👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

CALFAN syndrome is inherited in an autosomal recessive manner, caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in SCYL1; many reported cases occur in consanguineous families.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"Seven patients from five families with biallelic SCYL1 variants were identified."

Biallelic (homozygous or compound heterozygous) SCYL1 variants in the foundational cohort establish autosomal recessive inheritance.

⚙

Pathophysiology

5

SCYL1 Loss of Function

Biallelic loss-of-function variants in SCYL1 abolish or reduce functional SCY1-like pseudokinase 1 protein. SCYL1 is an N-terminal kinase-like scaffold that operates at the Golgi apparatus in COPI-dependent vesicular trafficking.

SCYL1 hgnc:14372

Downstream

Impaired COPI Retrograde Golgi-to-ER Trafficking Loss of SCYL1 scaffold function impairs COPI-mediated retrograde transport from the Golgi to the endoplasmic reticulum and disrupts Golgi architecture.

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"Functional studies emphasize that SCYL1 deficiency is linked to impaired intracellular trafficking."

Functional studies on patient fibroblasts directly link SCYL1 deficiency to impaired intracellular trafficking, the initiating molecular lesion.

Impaired COPI Retrograde Golgi-to-ER Trafficking

SCYL1 deficiency disrupts COPI-coated vesicle-mediated retrograde transport from the Golgi to the endoplasmic reticulum and alters Golgi organization. Mechanistic cell-biology work shows that the mTORC1-controlled phosphorylation status of SCYL1 (Ser754) regulates Golgi architecture, endolysosomal distribution, and extracellular vesicle secretion, and that loss-of-function of SCYL1 underlies CALFAN syndrome.

Retrograde Golgi-to-ER vesicle transport GO:0006890 ↓ DECREASED COPI coating of Golgi vesicle GO:0048205 ↓ DECREASED Golgi organization GO:0007030 ⚠ ABNORMAL

Golgi apparatus GO:0005794

Downstream

Hepatocyte and Neuronal Secretory and ER Stress Defective retrograde trafficking and Golgi homeostasis impose secretory and ER stress on highly secretory hepatocytes and on neurons, sensitizing these cells to injury.

Show evidence (3 references)

PMID:35948564 SUPPORT In Vitro

"Here, we characterize the N-terminal kinase-like protein SCYL1 as a Golgi-localized target through which mTORC1 controls organelle distribution and extracellular vesicle secretion in breast cancer cells."

Identifies SCYL1 as a Golgi-localized regulator of organelle distribution and vesicle secretion, supporting its role in COPI/Golgi trafficking.

PMID:35948564 SUPPORT In Vitro

"It may also explain the pathophysiology underlying human genetic diseases such as CALFAN syndrome, which is caused by loss-of-function of SCYL1."

Directly links SCYL1 trafficking/Golgi dysfunction to the pathophysiology of CALFAN syndrome.

PMID:39187475 SUPPORT Other

"We give examples of how intracellular trafficking hubs, such as the apical recycling endosome system, the trans-Golgi network, lysosomes, or the Golgi-to-endoplasmic reticulum transport are involved in the pathomechanism and lead to disease."

Review framing CALFAN among congenital intestinal/hepatic intracellular trafficking disorders implicating Golgi-to-ER transport.

Hepatocyte and Neuronal Secretory and ER Stress

Impaired Golgi-ER trafficking produces secretory stress and a proposed ER stress / unfolded protein response in hepatocytes and neurons (cerebellar Purkinje cells, motor neurons, peripheral neurons), rendering them vulnerable to injury and degeneration, particularly during the metabolic demands of febrile illness.

Hepatocyte CL:0000182 Cerebellar Purkinje cell CL:0000121 Motor neuron CL:0000100

Response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED Endoplasmic reticulum unfolded protein response GO:0030968 ↑ INCREASED

Downstream

Recurrent Hepatic Crises and Progressive Fibrosis Hepatocyte vulnerability manifests as recurrent low-GGT cholestasis and acute liver failure episodes, often febrile-triggered, with cumulative injury leading to hepatic fibrosis.

Progressive Neurodegeneration Neuronal vulnerability drives later-onset, variably progressive cerebellar atrophy/ataxia and peripheral sensorimotor neuropathy.

Show evidence (2 references)

PMID:29419818 SUPPORT Human Clinical

"The main clinical phenotype was recurrent low γ-glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy and a variable neurological phenotype of later onset (CALFAN syndrome)."

The combined hepatic and neurological phenotype reflects vulnerability of hepatocytes and neurons downstream of the trafficking defect.

PMID:35948564 SUPPORT In Vitro

"Peripheral, dephosphorylated SCYL1 causes Golgi enlargement, redistribution of early and late endosomes and increased extracellular vesicle release."

Demonstrates that perturbed SCYL1 function disrupts Golgi and endolysosomal homeostasis, the basis for cellular secretory stress.

Recurrent Hepatic Crises and Progressive Fibrosis

Episodic low/normal-GGT cholestasis and acute liver failure, frequently triggered by febrile infections, with onset in infancy. Crises are often transient with inter-episodic biochemical recovery, but hepatic fibrosis develops and can progress to cirrhosis in some patients.

Hepatocyte CL:0000182

Downstream

Low gamma-glutamyltransferase cholestasis Hepatic crises include recurrent low-GGT cholestasis, the laboratory clue reflected by reduced gamma-glutamyltransferase.

Cholestasis Recurrent hepatic crises manifest as infantile-onset cholestasis.

Acute hepatic failure Febrile-triggered hepatic crises can present as recurrent acute liver failure.

Hepatic fibrosis Repeated transient hepatic crises are followed by progressive hepatic fibrosis.

Show evidence (2 references)

PMID:29419818 SUPPORT Human Clinical

"Liver crises were triggered by febrile infections and were transient, but fibrosis developed."

Directly documents febrile-triggered transient liver crises with development of hepatic fibrosis in the foundational cohort.

PMID:37069859 SUPPORT Human Clinical

"He was admitted to the hospital twice by the age of two and five years due to acute hepatic failure triggered by a febrile illness."

Confirms recurrent febrile-triggered acute hepatic failure episodes in a genetically confirmed patient.

Progressive Neurodegeneration

Later-onset and variably progressive neurodegeneration including cerebellar atrophy with ataxia and peripheral sensorimotor (motor-sensory) neuropathy. Neurologic decline may continue independently of hepatic disease and can persist after liver transplantation.

Cerebellar Purkinje cell CL:0000121 Peripheral neuron CL:2000032

Downstream

Cerebellar atrophy Progressive neurodegeneration includes cerebellar atrophy.

Cerebellar ataxia Cerebellar neurodegeneration manifests as progressive cerebellar ataxia.

Peripheral sensorimotor neuropathy Peripheral neuronal involvement produces sensorimotor neuropathy.

Gait disturbance Progressive neurodegeneration causes worsening gait disturbance and eventual loss of ambulation in some patients.

Motor delay CALFAN neurologic involvement can include delayed gross motor development.

Show evidence (2 references)

PMID:29419818 SUPPORT Human Clinical

"Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure."

Establishes peripheral neuropathy, cerebellar atrophy, and ataxia as core neurodegenerative features of SCYL1 deficiency.

PMID:37069859 SUPPORT Human Clinical

"After the first episode of ALF, he had progressive difficulty in walking leading to frequent falls and ending with a complete inability to walk."

Documents progressive motor/neurologic decline following hepatic presentation, consistent with progressive neurodegeneration.

⬡

Pathograph

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

●

Phenotypes

11

Digestive 3

Cholestasis Cholestasis HP:0001396

Temporal: RECURRENT

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"The main clinical phenotype was recurrent low γ-glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy"

Recurrent cholestasis with infantile onset is a core feature.

Acute hepatic failure FREQUENT Acute hepatic failure HP:0006554

Temporal: RECURRENT

Show evidence (2 references)

PMID:29419818 SUPPORT Human Clinical

"The occurrence of SCYL1 deficiency among patients with previously undetermined infantile cholestasis or acute liver failure has not been studied"

Establishes acute liver failure as a defining hepatic manifestation of SCYL1 deficiency.

PMID:37069859 SUPPORT Human Clinical

"He was admitted to the hospital twice by the age of two and five years due to acute hepatic failure triggered by a febrile illness."

Documents recurrent febrile-triggered acute hepatic failure.

Hepatic fibrosis Hepatic fibrosis HP:0001395

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"Liver crises were triggered by febrile infections and were transient, but fibrosis developed."

Fibrosis developed in the foundational cohort despite transient crises.

Musculoskeletal 1

Scoliosis Scoliosis HP:0002650

Show evidence (1 reference)

PMID:35616485 SUPPORT Human Clinical

"The Cobb angle was increased by 2° in the thoracic region and reduced by 11° in the lumbar region."

Cobb-angle measurements document spinal curvature (scoliosis) managed with physical therapy in a CALFAN patient.

Nervous System 4

Cerebellar atrophy Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure."

Cerebellar atrophy is a defining neurologic feature.

Cerebellar ataxia Progressive cerebellar ataxia HP:0002073

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure."

Ataxia is a defining neurologic feature of SCYL1 deficiency.

Gait disturbance Gait disturbance HP:0001288

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:37069859 SUPPORT Human Clinical

"After the first episode of ALF, he had progressive difficulty in walking leading to frequent falls and ending with a complete inability to walk."

Documents progressive gait deterioration to loss of ambulation.

Motor delay Motor delay HP:0001270

Show evidence (1 reference)

PMID:37069859 SUPPORT Human Clinical

"The patient had delayed gross motor development as he started to walk at 20 months of age."

Documents delayed acquisition of gross motor milestones (walking at 20 months) in a genetically confirmed CALFAN patient.

Growth 1

Short stature Short stature HP:0004322

Show evidence (1 reference)

PMID:37554250 SUPPORT Human Clinical

"CALFAN syndrome is an extremely rare disease consisting of recurrent pediatric acute liver failure (PALF), neurodegenerative diseases, and skeletal abnormalities associated with SCYL1 gene mutation."

Establishes skeletal abnormalities as a component of the CALFAN triad. Short stature is reported among these skeletal/growth features in case series (Lenz et al. 2018); this abstract-level evidence supports the broader skeletal-abnormality category rather than short stature specifically.

Other 2

Low gamma-glutamyltransferase cholestasis Reduced gamma-glutamyltransferase level HP:0034445

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"The main clinical phenotype was recurrent low γ-glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy and a variable neurological phenotype of later onset (CALFAN syndrome)."

Identifies low-GGT cholestasis as the main hepatic phenotype.

Peripheral sensorimotor neuropathy Sensorimotor neuropathy HP:0007141

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure."

Peripheral neuropathy is a defining feature of CALFAN syndrome.

🧬

Genetic Associations

1

Biallelic SCYL1 loss-of-function variants (Causal gene; biallelic loss-of-function variants cause CALFAN syndrome)

Gene: SCYL1 hgnc:14372

Show evidence (2 references)

PMID:29419818 SUPPORT Human Clinical

"Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure."

Establishes SCYL1 as the causal gene with biallelic mutations producing the core neurohepatic phenotype.

PMID:37069859 SUPPORT Human Clinical

"A whole-exome sequencing (WES) test revealed that the patient has previously unreported autosomal recessive pathogenic non-sense variation c.895A>T (p.Lys299Ter) in exon 7 of the SCYL1 gene in a homozygous status."

Documents a homozygous nonsense (loss-of-function) SCYL1 variant causing the disorder, supporting the loss-of-function mechanism.

💊

Medical Actions

4

Supportive Care for Acute Liver Failure

Action: supportive care MAXO:0000950

Supportive, trigger-focused management of febrile-precipitated cholestatic and acute liver failure crises, including infection control, correction of coagulopathy, nutritional optimization with fat-soluble vitamins, and close monitoring of synthetic liver function. There is no established disease-modifying therapy; crises typically recover with supportive care.

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"Liver crises were triggered by febrile infections and were transient, but fibrosis developed."

Transient nature of crises supports a supportive-care management approach during febrile-triggered episodes.

Liver Transplantation

Action: organ transplantation MAXO:0010039

Liver transplantation for progressive or recurrent liver failure not controlled by supportive care. Reported in infancy/early childhood and, in one case, in early adulthood with favorable 3-year graft outcome. Transplantation addresses hepatic disease but does not arrest neurodegeneration, which may persist.

Show evidence (2 references)

PMID:37554250 SUPPORT Human Clinical

"To date, three of 18 patients reported underwent liver transplantation in infancy and early childhood (7-23 months)."

Documents liver transplantation as a management option in CALFAN syndrome.

PMID:37554250 SUPPORT Human Clinical

"At the most recent follow-up, 3 years after transplantation, the patient is doing well."

Reports favorable hepatic outcome 3 years after liver transplantation in early adulthood.

Physical Therapy and Rehabilitation

Action: physical therapy MAXO:0000011

Individualized physical therapy program (trunk stabilization, balance training, functional exercises) improving quality of life, functional independence, trunk control, and upper-extremity performance in a child with CALFAN syndrome.

Show evidence (1 reference)

PMID:35616485 SUPPORT Human Clinical

"Physical therapy improved quality of life, functional independence, trunk control, and upper extremity performance."

Demonstrates functional benefit of physical therapy in CALFAN syndrome.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Autosomal recessive recurrence-risk counseling, cascade testing, and reproductive options for at-risk families, including prenatal and preimplantation genetic testing.

Show evidence (1 reference)

PMID:29419818 SUPPORT Human Clinical

"Seven patients from five families with biallelic SCYL1 variants were identified."

Autosomal recessive inheritance with biallelic variants underpins the need for recurrence-risk genetic counseling.

🔬

Clinical Trials

1

NCT04653909 COMPLETED

Single-case interventional rehabilitation study evaluating an individualized physiotherapy and rehabilitation program in CALFAN syndrome, with outcomes including the Trunk Impairment Scale, International Cooperative Ataxia Rating Scale, Pediatric Quality of Life Inventory, and Functional Independence Measure for Children.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073 Scoliosis HP:0002650

Show evidence (1 reference)

clinicaltrials:NCT04653909 SUPPORT Human Clinical

"The aim of this study is to investigate the effectiveness of the physiotherapy and rehabilitation program in a rare case with Calfan syndrome."

Registered single-case rehabilitation study evaluating physiotherapy for CALFAN syndrome.

{ }

Source YAML

click to show

name: CALFAN Syndrome
creation_date: "2026-06-04T12:00:00Z"
category: Mendelian
description: >-
  CALFAN syndrome (low gamma-glutamyltransferase cholestasis, acute liver
  failure, and neurodegeneration; also known as autosomal recessive
  spinocerebellar ataxia type 21, SCAR21; MONDO:0014744, OMIM:616719) is an
  ultra-rare autosomal recessive disorder caused by biallelic loss-of-function
  variants in SCYL1. SCYL1 encodes an N-terminal kinase-like pseudokinase that
  acts as a scaffold in COPI-mediated retrograde Golgi-to-endoplasmic reticulum
  vesicular trafficking; its loss impairs intracellular trafficking and Golgi
  homeostasis, rendering hepatocytes and neurons (cerebellar Purkinje cells,
  motor and peripheral neurons) vulnerable to secretory/ER stress. The
  characteristic clinical triad comprises recurrent low/normal-GGT cholestasis
  or acute liver failure with onset in infancy, frequently triggered by febrile
  infections, together with later-onset and variably progressive
  neurodegeneration (cerebellar atrophy, ataxia, peripheral sensorimotor
  neuropathy) and frequent skeletal/growth abnormalities (short stature,
  scoliosis, hip dysplasia). Liver crises are often transient but progressive
  hepatic fibrosis develops; neurologic decline may continue independently of
  liver disease and can persist after liver transplantation.
synonyms:
- SCAR21
- spinocerebellar ataxia, autosomal recessive 21
- autosomal recessive spinocerebellar ataxia type 21
- SCYL1-related disease
- SCYL1 deficiency
- low gamma-glutamyltransferase cholestasis, acute liver failure, and neurodegeneration syndrome
disease_term:
  preferred_term: CALFAN Syndrome
  term:
    id: MONDO:0014744
    label: acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    CALFAN syndrome is inherited in an autosomal recessive manner, caused by
    biallelic (homozygous or compound heterozygous) loss-of-function variants
    in SCYL1; many reported cases occur in consanguineous families.
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven patients from five families with biallelic SCYL1 variants were
      identified.
    explanation: >-
      Biallelic (homozygous or compound heterozygous) SCYL1 variants in the
      foundational cohort establish autosomal recessive inheritance.

genetic:
- name: Biallelic SCYL1 loss-of-function variants
  gene_term:
    preferred_term: SCYL1
    term:
      id: hgnc:14372
      label: SCYL1
  association: Causal gene; biallelic loss-of-function variants cause CALFAN syndrome
  notes: >-
    SCYL1 (SCY1-like pseudokinase 1) on chromosome 11q13.1 encodes an
    N-terminal kinase-like protein that functions in COPI-mediated retrograde
    Golgi-to-ER vesicular trafficking. Reported pathogenic variants are
    predominantly truncating (nonsense/frameshift), consistent with a
    loss-of-function mechanism. Many reported cases occur in consanguineous
    families (homozygous), though compound heterozygosity also occurs.
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic mutations in SCYL1 were recently identified as causing a
      syndromal disorder characterized by peripheral neuropathy, cerebellar
      atrophy, ataxia, and recurrent episodes of liver failure.
    explanation: >-
      Establishes SCYL1 as the causal gene with biallelic mutations producing
      the core neurohepatic phenotype.
  - reference: PMID:37069859
    reference_title: "Recurrent Acute Liver Failure in a Bahraini Child With a Novel Mutation of Spinocerebellar Ataxia-21."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A whole-exome sequencing (WES) test revealed that the patient has
      previously unreported autosomal recessive pathogenic non-sense variation
      c.895A>T (p.Lys299Ter) in exon 7 of the SCYL1 gene in a homozygous status.
    explanation: >-
      Documents a homozygous nonsense (loss-of-function) SCYL1 variant causing
      the disorder, supporting the loss-of-function mechanism.

pathophysiology:
- name: SCYL1 Loss of Function
  description: >-
    Biallelic loss-of-function variants in SCYL1 abolish or reduce functional
    SCY1-like pseudokinase 1 protein. SCYL1 is an N-terminal kinase-like
    scaffold that operates at the Golgi apparatus in COPI-dependent vesicular
    trafficking.
  role: UPSTREAM
  gene:
    preferred_term: SCYL1
    term:
      id: hgnc:14372
      label: SCYL1
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional studies emphasize that SCYL1 deficiency is linked to impaired
      intracellular trafficking.
    explanation: >-
      Functional studies on patient fibroblasts directly link SCYL1 deficiency
      to impaired intracellular trafficking, the initiating molecular lesion.
  downstream:
  - target: Impaired COPI Retrograde Golgi-to-ER Trafficking
    description: >-
      Loss of SCYL1 scaffold function impairs COPI-mediated retrograde
      transport from the Golgi to the endoplasmic reticulum and disrupts Golgi
      architecture.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29419818
      reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Functional studies emphasize that SCYL1 deficiency is linked to impaired
        intracellular trafficking.
      explanation: >-
        SCYL1 loss of function directly impairs intracellular (COPI-mediated)
        trafficking.

- name: Impaired COPI Retrograde Golgi-to-ER Trafficking
  description: >-
    SCYL1 deficiency disrupts COPI-coated vesicle-mediated retrograde transport
    from the Golgi to the endoplasmic reticulum and alters Golgi organization.
    Mechanistic cell-biology work shows that the mTORC1-controlled
    phosphorylation status of SCYL1 (Ser754) regulates Golgi architecture,
    endolysosomal distribution, and extracellular vesicle secretion, and that
    loss-of-function of SCYL1 underlies CALFAN syndrome.
  role: INTERMEDIATE
  biological_processes:
  - preferred_term: Retrograde Golgi-to-ER vesicle transport
    term:
      id: GO:0006890
      label: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
    modifier: DECREASED
  - preferred_term: COPI coating of Golgi vesicle
    term:
      id: GO:0048205
      label: COPI coating of Golgi vesicle
    modifier: DECREASED
  - preferred_term: Golgi organization
    term:
      id: GO:0007030
      label: Golgi organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:35948564
    reference_title: "mTORC1 controls Golgi architecture and vesicle secretion by phosphorylation of SCYL1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we characterize the N-terminal kinase-like protein SCYL1 as a
      Golgi-localized target through which mTORC1 controls organelle
      distribution and extracellular vesicle secretion in breast cancer cells.
    explanation: >-
      Identifies SCYL1 as a Golgi-localized regulator of organelle distribution
      and vesicle secretion, supporting its role in COPI/Golgi trafficking.
  - reference: PMID:35948564
    reference_title: "mTORC1 controls Golgi architecture and vesicle secretion by phosphorylation of SCYL1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      It may also explain the pathophysiology underlying human genetic diseases
      such as CALFAN syndrome, which is caused by loss-of-function of SCYL1.
    explanation: >-
      Directly links SCYL1 trafficking/Golgi dysfunction to the pathophysiology
      of CALFAN syndrome.
  - reference: PMID:39187475
    reference_title: "Intracellular Trafficking Defects in Congenital Intestinal and Hepatic Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We give examples of how intracellular trafficking hubs, such as the
      apical recycling endosome system, the trans-Golgi network, lysosomes, or
      the Golgi-to-endoplasmic reticulum transport are involved in the
      pathomechanism and lead to disease.
    explanation: >-
      Review framing CALFAN among congenital intestinal/hepatic intracellular
      trafficking disorders implicating Golgi-to-ER transport.
  downstream:
  - target: Hepatocyte and Neuronal Secretory and ER Stress
    description: >-
      Defective retrograde trafficking and Golgi homeostasis impose secretory
      and ER stress on highly secretory hepatocytes and on neurons, sensitizing
      these cells to injury.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - disrupted Golgi architecture
    - impaired protein secretion and ER homeostasis
    evidence:
    - reference: PMID:35948564
      reference_title: "mTORC1 controls Golgi architecture and vesicle secretion by phosphorylation of SCYL1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Peripheral, dephosphorylated SCYL1 causes Golgi enlargement,
        redistribution of early and late endosomes and increased extracellular
        vesicle release.
      explanation: >-
        Disrupted SCYL1-dependent Golgi/endolysosomal homeostasis underlies the
        cellular secretory stress imposed on hepatocytes and neurons.

- name: Hepatocyte and Neuronal Secretory and ER Stress
  description: >-
    Impaired Golgi-ER trafficking produces secretory stress and a proposed ER
    stress / unfolded protein response in hepatocytes and neurons (cerebellar
    Purkinje cells, motor neurons, peripheral neurons), rendering them
    vulnerable to injury and degeneration, particularly during the metabolic
    demands of febrile illness.
  role: INTERMEDIATE
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: Motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  - preferred_term: Endoplasmic reticulum unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical phenotype was recurrent low γ-glutamyl-transferase
      (GGT) cholestasis or acute liver failure with onset in infancy and a
      variable neurological phenotype of later onset (CALFAN syndrome).
    explanation: >-
      The combined hepatic and neurological phenotype reflects vulnerability of
      hepatocytes and neurons downstream of the trafficking defect.
  - reference: PMID:35948564
    reference_title: "mTORC1 controls Golgi architecture and vesicle secretion by phosphorylation of SCYL1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Peripheral, dephosphorylated SCYL1 causes Golgi enlargement,
      redistribution of early and late endosomes and increased extracellular
      vesicle release.
    explanation: >-
      Demonstrates that perturbed SCYL1 function disrupts Golgi and
      endolysosomal homeostasis, the basis for cellular secretory stress.
  downstream:
  - target: Recurrent Hepatic Crises and Progressive Fibrosis
    description: >-
      Hepatocyte vulnerability manifests as recurrent low-GGT cholestasis and
      acute liver failure episodes, often febrile-triggered, with cumulative
      injury leading to hepatic fibrosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29419818
      reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Liver crises were triggered by febrile infections and were transient,
        but fibrosis developed.
      explanation: >-
        Hepatocyte injury manifests as febrile-triggered crises with
        progression to fibrosis.
  - target: Progressive Neurodegeneration
    description: >-
      Neuronal vulnerability drives later-onset, variably progressive
      cerebellar atrophy/ataxia and peripheral sensorimotor neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29419818
      reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biallelic mutations in SCYL1 were recently identified as causing a
        syndromal disorder characterized by peripheral neuropathy, cerebellar
        atrophy, ataxia, and recurrent episodes of liver failure.
      explanation: >-
        Neuronal vulnerability produces the peripheral neuropathy, cerebellar
        atrophy, and ataxia comprising the neurodegenerative phenotype.

- name: Recurrent Hepatic Crises and Progressive Fibrosis
  description: >-
    Episodic low/normal-GGT cholestasis and acute liver failure, frequently
    triggered by febrile infections, with onset in infancy. Crises are often
    transient with inter-episodic biochemical recovery, but hepatic fibrosis
    develops and can progress to cirrhosis in some patients.
  role: DOWNSTREAM
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver crises were triggered by febrile infections and were transient, but
      fibrosis developed.
    explanation: >-
      Directly documents febrile-triggered transient liver crises with
      development of hepatic fibrosis in the foundational cohort.
  - reference: PMID:37069859
    reference_title: "Recurrent Acute Liver Failure in a Bahraini Child With a Novel Mutation of Spinocerebellar Ataxia-21."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was admitted to the hospital twice by the age of two and five years due
      to acute hepatic failure triggered by a febrile illness.
    explanation: >-
      Confirms recurrent febrile-triggered acute hepatic failure episodes in a
      genetically confirmed patient.
  downstream:
  - target: Low gamma-glutamyltransferase cholestasis
    description: Hepatic crises include recurrent low-GGT cholestasis, the laboratory clue reflected by reduced gamma-glutamyltransferase.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29419818
      reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main clinical phenotype was recurrent low γ-glutamyl-transferase
        (GGT) cholestasis or acute liver failure with onset in infancy and a
        variable neurological phenotype of later onset (CALFAN syndrome).
      explanation: Low-GGT cholestasis is one of the main hepatic manifestations of CALFAN syndrome.
  - target: Cholestasis
    description: Recurrent hepatic crises manifest as infantile-onset cholestasis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29419818
      reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main clinical phenotype was recurrent low γ-glutamyl-transferase
        (GGT) cholestasis or acute liver failure with onset in infancy
      explanation: Identifies recurrent infantile-onset cholestasis as a core CALFAN hepatic phenotype.
  - target: Acute hepatic failure
    description: Febrile-triggered hepatic crises can present as recurrent acute liver failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37069859
      reference_title: "Recurrent Acute Liver Failure in a Bahraini Child With a Novel Mutation of Spinocerebellar Ataxia-21."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        He was admitted to the hospital twice by the age of two and five years due
        to acute hepatic failure triggered by a febrile illness.
      explanation: Documents recurrent febrile-triggered acute hepatic failure in a genetically confirmed patient.
  - target: Hepatic fibrosis
    description: Repeated transient hepatic crises are followed by progressive hepatic fibrosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29419818
      reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Liver crises were triggered by febrile infections and were transient, but
        fibrosis developed.
      explanation: Shows that fibrosis develops downstream of transient febrile-triggered liver crises.

- name: Progressive Neurodegeneration
  description: >-
    Later-onset and variably progressive neurodegeneration including cerebellar
    atrophy with ataxia and peripheral sensorimotor (motor-sensory) neuropathy.
    Neurologic decline may continue independently of hepatic disease and can
    persist after liver transplantation.
  role: DOWNSTREAM
  cell_types:
  - preferred_term: Cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: Peripheral neuron
    term:
      id: CL:2000032
      label: peripheral nervous system neuron
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic mutations in SCYL1 were recently identified as causing a
      syndromal disorder characterized by peripheral neuropathy, cerebellar
      atrophy, ataxia, and recurrent episodes of liver failure.
    explanation: >-
      Establishes peripheral neuropathy, cerebellar atrophy, and ataxia as core
      neurodegenerative features of SCYL1 deficiency.
  - reference: PMID:37069859
    reference_title: "Recurrent Acute Liver Failure in a Bahraini Child With a Novel Mutation of Spinocerebellar Ataxia-21."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After the first episode of ALF, he had progressive difficulty in walking
      leading to frequent falls and ending with a complete inability to walk.
    explanation: >-
      Documents progressive motor/neurologic decline following hepatic
      presentation, consistent with progressive neurodegeneration.
  downstream:
  - target: Cerebellar atrophy
    description: Progressive neurodegeneration includes cerebellar atrophy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29419818
      reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biallelic mutations in SCYL1 were recently identified as causing a
        syndromal disorder characterized by peripheral neuropathy, cerebellar
        atrophy, ataxia, and recurrent episodes of liver failure.
      explanation: Lists cerebellar atrophy among the neurodegenerative features of SCYL1 deficiency.
  - target: Cerebellar ataxia
    description: Cerebellar neurodegeneration manifests as progressive cerebellar ataxia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29419818
      reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biallelic mutations in SCYL1 were recently identified as causing a
        syndromal disorder characterized by peripheral neuropathy, cerebellar
        atrophy, ataxia, and recurrent episodes of liver failure.
      explanation: Lists ataxia among the neurodegenerative features of SCYL1 deficiency.
  - target: Peripheral sensorimotor neuropathy
    description: Peripheral neuronal involvement produces sensorimotor neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29419818
      reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biallelic mutations in SCYL1 were recently identified as causing a
        syndromal disorder characterized by peripheral neuropathy, cerebellar
        atrophy, ataxia, and recurrent episodes of liver failure.
      explanation: Lists peripheral neuropathy among the neurodegenerative features of SCYL1 deficiency.
  - target: Gait disturbance
    description: Progressive neurodegeneration causes worsening gait disturbance and eventual loss of ambulation in some patients.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37069859
      reference_title: "Recurrent Acute Liver Failure in a Bahraini Child With a Novel Mutation of Spinocerebellar Ataxia-21."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        After the first episode of ALF, he had progressive difficulty in walking
        leading to frequent falls and ending with a complete inability to walk.
      explanation: Documents progressive gait deterioration to loss of ambulation.
  - target: Motor delay
    description: CALFAN neurologic involvement can include delayed gross motor development.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37069859
      reference_title: "Recurrent Acute Liver Failure in a Bahraini Child With a Novel Mutation of Spinocerebellar Ataxia-21."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient had delayed gross motor development as he started to walk at
        20 months of age.
      explanation: Documents delayed gross motor development in a genetically confirmed CALFAN patient.

phenotypes:
- category: Laboratory
  name: Low gamma-glutamyltransferase cholestasis
  description: >-
    Characteristic low or normal serum gamma-glutamyltransferase (GGT) in the
    setting of cholestasis, an important diagnostic clue distinguishing CALFAN
    from high-GGT cholestatic disorders.
  phenotype_term:
    preferred_term: Reduced gamma-glutamyltransferase level
    term:
      id: HP:0034445
      label: Reduced gamma-glutamyltransferase level
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical phenotype was recurrent low γ-glutamyl-transferase
      (GGT) cholestasis or acute liver failure with onset in infancy and a
      variable neurological phenotype of later onset (CALFAN syndrome).
    explanation: >-
      Identifies low-GGT cholestasis as the main hepatic phenotype.

- category: Clinical
  name: Cholestasis
  description: Recurrent cholestasis with onset in infancy.
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
    temporality: RECURRENT
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical phenotype was recurrent low γ-glutamyl-transferase
      (GGT) cholestasis or acute liver failure with onset in infancy
    explanation: Recurrent cholestasis with infantile onset is a core feature.

- category: Clinical
  name: Acute hepatic failure
  description: >-
    Recurrent acute liver failure with onset in infancy or early childhood,
    frequently triggered by febrile infections.
  phenotype_term:
    preferred_term: Acute hepatic failure
    term:
      id: HP:0006554
      label: Acute hepatic failure
    temporality: RECURRENT
  frequency: FREQUENT
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The occurrence of SCYL1 deficiency among patients with previously
      undetermined infantile cholestasis or acute liver failure has not been
      studied
    explanation: >-
      Establishes acute liver failure as a defining hepatic manifestation of
      SCYL1 deficiency.
  - reference: PMID:37069859
    reference_title: "Recurrent Acute Liver Failure in a Bahraini Child With a Novel Mutation of Spinocerebellar Ataxia-21."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was admitted to the hospital twice by the age of two and five years due
      to acute hepatic failure triggered by a febrile illness.
    explanation: Documents recurrent febrile-triggered acute hepatic failure.

- category: Clinical
  name: Hepatic fibrosis
  description: >-
    Progressive hepatic fibrosis developing despite transient liver crises;
    may progress to cirrhosis.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver crises were triggered by febrile infections and were transient, but
      fibrosis developed.
    explanation: Fibrosis developed in the foundational cohort despite transient crises.

- category: Clinical
  name: Cerebellar atrophy
  description: Cerebellar atrophy, part of the later-onset neurodegenerative phenotype.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic mutations in SCYL1 were recently identified as causing a
      syndromal disorder characterized by peripheral neuropathy, cerebellar
      atrophy, ataxia, and recurrent episodes of liver failure.
    explanation: Cerebellar atrophy is a defining neurologic feature.

- category: Clinical
  name: Cerebellar ataxia
  description: >-
    Progressive cerebellar ataxia with gait impairment, often later-onset than
    the hepatic disease.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic mutations in SCYL1 were recently identified as causing a
      syndromal disorder characterized by peripheral neuropathy, cerebellar
      atrophy, ataxia, and recurrent episodes of liver failure.
    explanation: Ataxia is a defining neurologic feature of SCYL1 deficiency.

- category: Clinical
  name: Peripheral sensorimotor neuropathy
  description: >-
    Peripheral motor-sensory (sensorimotor) neuropathy, part of the progressive
    neurodegenerative phenotype.
  phenotype_term:
    preferred_term: Sensorimotor neuropathy
    term:
      id: HP:0007141
      label: Sensorimotor neuropathy
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic mutations in SCYL1 were recently identified as causing a
      syndromal disorder characterized by peripheral neuropathy, cerebellar
      atrophy, ataxia, and recurrent episodes of liver failure.
    explanation: Peripheral neuropathy is a defining feature of CALFAN syndrome.

- category: Clinical
  name: Gait disturbance
  description: Progressive difficulty walking, frequent falls, ultimately loss of ambulation.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37069859
    reference_title: "Recurrent Acute Liver Failure in a Bahraini Child With a Novel Mutation of Spinocerebellar Ataxia-21."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After the first episode of ALF, he had progressive difficulty in walking
      leading to frequent falls and ending with a complete inability to walk.
    explanation: Documents progressive gait deterioration to loss of ambulation.

- category: Clinical
  name: Motor delay
  description: >-
    Delayed acquisition of gross motor milestones reported in genetically
    confirmed CALFAN patients (e.g., delayed independent walking).
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:37069859
    reference_title: "Recurrent Acute Liver Failure in a Bahraini Child With a Novel Mutation of Spinocerebellar Ataxia-21."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had delayed gross motor development as he started to walk at
      20 months of age.
    explanation: >-
      Documents delayed acquisition of gross motor milestones (walking at 20
      months) in a genetically confirmed CALFAN patient.

- category: Clinical
  name: Scoliosis
  description: Scoliosis, among the skeletal abnormalities reported in CALFAN syndrome.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:35616485
    reference_title: "The Outcomes of an Individualized Physical Therapy Program in CALFAN Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Cobb angle was increased by 2° in the thoracic region and reduced by
      11° in the lumbar region.
    explanation: >-
      Cobb-angle measurements document spinal curvature (scoliosis) managed
      with physical therapy in a CALFAN patient.

- category: Clinical
  name: Short stature
  description: Short stature / growth retardation among skeletal-growth features.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:37554250
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CALFAN syndrome is an extremely rare disease consisting of recurrent
      pediatric acute liver failure (PALF), neurodegenerative diseases, and
      skeletal abnormalities associated with SCYL1 gene mutation.
    explanation: >-
      Establishes skeletal abnormalities as a component of the CALFAN triad.
      Short stature is reported among these skeletal/growth features in case
      series (Lenz et al. 2018); this abstract-level evidence supports the
      broader skeletal-abnormality category rather than short stature
      specifically.

clinical_trials:
- name: NCT04653909
  status: COMPLETED
  description: >-
    Single-case interventional rehabilitation study evaluating an individualized
    physiotherapy and rehabilitation program in CALFAN syndrome, with outcomes
    including the Trunk Impairment Scale, International Cooperative Ataxia Rating
    Scale, Pediatric Quality of Life Inventory, and Functional Independence
    Measure for Children.
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: clinicaltrials:NCT04653909
    reference_title: "The Effectiveness of Rehabilitation Program in an Ultra-rare Calfan Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The aim of this study is to investigate the effectiveness of the
      physiotherapy and rehabilitation program in a rare case with Calfan
      syndrome.
    explanation: >-
      Registered single-case rehabilitation study evaluating physiotherapy for
      CALFAN syndrome.

treatments:
- name: Supportive Care for Acute Liver Failure
  description: >-
    Supportive, trigger-focused management of febrile-precipitated cholestatic
    and acute liver failure crises, including infection control, correction of
    coagulopathy, nutritional optimization with fat-soluble vitamins, and close
    monitoring of synthetic liver function. There is no established
    disease-modifying therapy; crises typically recover with supportive care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver crises were triggered by febrile infections and were transient, but
      fibrosis developed.
    explanation: >-
      Transient nature of crises supports a supportive-care management approach
      during febrile-triggered episodes.

- name: Liver Transplantation
  description: >-
    Liver transplantation for progressive or recurrent liver failure not
    controlled by supportive care. Reported in infancy/early childhood and, in
    one case, in early adulthood with favorable 3-year graft outcome.
    Transplantation addresses hepatic disease but does not arrest
    neurodegeneration, which may persist.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:37554250
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, three of 18 patients reported underwent liver transplantation in
      infancy and early childhood (7-23 months).
    explanation: >-
      Documents liver transplantation as a management option in CALFAN
      syndrome.
  - reference: PMID:37554250
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the most recent follow-up, 3 years after transplantation, the patient
      is doing well.
    explanation: >-
      Reports favorable hepatic outcome 3 years after liver transplantation in
      early adulthood.

- name: Physical Therapy and Rehabilitation
  description: >-
    Individualized physical therapy program (trunk stabilization, balance
    training, functional exercises) improving quality of life, functional
    independence, trunk control, and upper-extremity performance in a child
    with CALFAN syndrome.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:35616485
    reference_title: "The Outcomes of an Individualized Physical Therapy Program in CALFAN Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical therapy improved quality of life, functional independence, trunk
      control, and upper extremity performance.
    explanation: >-
      Demonstrates functional benefit of physical therapy in CALFAN syndrome.

- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence-risk counseling, cascade testing, and
    reproductive options for at-risk families, including prenatal and
    preimplantation genetic testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29419818
    reference_title: "SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven patients from five families with biallelic SCYL1 variants were
      identified.
    explanation: >-
      Autosomal recessive inheritance with biallelic variants underpins the
      need for recurrence-risk genetic counseling.

notes: >-
  CALFAN syndrome is ultra-rare; the literature comprises individual case
  reports/series rather than population-level cohorts. A 2023 transplant case
  report stated that 18 CALFAN patients with SCYL1 mutation had been reported at
  that time. Reported pathogenic SCYL1 variants include c.895A>T (p.Lys299Ter),
  c.1567C>T (p.Arg523*), and a c.745_746insG frameshift, all consistent with
  loss of function. Differential diagnoses include PFIC and other low/normal-GGT
  cholestasis disorders, NBAS-related recurrent acute liver failure, and other
  fever-triggered genetic causes of infantile acute liver failure. A
  loss-of-Scyl1 mouse model recapitulates motor neuron disease and cerebellar
  degeneration, supporting the neurodegenerative arm of the human phenotype.
  The label "spinocerebellar ataxia, autosomal recessive 21 (SCAR21)" is used
  interchangeably with CALFAN in some literature (e.g., Demir et al. 2023,
  PMID:36503921; Isa et al. 2023, PMID:37069859).
  Additional high-frequency findings reported in the foundational Lenz et al.
  2018 cohort (7 patients) are documented in the full-text tables but not in the
  abstract, so they are recorded here as notes pending abstract-quotable or
  full-text-validated evidence: hepatomegaly (7/7), microcephaly (6/7),
  splenomegaly (4/7), and neonatal jaundice (3/7). These are biologically
  consistent with the multisystem CALFAN phenotype but were intentionally not
  added as evidence-backed phenotype entries because no exact-quote snippet is
  available from the cached abstracts (per the dismech anti-hallucination SOP).

📚

References & Deep Research

Deep Research

1

Falcon ▸

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

Edison Scientific Literature 37 citations 2026-06-04T16:16:28.894866

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

Disease: CALFAN syndrome is defined by the triad of low/normal-GGT cholestasis, acute liver failure, and neurodegeneration, caused by SCYL1 deficiency. (lenz2018scyl1variantscause pages 1-2, szabo2024intracellulartraffickingdefects pages 7-8)
Foundational description emphasizes infantile onset hepatic crises with later-onset neurologic manifestations and progressive hepatic fibrosis. (lenz2018scyl1variantscause pages 6-7)

1.2 Key identifiers

OMIM/MIM: MIM: 616719 (reported in a 2024 review). (szabo2024intracellulartraffickingdefects pages 7-8)
MONDO, Orphanet, ICD-10/ICD-11, MeSH: Not identified in the retrieved source set; should be verified in external disease ontologies for knowledge-base normalization. (szabo2024intracellulartraffickingdefects pages 7-8, szabo2024intracellulartraffickingdefects pages 1-2)

1.3 Synonyms / alternative names

SCYL1-related disease, SCYL1 deficiency, and overlapping label spinocerebellar ataxia, autosomal recessive type 21 (SCAR21) appear in the literature. (demir2023coexistenceofspinocerebellar pages 3-4, isa2023recurrentacuteliver pages 3-5)

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)

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

Genetic cause (primary): Biallelic pathogenic variants in SCYL1. (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 10-12)
Triggering factor (physiologic/environmental): Febrile infections/intercurrent illness frequently precipitate hepatic crises. (lenz2018scyl1variantscause pages 6-7, isa2023recurrentacuteliver pages 1-3, lenz2018scyl1variantscause pages 1-2)

2.2 Risk factors

Genetic: Autosomal recessive inheritance; many reported cases occur in consanguineous families (homozygosity), though compound heterozygosity occurs. (yadav2026infantileliverfailure pages 6-7, yadav2026infantileliverfailure pages 10-12)
Environmental/clinical: Febrile illness and intercurrent infections are repeatedly reported as triggers; modifiers (nutritional state, age at first decompensation) are proposed but not quantified in the retrieved evidence. (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 6-7)

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

Core hepatic phenotype: recurrent low/normal-GGT cholestasis or ALF starting in infancy, with crises often triggered by febrile infection. (lenz2018scyl1variantscause pages 6-7, lenz2018scyl1variantscause pages 1-2)
Progression: in the foundational cohort, crises were transient but fibrosis developed in all. (lenz2018scyl1variantscause pages 6-7)

3.2 Neurologic phenotypes

Later-onset and variably progressive: microcephaly, developmental/language delay, tremor, gait impairment/ataxia, peripheral neuropathy, cerebellar atrophy; seizures in a minority. (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 8-10, isa2023recurrentacuteliver pages 3-5)

3.3 Skeletal/growth phenotypes

Short stature/growth retardation, scoliosis, hip dysplasia and other musculoskeletal abnormalities are reported in many patients. (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 8-10)

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

SCYL1 (SCY1-like pseudokinase 1). (szabo2024intracellulartraffickingdefects pages 7-8, szabo2024intracellulartraffickingdefects pages 1-2)

4.2 Pathogenic variants (examples from recent and foundational reports)

c.895A>T (p.Lys299Ter), homozygous nonsense; described as novel/likely pathogenic in a 2023 case with recurrent ALF and neurodevelopmental impairment. (isa2023recurrentacuteliver pages 3-5, isa2023recurrentacuteliver pages 1-3)
c.1567C>T (p.Arg523*), homozygous nonsense in a consanguineous family; presented as infantile fever-triggered ALF/cholestasis without initial neurologic signs (reported in a later case-based review). (yadav2026infantileliverfailure pages 6-7)
c.745_746insG (frameshift insertion) reported in a pediatric case with severe hepatic phenotype. (suenera2025acuteonchronica pages 4-6, suenera2025acuteonchronic pages 4-6)

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)

SCYL1 loss-of-function →
Impaired intracellular trafficking, especially COPI-mediated Golgi–ER retrograde trafficking →
Hepatocyte secretory stress and (proposed) ER stress/unfolded protein response, culminating in susceptibility to hepatocellular injury/apoptosis, particularly during febrile illness →
Recurrent cholestasis/ALF episodes with cumulative injury leading to fibrosis/cirrhosis in some →
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

Vesicular trafficking (Golgi–ER retrograde transport; COPI-related processes) are central, with SCYL1 acting as a scaffold/regulator. (yadav2026infantileliverfailure pages 6-7, hellicar2021investigatingtherole pages 35-38)
mTORC1–SCYL1 axis: mechanistic cell biology work shows mTORC1 phosphorylates SCYL1 (Ser754) to control Golgi architecture, endolysosomal distribution, and extracellular vesicle secretion; authors suggest relevance to CALFAN pathophysiology. (kaeserpebernard2022mtorc1controlsgolgi pages 1-2, kaeserpebernard2022mtorc1controlsgolgi pages 7-8)

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

A mechanistic dissertation reports that loss of Scyl1 in mice causes motor neuron disease and cerebellar degeneration and provides biochemical trafficking interaction data (e.g., COPI/COPII interactions). (hellicar2021investigatingtherole pages 106-111, hellicar2021investigatingtherole pages 35-38)

7. Anatomical structures affected (suggested UBERON)

Primary organ: liver (UBERON: liver). (lenz2018scyl1variantscause pages 6-7, lenz2018scyl1variantscause pages 1-2)
Nervous system: cerebellum (cerebellar atrophy), peripheral nerves (neuropathy). (yadav2026infantileliverfailure pages 8-10, youssef2023calfan(lowγglutamyl pages 3-5)
Musculoskeletal system: spine (scoliosis), hip (hip dysplasia). (lenz2018scyl1variantscause pages 6-7, NCT04653909 chunk 1)
Subcellular compartments: Golgi apparatus, ER–Golgi intermediate compartment, endosomes/lysosomes (based on SCYL1 localization and mTORC1-regulated redistribution). (kaeserpebernard2022mtorc1controlsgolgi pages 1-2, hellicar2021investigatingtherole pages 35-38)

8. Temporal development

Onset: hepatic disease typically begins in infancy/early childhood, with crises reported in the first 18 months in the foundational cohort. (lenz2018scyl1variantscause pages 6-7)
Progression: hepatic crises may be transient with inter-episodic normalization, yet fibrosis can progress; neurologic manifestations often emerge later and may be progressive. (lenz2018scyl1variantscause pages 6-7, yadav2026infantileliverfailure pages 8-10)

9. Inheritance and population

9.1 Inheritance

Autosomal recessive. (yadav2026infantileliverfailure pages 10-12, demir2023coexistenceofspinocerebellar pages 3-4)

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

Low-to-normal GGT cholestasis in the setting of fever-triggered cholestatic hepatitis/ALF is repeatedly emphasized as a key clue. (yadav2026infantileliverfailure pages 8-10, yadav2026infantileliverfailure pages 3-6)
Episodes can show marked transaminase elevations and coagulopathy; ALF definition includes INR criteria not corrected by vitamin K in at least one report. (yadav2026infantileliverfailure pages 1-3, yadav2026infantileliverfailure pages 3-6)

10.2 Genetic testing approach

Whole-exome sequencing (WES) is repeatedly described as diagnostic and is recommended early in infants/children with fever-triggered ALF and low/normal-GGT cholestasis, particularly with consanguinity or family history. (isa2023recurrentacuteliver pages 1-3, yadav2026infantileliverfailure pages 8-10)

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

Hepatic course: crises may resolve but fibrosis can accumulate; in the foundational 7-patient cohort, fibrosis developed in all patients. (lenz2018scyl1variantscause pages 6-7)
Neurologic course: neurodegeneration may be progressive and can persist after liver transplantation. (youssef2023calfan(lowγglutamyl pages 3-5, yadav2026infantileliverfailure pages 8-10)

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)

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

Primary prevention: not available for an inherited SCYL1 loss-of-function disorder.
Secondary/tertiary prevention (practical): anticipatory guidance and rapid evaluation/treatment of febrile illnesses; avoidance of hepatotoxic exposures; longitudinal monitoring for hepatic decompensation and neurologic progression. (yadav2026infantileliverfailure pages 10-12, yadav2026infantileliverfailure pages 8-10)
Genetic counseling: autosomal recessive recurrence-risk counseling and reproductive options (prenatal/preimplantation genetic testing) are recommended in case-based literature. (yadav2026infantileliverfailure pages 6-7, yadav2026infantileliverfailure pages 10-12)

14. Other species / natural disease

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

15. Model organisms

Evidence from an experimental dissertation indicates mouse Scyl1 loss causes motor neuron disease and cerebellar degeneration and provides trafficking interaction insights (COPI/COPII). (hellicar2021investigatingtherole pages 106-111, hellicar2021investigatingtherole pages 35-38)

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

(lenz2018scyl1variantscause pages 6-7): Dominic Lenz, Patricia McClean, Aydan Kansu, Penelope E. Bonnen, Giusy Ranucci, Christian Thiel, Beate K. Straub, Inga Harting, Bader Alhaddad, Bianca Dimitrov, Urania Kotzaeridou, Daniel Wenning, Raffaele Iorio, Ryan W. Himes, Zarife Kuloğlu, Emma L. Blakely, Robert W. Taylor, Thomas Meitinger, Stefan Kölker, Holger Prokisch, Georg F. Hoffmann, Tobias B. Haack, and Christian Staufner. Scyl1 variants cause a syndrome with lowγ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (calfan). Genetics in Medicine, 20:1255-1265, Oct 2018. URL: https://doi.org/10.1038/gim.2017.260, doi:10.1038/gim.2017.260. This article has 78 citations and is from a highest quality peer-reviewed journal.
(lenz2018scyl1variantscause pages 1-2): Dominic Lenz, Patricia McClean, Aydan Kansu, Penelope E. Bonnen, Giusy Ranucci, Christian Thiel, Beate K. Straub, Inga Harting, Bader Alhaddad, Bianca Dimitrov, Urania Kotzaeridou, Daniel Wenning, Raffaele Iorio, Ryan W. Himes, Zarife Kuloğlu, Emma L. Blakely, Robert W. Taylor, Thomas Meitinger, Stefan Kölker, Holger Prokisch, Georg F. Hoffmann, Tobias B. Haack, and Christian Staufner. Scyl1 variants cause a syndrome with lowγ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (calfan). Genetics in Medicine, 20:1255-1265, Oct 2018. URL: https://doi.org/10.1038/gim.2017.260, doi:10.1038/gim.2017.260. This article has 78 citations and is from a highest quality peer-reviewed journal.
(isa2023recurrentacuteliver pages 3-5): Hasan M Isa, Jawaher F Alkaabi, Wasan H Alhammadi, and Khadija A Marjan. Recurrent acute liver failure in a bahraini child with a novel mutation of spinocerebellar ataxia-21. Cureus, Mar 2023. URL: https://doi.org/10.7759/cureus.36249, doi:10.7759/cureus.36249. This article has 6 citations.
(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.
(szabo2024intracellulartraffickingdefects pages 7-8): Luca Szabó, Adam R. Pollio, and Georg Friedrich Vogel. Intracellular trafficking defects in congenital intestinal and hepatic diseases. Traffic, Aug 2024. URL: https://doi.org/10.1111/tra.12954, doi:10.1111/tra.12954. This article has 2 citations and is from a peer-reviewed journal.
(szabo2024intracellulartraffickingdefects pages 1-2): Luca Szabó, Adam R. Pollio, and Georg Friedrich Vogel. Intracellular trafficking defects in congenital intestinal and hepatic diseases. Traffic, Aug 2024. URL: https://doi.org/10.1111/tra.12954, doi:10.1111/tra.12954. This article has 2 citations and is from a peer-reviewed journal.
(demir2023coexistenceofspinocerebellar pages 3-4): Engin Demir, Ümmühan Öncül, Merve Havan, Ceyda Tuna Kirsaçlioğlu, Fatma Tuba Eminoğlu, Tanil Kendirli, Zarife Kuloğlu, and Aydan Kansu. Coexistence of spinocerebellar ataxia autosomal recessive type 21 and ehlers-danlos syndrome spondylodysplastic type 3 in a patient. Clinical dysmorphology, 32 1:25-28, Nov 2023. URL: https://doi.org/10.1097/mcd.0000000000000435, doi:10.1097/mcd.0000000000000435. This article has 0 citations and is from a peer-reviewed journal.
(yadav2026infantileliverfailure pages 6-7): Deepika Yadav, Nishant Wadhwa, and Megha Sharma. Infantile liver failure as the initial manifestation of scyl1-related calfan syndrome: a case report and literature review. Archives of Pediatric Gastroenterology, Hepatology, and Nutrition, 5:86-97, May 2026. URL: https://doi.org/10.58427/apghn.5.2.2026.86-97, doi:10.58427/apghn.5.2.2026.86-97. This article has 0 citations.
(yadav2026infantileliverfailure pages 10-12): Deepika Yadav, Nishant Wadhwa, and Megha Sharma. Infantile liver failure as the initial manifestation of scyl1-related calfan syndrome: a case report and literature review. Archives of Pediatric Gastroenterology, Hepatology, and Nutrition, 5:86-97, May 2026. URL: https://doi.org/10.58427/apghn.5.2.2026.86-97, doi:10.58427/apghn.5.2.2026.86-97. This article has 0 citations.
(yadav2026infantileliverfailure pages 8-10): Deepika Yadav, Nishant Wadhwa, and Megha Sharma. Infantile liver failure as the initial manifestation of scyl1-related calfan syndrome: a case report and literature review. Archives of Pediatric Gastroenterology, Hepatology, and Nutrition, 5:86-97, May 2026. URL: https://doi.org/10.58427/apghn.5.2.2026.86-97, doi:10.58427/apghn.5.2.2026.86-97. This article has 0 citations.
(NCT04653909 chunk 1): Serkan Usgu. The Physiotherapy and Rehabilitation in Calfan Syndrome. Hasan Kalyoncu University. 2020. ClinicalTrials.gov Identifier: NCT04653909
(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.
(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.
(isa2023recurrentacuteliver pages 1-3): Hasan M Isa, Jawaher F Alkaabi, Wasan H Alhammadi, and Khadija A Marjan. Recurrent acute liver failure in a bahraini child with a novel mutation of spinocerebellar ataxia-21. Cureus, Mar 2023. URL: https://doi.org/10.7759/cureus.36249, doi:10.7759/cureus.36249. This article has 6 citations.
(isa2023recurrentacuteliver pages 5-6): Hasan M Isa, Jawaher F Alkaabi, Wasan H Alhammadi, and Khadija A Marjan. Recurrent acute liver failure in a bahraini child with a novel mutation of spinocerebellar ataxia-21. Cureus, Mar 2023. URL: https://doi.org/10.7759/cureus.36249, doi:10.7759/cureus.36249. This article has 6 citations.
(youssef2023calfan(lowγglutamyl pages 2-3): 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.
(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.
(yigit2022theoutcomesof pages 5-6): 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.
(yigit2022theoutcomesof pages 2-3): 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.
(suenera2025acuteonchronica 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.
(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.
(isa2023recurrentacuteliver pages 7-8): Hasan M Isa, Jawaher F Alkaabi, Wasan H Alhammadi, and Khadija A Marjan. Recurrent acute liver failure in a bahraini child with a novel mutation of spinocerebellar ataxia-21. Cureus, Mar 2023. URL: https://doi.org/10.7759/cureus.36249, doi:10.7759/cureus.36249. This article has 6 citations.
(youssef2023calfan(lowγglutamyl pages 1-2): 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.
(suenera2025acuteonchronicc 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.
(suenera2025acuteonchronicd 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.
(hellicar2021investigatingtherole pages 35-38): JP Hellicar. Investigating the role of scyl1 in the secretory pathway and how its loss causes disease in humans. Unknown journal, 2021.
(kaeserpebernard2022mtorc1controlsgolgi pages 7-8): 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.
(hellicar2021investigatingtherole pages 106-111): JP Hellicar. Investigating the role of scyl1 in the secretory pathway and how its loss causes disease in humans. Unknown journal, 2021.
(yadav2026infantileliverfailure pages 1-3): Deepika Yadav, Nishant Wadhwa, and Megha Sharma. Infantile liver failure as the initial manifestation of scyl1-related calfan syndrome: a case report and literature review. Archives of Pediatric Gastroenterology, Hepatology, and Nutrition, 5:86-97, May 2026. URL: https://doi.org/10.58427/apghn.5.2.2026.86-97, doi:10.58427/apghn.5.2.2026.86-97. This article has 0 citations.
(yadav2026infantileliverfailure pages 3-6): Deepika Yadav, Nishant Wadhwa, and Megha Sharma. Infantile liver failure as the initial manifestation of scyl1-related calfan syndrome: a case report and literature review. Archives of Pediatric Gastroenterology, Hepatology, and Nutrition, 5:86-97, May 2026. URL: https://doi.org/10.58427/apghn.5.2.2026.86-97, doi:10.58427/apghn.5.2.2026.86-97. This article has 0 citations.
(yigit2022theoutcomesof pages 3-4): 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.
(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.

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

Executive summary

1. Disease information

1.1 Definition and overview

1.2 Key identifiers

1.3 Synonyms / alternative names

1.4 Evidence source type

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes (with suggested HPO terms)

3.1 Hepatic phenotypes

3.2 Neurologic phenotypes

3.3 Skeletal/growth phenotypes

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variants (examples from recent and foundational reports)

4.3 Functional consequences

4.4 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Current mechanistic understanding (causal chain)

6.2 Pathways and cellular processes

6.3 Suggested ontology terms

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

10. Diagnostics

10.1 Clinical/laboratory hallmarks

10.2 Genetic testing approach

10.3 Differential diagnosis

11. Outcome / prognosis

12. Treatment

12.1 Acute and chronic medical management (supportive)

12.2 Liver transplantation

12.3 Rehabilitation / physical therapy (real-world implementation)

13. Prevention

14. Other species / natural disease

15. Model organisms

Direct quotes from abstracts (available in retrieved evidence)

Notes on evidence gaps and recommended next steps for curation

Artifacts