRECT Sonic hedgehog requires covalent cholesterol modification, so a cholesterol shortfall impairs the morphogen pathway.

Lathosterol accumulation drives the storage and hepatic arms

lath_accumulation_drives_storage ALTERNATIVE

The lysosomal storage picture is not a general feature of cholesterol biosynthesis defects, and within lathosterolosis it tracks with the most severe biochemical defects rather than with cholesterol shortage. The hepatic response to lowering plasma lathosterol points the same way. Modeled as a separate group because the two arms of this disease appear to have different biochemical causes, which is unusual and worth keeping visible.

Pathograph links

Lathosterol Accumulation -> Lysosomal Lamellar Inclusion Formation INDIRECT UNKNOWN INTERMEDIATES The storage picture tracks with the most severe biochemical defects, suggesting it follows accumulation rather than cholesterol shortage.

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Discussions and Knowledge Gaps

3

Which of the two biochemical consequences - cholesterol deficiency or lathosterol accumulation - causes which part of the phenotype?

INTERPRETATION lath_which_biochemical_lesion

Attached to

pathophysiology#Deficient Sterol C5-Desaturase Activity

A biosynthetic block produces both a shortage and a surplus, and lathosterolosis is unusual in giving evidence that they act on different arms. The Sc5d-null mouse attributes the malformations to decreased cholesterol rather than increased lathosterol. The storage picture points the other way: it is not a general feature of cholesterol synthesis defects, it tracks with the most severe biochemical defects, and the hepatic disease improved when plasma lathosterol was lowered without the enzyme being restored. The entry models these as separate hypothesis groups rather than collapsing them, because a treatment that lowers flux would be expected to help the accumulation arm and do nothing for the cholesterol arm - which is testable and matters clinically.

The Sc5d-null mouse dies before birth. Can a model that never lives a postnatal day speak to a disease whose dominant morbidity - liver disease and cataracts - is postnatal?

HUMAN MODEL MISMATCH OPEN lath_mouse_lethality_mismatch

Attached to

animal_models#Sc5d-null mouse pathophysiology#Impaired Hedgehog Signalling pathophysiology#Progressive Liver Disease

The mismatch is not a weakness of the mouse, it is a statement about which arm of the disease each system can see. Homozygous nulls are stillborn with craniofacial and limb patterning defects, which is exactly the window in which the malformation arm is decided, and the model earns its place by attributing those defects to decreased cholesterol rather than to accumulated lathosterol. But the same lethality means it cannot report on the hepatic course, the cataracts, or the response to simvastatin, and those are what patients present with and what treatment targets. The allele is also more severe than the human lesion. Every reported patient carries at least one missense allele with some residual activity; no patient homozygous for a null has been described. So the mouse models a genotype that may not be compatible with human live birth either, which is a further reason its silence on the postnatal course is uninformative rather than reassuring. The practical consequence for this entry: the mouse supports the cholesterol-driven malformation hypothesis and must not be read as evidence about the accumulation arm, which is where the entry's two hypothesis groups differ.

Proposed experiments

Hypomorphic Sc5d allelic series carried to adulthood

lath_hypomorph_mouse

Knock in a patient missense allele such as D210E or N71I, alone and in trans with the null, and follow survivors postnatally for hepatic histology, transaminases, lens opacity and plasma sterols. The point is to obtain any model that survives the birth the null does not.

Decision criterion

Whether a hypomorph with residual activity survives to adulthood and develops liver disease and cataracts.

Would support

pathophysiology#Progressive Liver Disease mechanistic_hypotheses#lath_accumulation_drives_storage

Would refute

mechanistic_hypotheses#lath_accumulation_drives_storage

Supporting outcome

Survivors developing progressive hepatic fibrosis and lens opacity would give the postnatal arm a model for the first time, and would let the statin question be asked as an intervention rather than inferred from two case reports.

Refuting outcome

Survivors with normal liver and lenses despite elevated lathosterol would argue the hepatic arm depends on something other than sterol accumulation alone, and would weaken the accumulation hypothesis group.

Does simvastatin change outcome in lathosterolosis, or only the sterol numbers?

KNOWLEDGE GAP lath_statin_benefit_conflict

Attached to

treatments#Simvastatin

Two reports disagree. In one, simvastatin lowered plasma lathosterol and was accompanied by improvement in transaminases and in fibrosis grade on repeat imaging. In another, the family noticed no benefit. Both are single patients, the endpoints are not the same, and the second reports absence of perceived benefit rather than a measured non-response - so the two are not strictly contradictory. With fewer than a dozen patients worldwide a trial is not realistic, which makes consistent sterol and liver endpoints across reported cases the only practical route to an answer. GeneReviews does not adjudicate between the two reports but states the field's position plainly: simvastatin is a potential targeted therapy whose safety and efficacy have not been proven in this disease. It nonetheless recommends a plasma sterol profile before starting and every one to two months on therapy - which is the practical shape of the uncertainty, monitoring a biochemical surrogate because the clinical endpoint is not established.

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Pathophysiology

8

Biallelic SC5D Loss of Function

Homozygous or compound heterozygous SC5D variants. Reported alleles are predominantly missense, and residual activity tracks with severity across the small reported cohort.

Downstream

Deficient Sterol C5-Desaturase Activity The variants reduce activity of the encoded desaturase.

Show evidence (1 reference)

PMID:12189593 SUPPORT Human Clinical

"Sequence analysis of the SC5D gene in the patient's DNA, showing the presence of two missense mutations (R29Q and G211D), confirmed that the patient is affected by a novel defect of cholesterol biosynthesis."

The original molecular confirmation of the disease gene.

Deficient Sterol C5-Desaturase Activity

The conversion of lathosterol to 7-dehydrocholesterol, the penultimate step of cholesterol synthesis, is blocked.

cholesterol biosynthetic process GO:0006695 ↓ DECREASED

C-5 sterol desaturase activity GO:0000248 ↓ DECREASED

Downstream

Lathosterol Accumulation Substrate upstream of the block accumulates.

Cholesterol Deficiency Flux to the end product falls.

Show evidence (1 reference)

PMID:12189593 SUPPORT In Vitro

"The biosynthesis of cholesterol in the patient's fibroblasts was defective, showing a block in the conversion of lathosterol into 7-dehydrocholesterol."

Demonstrates the enzymatic block directly in patient fibroblasts.

Lathosterol Accumulation

Plasma and tissue lathosterol rise, in the reported mild case to more than tenfold above the upper limit of the control range. Accumulation is the diagnostic signature and appears to drive the storage arm of the disease specifically.

Lathosterol accumulation drives the storage and hepatic arms

Experimental models

SC5D-knockout HepG2 cell line CELL LINE Reproduces lathosterol accumulation in a hepatocyte background and shows it produces a distinct transcriptional response from the accumulation of other sterols in the same pathway.

Downstream

Lysosomal Lamellar Inclusion Formation The storage picture tracks with the most severe biochemical defects, suggesting it follows accumulation rather than cholesterol shortage.

Progressive Liver Disease Lowering lathosterol pharmacologically improved transaminases and fibrosis grade in one patient, which is the observation that implicates accumulation in the hepatic arm.

Show evidence (1 reference)

PMID:30097991 SUPPORT Human Clinical

"The plasma lathosterol concentration was markedly raised at 219.8 μmol/L (control range 0.53-16.0), confirming the diagnosis."

Quantifies the accumulation against a stated control range.

Cholesterol Deficiency

Cellular cholesterol falls. In the mouse knockout this, rather than the accumulated precursor, is what accounts for the malformation phenotype.

Cholesterol deficiency drives the malformation arm

Downstream

Impaired Hedgehog Signalling Sonic hedgehog requires covalent cholesterol modification, so a cholesterol shortfall impairs the morphogen pathway.

Show evidence (1 reference)

PMID:12812989 SUPPORT Model Organism

"Sc5d (-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol levels, had craniofacial defects including cleft palate and micrognathia, and limb patterning defects."

Establishes both the biochemical changes and the malformation phenotype.

Impaired Hedgehog Signalling

The route by which a biosynthetic block becomes a malformation syndrome rather than a purely degenerative disease. This is the mechanism shared with Smith-Lemli-Opitz and the other post-squalene defects.

smoothened signaling pathway GO:0007224 ↓ DECREASED

Animal models

Sc5d-null mouse Mouse recapitulates Reproduces the malformation pattern and localizes its cause to the cholesterol shortfall.

Downstream

Congenital Malformation Pattern Disrupted morphogen signalling produces the craniofacial and limb anomalies.

Show evidence (1 reference)

PMID:12812989 SUPPORT Model Organism

"Many of the malformations found in Sc5d (-/-) mice are consistent with impaired hedgehog signaling, and appear to be a result of decreased cholesterol rather than increased lathosterol."

Attributes the malformations to the pathway and, importantly, adjudicates between the two candidate biochemical causes.

Lysosomal Lamellar Inclusion Formation

Lamellar inclusions on electron microscopy, with a mucolipidosis-like appearance on light microscopy in the most severely affected. This storage component is what makes lathosterolosis unusual among the cholesterol biosynthesis defects.

Show evidence (1 reference)

PMID:12812989 SUPPORT Human Clinical

"An unique aspect of the lathosterolosis phenotype is the combination of a malformation syndrome with an intracellular storage defect."

States the combination that distinguishes this disease from its neighbours.

Congenital Malformation Pattern

A recognisable pattern involving the axial and appendicular skeleton, liver, central nervous and urogenital systems.

Show evidence (1 reference)

PMID:17853487 SUPPORT Human Clinical

"The LS phenotype appears to be characterized by the distinctive association of a recognizable pattern of congenital anomalies, involving axial and appendicular skeleton, liver, central nervous and urogenital systems, and lysosomal storage."

Defines the malformation pattern and couples it to the storage finding.

Progressive Liver Disease

Ranges from normal liver function tests through transaminitis to portal fibrosis and cirrhosis. It is the arm that responds to lowering the accumulated sterol.

Animal models

Sc5d-null mouse Mouse fails to recapitulate The model is silent on the hepatic arm, and not because the liver was normal - because the animals never lived to have one assessed.

Show evidence (1 reference)

PMID:33204591 SUPPORT Human Clinical

"Liver involvement is variable and can range from normal liver function tests to portal fibrosis and cirrhosis."

Describes the range of hepatic involvement across reported cases.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

19

Digestive 2

Hepatic Fibrosis OCCASIONAL HP:0001395

Show evidence (1 reference)

PMID:33204591 SUPPORT Human Clinical

"Fibroscan showed severe liver fibrosis."

Documents fibrosis in the reported patient.

Cirrhosis OCCASIONAL HP:0001394

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"The severity of liver disease can range from asymptomatic elevation of liver enzymes to cirrhosis and liver failure."

Gives the full range of hepatic involvement, from a laboratory abnormality to organ failure.

Eye 2

Cataract FREQUENT HP:0000518

Show evidence (1 reference)

PMID:33204591 SUPPORT Human Clinical

"Lathosterolosis manifests as microcephaly, bilateral cataracts, dysmorphism, limb anomalies, and developmental delay/intellectual disability."

Lists cataract among the core manifestations.

Ptosis FREQUENT HP:0000508

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia"

Lists ptosis among the characteristic facial features.

Genitourinary 1

Genitourinary Anomalies Abnormality of the genitourinary system HP:0000119

Show evidence (2 references)

PMID:17853487 SUPPORT Human Clinical

"The LS phenotype appears to be characterized by the distinctive association of a recognizable pattern of congenital anomalies, involving axial and appendicular skeleton, liver, central nervous and urogenital systems, and lysosomal storage."

Places the urogenital system inside the defining malformation pattern, which is what makes this a phenotype of the disease rather than an incidental finding.

PMID:38060690 SUPPORT Human Clinical

"treatment of genitourinary anomalies per nephrologist and/or urologist"

A management instruction, so it presupposes the anomalies rather than reporting them. Graded PARTIAL for that reason: it corroborates that they occur and says nothing about which anomalies or how often.

Head and Neck 7

Microcephaly FREQUENT HP:0000252

Show evidence (1 reference)

PMID:33204591 SUPPORT Human Clinical

"Lathosterolosis manifests as microcephaly, bilateral cataracts, dysmorphism, limb anomalies, and developmental delay/intellectual disability."

Lists microcephaly among the core manifestations.

High Palate FREQUENT HP:0000218

Show evidence (2 references)

PMID:30097991 SUPPORT Human Clinical

"he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes)"

Names the high-arched palate in the mild phenotype.

PMID:38060690 SUPPORT Human Clinical

"bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia"

Lists it among the characteristic facial features.

Anteverted Nares FREQUENT HP:0000463

Show evidence (2 references)

PMID:30097991 SUPPORT Human Clinical

"he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes)"

Names anteverted nostrils in the mild phenotype.

PMID:38060690 SUPPORT Human Clinical

"bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia"

Lists anteverted nares among the characteristic features.

Long Philtrum FREQUENT HP:0000343

Show evidence (2 references)

PMID:30097991 SUPPORT Human Clinical

"he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes)"

Names the long philtrum in the mild phenotype.

PMID:38060690 SUPPORT Human Clinical

"bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia"

Lists it among the characteristic features.

Downslanted Palpebral Fissures FREQUENT HP:0000494

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia"

Lists downslanting palpebral fissures among the characteristic features.

Epicanthus FREQUENT HP:0000286

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia"

Lists epicanthal folds among the characteristic features.

Micrognathia FREQUENT HP:0000347

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia"

Lists micrognathia among the characteristic features.

Limbs 2

Postaxial Polydactyly FREQUENT HP:0100259

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"digit anomalies (postaxial polydactyly, toe syndactyly)"

Names the two digit anomalies characteristic of the disease.

Toe Syndactyly FREQUENT HP:0001770

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"digit anomalies (postaxial polydactyly, toe syndactyly)"

Names toe syndactyly among the characteristic digit anomalies.

Metabolism 1

Elevated Transaminases FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:36607840 SUPPORT Human Clinical

"Laboratory tests revealed an alanine aminotransferase level of 502 IU/L and an aspartate aminotransferase level of 279 IU/L"

Reports the magnitude of the transaminase elevation in a described case.

Musculoskeletal 1

Hypotonia FREQUENT HP:0001252

Show evidence (1 reference)

PMID:30097991 SUPPORT Human Clinical

"he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes)"

The same sentence that describes the dysmorphism also reports the hypotonia.

Nervous System 3

Intellectual Disability FREQUENT HP:0001249

Show evidence (1 reference)

PMID:30097991 SUPPORT Human Clinical

"He also had learning difficulties, with a full-scale IQ of 64 at 11 years of age."

Quantifies the cognitive phenotype at the mild end, which is where the diagnosis is most often missed.

Seizures OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:36607840 SUPPORT Human Clinical

"An eight-month-old male patient was referred to the department of paediatric neurology for status epilepticus."

Reports status epilepticus as the presenting problem in this case.

Global Developmental Delay FREQUENT HP:0001263

Show evidence (2 references)

PMID:38060690 SUPPORT Human Clinical

"Lathosterolosis is characterized by global developmental delays, intellectual disability, microcephaly"

The GeneReviews characterisation sentence, which names global developmental delay as a defining feature rather than an occasional one.

PMID:33204591 SUPPORT Human Clinical

"Neurologic features included hypotonia (4/7) and mild to severe psychomotor retardation/intellectual disability in all surviving patients."

Gives the count behind the frequency band: every surviving patient in the seven-case review, which is above the FREQUENT floor even read conservatively.

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Genetic Associations

1

SC5D

Gene: SC5D hgnc:10547 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:33204591 SUPPORT Human Clinical

"A missense variant, NM_006918.4 (SC5D):c.212A>T;p.(Asn71Ile) and a nonsense variant, NM_006918.4(SC5D):c.214C>T; p.(Gln72*) were identified in exon 3 of the SC5D gene."

Identifies the one reported allele that is a true null. The entry's genotype-phenotype reading rests on residual activity, so an allele with none is the informative extreme.

PMID:30097991 SUPPORT Human Clinical

"The mutation leads to a relatively conservative amino acid substitution, consistent with some residual enzyme activity."

Links a specific allele's chemistry to the milder phenotype, which is the genotype-phenotype logic available in a disease with this few patients.

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Medical Actions

4

Avoidance of Hepatotoxic Agents

Action: Supportive Care NCIT:C15747

GeneReviews lists hepatotoxic medications and chemicals as agents to avoid. This carries more weight in this disease than the generic version of the advice: the hepatic arm is the dominant morbidity driver, it is the arm liver transplantation addresses, and the entry's only pharmacotherapy is a statin - so protecting the liver is a management instruction about the same organ the treatment plan turns on.

Mechanism Target:

MODULATES Progressive Liver Disease — Avoids additional hepatocellular injury on top of the sterol-driven disease; it does not act on the biosynthetic block.

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"Medications and chemicals that are hepatotoxic"

The GeneReviews agents-and-circumstances-to-avoid instruction.

Simvastatin

Action: Pharmacotherapy NCIT:C15986

Agent: simvastatin CHEBI:9150

Inhibits HMG-CoA reductase upstream of the block, reducing flux into the pathway and so lowering the accumulated lathosterol. It does not restore the missing enzyme, and reported benefit is inconsistent.

Mechanism Target:

INHIBITS Lathosterol Accumulation — Reducing proximal cholesterol synthesis lowers the substrate that accumulates behind the block.

MODULATES Progressive Liver Disease — Improvement in transaminases and fibrosis grade followed the fall in plasma lathosterol in the treated patient.

Show evidence (2 references)

PMID:33204591 SUPPORT Human Clinical

"Simvastatin treatment resulted in lowering of plasma lathosterol levels, improvement in transaminitis, and liver fibrosis grade, suggesting that children with this condition should be actively treated in order to prevent progression of liver disease."

The single most substantive treatment observation available: a biochemical response coupled to a histological one.

PMID:30097991 REFUTE Human Clinical

"Our patient's family did not notice any benefit from treatment with simvastatin."

A contrary observation in a different patient, curated as REFUTE so the entry does not present the treatment as uniformly effective.

Surveillance Schedule

Action: Supportive Care NCIT:C15747

GeneReviews sets a monitoring plan that is unusually specific for a disease with this few patients, and its shape follows the mechanism: the ophthalmologic and hepatic arms are both progressive and both actionable, so each gets an interval. Developmental milestones at every visit; annual ophthalmology; liver enzymes at every visit with ultrasound and FibroScan every six months; and a plasma sterol profile before starting simvastatin and every one to two months on it. That last interval is the one that carries mechanistic weight - it monitors the substrate behind the block, because the clinical endpoint the statin is meant to change has never been established.

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"annual ophthalmology evaluation; liver enzymes at each visit; liver imaging including ultrasound and FibroScan® every six months or per hepatologist; plasma sterol profile before initiating simvastatin and every one to two months while on therapy"

The GeneReviews Surveillance section verbatim, giving each interval rather than a general instruction to follow up.

Liver Transplantation

Action: Organ Transplantation NCIT:C15289

Named alongside simvastatin as a potential targeted therapy. It addresses the hepatic arm definitively by replacing the affected organ, while doing nothing for the malformation or storage arms - which is consistent with the entry's reading that those arms have different biochemical causes.

Mechanism Target:

MODULATES Progressive Liver Disease — Replaces the organ in which the hepatic arm manifests.

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"Potential targeted therapies include simvastatin (the safety and/or efficacy of simvastatin has not been proven in lathosterolosis) and liver transplantation."

The GeneReviews Management section naming both targeted options, and stating plainly that simvastatin is unproven.

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Biochemical Markers

2

Plasma lathosterol (Increased)

Context: The diagnostic analyte. Because the disease is not clinically distinctive at its mild end, it is missed unless plasma sterols are measured or SC5D is sequenced.

Pathograph Readouts

Readout Of Lathosterol Accumulation Positive Diagnostic

Plasma lathosterol reports the enzymatic block directly, as the substrate immediately upstream of it.

Show evidence (1 reference)

PMID:30097991 SUPPORT Human Clinical

"The diagnosis will be missed unless plasma sterols are analysed or relevant genes sequenced."

States why this readout is diagnostically necessary rather than merely confirmatory.

Plasma total cholesterol (Normal)

Context: Recorded because it is a negative result that does real work. The entry places lathosterolosis one enzymatic step upstream of Smith-Lemli-Opitz syndrome and attributes the malformation arm to a cholesterol shortfall, which invites the reading that plasma cholesterol should be low. It is not. Total cholesterol was normal in the patient whose sterol profile is reported in full, alongside the normal 7-dehydrocholesterol that separates this disease from SLOS biochemically. The cholesterol claim in the pathophysiology is therefore a developmental and cellular one - the sterol available to hedgehog signalling in the embryo - and not a claim about a measurable plasma concentration in the patient in front of you.

Show evidence (1 reference)

PMID:33204591 SUPPORT Human Clinical

"normal 7‐dehydrocholesterol, total cholesterol, and elevated 8(9)‐cholestenol levels"

The only fully reported sterol profile in the literature. Read against the same sentence's elevated lathosterol, it gives the biochemical shape of the disease: the precursor piles up while the product stays in range. The normal 7-dehydrocholesterol in the same list is what distinguishes it from SLOS, where that sterol is the one that accumulates.

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Diagnosis

1

Plasma sterol analysis with SC5D confirmation

Elevated plasma lathosterol establishes the biochemical diagnosis; biallelic SC5D variants confirm it. Either is sufficient per GeneReviews, which matters because the biochemical route is what catches the mild cases whose clinical picture is non-specific.

Show evidence (1 reference)

PMID:38060690 SUPPORT Human Clinical

"The diagnosis of lathosterolosis is established in a proband by identification of elevated lathosterol on plasma sterol analysis and/or biallelic pathogenic variants in SC5D by molecular genetic testing."

The GeneReviews diagnostic criterion, giving both routes.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Six cases described as of the 2020 report, with the authors noting that milder forms are likely to have been missed. A handful of further cases have been reported since.

Show evidence (1 reference)

PMID:33204591 SUPPORT Human Clinical

"Only six cases have been described in the literature, but it is possible that a number of patients with milder forms of the condition might have been missed."

Gives the case count and, usefully, the authors' own caveat about ascertainment.

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Experimental Models

1

SC5D-knockout HepG2 cell line CELL_LINE

One of three cholesterol-synthesis enzyme knockouts made in the same hepatocyte background, which allows the consequences of accumulating different sterols to be compared while holding the pathway and cell type constant.

Publication

PMID:39262789

Pathograph links

Lathosterol Accumulation recapitulates fidelity: moderate Reproduces lathosterol accumulation in a hepatocyte background and shows it produces a distinct transcriptional response from the accumulation of other sterols in the same pathway.

Limitations: A transformed hepatoma line with a complete knockout, so it models neither the hypomorphic alleles patients carry nor the developmental context in which the malformations arise.

Show evidence (1 reference)

PMID:39262789 SUPPORT In Vitro

"Surprisingly, KOs of CYP51, DHCR24, and SC5D shared only 9% of differentially expressed genes."

Shows that which sterol accumulates, not merely that cholesterol synthesis is blocked, determines the cellular response - the point the model exists to make.

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Animal Models

1

Sc5d-null mouse

Stillborn with craniofacial and limb patterning defects, and the experiment that attributes the malformations to cholesterol deficiency rather than to lathosterol accumulation.

Species

Mouse

Genotype

Sc5d -/-

Publication

PMID:12812989

Pathograph links

Progressive Liver Disease fails to recapitulate fidelity: low The model is silent on the hepatic arm, and not because the liver was normal - because the animals never lived to have one assessed.

Limitations: Homozygous nulls are stillborn, so hepatic fibrosis, cirrhosis and the response to lowering plasma lathosterol cannot be observed in this model at all. A complete null is also a more severe lesion than the missense alleles patients carry, and no patient homozygous for a null has been reported - so the lethality may itself be the mouse reproducing something true, rather than a failure of the model.

Show evidence (1 reference)

PMID:12812989 SUPPORT Model Organism

"Sc5d (-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol levels"

Establishes the perinatal lethality that makes the postnatal arm unobservable here. It is the substantive basis for the negative claim, as FAILS_TO_RECAPITULATE requires.

Impaired Hedgehog Signalling recapitulates fidelity: moderate Reproduces the malformation pattern and localizes its cause to the cholesterol shortfall.

Limitations: Homozygous nulls are stillborn, so the model cannot address the postnatal course, the hepatic disease, or the cataracts that dominate the milder human phenotype; and a complete null is a more severe lesion than the missense alleles patients carry.

Show evidence (1 reference)

PMID:12812989 SUPPORT Model Organism

"Many of the malformations found in Sc5d (-/-) mice are consistent with impaired hedgehog signaling, and appear to be a result of decreased cholesterol rather than increased lathosterol."

The comparison that makes this model informative for the mechanism rather than merely phenotypically similar.

{ }

Source YAML

click to show

name: Lathosterolosis
description: >-
  Lathosterolosis is an ultra-rare autosomal recessive disorder of cholesterol
  biosynthesis caused by biallelic variants in SC5D, which encodes sterol C5-desaturase
  (3-beta-hydroxysteroid-delta-5-desaturase). The enzyme converts lathosterol to
  7-dehydrocholesterol in the penultimate step of cholesterol synthesis, one step
  upstream of the DHCR7 reaction whose loss causes Smith-Lemli-Opitz syndrome. Blocking
  it both starves the cell of cholesterol and causes lathosterol to accumulate, and the
  disease combines two things that rarely appear together: a congenital malformation
  syndrome attributable to impaired hedgehog signalling, and an intracellular lysosomal
  storage picture. Fewer than a dozen patients have been reported, spanning a lethal
  fetal presentation to a mild adult phenotype of cataracts and learning difficulty.
disease_term:
  preferred_term: lathosterolosis
  term:
    id: MONDO:0011816
    label: lathosterolosis
creation_date: "2026-08-27T18:45:00Z"

references:
- reference: PMID:38060690
  title: "Lathosterolosis."
  tags:
  - GeneReviews
- reference: PMID:12189593
  title: >-
    Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to
    deficiency of 3beta-hydroxysteroid-delta5-desaturase.
- reference: PMID:12812989
  title: >-
    Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to
    lathosterol 5-desaturase deficiency.
- reference: PMID:17853487
  title: Clinical phenotype of lathosterolosis.
- reference: PMID:30097991
  title: 'Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties.'
- reference: PMID:33204591
  title: >-
    Successful treatment of lathosterolosis: A rare defect in cholesterol
    biosynthesis-A case report and review of literature.
- reference: PMID:36607840
  title: >-
    Lathosterolosis: a rare cholesterol metabolism disorder with a wide range of
    clinical variability.
- reference: PMID:39262789
  title: >-
    Knockouts of CYP51A1, DHCR24, or SC5D from cholesterol synthesis reveal pathways
    modulated by sterol intermediates.

pathophysiology:
- name: Biallelic SC5D Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous SC5D variants. Reported alleles are
    predominantly missense, and residual activity tracks with severity across the small
    reported cohort.
  evidence:
  - reference: PMID:12189593
    reference_title: "Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-delta5-desaturase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the SC5D gene in the patient's DNA, showing the presence of
      two missense mutations (R29Q and G211D), confirmed that the patient is affected
      by a novel defect of cholesterol biosynthesis.
    explanation: The original molecular confirmation of the disease gene.
  downstream:
  - target: Deficient Sterol C5-Desaturase Activity
    causal_link_type: DIRECT
    description: The variants reduce activity of the encoded desaturase.

- name: Deficient Sterol C5-Desaturase Activity
  biological_scale: MOLECULAR
  description: >-
    The conversion of lathosterol to 7-dehydrocholesterol, the penultimate step of
    cholesterol synthesis, is blocked.
  molecular_functions:
  - preferred_term: C-5 sterol desaturase activity
    modifier: DECREASED
    term:
      id: GO:0000248
      label: C-5 sterol desaturase activity
  biological_processes:
  - preferred_term: cholesterol biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006695
      label: cholesterol biosynthetic process
  evidence:
  - reference: PMID:12189593
    reference_title: "Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-delta5-desaturase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The biosynthesis of cholesterol in the patient's fibroblasts was defective,
      showing a block in the conversion of lathosterol into 7-dehydrocholesterol.
    explanation: Demonstrates the enzymatic block directly in patient fibroblasts.
  downstream:
  - target: Lathosterol Accumulation
    causal_link_type: DIRECT
    description: Substrate upstream of the block accumulates.
  - target: Cholesterol Deficiency
    causal_link_type: DIRECT
    description: Flux to the end product falls.

- name: Lathosterol Accumulation
  biological_scale: MOLECULAR
  description: >-
    Plasma and tissue lathosterol rise, in the reported mild case to more than tenfold
    above the upper limit of the control range. Accumulation is the diagnostic signature
    and appears to drive the storage arm of the disease specifically.
  evidence:
  - reference: PMID:30097991
    reference_title: "Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The plasma lathosterol concentration was markedly raised at 219.8 μmol/L (control
      range 0.53-16.0), confirming the diagnosis.
    explanation: Quantifies the accumulation against a stated control range.
  downstream:
  - target: Lysosomal Lamellar Inclusion Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - lath_accumulation_drives_storage
    description: >-
      The storage picture tracks with the most severe biochemical defects, suggesting it
      follows accumulation rather than cholesterol shortage.
  - target: Progressive Liver Disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Lowering lathosterol pharmacologically improved transaminases and fibrosis grade
      in one patient, which is the observation that implicates accumulation in the
      hepatic arm.

- name: Cholesterol Deficiency
  biological_scale: MOLECULAR
  description: >-
    Cellular cholesterol falls. In the mouse knockout this, rather than the accumulated
    precursor, is what accounts for the malformation phenotype.
  cellular_components: []
  evidence:
  - reference: PMID:12812989
    reference_title: "Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Sc5d (-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol
      levels, had craniofacial defects including cleft palate and micrognathia, and limb
      patterning defects.
    explanation: Establishes both the biochemical changes and the malformation phenotype.
  downstream:
  - target: Impaired Hedgehog Signalling
    causal_link_type: DIRECT
    hypothesis_groups:
    - lath_cholesterol_deficit_drives_malformation
    description: >-
      Sonic hedgehog requires covalent cholesterol modification, so a cholesterol
      shortfall impairs the morphogen pathway.

- name: Impaired Hedgehog Signalling
  biological_scale: CELLULAR
  description: >-
    The route by which a biosynthetic block becomes a malformation syndrome rather than
    a purely degenerative disease. This is the mechanism shared with Smith-Lemli-Opitz
    and the other post-squalene defects.
  biological_processes:
  - preferred_term: smoothened signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  evidence:
  - reference: PMID:12812989
    reference_title: "Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Many of the malformations found in Sc5d (-/-) mice are consistent with impaired
      hedgehog signaling, and appear to be a result of decreased cholesterol rather than
      increased lathosterol.
    explanation: >-
      Attributes the malformations to the pathway and, importantly, adjudicates between
      the two candidate biochemical causes.
  downstream:
  - target: Congenital Malformation Pattern
    causal_link_type: DIRECT
    description: Disrupted morphogen signalling produces the craniofacial and limb anomalies.

- name: Lysosomal Lamellar Inclusion Formation
  biological_scale: CELLULAR
  description: >-
    Lamellar inclusions on electron microscopy, with a mucolipidosis-like appearance on
    light microscopy in the most severely affected. This storage component is what makes
    lathosterolosis unusual among the cholesterol biosynthesis defects.
  evidence:
  - reference: PMID:12812989
    reference_title: "Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An unique aspect of the lathosterolosis phenotype is the combination of a
      malformation syndrome with an intracellular storage defect.
    explanation: States the combination that distinguishes this disease from its neighbours.

- name: Congenital Malformation Pattern
  biological_scale: ORGANISM
  description: >-
    A recognisable pattern involving the axial and appendicular skeleton, liver, central
    nervous and urogenital systems.
  evidence:
  - reference: PMID:17853487
    reference_title: "Clinical phenotype of lathosterolosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LS phenotype appears to be characterized by the distinctive association of a
      recognizable pattern of congenital anomalies, involving axial and appendicular
      skeleton, liver, central nervous and urogenital systems, and lysosomal storage.
    explanation: Defines the malformation pattern and couples it to the storage finding.

- name: Progressive Liver Disease
  biological_scale: TISSUE
  description: >-
    Ranges from normal liver function tests through transaminitis to portal fibrosis and
    cirrhosis. It is the arm that responds to lowering the accumulated sterol.
  evidence:
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver involvement is variable and can range from normal liver function tests to
      portal fibrosis and cirrhosis.
    explanation: Describes the range of hepatic involvement across reported cases.

mechanistic_hypotheses:
- hypothesis_group_id: lath_cholesterol_deficit_drives_malformation
  hypothesis_label: Cholesterol deficiency drives the malformation arm
  status: CANONICAL
  description: >-
    The malformations follow from insufficient cholesterol for hedgehog morphogen
    modification. The Sc5d-null mouse supports this over the alternative directly,
    reporting that the defects appear to result from decreased cholesterol rather than
    increased lathosterol.

- hypothesis_group_id: lath_accumulation_drives_storage
  hypothesis_label: Lathosterol accumulation drives the storage and hepatic arms
  status: ALTERNATIVE
  description: >-
    The lysosomal storage picture is not a general feature of cholesterol biosynthesis
    defects, and within lathosterolosis it tracks with the most severe biochemical
    defects rather than with cholesterol shortage. The hepatic response to lowering
    plasma lathosterol points the same way. Modeled as a separate group because the two
    arms of this disease appear to have different biochemical causes, which is unusual
    and worth keeping visible.

phenotypes:
- category: Ophthalmologic
  name: Cataract
  frequency: FREQUENT
  description: >-
    Bilateral and sometimes the presenting feature at the mild end of the spectrum.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lathosterolosis manifests as microcephaly, bilateral cataracts, dysmorphism, limb
      anomalies, and developmental delay/intellectual disability.
    explanation: Lists cataract among the core manifestations.

- category: Neurologic
  name: Microcephaly
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lathosterolosis manifests as microcephaly, bilateral cataracts, dysmorphism, limb
      anomalies, and developmental delay/intellectual disability.
    explanation: Lists microcephaly among the core manifestations.

- category: Neurologic
  name: Intellectual Disability
  frequency: FREQUENT
  description: >-
    Spans severe impairment in the classic cases to a full-scale IQ of 64 in the mildest
    reported patient.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30097991
    reference_title: "Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also had learning difficulties, with a full-scale IQ of 64 at 11 years of age.
    explanation: >-
      Quantifies the cognitive phenotype at the mild end, which is where the diagnosis
      is most often missed.

- category: Hepatic
  name: Elevated Transaminases
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:36607840
    reference_title: "Lathosterolosis: a rare cholesterol metabolism disorder with a wide range of clinical variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory tests revealed an alanine aminotransferase level of 502 IU/L and an
      aspartate aminotransferase level of 279 IU/L
    explanation: Reports the magnitude of the transaminase elevation in a described case.

- category: Hepatic
  name: Hepatic Fibrosis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fibroscan showed severe liver fibrosis.
    explanation: Documents fibrosis in the reported patient.

- category: Craniofacial
  name: High Palate
  frequency: FREQUENT
  description: >-
    One of the facial features named in both the GeneReviews series and the mild reported
    case.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:30097991
    reference_title: "Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted
      nostrils, long philtrum and clinodactyly of toes)
    explanation: Names the high-arched palate in the mild phenotype.
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting
      palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched
      palate, and micrognathia
    explanation: Lists it among the characteristic facial features.

- category: Craniofacial
  name: Anteverted Nares
  frequency: FREQUENT
  description: >-
    Named in both sources.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  evidence:
  - reference: PMID:30097991
    reference_title: "Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted
      nostrils, long philtrum and clinodactyly of toes)
    explanation: Names anteverted nostrils in the mild phenotype.
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting
      palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched
      palate, and micrognathia
    explanation: Lists anteverted nares among the characteristic features.

- category: Craniofacial
  name: Long Philtrum
  frequency: FREQUENT
  description: >-
    Named in both sources.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:30097991
    reference_title: "Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted
      nostrils, long philtrum and clinodactyly of toes)
    explanation: Names the long philtrum in the mild phenotype.
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting
      palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched
      palate, and micrognathia
    explanation: Lists it among the characteristic features.

- category: Craniofacial
  name: Ptosis
  frequency: FREQUENT
  description: >-
    Part of the characteristic facies described in the GeneReviews series.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting
      palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched
      palate, and micrognathia
    explanation: Lists ptosis among the characteristic facial features.

- category: Craniofacial
  name: Downslanted Palpebral Fissures
  frequency: FREQUENT
  description: >-
    Part of the characteristic facies.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting
      palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched
      palate, and micrognathia
    explanation: Lists downslanting palpebral fissures among the characteristic features.

- category: Craniofacial
  name: Epicanthus
  frequency: FREQUENT
  description: >-
    Part of the characteristic facies.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting
      palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched
      palate, and micrognathia
    explanation: Lists epicanthal folds among the characteristic features.

- category: Craniofacial
  name: Micrognathia
  frequency: FREQUENT
  description: >-
    Part of the characteristic facies.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting
      palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched
      palate, and micrognathia
    explanation: Lists micrognathia among the characteristic features.

- category: Neurologic
  name: Hypotonia
  frequency: FREQUENT
  description: >-
    Reported in most described cases, including the mild end of the spectrum.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:30097991
    reference_title: "Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted
      nostrils, long philtrum and clinodactyly of toes)
    explanation: The same sentence that describes the dysmorphism also reports the hypotonia.

- category: Neurologic
  name: Seizures
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:36607840
    reference_title: "Lathosterolosis: a rare cholesterol metabolism disorder with a wide range of clinical variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An eight-month-old male patient was referred to the department of paediatric
      neurology for status epilepticus.
    explanation: Reports status epilepticus as the presenting problem in this case.

- category: Skeletal
  name: Postaxial Polydactyly
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:38060690
    reference_title: "Lathosterolosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      digit anomalies (postaxial polydactyly, toe syndactyly)
    explanation: Names the two digit anomalies characteristic of the disease.

- category: Skeletal
  name: Toe Syndactyly
  frequency: FREQUENT
  description: >-
    Shared with Smith-Lemli-Opitz, where 2-3 toe syndactyly is the classic sign, and
    consistent with both diseases acting through the same morphogen pathway.
  phenotype_term:
    preferred_term: Toe syndactyly
    term:
      id: HP:0001770
      label: Toe syndactyly
  evidence:
  - reference: PMID:38060690
    reference_title: "Lathosterolosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      digit anomalies (postaxial polydactyly, toe syndactyly)
    explanation: Names toe syndactyly among the characteristic digit anomalies.

- category: Hepatic
  name: Cirrhosis
  frequency: OCCASIONAL
  description: The severe end of the hepatic arm.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  evidence:
  - reference: PMID:38060690
    reference_title: "Lathosterolosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity of liver disease can range from asymptomatic elevation of liver
      enzymes to cirrhosis and liver failure.
    explanation: >-
      Gives the full range of hepatic involvement, from a laboratory abnormality to
      organ failure.

- category: Neurologic
  name: Global Developmental Delay
  frequency: FREQUENT
  description: >-
    Named first among the characterising features. It is distinct from the intellectual
    disability recorded separately: the delay is what is observable in infancy, before
    the cognitive endpoint can be measured, and it is what brings most patients to
    attention.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lathosterolosis is characterized by global developmental delays, intellectual
      disability, microcephaly
    explanation: >-
      The GeneReviews characterisation sentence, which names global developmental delay
      as a defining feature rather than an occasional one.
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurologic features included hypotonia (4/7) and mild to severe psychomotor
      retardation/intellectual disability in all surviving patients.
    explanation: >-
      Gives the count behind the frequency band: every surviving patient in the
      seven-case review, which is above the FREQUENT floor even read conservatively.

- category: Genitourinary
  name: Genitourinary Anomalies
  description: >-
    Part of the malformation pattern rather than a consequence of the metabolic disease,
    and the reason the entry's Congenital Malformation Pattern node names the urogenital
    system. The reported anomalies are structural - the patient in the 2020 report had a
    horseshoe kidney detected antenatally. No frequency is recorded: GeneReviews places
    them in Management rather than in Clinical Characteristics, so the source establishes
    that they occur without stating how often.
  phenotype_term:
    preferred_term: Genitourinary anomaly
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
  evidence:
  - reference: PMID:17853487
    reference_title: Clinical phenotype of lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LS phenotype appears to be characterized by the distinctive association of a
      recognizable pattern of congenital anomalies, involving axial and appendicular
      skeleton, liver, central nervous and urogenital systems, and lysosomal storage.
    explanation: >-
      Places the urogenital system inside the defining malformation pattern, which is
      what makes this a phenotype of the disease rather than an incidental finding.
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment of genitourinary anomalies per nephrologist and/or urologist
    explanation: >-
      A management instruction, so it presupposes the anomalies rather than reporting
      them. Graded PARTIAL for that reason: it corroborates that they occur and says
      nothing about which anomalies or how often.

biochemical:
- name: Plasma lathosterol
  presence: Increased
  context: >-
    The diagnostic analyte. Because the disease is not clinically distinctive at its
    mild end, it is missed unless plasma sterols are measured or SC5D is sequenced.
  biomarker_term:
    preferred_term: lathosterol
    term:
      id: CHEBI:17168
      label: 5alpha-cholest-7-en-3beta-ol
  readouts:
  - target: Lathosterol Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Plasma lathosterol reports the enzymatic block directly, as the substrate
      immediately upstream of it.
    evidence:
    - reference: PMID:30097991
      reference_title: "Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The diagnosis will be missed unless plasma sterols are analysed or relevant
        genes sequenced.
      explanation: >-
        States why this readout is diagnostically necessary rather than merely
        confirmatory.

- name: Plasma total cholesterol
  presence: Normal
  context: >-
    Recorded because it is a negative result that does real work. The entry places
    lathosterolosis one enzymatic step upstream of Smith-Lemli-Opitz syndrome and
    attributes the malformation arm to a cholesterol shortfall, which invites the
    reading that plasma cholesterol should be low. It is not. Total cholesterol was
    normal in the patient whose sterol profile is reported in full, alongside the
    normal 7-dehydrocholesterol that separates this disease from SLOS biochemically.
    The cholesterol claim in the pathophysiology is therefore a developmental and
    cellular one - the sterol available to hedgehog signalling in the embryo - and not
    a claim about a measurable plasma concentration in the patient in front of you.
  evidence:
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal 7‐dehydrocholesterol, total cholesterol, and elevated 8(9)‐cholestenol levels"
    explanation: >-
      The only fully reported sterol profile in the literature. Read against the same
      sentence's elevated lathosterol, it gives the biochemical shape of the disease:
      the precursor piles up while the product stays in range. The normal
      7-dehydrocholesterol in the same list is what distinguishes it from SLOS, where
      that sterol is the one that accumulates.

genetic:
- name: SC5D
  gene_term:
    preferred_term: SC5D
    term:
      id: hgnc:10547
      label: SC5D
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic variants, predominantly missense. Reported alleles include R29Q, G211D,
    Y46S, P160R, D210E and L219S. D210E is a conservative substitution reported in two
    patients who both had relatively mild disease, consistent with residual activity.
    The one reported allele that cannot encode a functional enzyme is the nonsense
    variant Q72*, carried in trans with the missense N71I by a patient whose FibroScan
    read 15.6 kPa against a paediatric normal of 2.5 to 8.5. It anchors the severe end
    of the same residual-activity argument that D210E anchors at the mild end. No
    patient homozygous for a null has been reported, which is consistent with the
    Sc5d-null mouse being stillborn.
  evidence:
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A missense variant, NM_006918.4 (SC5D):c.212A>T;p.(Asn71Ile) and a nonsense
      variant, NM_006918.4(SC5D):c.214C>T; p.(Gln72*) were identified in exon 3 of the
      SC5D gene.
    explanation: >-
      Identifies the one reported allele that is a true null. The entry's
      genotype-phenotype reading rests on residual activity, so an allele with none is
      the informative extreme.
  - reference: PMID:30097991
    reference_title: "Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation leads to a relatively conservative amino acid substitution,
      consistent with some residual enzyme activity.
    explanation: >-
      Links a specific allele's chemistry to the milder phenotype, which is the
      genotype-phenotype logic available in a disease with this few patients.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lathosterolosis is a rare autosomal recessive disorder of cholesterol biosynthesis.
    explanation: States the inheritance pattern.
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      each sib of an affected individual has at conception a 25% chance of being
      affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being
      unaffected and not a carrier
    explanation: >-
      The GeneReviews Genetic Counseling transmission risks, which the inheritance mode
      alone does not give.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Six cases described as of the 2020 report, with the authors noting that milder forms
    are likely to have been missed. A handful of further cases have been reported since.
  evidence:
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only six cases have been described in the literature, but it is possible that a
      number of patients with milder forms of the condition might have been missed.
    explanation: >-
      Gives the case count and, usefully, the authors' own caveat about ascertainment.

treatments:
- name: Avoidance of Hepatotoxic Agents
  description: >-
    GeneReviews lists hepatotoxic medications and chemicals as agents to avoid. This
    carries more weight in this disease than the generic version of the advice: the
    hepatic arm is the dominant morbidity driver, it is the arm liver transplantation
    addresses, and the entry's only pharmacotherapy is a statin - so protecting the
    liver is a management instruction about the same organ the treatment plan turns on.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Progressive Liver Disease
    treatment_effect: MODULATES
    description: >-
      Avoids additional hepatocellular injury on top of the sterol-driven disease; it
      does not act on the biosynthetic block.
  evidence:
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Medications and chemicals that are hepatotoxic
    explanation: The GeneReviews agents-and-circumstances-to-avoid instruction.

- name: Simvastatin
  description: >-
    Inhibits HMG-CoA reductase upstream of the block, reducing flux into the pathway and
    so lowering the accumulated lathosterol. It does not restore the missing enzyme, and
    reported benefit is inconsistent.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: simvastatin
      term:
        id: CHEBI:9150
        label: simvastatin
  target_mechanisms:
  - target: Lathosterol Accumulation
    treatment_effect: INHIBITS
    description: >-
      Reducing proximal cholesterol synthesis lowers the substrate that accumulates
      behind the block.
  - target: Progressive Liver Disease
    treatment_effect: MODULATES
    description: >-
      Improvement in transaminases and fibrosis grade followed the fall in plasma
      lathosterol in the treated patient.
  evidence:
  - reference: PMID:33204591
    reference_title: "Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Simvastatin treatment resulted in lowering of plasma lathosterol levels,
      improvement in transaminitis, and liver fibrosis grade, suggesting that children
      with this condition should be actively treated in order to prevent progression of
      liver disease.
    explanation: >-
      The single most substantive treatment observation available: a biochemical
      response coupled to a histological one.
  - reference: PMID:30097991
    reference_title: "Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Our patient's family did not notice any benefit from treatment with simvastatin.
    explanation: >-
      A contrary observation in a different patient, curated as REFUTE so the entry does
      not present the treatment as uniformly effective.

- name: Surveillance Schedule
  description: >-
    GeneReviews sets a monitoring plan that is unusually specific for a disease with
    this few patients, and its shape follows the mechanism: the ophthalmologic and
    hepatic arms are both progressive and both actionable, so each gets an interval.
    Developmental milestones at every visit; annual ophthalmology; liver enzymes at
    every visit with ultrasound and FibroScan every six months; and a plasma sterol
    profile before starting simvastatin and every one to two months on it. That last
    interval is the one that carries mechanistic weight - it monitors the substrate
    behind the block, because the clinical endpoint the statin is meant to change has
    never been established.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    Deliberately carries no target_mechanisms. Surveillance detects the arms of the
    disease, it does not act on them, and the available treatment_effect values all
    assert a causal action on the target.
  evidence:
  - reference: PMID:38060690
    reference_title: Lathosterolosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      annual ophthalmology evaluation; liver enzymes at each visit; liver imaging
      including ultrasound and FibroScan® every six months or per hepatologist;
      plasma sterol profile before initiating simvastatin and every one to two months
      while on therapy
    explanation: >-
      The GeneReviews Surveillance section verbatim, giving each interval rather than a
      general instruction to follow up.

- name: Liver Transplantation
  description: >-
    Named alongside simvastatin as a potential targeted therapy. It addresses the
    hepatic arm definitively by replacing the affected organ, while doing nothing for
    the malformation or storage arms - which is consistent with the entry's reading
    that those arms have different biochemical causes.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Organ Transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Progressive Liver Disease
    treatment_effect: MODULATES
    description: Replaces the organ in which the hepatic arm manifests.
  evidence:
  - reference: PMID:38060690
    reference_title: "Lathosterolosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Potential targeted therapies include simvastatin (the safety and/or efficacy of
      simvastatin has not been proven in lathosterolosis) and liver transplantation.
    explanation: >-
      The GeneReviews Management section naming both targeted options, and stating
      plainly that simvastatin is unproven.

diagnosis:
- name: Plasma sterol analysis with SC5D confirmation
  description: >-
    Elevated plasma lathosterol establishes the biochemical diagnosis; biallelic SC5D
    variants confirm it. Either is sufficient per GeneReviews, which matters because
    the biochemical route is what catches the mild cases whose clinical picture is
    non-specific.
  evidence:
  - reference: PMID:38060690
    reference_title: "Lathosterolosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of lathosterolosis is established in a proband by identification of
      elevated lathosterol on plasma sterol analysis and/or biallelic pathogenic
      variants in SC5D by molecular genetic testing.
    explanation: The GeneReviews diagnostic criterion, giving both routes.

experimental_models:
- name: SC5D-knockout HepG2 cell line
  experimental_model_type: CELL_LINE
  description: >-
    One of three cholesterol-synthesis enzyme knockouts made in the same hepatocyte
    background, which allows the consequences of accumulating different sterols to be
    compared while holding the pathway and cell type constant.
  publication: PMID:39262789
  modeled_mechanisms:
  - target: Lathosterol Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces lathosterol accumulation in a hepatocyte background and shows it
      produces a distinct transcriptional response from the accumulation of other
      sterols in the same pathway.
    limitations: >-
      A transformed hepatoma line with a complete knockout, so it models neither the
      hypomorphic alleles patients carry nor the developmental context in which the
      malformations arise.
    evidence:
    - reference: PMID:39262789
      reference_title: "Knockouts of CYP51A1, DHCR24, or SC5D from cholesterol synthesis reveal pathways modulated by sterol intermediates."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Surprisingly, KOs of CYP51, DHCR24, and SC5D shared only 9% of differentially
        expressed genes.
      explanation: >-
        Shows that which sterol accumulates, not merely that cholesterol synthesis is
        blocked, determines the cellular response - the point the model exists to make.

animal_models:
- name: Sc5d-null mouse
  species: Mouse
  genotype: Sc5d -/-
  publication: PMID:12812989
  description: >-
    Stillborn with craniofacial and limb patterning defects, and the experiment that
    attributes the malformations to cholesterol deficiency rather than to lathosterol
    accumulation.
  modeled_mechanisms:
  - target: Progressive Liver Disease
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The model is silent on the hepatic arm, and not because the liver was normal -
      because the animals never lived to have one assessed.
    limitations: >-
      Homozygous nulls are stillborn, so hepatic fibrosis, cirrhosis and the response
      to lowering plasma lathosterol cannot be observed in this model at all. A complete
      null is also a more severe lesion than the missense alleles patients carry, and no
      patient homozygous for a null has been reported - so the lethality may itself be
      the mouse reproducing something true, rather than a failure of the model.
    evidence:
    - reference: PMID:12812989
      reference_title: "Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Sc5d (-/-) pups were stillborn, had elevated lathosterol and decreased
        cholesterol levels
      explanation: >-
        Establishes the perinatal lethality that makes the postnatal arm unobservable
        here. It is the substantive basis for the negative claim, as
        FAILS_TO_RECAPITULATE requires.

  - target: Impaired Hedgehog Signalling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the malformation pattern and localizes its cause to the cholesterol
      shortfall.
    limitations: >-
      Homozygous nulls are stillborn, so the model cannot address the postnatal course,
      the hepatic disease, or the cataracts that dominate the milder human phenotype;
      and a complete null is a more severe lesion than the missense alleles patients
      carry.
    evidence:
    - reference: PMID:12812989
      reference_title: "Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Many of the malformations found in Sc5d (-/-) mice are consistent with impaired
        hedgehog signaling, and appear to be a result of decreased cholesterol rather
        than increased lathosterol.
      explanation: >-
        The comparison that makes this model informative for the mechanism rather than
        merely phenotypically similar.

discussions:
- discussion_id: lath_which_biochemical_lesion
  kind: INTERPRETATION
  prompt: >-
    Which of the two biochemical consequences - cholesterol deficiency or lathosterol
    accumulation - causes which part of the phenotype?
  attaches_to:
  - pathophysiology#Deficient Sterol C5-Desaturase Activity
  rationale: >-
    A biosynthetic block produces both a shortage and a surplus, and lathosterolosis is
    unusual in giving evidence that they act on different arms. The Sc5d-null mouse
    attributes the malformations to decreased cholesterol rather than increased
    lathosterol. The storage picture points the other way: it is not a general feature
    of cholesterol synthesis defects, it tracks with the most severe biochemical
    defects, and the hepatic disease improved when plasma lathosterol was lowered
    without the enzyme being restored. The entry models these as separate hypothesis
    groups rather than collapsing them, because a treatment that lowers flux would be
    expected to help the accumulation arm and do nothing for the cholesterol arm - which
    is testable and matters clinically.

- discussion_id: lath_mouse_lethality_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    The Sc5d-null mouse dies before birth. Can a model that never lives a postnatal day
    speak to a disease whose dominant morbidity - liver disease and cataracts - is
    postnatal?
  attaches_to:
  - animal_models#Sc5d-null mouse
  - pathophysiology#Impaired Hedgehog Signalling
  - pathophysiology#Progressive Liver Disease
  rationale: >-
    The mismatch is not a weakness of the mouse, it is a statement about which arm of
    the disease each system can see. Homozygous nulls are stillborn with craniofacial
    and limb patterning defects, which is exactly the window in which the malformation
    arm is decided, and the model earns its place by attributing those defects to
    decreased cholesterol rather than to accumulated lathosterol. But the same
    lethality means it cannot report on the hepatic course, the cataracts, or the
    response to simvastatin, and those are what patients present with and what
    treatment targets.

    The allele is also more severe than the human lesion. Every reported patient
    carries at least one missense allele with some residual activity; no patient
    homozygous for a null has been described. So the mouse models a genotype that may
    not be compatible with human live birth either, which is a further reason its
    silence on the postnatal course is uninformative rather than reassuring.

    The practical consequence for this entry: the mouse supports the cholesterol-driven
    malformation hypothesis and must not be read as evidence about the accumulation
    arm, which is where the entry's two hypothesis groups differ.
  proposed_experiments:
  - experiment_id: lath_hypomorph_mouse
    name: Hypomorphic Sc5d allelic series carried to adulthood
    description: >-
      Knock in a patient missense allele such as D210E or N71I, alone and in trans with
      the null, and follow survivors postnatally for hepatic histology, transaminases,
      lens opacity and plasma sterols. The point is to obtain any model that survives
      the birth the null does not.
    decision_criterion: >-
      Whether a hypomorph with residual activity survives to adulthood and develops
      liver disease and cataracts.
    would_support:
    - pathophysiology#Progressive Liver Disease
    - mechanistic_hypotheses#lath_accumulation_drives_storage
    supporting_outcome:
    - >-
      Survivors developing progressive hepatic fibrosis and lens opacity would give the
      postnatal arm a model for the first time, and would let the statin question be
      asked as an intervention rather than inferred from two case reports.
    would_refute:
    - mechanistic_hypotheses#lath_accumulation_drives_storage
    refuting_outcome:
    - >-
      Survivors with normal liver and lenses despite elevated lathosterol would argue
      the hepatic arm depends on something other than sterol accumulation alone, and
      would weaken the accumulation hypothesis group.

- discussion_id: lath_statin_benefit_conflict
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does simvastatin change outcome in lathosterolosis, or only the sterol numbers?
  attaches_to:
  - treatments#Simvastatin
  rationale: >-
    Two reports disagree. In one, simvastatin lowered plasma lathosterol and was
    accompanied by improvement in transaminases and in fibrosis grade on repeat
    imaging. In another, the family noticed no benefit. Both are single patients, the
    endpoints are not the same, and the second reports absence of perceived benefit
    rather than a measured non-response - so the two are not strictly contradictory.
    With fewer than a dozen patients worldwide a trial is not realistic, which makes
    consistent sterol and liver endpoints across reported cases the only practical route
    to an answer.

    GeneReviews does not adjudicate between the two reports but states the field's
    position plainly: simvastatin is a potential targeted therapy whose safety and
    efficacy have not been proven in this disease. It nonetheless recommends a plasma
    sterol profile before starting and every one to two months on therapy - which is the
    practical shape of the uncertainty, monitoring a biochemical surrogate because the
    clinical endpoint is not established.

notes: >-
  GeneReviews. PMID:38060690 is a dedicated lathosterolosis chapter and is tagged and
  mined across all four sections. The first version of this entry missed it entirely -
  the deep-research report cited the bookshelf ID but not a PMID, and I did not search
  for one. It supplies the diagnostic criterion, liver transplantation as a second
  targeted therapy, the digit anomalies, and the statement that simvastatin's safety
  and efficacy are unproven here.

  Relationship to Smith-Lemli-Opitz syndrome. SC5D acts one step before DHCR7, and
  kb/disorders/Smith-Lemli-Opitz_syndrome.yaml is already curated. The two share the
  hedgehog mechanism and much of the malformation pattern, which is why lathosterolosis
  was initially described as atypical SLOS. They differ in the storage component, which
  is a feature of lathosterolosis and not of SLOS.

  Named Entity Confusion. The preflight passed for this report, with DHCR7 mentioned
  only five times against SC5D's thirty-three. Sentences describing SLOS were still used
  only for pathway context; no SLOS observation is cited here as a lathosterolosis
  finding.

  Ontology correction. The research report offered CHEBI:16833 for lathosterol. That
  term is neurosporene, a carotenoid. The correct term is CHEBI:17168
  (5alpha-cholest-7-en-3beta-ol), whose canonical label is the systematic name rather
  than the common one, so preferred_term carries "lathosterol" for display.

  Evidence for a disease with this few patients. Frequencies are graded against a
  literature of roughly a dozen cases and should be read as "reported in most described
  patients", not as cohort statistics. The prevalence record is deliberately
  CASES_IN_LITERATURE rather than a rate.

📚

References & Deep Research

References

8

PMID:38060690

Lathosterolosis.

No top-level findings curated for this source.

PMID:12189593

Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-delta5-desaturase.

No top-level findings curated for this source.

PMID:12812989

Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency.

No top-level findings curated for this source.

PMID:17853487

Clinical phenotype of lathosterolosis.

No top-level findings curated for this source.

PMID:30097991

Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties.

No top-level findings curated for this source.

PMID:33204591

Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature.

No top-level findings curated for this source.

PMID:36607840

Lathosterolosis: a rare cholesterol metabolism disorder with a wide range of clinical variability.

No top-level findings curated for this source.

PMID:39262789

Knockouts of CYP51A1, DHCR24, or SC5D from cholesterol synthesis reveal pathways modulated by sterol intermediates.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Lathosterolosis: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 21 citations 2026-08-27T18:57:25.698580

Lathosterolosis: Comprehensive Research Report

1. Disease Information

Overview. Lathosterolosis (LATHOS) is an ultra-rare, autosomal recessive inborn error of post-squalene cholesterol biosynthesis caused by deficiency of sterol-C5-desaturase (lathosterol oxidase), which catalyzes the penultimate step of cholesterol synthesis — dehydrogenation of lathosterol to 7-dehydrocholesterol (7-DHC). It presents as a multiple-congenital-anomaly/intellectual-disability syndrome with a phenotype that overlaps substantially with Smith-Lemli-Opitz syndrome (SLOS), the biosynthetic-pathway neighbor caused by 7-dehydrocholesterol reductase (DHCR7) deficiency one step downstream (Wikipedia; PMC3897790).

Key identifiers: - OMIM disease: #607330 (LATHOS) (OMIM) - OMIM gene: 602286 (SC5D, formerly SC5DL) (OMIM) - Orphanet: ORPHA:46059 (Orphanet) - MONDO: MONDO:0011816 - MedGen: C1846421 - Gene location: SC5D, 11q23.3 (per GeneReviews; some sources cite 11q23.3-q24.1) - Synonyms/alt names:* Sterol-C5-desaturase deficiency; SC5D deficiency; lathosterol oxidase deficiency; 3β-hydroxysteroid-Δ5-desaturase deficiency

Nature of evidence base. All information derives from aggregated case reports (individual-patient case series and reviews), not large disease registries or EHR aggregation — the condition is defined almost entirely by a handful of published cases plus a knockout mouse model and, more recently, cell-line (CRISPR knockout) mechanistic work.

Sources: OMIM #607330, GeneReviews NBK597809, Orphanet ORPHA:46059, GARD

2. Etiology

Primary cause. Biallelic pathogenic variants in SC5D (11q23.3), encoding lathosterol oxidase (EC 1.14.19.20), an ER-membrane iron-dependent oxidoreductase of the sterol desaturase family. Loss of enzymatic activity blocks the lathosterol→7-DHC step, causing lathosterol accumulation with variably reduced downstream cholesterol synthesis (GeneCards SC5D; Reactome R-HSA-195662).

Genetic risk factors. Purely monogenic/Mendelian — no known susceptibility loci or modifier genes have been reported; the extreme rarity (fewer than a dozen molecularly confirmed patients worldwide as of 2023) precludes genotype-phenotype correlation studies. Reported pathogenic alleles include: - p.Arg29Gln (R29Q) and p.Gly211Asp (G211D) — original index patient, compound heterozygous (Brunetti-Pierri et al. 2002, PMID: 12189593) - p.Lys148Glu (K148E) and p.Asp210Glu (D210E) — Rossi et al. 2007 fetal case, PMID: 17853487 - p.Pro160Arg (c.479C>G) and p.Asp210Glu (c.630C>A) — Anderson et al. 2019, PMID: 30097991 - p.Asn71Ile (c.212A>T) and p.Gln72* nonsense (c.214C>T) — Yaplito-Lee/Verma et al. 2020, PMID: 33204591 - p.Leu219Ser (biallelic missense, c.656T>C) — Söbü et al. 2023, PMID: 36607840

Population frequency data are sparse; individual reported SC5D variants appear in gnomAD only as ultra-rare singletons (e.g., allele frequency ~7×10⁻⁶ for specific alleles such as rs104894297), consistent with a disease affecting well under 1 in 1,000,000 births, though under-ascertainment of mild cases is suspected.

Environmental/infectious risk factors. None identified — this is a pure inborn metabolic error with no known environmental trigger, teratogen interaction, or infectious contribution.

Protective factors. None reported (genetic or environmental); no protective alleles or exposures are documented.

Gene-environment interaction. Not applicable/undocumented; disease expressivity variation (from prenatal-lethal to mild adult-surviving phenotypes) is presumed related to residual enzyme activity from the specific allele combination rather than to environmental modulation.

Sources: GeneReviews NBK597809, PubMed 12189593, 17853487, 30097991, 33204591, 36607840

3. Phenotypes

Lathosterolosis spans a continuum from prenatal-lethal multiple-malformation syndrome to a mild, largely neurodevelopmental/ophthalmologic phenotype recognized only in later childhood. GeneReviews summarizes: "global developmental delays, intellectual disability, microcephaly, characteristic facial features... bilateral cataracts; digit anomalies... and variable liver disease ranging from asymptomatic elevation of liver enzymes to cirrhosis and liver failure" (NBK597809).

Craniofacial

Microcephaly (congenital; suggested term: HP:0000252 Microcephaly)
Bitemporal narrowing (HP:0000341)
Sloping/narrow forehead (HP:0000340)
Ptosis (HP:0000508)
Puffy cheeks
Micrognathia (HP:0000347)
Epicanthal folds (HP:0000286)
Downslanting palpebral fissures (HP:0000494)
Anteverted nares (HP:0000463)
Broad/bulbous nasal tip (HP:0000414)
Long philtrum (HP:0000343)
High-arched palate (HP:0000218)
Cleft palate — reported in the mouse model and general SC5D-mutant craniofacial literature, but notably absent in the human index case series reviewed in PMC3897790, distinguishing it somewhat from SLOS

Ocular

Bilateral (or unilateral) posterior cataracts (HP:0000519/HP:0000665) — a relatively distinguishing feature versus SLOS, present in most surviving cases including the "relatively mild" Anderson et al. 2019 patient, who presented at age 5 with cataracts and learning difficulties and had a full-scale IQ of 64 at age 11 (PubMed 30097991)
Microcornea (HP:0000482)
Corneal stromal opacity (HP:0007957)

Neurological

Global developmental delay / intellectual disability (HP:0001263/HP:0001249) — present in essentially all reported living patients, variable severity from mild learning difficulty to severe delay
Hypotonia (HP:0001252) — in most cases
Seizures (HP:0001250) — reported in the 2023 case (8-month-old with seizures and brain atrophy, PMID: 36607840)
Cerebellar cortical atrophy, cerebral calcification, Chiari malformation, myoclonus — reported in the aggregate GARD symptom list

Skeletal/limb

Postaxial polydactyly (upper and/or lower limb, predominantly feet) (HP:0100259/HP:0012470)
Bilateral 2nd–3rd or 2nd–4th toe syndactyly (HP:0001770)
Bilateral clubfoot/talipes (HP:0001762)
5th finger clinodactyly (HP:0030084)

Hepatic

Elevated liver transaminases (asymptomatic to marked): e.g., ALT 321–364 IU/L, GGT 317–414 U/L in the Verma/Yaplito-Lee case (PMC7653246)
Progressive fibrosis to cirrhosis and liver failure in severe cases (Fibroscan 15.6 kPa vs. normal 2.5–8.5 kPa in one case)
This spectrum is the principal severity-determining organ system: prognosis tracks liver involvement more than any other feature

Other/systemic

Failure to thrive (HP:0001508)
Kidney anomalies (HP:0000077)
Hearing impairment (HP:0000365)
Thrombocytopenia (HP:0001873)
Lysosomal/mucolipidosis-like storage — lamellar cytoplasmic inclusions on ultrastructural/histopathological exam (Rossi et al. 2007, PMID: 17853487), a distinctive secondary storage phenomenon
Neural tube defect and prenatal liver involvement reported in a fetal case (Rossi et al. 2007)

Onset: Congenital/neonatal for the classic severe phenotype (recognizable pattern of malformation at birth); later childhood presentation (age ~5–8 years, via cataracts/learning difficulty) in mild cases — indicating a true clinical spectrum rather than a single fixed presentation.

Progression: Variable — stable/mild in some, progressive hepatic fibrosis/cirrhosis in others. Neurodevelopmental impairment appears nonprogressive once established but is present from early childhood in nearly all cases.

Frequency (population-level): With only ~7 molecularly confirmed reported patients as of the most recent GeneReviews update, per-symptom frequency percentages are not statistically meaningful; qualitative frequency terms ("most," "all reported," "variable") are used throughout the literature instead of numeric percentages.

Quality of life impact: Not formally studied with validated instruments (no EQ-5D/SF-36 data identified); qualitatively, developmental/intellectual disability and progressive liver disease are the dominant drivers of long-term burden, with milder patients able to reach adulthood.

Sources: GeneReviews NBK597809, Orphanet ORPHA:46059, PMC3897790, PMC7653246, GARD, PMIDs 12189593, 17853487, 24142275, 30097991, 31259789, 33204591, 36607840

4. Genetic/Molecular Information

Causal gene: SC5D (HGNC:10547; formerly SC5DL), OMIM *602286, chromosome 11q23.3, encoding lathosterol oxidase / sterol-C5-desaturase (UniProt O75845).

Variant spectrum: All reported disease alleles to date are missense or one nonsense variant, in compound-heterozygous or (rarely) homozygous configuration — no large deletions/duplications have been identified by deletion/duplication analysis in the diagnosed cases (per GeneReviews). Representative pathogenic variants (NM_006918 transcript numbering where given):

Study	Variant 1	Variant 2	PMID
Brunetti-Pierri 2002 (index case)	p.R29Q	p.G211D	12189593
Rossi 2007 (fetal case)	p.K148E	p.D210E	17853487
Anderson 2019 (mild case)	c.479C>G p.(P160R)	c.630C>A p.(D210E)	30097991
Yaplito-Lee/Verma 2020	c.212A>T p.(N71I)	c.214C>T p.(Q72*)	33204591
Söbü 2023	c.656T>C p.(L219S)	(biallelic, homozygous)	36607840

Note: p.D210E recurred independently in two unrelated families (Rossi 2007 and Anderson 2019), suggesting it may be a recurrent or mutational-hotspot allele, though this has not been formally established as a founder variant.

Variant classification: Per ClinVar, several SC5D variants are submitted with classifications ranging from pathogenic to variants of uncertain significance (e.g., RCV000401412, RCV000340453); given the extreme rarity of ascertained cases, ACMG/AMP classification confidence intervals are wide, and functional/fibroblast enzyme assay confirmation (elevated lathosterol, blocked conversion to 7-DHC) remains the most robust classification evidence.

Population/allele frequency: Individual SC5D pathogenic alleles are essentially private, ultra-rare variants in gnomAD (allele frequency ~7×10⁻⁶ reported for specific alleles such as rs104894297 and rs1313359281) — consistent with autosomal recessive disease well below 1:1,000,000 birth prevalence, though possible underascertainment of milder cases is repeatedly flagged in the literature.

Somatic vs. germline: Exclusively germline; no somatic/mosaic cases reported.

Functional consequences: Missense variants are presumed to reduce or abolish lathosterol-oxidase catalytic activity (loss-of-function mechanism), confirmed functionally via fibroblast sterol profiling (elevated lathosterol, near-absent conversion to 7-DHC) rather than by direct enzymatic assay of recombinant protein in most reports.

Modifier genes: None identified.

Epigenetics/chromosomal abnormalities: No epigenetic or large chromosomal (aneuploidy/translocation) mechanism has been reported; disease is exclusively due to point/small-indel-type coding variants in SC5D.

Molecular mechanism (protein level): SC5D/lathosterol oxidase is an ER-membrane, iron-binding, C-5(6) sterol desaturase (EC 1.14.19.20) that introduces a Δ5,6 double bond into lathosterol to yield 7-dehydrocholesterol — the penultimate step of the Kandutsch–Russell branch of cholesterol biosynthesis, immediately upstream of the DHCR7-catalyzed step defective in Smith-Lemli-Opitz syndrome (GeneCards; Reactome R-HSA-195662).

Suggested ontology bindings: HGNC:10547 (SC5D); GO:0006695 (cholesterol biosynthetic process); GO:0016132 (brassinosteroid — n/a) — more precisely GO:0000247 (C-5 sterol desaturase activity) and GO:0000253 (3-keto-sterol reductase — n/a, adjacent pathway step); protein term CHEBI:17168 (lathosterol) → CHEBI:17759 (7-dehydrocholesterol) → CHEBI:16113 (cholesterol).

Sources: OMIM *602286, GeneCards SC5D, UniProt O75845, Reactome R-HSA-195662, PMIDs 12189593, 17853487, 30097991, 33204591, 36607840

5. Environmental Information

Lathosterolosis is a purely monogenic inborn error of metabolism; no environmental factors (toxins, occupational exposures), lifestyle factors, or infectious agents have been implicated as causal or risk-modifying in any published report. This section is essentially not applicable for this disease — a search of CTD/TOXNET-type literature and the primary case reports returned no gene-environment or exposure findings.

6. Mechanism / Pathophysiology

Molecular pathway

SC5D acts in the post-squalene, post-lanosterol segment of the Kandutsch–Russell cholesterol biosynthetic pathway (KEGG map00100, "Steroid biosynthesis"), immediately downstream of lanosterol 14α-demethylase (CYP51A1) and upstream of 7-dehydrocholesterol reductase (DHCR7). Loss of SC5D activity blocks lathosterol → 7-dehydrocholesterol conversion, causing: 1. Substrate accumulation: marked elevation of lathosterol (and, to lesser degree, its metabolites 24-dehydrolathosterol and zymostenol) in plasma, fibroblasts, and tissues. 2. Product deficiency: reduced flux to 7-DHC and downstream cholesterol, though — importantly — total plasma cholesterol is typically normal, distinguishing lathosterolosis biochemically from SLOS, where cholesterol is characteristically low (PMC3897790).

Causal chain — from initial defect to clinical manifestation

Loss-of-function SC5D variant → reduced/absent lathosterol oxidase activity → lathosterol accumulation + reduced distal-pathway sterol flux → (a) direct lathosterol/intermediate cytotoxicity and lysosomal storage-like lamellar inclusions; (b) impaired cholesterol-dependent Hedgehog signaling during embryogenesis (cholesterol is required for post-translational modification and signaling range of Sonic hedgehog, SHH) → limb patterning defects (polydactyly, syndactyly), craniofacial malformation, and CNS developmental anomalies; (c) hepatocyte lipid/sterol stress → progressive liver injury/fibrosis/cirrhosis.

The Krakowiak et al. 2003 mouse knockout study (PMID: 12812989) established that malformations in Sc5d-null mice — stillbirth, cleft palate, micrognathia, and limb defects — occur despite normal/near-normal residual cholesterol in some tissues, arguing that reduced cholesterol availability during embryogenesis, rather than lathosterol toxicity per se, drives the malformation phenotype, while intracellular sterol/lathosterol storage represents an additional, largely postnatal pathology (a distinct storage-disease-like component).

Cellular/mechanistic detail from recent (2024) work

A CRISPR-Cas9 SC5D-knockout HepG2 hepatoma cell model (part of a broader CYP51A1/DHCR24/SC5D knockout comparison, PMC11387598, 2024) found: - ~100-fold accumulation of lathosterol, with secondary elevation of 24-dehydrolathosterol (~10-fold) and zymostenol (~6-fold) - Slower proliferation and G0/G1 cell-cycle arrest, especially under lipid-depleted conditions - Activation of ER-stress (XBP1) and SREBF1/2 (cholesterol/lipid-sensing) transcriptional programs, with CCND1/EGR1 modulation of the G1/S transition - Upregulated fatty-acid metabolism and PPAR-signaling genes (FADS2, ELOVL6, HSD17B12, CYP2J2), suggesting a compensatory metabolic shift when sterol synthesis is blocked

This is the most direct recent (2024) molecular-mechanism evidence and is classified as IN_VITRO/cell-line evidence — it models a plausible hepatocellular contribution to the clinical liver phenotype but has not been directly confirmed in patient liver tissue.

Immune/tissue-damage mechanisms

No autoimmune or classical inflammatory mechanism is implicated. Tissue injury appears driven by (1) developmental morphogen (Hedgehog) signaling disruption during embryogenesis and (2) chronic sterol/lipid metabolic stress in postnatal hepatocytes leading to fibrosis.

Suggested ontology terms

GO:0006695 cholesterol biosynthetic process
GO:0016125 sterol metabolic process
GO:0007224 smoothened signaling pathway (Hedgehog pathway proxy)
GO:0034976 response to endoplasmic reticulum stress
CL:0000182 hepatocyte
CL:0000586 germ cell / CL:0000047 neural stem cell (embryonic limb/CNS morphogenesis context — refine per specific node)
UBERON:0002107 liver; UBERON:0002101 limb; UBERON:0000411 vertebrate limb bud

Sources: PMC3897790, Krakowiak et al. 2003 PMID 12812989 (Human Molecular Genetics), PMC11387598 (2024, iScience), Reactome R-HSA-195662

7. Anatomical Structures Affected

Organ level (primary): - Liver — the dominant morbidity/mortality-determining organ; ranges from asymptomatic transaminitis to cirrhosis/liver failure (UBERON:0002107) - Eye/lens — cataracts (UBERON:0000965 lens of camera-type eye) - CNS/brain — developmental delay, seizures, cerebellar atrophy, calcifications, Chiari malformation (UBERON:0000955 brain; UBERON:0002037 cerebellum) - Skeletal system, especially craniofacial and limb — micrognathia, malformed facies, polydactyly/syndactyly, clubfoot (UBERON:0001456 face; UBERON:0002101 limb) - Kidney — structural anomalies (UBERON:0002113) - Ear — hearing impairment (UBERON:0001690)

Secondary/complication-level involvement: Hematologic (thrombocytopenia), consistent with hepatic synthetic/portal-hypertension sequelae in severe cases.

Body systems: Hepatobiliary, skeletal/musculoskeletal, ophthalmologic, nervous, urogenital, integumentary (in the mouse model — skin barrier).

Tissue/cell level: - Hepatocytes (CL:0000182) — lipid/sterol storage, fibrosis - Lens epithelial cells — cataract formation - Chondrocytes/osteoblasts in limb bud mesenchyme — polydactyly/limb patterning (Hedgehog-dependent) - Neural progenitor cells — CNS developmental anomalies

Subcellular level: - Endoplasmic reticulum (site of SC5D enzymatic activity; GO:0005789 ER membrane) - Lysosome-like storage vesicles — lamellar inclusions on electron microscopy (mucolipidosis-like storage), suggesting secondary lysosomal/autophagic pathway involvement (GO:0005764 lysosome)

Localization/laterality: Cataracts and limb anomalies reported as both unilateral and bilateral across cases; no consistent lateralization pattern.

Sources: GeneReviews NBK597809, PMC3897790, Rossi et al. 2007 PMID 17853487

8. Temporal Development

Onset: Congenital for the classic multiple-malformation phenotype (recognizable at birth or prenatally via ultrasound anomalies in the most severe/fetal cases); however, milder patients are first recognized later — bilateral cataracts and learning difficulty identified around age 5 years in the Anderson et al. 2019 patient, and seizures/brain atrophy noted at 8 months in the Söbü et al. 2023 patient.

Onset pattern: Generally insidious for the neurodevelopmental/hepatic components; can be acute in fetal/perinatal lethal presentations (stillbirth in the mouse model and presumably in the most severe human end of the spectrum, though a live-born severely affected human case has not been separately documented as stillborn in the literature reviewed here — the mouse null is embryonic/perinatal lethal).

Progression: - Liver disease is the most clearly progressive feature — documented natural progression from elevated transaminases to fibrosis (Fibroscan-confirmed) to cirrhosis/liver failure in the most severe reported cases, with two cases requiring/undergoing liver transplantation (per GeneReviews management section, citing Ho et al. 2014 and related cases). - Neurodevelopmental impairment is present from early life and is not clearly progressive once established (static encephalopathy-like course), though seizures may emerge later. - With simvastatin treatment, biochemical (lathosterol) normalization and histologic (fibrosis) improvement have been documented over a ~2-year follow-up in one case (PMC7653246).

Disease course pattern: Chronic, with a spectrum from static/stable (mild cases reaching adulthood) to progressive hepatic deterioration (severe cases).

Critical periods: Embryonic/fetal period is critical for the Hedgehog-signaling-dependent malformation component (limb, craniofacial, neural tube); this window is not modifiable postnatally. Early childhood appears to be a window where statin therapy has been trialed with apparent biochemical and modest developmental benefit, though causality is unproven (single-patient experience, per GeneReviews).

Sources: GeneReviews NBK597809, PMC7653246, PMID 36607840

9. Inheritance and Population

Epidemiology: Extremely rare — GeneReviews states only seven individuals have been molecularly/biochemically confirmed and reported in the literature to date (as of its most recent update), with likely underdiagnosis of milder phenotypes given nonspecific presentation (learning difficulty + cataracts). No formal prevalence or incidence estimate (cases per 100,000) exists; the disease is best characterized as "ultra-rare, case-report-level" rather than registry-quantified.

Inheritance pattern: Autosomal recessive (HP:0000007). For carrier (heterozygous) × carrier matings: 25% affected, 50% carrier, 25% unaffected/non-carrier per pregnancy (Mendelian expectation, per GeneReviews).

Penetrance: Full penetrance is presumed for biallelic loss-of-function combinations causing the classic severe phenotype; however, the existence of "relatively mild" cases identified only via cataracts/learning difficulty in later childhood suggests substantial variable expressivity depending on residual enzyme activity from specific missense combinations (e.g., hypomorphic alleles like p.D210E, recurrent across two unrelated mild-to-moderate cases).

Expressivity: Highly variable — from prenatal/perinatal-lethal multiple-malformation syndrome to a mild neurodevelopmental/ophthalmologic phenotype recognized in later childhood; likely genotype-dependent (missense vs. nonsense, position/severity of the substitution) though formal genotype-phenotype correlation has not been statistically established given small case numbers.

Genetic anticipation: Not applicable — not a repeat-expansion disorder.

Germline mosaicism, founder effects: Not documented in the literature reviewed; p.D210E's recurrence in two unrelated families (Rossi 2007, Anderson 2019) could suggest a mutational hotspot, but no formal founder-haplotype study has been published.

Consanguinity: Not specifically flagged as a major risk factor across the reported cases reviewed (most cases were compound heterozygous, implying non-consanguineous or at least non-obviously consanguineous unions in most families, though this is not exhaustively confirmed here).

Carrier frequency: Not established at a population level; individual known pathogenic SC5D alleles are present in gnomAD only as private/ultra-rare variants (allele frequency on the order of 10⁻⁶), consistent with a carrier frequency far below that of common recessive conditions.

Population demographics: No specific ethnic or geographic enrichment has been reported; cases have been described in multiple ancestries/countries (Italy — Brunetti-Pierri/Rossi groups; UK — Anderson et al.; Hong Kong — Ho et al.; USA — Prasun et al.; Australia — Yaplito-Lee/Verma et al.; Turkey — Söbü et al.), suggesting pan-ethnic occurrence without an identified founder population.

Sex ratio: No consistent sex predominance reported across the small case series (both male and female patients described).

Sources: GeneReviews NBK597809, Orphanet ORPHA:46059

10. Diagnostics

Clinical/biochemical tests

Plasma sterol profiling (GC/MS) — the primary diagnostic biochemical test: markedly elevated lathosterol (reported values as high as 54–82 μmol/L vs. normal <10–18 μmol/L depending on the reference lab), with normal or low 7-dehydrocholesterol and normal total cholesterol — this normal-cholesterol pattern is a key distinguishing feature from SLOS.
Fibroblast sterol analysis — demonstrates block in lathosterol→7-DHC conversion; filipin staining may show a "variant" cholesterol storage pattern.
Liver enzymes (ALT, GGT) — elevated in hepatic involvement; used for both diagnosis and longitudinal monitoring.
Fibroscan/elastography — used to quantify and monitor hepatic fibrosis (e.g., 15.6 kPa vs. normal 2.5–8.5 kPa in one reported case).
Histopathology/electron microscopy — lamellar cytoplasmic inclusions (mucolipidosis-like lysosomal storage pattern) on liver or other tissue biopsy.

Genetic testing

Single-gene SC5D sequencing or multigene sterol-biosynthesis-disorder panel (including SC5D, DHCR7, DHCR24, MSMO1, CYP51A1, LSS, and related genes) or exome/genome sequencing — GeneReviews states sequence analysis detects essentially all known pathogenic variants; no deletion/duplication (CNV) pathogenic variant has yet been identified in this gene for this disease.
Chromosomal microarray/karyotype: not informative (this is a point-variant, not a CNV, disorder).

Differential diagnosis

The central differential is Smith-Lemli-Opitz syndrome (SLOS, DHCR7 deficiency), sharing developmental delay, microcephaly, and facial dysmorphism, but distinguishable because: - Cataracts and liver disease are common in lathosterolosis but relatively uncommon in SLOS - Cholesterol is typically low in SLOS but normal in lathosterolosis - 7-DHC is markedly elevated in SLOS but normal in lathosterolosis - Cleft palate is common in SLOS but was absent across the reviewed lathosterolosis case series

Other differentials in the sterol-biosynthesis-disorder category: squalene synthase deficiency, lanosterol synthase deficiency, desmosterolosis (DHCR24 deficiency), CHILD syndrome (NSDHL), and CK syndrome/other X-linked sterol disorders (per GeneReviews).

Screening

No newborn screening or population carrier-screening program exists for this ultra-rare condition; diagnosis is case-by-case based on clinical suspicion (malformation pattern, cataracts + developmental delay + liver disease) followed by targeted sterol/molecular testing.

Sources: GeneReviews NBK597809, PMC3897790, PMC7653246

11. Outcome/Prognosis

Survival/mortality: No formal survival statistics exist given the tiny case count. GeneReviews notes prognosis depends heavily on liver disease severity: individuals with mild hepatic involvement may reach adulthood, while those with progressive cirrhosis/liver failure have poorer outcomes; two reported cases underwent (or were candidates for) liver transplantation, after which plasma lathosterol normalized and quality of life reportedly improved.

Morbidity: Chronic developmental/intellectual disability is near-universal among survivors; hepatic morbidity (fibrosis/cirrhosis) is the dominant driver of serious long-term complications and mortality risk.

Prognostic factors: Degree of residual SC5D enzymatic activity (genotype-dependent), severity/timing of liver disease onset, and response to statin therapy appear to be the principal modifiers of outcome, though this is based on very limited case experience rather than statistically validated prognostic modeling.

Complications: Cirrhosis, liver failure (requiring transplantation in severe cases), thrombocytopenia (likely secondary to portal hypertension/hypersplenism in advanced liver disease), seizures, hearing impairment.

Sources: GeneReviews NBK597809, PMC7653246

12. Treatment

Pharmacotherapy

Simvastatin (HMG-CoA reductase inhibitor), dosed roughly 0.2–1 mg/kg/day, is the principal reported targeted therapy. Rationale: inhibiting upstream HMG-CoA reductase reduces overall flux through the sterol pathway, thereby lowering substrate (lathosterol) accumulation.
Ho et al. 2014: simvastatin normalized blood lathosterol and was associated with improved neurodevelopmental profile (PMID 24142275).
Yaplito-Lee/Verma et al. 2020 (PMC7653246): simvastatin 5→10 mg/day (0.2→0.4 mg/kg/day) normalized plasma lathosterol, reduced ALT (364→69 IU/L) and GGT (414→136 U/L) over 2 years, and improved liver fibrosis on Fibroscan (15.6→12.8 kPa) — the most detailed documented biochemical/hepatic response to date.
Prasun et al. 2019: first documented therapeutic statin trial in this specific patient, reducing lathosterol from 81.6 to 7.2 μmol/L within 4 weeks at 1 mg/kg/day, with developmental quotient improvement from 55 to 64 (causality uncertain, single-case).
GeneReviews explicitly notes: efficacy remains unproven in controlled trials — all evidence is single-patient, uncontrolled, observational.
Creatine kinase monitoring is used for statin-related myopathy surveillance in the pediatric off-label use context.

Advanced/definitive therapy

Liver transplantation — used in at least two reported cases with progressive/severe hepatic failure, resulting in normalization of plasma lathosterol (since the graft liver has functional SC5D) and reported improvement in quality of life. This is the only "curative" intervention for the hepatic component but does not address extrahepatic (CNS, skeletal) manifestations, which are fixed by the time of any intervention.
No gene therapy, enzyme replacement, RNA-based therapy, or cell therapy has been developed or trialed for this condition — it remains an off-label small-molecule (statin) management approach plus organ transplantation for end-stage liver disease.

Supportive/rehabilitative care

Developmental/early intervention therapy for intellectual disability
Ophthalmology management (cataract surgery as needed) — suggested NCIT term: NCIT:C15329 (Surgical Procedure) for cataract extraction
Orthopedic intervention for limb anomalies (e.g., polydactyly correction, clubfoot management) — NCIT:C16186 (Orthopedic Surgical Procedure)
Hepatology coordination/monitoring
Educational support services

Surveillance (per GeneReviews management guidelines)

Developmental milestone assessment at each visit
Annual ophthalmology evaluation
Liver enzymes at each visit; liver imaging every 6 months

Suggested treatment ontology terms

NCIT:C15986 Pharmacotherapy (simvastatin) with therapeutic_agent → CHEBI:9150 simvastatin
NCIT:C15289 Organ Transplantation (liver transplantation)
NCIT:C15302 Physical Therapy / NCIT:C121351 Occupational Therapy (developmental support)
NCIT:C15240 Genetic Counseling

Sources: GeneReviews NBK597809, PMC7653246, PMID 24142275, PMID 31259789 (Prasun et al., "Lathosterolosis: An Extremely Rare Inherited Condition Associated With Progressive Liver Disease")

13. Prevention

Primary prevention: None possible for de novo occurrence given the recessive Mendelian mechanism; no vaccination, risk-factor modification, or environmental intervention applies (this is not an environmentally modifiable disease).

Secondary prevention / screening: - Carrier testing for at-risk family members once familial pathogenic variants are identified (per GeneReviews genetic counseling section) - Prenatal diagnosis (chorionic villus sampling/amniocentesis with molecular testing) and preimplantation genetic testing (PGT) are technically available once the familial SC5D variants are known - No population-based newborn or carrier screening program exists given the extreme rarity

Genetic counseling: Standard autosomal recessive counseling — 25% recurrence risk per pregnancy for carrier couples; GeneReviews explicitly recommends DNA banking of affected individuals' samples given the likelihood that testing methodology will continue to improve for this rare condition.

Tertiary prevention: Early biochemical/molecular diagnosis followed by simvastatin initiation and close hepatology surveillance is the closest analog to tertiary prevention (aiming to slow or prevent progression to cirrhosis), though as noted, efficacy is not established in controlled trials.

Sources: GeneReviews NBK597809

14. Other Species / Natural Disease

No naturally occurring veterinary/companion-animal or wildlife cases of SC5D-deficiency disease have been reported in the literature reviewed (no OMIA entry or veterinary case series identified). All non-human data derive from engineered laboratory models (see Section 15) rather than natural disease.

15. Model Organisms

Mouse (Mus musculus) — primary model

Sc5d knockout mouse (targeted homologous recombination in ES cells; Krakowiak et al. 2003, PMID 12812989, Human Molecular Genetics): Sc5d⁻/⁻ pups are stillborn, with micrognathia, cleft palate, and limb-patterning defects (postaxial polydactyly), plus elevated tissue/serum lathosterol and reduced cholesterol.
Phenotype recapitulation: High fidelity for the craniofacial/limb malformation spectrum (micrognathia, abnormal nasal structure, cleft palate, postaxial polydactyly), and for the core biochemical signature (elevated lathosterol, reduced cholesterol). The paper's central conclusion — that malformations are driven more by reduced cholesterol (impairing Hedgehog signaling) than by lathosterol accumulation per se — was a key mechanistic insight informing understanding of the human disease and of SLOS more broadly.
Limitation: The mouse model is embryonic/perinatal lethal (stillborn), so it cannot model the postnatal, milder end of the human clinical spectrum (later-childhood cataracts/learning-difficulty presentation) or the progressive liver disease course seen in surviving human patients — this is a clear human-model fidelity gap between the severe (embryonic-lethal, mouse-modeled) and mild (postnatally surviving, human-only) ends of the phenotypic spectrum.
A related keratinocyte-specific Sc5d-deleted mouse model was used to study attenuation of UVR-induced vitamin D3 synthesis in skin, reflecting the enzyme's additional dermatologic/vitamin-D-synthesis role (a tissue-specific, disease-adjacent application rather than a direct disease model) — Sigma-Aldrich/ScienceDirect summary.

Cell-based / in vitro models

CRISPR-Cas9 SC5D-knockout HepG2 hepatoma cell line (2024, PMC11387598) — models cholesterol-pathway disruption at the hepatocyte level; recapitulates lathosterol/24-dehydrolathosterol/zymostenol accumulation and reveals downstream ER-stress (XBP1), SREBF, cell-cycle, and fatty-acid-metabolism pathway perturbations. This is the most direct available cellular model of the hepatic component of human disease, though it has not been benchmarked against patient liver tissue for fidelity.
Patient-derived skin fibroblasts (used diagnostically across essentially all reported human cases) also serve as a natural "disease-in-a-dish" model confirming the enzymatic block (lathosterol accumulation, blocked 7-DHC synthesis) and abnormal filipin-staining cholesterol storage pattern.

Applications

The mouse model has been central to (1) confirming SC5D as the causal gene in parallel with human genetic discovery, (2) establishing the "cholesterol deficiency vs. lathosterol toxicity" mechanistic question central to understanding both lathosterolosis and SLOS pathogenesis via Hedgehog signaling, and (3) providing embryonic material for developmental-biology dissection of limb/craniofacial patterning defects. The HepG2 knockout model is beginning to open a route to studying hepatocyte-intrinsic disease mechanisms and potential pharmacologic (e.g., statin) rescue at a cellular level.

Sources: Krakowiak et al. 2003, PMID 12812989; PMC11387598 (2024); ScienceDirect keratinocyte Sc5d model

Summary Table — Key Ontology Term Suggestions for KB Curation

Category	Suggested term
Disease	MONDO:0011816; OMIM:607330; ORPHA:46059
Gene	hgnc:10547 (SC5D)
Molecular function	GO:0000247 (C-5 sterol desaturase activity)
Biological process	GO:0006695 (cholesterol biosynthetic process); GO:0007224 (smoothened/Hedgehog signaling)
Cellular component	GO:0005789 (endoplasmic reticulum membrane)
Chemicals	CHEBI:17168 (lathosterol); CHEBI:17759 (7-dehydrocholesterol); CHEBI:16113 (cholesterol); CHEBI:9150 (simvastatin)
Phenotypes (HP)	HP:0000252 microcephaly; HP:0000519/0000665 cataract; HP:0001263 global developmental delay; HP:0100259/0012470 postaxial polydactyly; HP:0001770 syndactyly; HP:0001762 talipes; HP:0000347 micrognathia; HP:0001250 seizure
Cell types	CL:0000182 hepatocyte
Anatomy	UBERON:0002107 liver; UBERON:0000965 lens; UBERON:0002101 limb; UBERON:0001456 face
Treatment	NCIT:C15986 Pharmacotherapy; NCIT:C15289 Organ Transplantation

Notes on Evidence Gaps for Curation

No large-scale registry or systematic-review-level prevalence data exist — all epidemiology is case-report aggregation (n≈7–10 reported patients total worldwide).
No controlled treatment trial — simvastatin efficacy claims all derive from single-patient, uncontrolled observational reports; this should be flagged explicitly if curated (derivation_basis/evidence caveats).
Human-model mismatch: the Sc5d-null mouse is embryonic/perinatal lethal and does not model the surviving, milder human phenotype spectrum — a good candidate for a HUMAN_MODEL_MISMATCH discussion if curated per the dismech schema conventions.
Full-text access to several primary PMIDs (12189593, 12812989, 24142275, 17853487, 31259789, 30097991) was limited by publisher access barriers during this research; abstracts were retrieved via Europe PMC and secondary reviews (GeneReviews, PMC3897790, PMC7653246) that quote and cite them — exact-quote verification against the primary abstract/full text is still recommended before using any of the above as curated evidence snippets.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	11
On topic	10
Off topic	0

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Deep Research

Lathosterolosis: Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Craniofacial

Ocular

Neurological

Skeletal/limb

Hepatic

Other/systemic

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Molecular pathway

Causal chain — from initial defect to clinical manifestation

Cellular/mechanistic detail from recent (2024) work

Immune/tissue-damage mechanisms

Suggested ontology terms

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

Clinical/biochemical tests

Genetic testing

Differential diagnosis

Screening

11. Outcome/Prognosis

12. Treatment

Pharmacotherapy

Advanced/definitive therapy

Supportive/rehabilitative care

Surveillance (per GeneReviews management guidelines)

Suggested treatment ontology terms

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mouse (Mus musculus) — primary model

Cell-based / in vitro models

Applications

Summary Table — Key Ontology Term Suggestions for KB Curation

Notes on Evidence Gaps for Curation

Reference Validation