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CALFAN Syndrome

CALFAN Syndrome (SCYL1-related disease / SCAR21): Disease Characteristics Research Report

2026-06-04
Falcon MONDO:0014744 Model: Edison Scientific Literature 37 citations

CALFAN Syndrome (SCYL1-related disease / SCAR21): Disease Characteristics Research Report

Executive summary

CALFAN syndrome is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in SCYL1, characterized by infantile/childhood-onset low/normal-γ-glutamyltransferase (GGT) cholestasis and/or recurrent acute liver failure (ALF), often triggered by febrile infections, with later-onset and variably progressive neurodegeneration (cerebellar ataxia, neuropathy) and frequent skeletal/growth abnormalities. The foundational cohort identified 7 patients from 5 families, documenting febrile-triggered hepatic crises in early life and fibrosis in all patients, with variable neurologic and skeletal involvement. (lenz2018scyl1variantscause pages 6-7, lenz2018scyl1variantscause pages 1-2)

Recent literature (2023–2024) includes: (i) a novel homozygous nonsense SCYL1 variant in a Bahraini child with recurrent ALF and neurodevelopmental impairment; (ii) a 2023 adult liver transplantation case with 3-year favorable graft outcome and an updated statement that 18 total CALFAN patients had been reported at that time; and (iii) a 2024 review framing CALFAN as a congenital disorder of intracellular trafficking and providing MIM: 616719. (isa2023recurrentacuteliver pages 3-5, youssef2023calfan(lowγglutamyl pages 3-5, szabo2024intracellulartraffickingdefects pages 7-8)

1. Disease information

1.1 Definition and overview

1.2 Key identifiers

1.3 Synonyms / alternative names

1.4 Evidence source type

The knowledge base for CALFAN syndrome is derived primarily from individual case reports/series and reviews, rather than population-level EHR cohorts, consistent with its extreme rarity. (lenz2018scyl1variantscause pages 6-7, youssef2023calfan(lowγglutamyl pages 3-5, szabo2024intracellulartraffickingdefects pages 7-8)

Table (click to expand)
Category Value Notes Evidence
Disease name CALFAN syndrome Acronym for low gamma-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (lenz2018scyl1variantscause pages 1-2, szabo2024intracellulartraffickingdefects pages 7-8)
Expanded name / defining triad Low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration Core syndrome definition used in primary and review literature (lenz2018scyl1variantscause pages 1-2, szabo2024intracellulartraffickingdefects pages 7-8)
Alternative disease labels SCYL1-related disease; SCYL1 deficiency; SCAR21 / spinocerebellar ataxia, autosomal recessive 21 Literature uses both CALFAN and SCAR21 for overlapping SCYL1-related phenotype spectrum (demir2023coexistenceofspinocerebellar pages 3-4, isa2023recurrentacuteliver pages 3-5)
Causal gene SCYL1 Encodes SCY1-like pseudokinase 1 (szabo2024intracellulartraffickingdefects pages 7-8, szabo2024intracellulartraffickingdefects pages 1-2)
Molecular etiology Biallelic pathogenic variants in SCYL1 Typically homozygous in consanguineous families, though compound heterozygosity is also reported (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 6-7)
Inheritance Autosomal recessive Mendelian recessive disorder (yadav2026infantileliverfailure pages 10-12, demir2023coexistenceofspinocerebellar pages 3-4)
OMIM / MIM MIM: 616719 Reported in 2024 review; refers to CALFAN syndrome in provided source context (szabo2024intracellulartraffickingdefects pages 7-8)
MONDO ID Not identified in provided sources No MONDO identifier was found in the retrieved evidence (szabo2024intracellulartraffickingdefects pages 7-8, szabo2024intracellulartraffickingdefects pages 1-2)
Orphanet ID Not identified in provided sources Not reported in retrieved evidence (szabo2024intracellulartraffickingdefects pages 7-8, szabo2024intracellulartraffickingdefects pages 1-2)
ICD-10 / ICD-11 Not identified in provided sources Not reported in retrieved evidence (szabo2024intracellulartraffickingdefects pages 7-8, szabo2024intracellulartraffickingdefects pages 1-2)
MeSH Not identified in provided sources Not reported in retrieved evidence (szabo2024intracellulartraffickingdefects pages 7-8, szabo2024intracellulartraffickingdefects pages 1-2)
Key hepatic features Recurrent low/normal-GGT cholestasis; infantile or early-childhood acute liver failure; hepatomegaly; progressive fibrosis/cirrhosis in some patients Liver crises are often febrile-illness triggered and may resolve between episodes (lenz2018scyl1variantscause pages 6-7, lenz2018scyl1variantscause pages 1-2, youssef2023calfan(lowγglutamyl pages 3-5)
Key neurologic features Cerebellar ataxia, tremor, gait disorder, peripheral neuropathy, cerebellar atrophy, developmental delay/language delay, occasional seizures Neurologic manifestations often appear later than liver disease and may progress despite liver transplant (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 8-10, youssef2023calfan(lowγglutamyl pages 3-5, isa2023recurrentacuteliver pages 3-5)
Skeletal / growth features Short stature, scoliosis, vertebral anomalies, hip dysplasia, delayed bone age, other musculoskeletal abnormalities Variable expressivity across reported patients (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 8-10, NCT04653909 chunk 1)
Pathobiology summary Intracellular trafficking disorder involving impaired COPI-mediated Golgi-ER retrograde trafficking and Golgi/vesicle homeostasis SCYL1 loss is linked to trafficking defects; broader mechanistic work implicates Golgi architecture, endolysosomal distribution, and vesicle secretion (yadav2026infantileliverfailure pages 6-7, kaeserpebernard2022mtorc1controlsgolgi pages 2-3, kaeserpebernard2022mtorc1controlsgolgi pages 1-2)
Typical trigger of hepatic crises Febrile infection / intercurrent illness Recurrently emphasized across case series and reviews (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 1-3, lenz2018scyl1variantscause pages 1-2)
Data source type Aggregated disease-level literature derived from individual case reports/series and reviews Evidence base is rare-disease literature rather than EHR-derived population datasets (lenz2018scyl1variantscause pages 6-7, youssef2023calfan(lowγglutamyl pages 3-5, szabo2024intracellulartraffickingdefects pages 7-8)

Table: This table summarizes the main identifiers, synonyms, gene, inheritance pattern, and defining clinical features of CALFAN syndrome from the retrieved evidence. It is useful as a compact normalization reference for a disease knowledge base entry.

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

No validated genetic or environmental protective factors were identified in the retrieved sources.

2.4 Gene–environment interactions

The best-supported interaction is fever/infection-triggered decompensation in a genetically susceptible background (SCYL1 deficiency). (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 1-3)

3. Phenotypes (with suggested HPO terms)

Key manifestations span hepatic, neurologic, and skeletal domains with variable expressivity.

3.1 Hepatic phenotypes

3.2 Neurologic phenotypes

3.3 Skeletal/growth phenotypes

Table (click to expand)
Group Phenotype description Suggested HPO term Typical onset Frequency / number reported Key citations
Hepatic Recurrent low/normal-GGT cholestasis HP: Cholestasis Infancy Main hepatic presentation in 7/7 patients in the 2018 series; described as recurrent low-GGT cholestasis or acute liver failure (lenz2018scyl1variantscause pages 6-7, lenz2018scyl1variantscause pages 1-2)
Hepatic Acute liver failure / recurrent acute liver failure, often fever-triggered HP: Acute hepatic failure Infancy to early childhood 7/7 had severe cholestatic liver crises in first 18 months in Lenz 2018; recurrent ALF also documented in later case reports (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 1-3, lenz2018scyl1variantscause pages 1-2)
Hepatic Febrile-illness-triggered liver crises HP: Recurrent fever-triggered episodes (suggest phenotype annotation as recurrent acute hepatic failure triggered by febrile infection) Infancy to childhood Trigger emphasized across core series/case reports; in Lenz 2018 crises were triggered by febrile infections (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 1-3, lenz2018scyl1variantscause pages 1-2)
Hepatic Hepatomegaly HP: Hepatomegaly Infancy 7/7 in Lenz 2018; also reported in later cases (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 1-3)
Hepatic Splenomegaly / hepatosplenomegaly HP: Splenomegaly Infancy to childhood 4/7 in Lenz 2018; hepatosplenomegaly also reported in later single cases (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 5-6)
Hepatic Neonatal jaundice HP: Neonatal jaundice Neonatal 3/7 in Lenz 2018 (lenz2018scyl1variantscause pages 6-7)
Hepatic Liver fibrosis progressing to cirrhosis in some cases HP: Hepatic fibrosis Infancy onward Fibrosis developed in all 7/7 in Lenz 2018; cirrhosis documented in explant after adult liver transplant (lenz2018scyl1variantscause pages 6-7, youssef2023calfan(lowγglutamyl pages 2-3)
Neurologic Microcephaly HP: Microcephaly Infancy/childhood 6/7 in Lenz 2018 (lenz2018scyl1variantscause pages 6-7)
Neurologic Mild language delay / speech delay HP: Delayed speech and language development Childhood 6/7 in Lenz 2018; severe speech delay also reported in 2023 Bahraini case (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 3-5)
Neurologic Gait abnormality / progressive difficulty walking HP: Abnormal gait Childhood Motor dysfunction in 5/7 in Lenz 2018; progressive gait deterioration in 2023 case (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 1-3)
Neurologic Cerebellar ataxia HP: Cerebellar ataxia Childhood Reported across core series and later reviews/cases; often progressive and later-onset than liver disease (yadav2026infantileliverfailure pages 8-10, demir2023coexistenceofspinocerebellar pages 3-4, isa2023recurrentacuteliver pages 5-6)
Neurologic Tremor / intention tremor HP: Tremor Childhood Present among motor dysfunction features in Lenz 2018 and clearly documented in 2023 case (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 3-5, isa2023recurrentacuteliver pages 5-6)
Neurologic Peripheral neuropathy / motor-sensory neuropathy HP: Peripheral neuropathy Late childhood to adolescence Reported as part of progressive neurologic phenotype across reviews and case descriptions (yadav2026infantileliverfailure pages 8-10, demir2023coexistenceofspinocerebellar pages 3-4)
Neurologic Cerebellar atrophy HP: Cerebellar atrophy Childhood to adolescence Reported in CALFAN/SCYL1 disease and persisted after transplant in adult follow-up case (youssef2023calfan(lowγglutamyl pages 3-5, demir2023coexistenceofspinocerebellar pages 3-4)
Neurologic Seizures HP: Seizure Childhood 1/7 in Lenz 2018 required transient therapy (lenz2018scyl1variantscause pages 6-7)
Neurologic Hypotonia HP: Hypotonia Childhood Reported in broader SCYL1/CALFAN phenotype summaries (yadav2026infantileliverfailure pages 8-10)
Neurologic Optic atrophy HP: Optic atrophy Childhood Reported in broader literature review summaries, not quantified in core 7-patient series excerpt (yadav2026infantileliverfailure pages 8-10)
Skeletal/Other Short stature / growth retardation HP: Short stature Childhood Skeletal abnormalities in 5/7 in Lenz 2018 included short stature; growth retardation also noted in reviews (lenz2018scyl1variantscause pages 6-7, szabo2024intracellulartraffickingdefects pages 7-8)
Skeletal/Other Scoliosis / kyphoscoliosis HP: Scoliosis Childhood to adolescence Included among skeletal abnormalities in Lenz 2018; also prominent in rehabilitation case and trial record (lenz2018scyl1variantscause pages 6-7, NCT04653909 chunk 1, yigit2022theoutcomesof pages 1-2)
Skeletal/Other Hip dysplasia HP: Hip dysplasia Childhood Included among skeletal abnormalities in Lenz 2018; also listed in trial record phenotype summary (lenz2018scyl1variantscause pages 6-7, NCT04653909 chunk 1)
Skeletal/Other Vertebral anomalies / rib clefting HP: Abnormality of the vertebral column Childhood Reported among skeletal abnormalities in Lenz 2018; vertebral anomalies also summarized in later reviews (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 8-10)
Skeletal/Other Delayed bone age HP: Delayed bone age Childhood Reported in later literature review summaries; not quantified in core 7-patient excerpt (yadav2026infantileliverfailure pages 8-10)
Skeletal/Other Developmental delay / mild intellectual disability / cognitive impairment HP: Global developmental delay Childhood Variable; developmental delay and cognitive issues reported in later cases and trial description, though cognition can be preserved in some patients (isa2023recurrentacuteliver pages 3-5, NCT04653909 chunk 1)
Skeletal/Other Recurrent respiratory failure / respiratory involvement HP: Respiratory failure Childhood Rare/expanded phenotype reported outside initial core series; trial/case literature indicates musculoskeletal factors may affect respiratory function (demir2023coexistenceofspinocerebellar pages 3-4, yigit2022theoutcomesof pages 5-6)

Table: This table groups reported CALFAN syndrome manifestations into hepatic, neurologic, and skeletal/other domains, with suggested HPO terms, usual timing, and frequencies where the literature provides counts. It is useful for phenotype annotation and disease knowledge base curation.

Quality-of-life impact is best documented through rehabilitation outcomes (see Treatment/Supportive Care), where functional independence and PedsQL measures improved with physiotherapy in a single case. (yigit2022theoutcomesof pages 2-3)

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variants (examples from recent and foundational reports)

Table (click to expand)
Paper (year, URL) Patient count Inheritance Variant(s) (HGVS c./p.) Variant type Key phenotypes Outcomes / notes
Lenz et al. (2018), https://doi.org/10.1038/gim.2017.260 7 patients from 5 families Autosomal recessive; biallelic SCYL1 variants Specific HGVS variants not extracted in evidence; reported as biallelic SCYL1 variants Not extracted in evidence Recurrent low/normal-GGT cholestasis or acute liver failure in infancy; febrile infection-triggered liver crises; hepatomegaly; splenomegaly in some; fibrosis in all reported patients; later variable neurologic phenotype including microcephaly, language delay, motor dysfunction, tremor, gait abnormality; skeletal abnormalities in some (lenz2018scyl1variantscause pages 6-7, lenz2018scyl1variantscause pages 1-2) One child underwent liver transplantation at 23 months; crises were transient but fibrosis developed (lenz2018scyl1variantscause pages 6-7)
Isa et al. (2023), https://doi.org/10.7759/cureus.36249 1 Autosomal recessive; homozygous c.895A>T; p.Lys299Ter Nonsense Recurrent febrile-illness–triggered acute liver failure; hepatomegaly/hepatosplenomegaly; developmental delay; progressive gait deterioration; intention tremor; severe speech delay; mild/moderate intellectual disability; minimal periventricular white matter MRI changes (isa2023recurrentacuteliver pages 3-5, isa2023recurrentacuteliver pages 1-3, isa2023recurrentacuteliver pages 5-6) Managed supportively; liver transplantation discussed but not performed; variant described as novel and likely pathogenic (isa2023recurrentacuteliver pages 3-5, isa2023recurrentacuteliver pages 7-8)
Youssef et al. (2023), https://doi.org/10.1155/2023/3010131 1 SCYL1-associated CALFAN syndrome; inheritance not explicitly extracted in evidence for this case SCYL1 mutation; specific variant not fully specified in evidence Not fully extracted in evidence Infantile-onset recurrent jaundice / pediatric acute liver failure with later neurologic sequelae; explant pathology showed cirrhosis, cholestatic liver injury, and bile ductular proliferation; persistent cerebellar atrophy and neurologic deficits after transplant (youssef2023calfan(lowγglutamyl pages 3-5, youssef2023calfan(lowγglutamyl pages 2-3) Liver transplantation at age 20; doing well at 3-year follow-up; biliary stricture resolved; no acute cellular rejection reported (youssef2023calfan(lowγglutamyl pages 3-5, youssef2023calfan(lowγglutamyl pages 1-2, youssef2023calfan(lowγglutamyl pages 2-3)
Suenera & Navinummapathy (2025), URL not available in retrieved evidence 1 Autosomal recessive; homozygous c.745_746insG; protein consequence not extracted in evidence Truncating / frameshift insertion Recurrent pediatric acute liver failure with cholestasis; hepatosplenomegaly; canalicular cholestasis; degeneration and mild fibrosis; evolving neurologic features including cerebellar atrophy and peripheral neuropathy; PFIC-like overlap (suenera2025acuteonchronica pages 4-6, suenera2025acuteonchronic pages 4-6, suenera2025acuteonchronicc pages 4-6) Supportive/emergency management described (infection control, IV NAC, correction of coagulopathy, fat-soluble vitamins, ursodeoxycholic acid, lactulose); liver transplantation considered for progressive failure (suenera2025acuteonchronica pages 4-6, suenera2025acuteonchronic pages 4-6, suenera2025acuteonchronicd pages 4-6)
Yadav et al. (2026), https://doi.org/10.58427/apghn.5.2.2026.86-97 1 Autosomal recessive; homozygous c.1567C>T; p.Arg523* Nonsense / null 9-month-old infant with fever-triggered cholestatic jaundice and acute liver failure; low/normal-GGT cholestasis; no neurologic, neuroimaging, or skeletal abnormalities at presentation; family history of sibling death from infantile liver failure (yadav2026infantileliverfailure pages 6-7) Emphasized early genomic testing, longitudinal neurologic surveillance, transplant referral when indicated, and recurrence-risk counseling; expands spectrum by showing isolated infantile hepatic presentation initially (yadav2026infantileliverfailure pages 6-7, yadav2026infantileliverfailure pages 10-12)

Table: This table summarizes SCYL1 pathogenic variants and associated clinical notes for CALFAN syndrome from the retrieved literature. It highlights reported HGVS changes, inheritance, major phenotypes, and clinically important outcomes such as liver transplantation.

4.3 Functional consequences

The retrieved evidence is consistent with loss-of-function (truncating/nonsense/frameshift) as a major mechanism. (isa2023recurrentacuteliver pages 3-5, suenera2025acuteonchronic pages 4-6)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

No validated modifier genes, epigenetic signatures, or recurrent chromosomal abnormalities were identified in the retrieved sources.

5. Environmental information

No established non-genetic causes are implicated; the dominant “environmental” component in the retrieved evidence is infection/fever as a trigger for hepatic decompensation. (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 1-3)

6. Mechanism / pathophysiology

6.1 Current mechanistic understanding (causal chain)

  1. SCYL1 loss-of-function →
  2. Impaired intracellular trafficking, especially COPI-mediated Golgi–ER retrograde trafficking →
  3. Hepatocyte secretory stress and (proposed) ER stress/unfolded protein response, culminating in susceptibility to hepatocellular injury/apoptosis, particularly during febrile illness →
  4. Recurrent cholestasis/ALF episodes with cumulative injury leading to fibrosis/cirrhosis in some →
  5. Later-onset neurodegeneration (cerebellar atrophy/ataxia, neuropathy), which may progress independently of liver disease and can persist after transplant. (lenz2018scyl1variantscause pages 1-2, yadav2026infantileliverfailure pages 6-7, youssef2023calfan(lowγglutamyl pages 3-5)

6.2 Pathways and cellular processes

6.3 Suggested ontology terms

  • GO Biological Process (suggested): COPI-mediated vesicle transport; Golgi-to-ER retrograde transport; ER stress / unfolded protein response; regulation of Golgi organization; autophagy/endolysosomal organization (supported conceptually by trafficking and stress mechanisms described). (yadav2026infantileliverfailure pages 6-7, kaeserpebernard2022mtorc1controlsgolgi pages 1-2)
  • Cell types (CL, suggested): hepatocyte; cerebellar Purkinje cell; peripheral neuron/Schwann cell (reflecting hepatic and neurodegenerative involvement; specific CL IDs should be mapped during curation). (yadav2026infantileliverfailure pages 6-7, youssef2023calfan(lowγglutamyl pages 3-5)

6.4 Model organisms / experimental systems

7. Anatomical structures affected (suggested UBERON)

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology and case counts

  • No population prevalence/incidence estimates were identified in the retrieved sources.
  • A 2023 transplant case report states: “To date, 18 patients of CALFAN syndrome with SCYL1 mutation including our case have been reported.” (human case report literature count; not a registry estimate). (youssef2023calfan(lowγglutamyl pages 3-5)
  • A later review/case discussion indicates “fewer than 25 reported cases worldwide” (summary statement). (yadav2026infantileliverfailure pages 1-3)
  • A clinical trial registry entry (single-case physiotherapy study) described CALFAN as ultra-rare with ~11 reported patients at the time of registration (reflecting contemporaneous knowledge in 2020, not a definitive count). (NCT04653909 chunk 1)

10. Diagnostics

10.1 Clinical/laboratory hallmarks

10.2 Genetic testing approach

10.3 Differential diagnosis

Differentials with overlapping presentations include: - PFIC and other low/normal-GGT cholestasis disorders (e.g., bile acid synthesis defects). (yadav2026infantileliverfailure pages 1-3, yadav2026infantileliverfailure pages 3-6) - NBAS-related recurrent ALF, and other fever-triggered genetic ALF causes (e.g., TRMU, LARS1). (yadav2026infantileliverfailure pages 1-3, yadav2026infantileliverfailure pages 3-6) - Wilson disease, autoimmune hepatitis, peroxisomal disorders and other intracellular trafficking disorders. (suenera2025acuteonchronicd pages 4-6, suenera2025acuteonchronic pages 4-6)

11. Outcome / prognosis

12. Treatment

12.1 Acute and chronic medical management (supportive)

There is no established disease-modifying therapy in the retrieved sources; care is supportive and trigger-focused. - Acute crisis measures reported include infection control, correction of coagulopathy, and sometimes IV NAC (example dosing reported in one case report). (suenera2025acuteonchronic pages 4-6, suenera2025acuteonchronicd pages 4-6) - Chronic measures include nutritional optimization and fat-soluble vitamins, cholestasis-directed therapy, and multidisciplinary follow-up. (yadav2026infantileliverfailure pages 8-10, yadav2026infantileliverfailure pages 10-12)

12.2 Liver transplantation

  • A 2023 case report describes transplantation at age 20 with 3-year favorable follow-up and no reported acute rejection; neurologic deficits persisted. (youssef2023calfan(lowγglutamyl pages 3-5, youssef2023calfan(lowγglutamyl pages 2-3)
  • The same report notes three earlier transplants in infancy/early childhood (7–23 months) among reported cases and states no graft failure was reported with 8–11 years follow-up in prior transplant recipients. (youssef2023calfan(lowγglutamyl pages 3-5)

12.3 Rehabilitation / physical therapy (real-world implementation)

  • Case report evidence (2022): A 12-week trunk stabilization/balance/functional program improved multiple functional and QoL measures (ICARS 47→42; TIS 9→13; WeeFIM 79→83; PedsQL 47.11→52.17; 9-HPT times improved). (yigit2022theoutcomesof pages 2-3, yigit2022theoutcomesof pages 3-4)
  • ClinicalTrials.gov (NCT04653909): single-case interventional rehabilitation study (start 2020-03-01; completion 2020-11-17) with outcomes including TIS, ICARS, PedsQL, WeeFIM. (NCT04653909 chunk 1)

Suggested MAXO terms (curation suggestions): physical therapy; rehabilitation therapy; liver transplantation; genetic counseling; supportive care for acute liver failure (mapping to MAXO IDs should be completed during ontology curation). (NCT04653909 chunk 1, youssef2023calfan(lowγglutamyl pages 3-5)

Table (click to expand)
Management domain Real-world implementation Key details / quantitative data Evidence / outcomes Citations
Acute liver crisis management Supportive, emergency-focused inpatient care during febrile-triggered cholestatic/ALF episodes Reported measures include infection control, IV N-acetylcysteine (example dose 100 mg/kg/day in one report), correction of coagulopathy with fresh frozen plasma/platelets, antibiotics when indicated, ursodeoxycholic acid, fat-soluble vitamin supplementation, lactulose as needed, and close monitoring of bilirubin, INR, transaminases, glucose, ammonia, and encephalopathy Most liver crises can recover with supportive treatment, but fibrosis may accumulate over time; crises are commonly triggered by febrile illnesses/intercurrent infections (lenz2018scyl1variantscause pages 6-7, suenera2025acuteonchronica pages 4-6, suenera2025acuteonchronic pages 4-6, suenera2025acuteonchronicd pages 4-6, yadav2026infantileliverfailure pages 10-12, lenz2018scyl1variantscause pages 1-2)
Chronic hepatic monitoring Longitudinal hepatology follow-up between crises Serial liver biochemistry and synthetic function monitoring; nutritional optimization; cholestasis/pruritus management; surveillance for fibrosis/cirrhosis; monitoring for hepatosplenomegaly and growth failure Lenz et al. reported fibrosis in all 7/7 patients despite transient crises; later reports emphasize chronic surveillance because apparent inter-episodic recovery does not exclude progression (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 8-10, yadav2026infantileliverfailure pages 10-12)
Neurologic monitoring Serial neurology assessment and imaging Ongoing assessment for gait decline, tremor, peripheral neuropathy, speech/language delay, cerebellar ataxia/atrophy; repeat brain MRI may be needed because early imaging can be nondiagnostic Neurologic progression may continue even when hepatic disease stabilizes or after liver transplantation (yadav2026infantileliverfailure pages 8-10, youssef2023calfan(lowγglutamyl pages 3-5, isa2023recurrentacuteliver pages 3-5, isa2023recurrentacuteliver pages 7-8)
Liver transplantation Used for progressive/recurrent liver failure not controlled by supportive care In the foundational cohort, 1 child underwent transplant at 23 months; by 2023 literature review, 3 prior CALFAN patients had undergone transplant in infancy/early childhood at 7, 21, and 23 months; Youssef et al. added a transplant in adulthood at age 20 years Adult-transplanted patient was doing well at 3-year follow-up; no acute cellular rejection reported; prior transplanted cases reportedly had no graft failure with 8-11 years follow-up; neurologic deficits may persist/progress despite hepatic stabilization (lenz2018scyl1variantscause pages 6-7, youssef2023calfan(lowγglutamyl pages 3-5, youssef2023calfan(lowγglutamyl pages 1-2, youssef2023calfan(lowγglutamyl pages 2-3)
Post-transplant expectations Hepatic benefit but incomplete extrahepatic rescue Adult case most recent labs after transplant: TB 2.1 mg/dL, direct bilirubin 0.4 mg/dL, ALP 72 IU/L, ALT 18 IU/L, AST 13 IU/L, GGT 4 U/L; persistent cerebellar atrophy, leg-brace use, and limited expressive language remained Supports transplant as liver-directed therapy rather than cure of neurodegeneration (youssef2023calfan(lowγglutamyl pages 3-5, youssef2023calfan(lowγglutamyl pages 2-3)
Rehabilitation / physiotherapy (published case report) Individualized 12-week physical therapy program 45-minute sessions, 3 days/week; trunk stabilization, balance training, functional exercises, Swiss-ball and perturbation-based training, scoliosis brace/orthosis support, thoracic expansion and diaphragmatic breathing exercises Quantitative changes: ICARS 47→42; TIS 9→13; WeeFIM 79→83; PedsQL 47.11→52.17; Q-DASH 59→56; 9-HPT right 48.8s→42.9s, left 66.1s→56.4s; thoracic Cobb 34°→36°, lumbar Cobb 32°→21° (yigit2022theoutcomesof pages 3-4, yigit2022theoutcomesof pages 2-3, yigit2022theoutcomesof pages 1-2, yigit2022theoutcomesof pages 5-6)
Rehabilitation / physiotherapy (registered study) Prospective single-case interventional rehabilitation study ClinicalTrials.gov NCT04653909; single-group, enrollment=1; start 2020-03-01, primary completion 2020-10-20, study completion 2020-11-17; intervention included abdominal/back strengthening, perturbation training in sitting/standing, functional ADL-simulating exercises, scoliosis stretching/strengthening, and trunk orthoses Primary outcomes: TIS, ICARS, PedsQL, WeeFIM; secondary: 9-Hole Peg Test and Q-DASH; record describes CALFAN as ultra-rare with ~11 reported patients at time of registration (NCT04653909 chunk 1)
Diagnostic implementation in acute care Early exome/genomic testing to clarify etiology of indeterminate pediatric ALF / low-GGT cholestasis Whole-exome sequencing repeatedly enabled diagnosis in reported patients, including urgent-care contexts and cases considered for transplant; suggested especially when fever-triggered recurrent ALF occurs with neurologic signs or consanguinity/family history Rapid molecular diagnosis informs prognosis, recurrence risk, and transplant decision-making (isa2023recurrentacuteliver pages 1-3, isa2023recurrentacuteliver pages 7-8, lenz2018scyl1variantscause pages 1-2)
Genetic counseling / prevention Family counseling, cascade testing, reproductive planning Autosomal recessive inheritance; recurrence-risk counseling recommended; prenatal and preimplantation genetic testing options noted in recent review/case literature; family history of unexplained infantile liver failure is an important clue No primary prevention for the genetic disorder itself; practical prevention focuses on anticipatory guidance, early evaluation of febrile illnesses, and reproductive counseling for at-risk families (yadav2026infantileliverfailure pages 6-7, yadav2026infantileliverfailure pages 10-12, isa2023recurrentacuteliver pages 1-3)
Tertiary prevention / complication reduction Avoidance of hepatotoxic stressors and prompt treatment of intercurrent infections Suggested measures include early treatment/prevention of infections, hydration/nutritional support during illness, avoidance of hepatotoxic drugs, and multidisciplinary follow-up (hepatology, neurology, genetics, rehabilitation) Intended to reduce severity of recurrent decompensation and preserve function/QoL, though controlled evidence is lacking because of extreme rarity (suenera2025acuteonchronic pages 4-6, suenera2025acuteonchronicd pages 4-6, yadav2026infantileliverfailure pages 10-12, yigit2022theoutcomesof pages 4-5)

Table: This table summarizes current real-world management approaches reported for CALFAN syndrome, including acute liver crisis care, chronic surveillance, transplantation, rehabilitation, and genetic counseling. It also captures the limited quantitative outcome data available from case reports and the single registered rehabilitation study.

13. Prevention

14. Other species / natural disease

No naturally occurring veterinary CALFAN/SCYL1-deficiency syndrome data were identified in the retrieved sources.

15. Model organisms

Direct quotes from abstracts (available in retrieved evidence)

  • Foundational cohort definition: “SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN).” (Genetics in Medicine; 2018) (lenz2018scyl1variantscause pages 1-2)
  • Trafficking/therapeutic framing: the 2024 review notes it “explore[s] the emerging knowledge on intracellular trafficking defects and their clinical manifestations … [and that] understanding these processes could spark novel therapeutic approaches.” (Traffic; 2024) (szabo2024intracellulartraffickingdefects pages 1-2)

Notes on evidence gaps and recommended next steps for curation

  • Ontology identifiers (MONDO/Orphanet/ICD/MeSH) were not present in the retrieved texts; verify in OMIM/Orphanet/MONDO directly.
  • Variant catalog completeness: the foundational cohort’s specific HGVS variants were not extracted from the available evidence snippets; full-text variant tables should be consulted to populate ClinVar-style variant lists.
  • Epidemiology: only case-count statements are available; no population prevalence data identified.

References

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  4. (youssef2023calfan(lowγglutamyl pages 3-5): Mariam Youssef, Katherine L. Mascia, Brendan McGuire, Chirag R. Patel, Sameer Al Diffalha, Deepti Dhall, and Goo Lee. Calfan (low γ-glutamyl transpeptidase (ggt) cholestasis, acute liver failure, and neurodegeneration) syndrome: a case report with 3-year follow-up after liver transplantation in early adulthood. Case Reports in Hepatology, 2023:1-5, Jul 2023. URL: https://doi.org/10.1155/2023/3010131, doi:10.1155/2023/3010131. This article has 6 citations.

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  11. (NCT04653909 chunk 1): Serkan Usgu. The Physiotherapy and Rehabilitation in Calfan Syndrome. Hasan Kalyoncu University. 2020. ClinicalTrials.gov Identifier: NCT04653909

  12. (kaeserpebernard2022mtorc1controlsgolgi pages 2-3): Stéphanie Kaeser-Pebernard, Christine Vionnet, Muriel Mari, Devanarayanan Siva Sankar, Zehan Hu, Carole Roubaty, Esther Martínez-Martínez, Huiyuan Zhao, Miguel Spuch-Calvar, Alke Petri-Fink, Gregor Rainer, Florian Steinberg, Fulvio Reggiori, and Jörn Dengjel. Mtorc1 controls golgi architecture and vesicle secretion by phosphorylation of scyl1. Nature Communications, Aug 2022. URL: https://doi.org/10.1038/s41467-022-32487-7, doi:10.1038/s41467-022-32487-7. This article has 35 citations and is from a highest quality peer-reviewed journal.

  13. (kaeserpebernard2022mtorc1controlsgolgi pages 1-2): Stéphanie Kaeser-Pebernard, Christine Vionnet, Muriel Mari, Devanarayanan Siva Sankar, Zehan Hu, Carole Roubaty, Esther Martínez-Martínez, Huiyuan Zhao, Miguel Spuch-Calvar, Alke Petri-Fink, Gregor Rainer, Florian Steinberg, Fulvio Reggiori, and Jörn Dengjel. Mtorc1 controls golgi architecture and vesicle secretion by phosphorylation of scyl1. Nature Communications, Aug 2022. URL: https://doi.org/10.1038/s41467-022-32487-7, doi:10.1038/s41467-022-32487-7. This article has 35 citations and is from a highest quality peer-reviewed journal.

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  17. (yigit2022theoutcomesof pages 1-2): Sedat Yigit, Hatice Mutlu Albayrak, Peren Perk Yücel, Serkan Usgu, and Yavuz Yakut. The outcomes of an individualized physical therapy program in calfan syndrome: a case report. Pediatric Physical Therapy, 34:432-437, May 2022. URL: https://doi.org/10.1097/pep.0000000000000903, doi:10.1097/pep.0000000000000903. This article has 3 citations and is from a peer-reviewed journal.

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  21. (suenera2025acuteonchronic pages 4-6): DR SUENERA and DR NAVINUMAPATHY. Acute on chronic liver disease in a child with scyl1 mutation: a rare pediatric case report. Unknown journal, 2025.

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  32. (yigit2022theoutcomesof pages 4-5): Sedat Yigit, Hatice Mutlu Albayrak, Peren Perk Yücel, Serkan Usgu, and Yavuz Yakut. The outcomes of an individualized physical therapy program in calfan syndrome: a case report. Pediatric Physical Therapy, 34:432-437, May 2022. URL: https://doi.org/10.1097/pep.0000000000000903, doi:10.1097/pep.0000000000000903. This article has 3 citations and is from a peer-reviewed journal.

Artifacts