Autosomal Recessive Spinocerebellar Ataxia 21 with Hepatopathy

Autosomal recessive spinocerebellar ataxia 21 with hepatopathy is a very rare inherited disorder caused by harmful changes in the SCYL1 gene. “Autosomal recessive” means a child is affected only when they receive one non-working copy of the gene from each parent. The condition has two main parts. The first part is ataxia, which means unsteady movement and poor balance because the cerebellum (the balance center in the brain) does not work well and may shrink. The second part is hepatopathy, which means the liver can have repeated attacks of illness—often during fevers—showing jaundice, very high liver enzymes, and sometimes acute liver failure in infancy or childhood. Many children recover between attacks, but some can develop scarring of the liver over time. Nerve problems in the legs and hands (neuropathy) can appear later. This disorder is also called CALFAN syndrome (cerebellar ataxia, neuropathy, and episodic liver failure). PMC+1NCBIMalaCards

Autosomal recessive spinocerebellar ataxia 21 with hepatopathy is a very rare genetic disease. It is caused by harmful changes (pathogenic variants) in a gene called SCYL1. Children usually look healthy at birth. In early childhood they develop problems with balance and coordination because the cerebellum (the brain’s balance center) slowly shrinks and works poorly. Many children also have a peripheral neuropathy, which means the long nerves in the arms and legs are damaged, leading to weakness, numbness, and loss of reflexes. A key feature is recurrent attacks of liver trouble, often after a fever or infection. During attacks, lab tests show low-GGT cholestasis and sometimes acute liver failure with jaundice and bleeding problems. Between attacks the liver can improve, but some people develop scarring (fibrosis) over time. The condition is inherited in an autosomal recessive pattern, so a child is affected when they receive one non-working copy of SCYL1 from each parent. PMC+2PMC+2NCBI

Other names

This condition is also called: CALFAN syndrome (low-GGT Cholestasis/Acute Liver Failure/Ataxia/Neurodegeneration), SCYL1 deficiency syndrome, spinocerebellar ataxia, autosomal recessive 21 (SCAR21), and acute infantile liver failure–cerebellar ataxia–peripheral sensory-motor neuropathy syndrome. All these names describe the same SCYL1-related disorder with episodes of liver injury and progressive neurologic problems. PMCOrphaNCBI

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Types

There is no single official “type” system, but clinicians often recognize patterns along a spectrum:

1) Classic CALFAN / SCAR21.
Early-childhood cerebellar ataxia and peripheral neuropathy, plus repeated liver crises with low-GGT cholestasis—often after febrile illnesses. Brain MRI shows cerebellar atrophy. PMC+1

2) Hepatopathy-predominant childhood form.
First signs are repeated liver attacks in infancy or early childhood; neurological signs (ataxia, neuropathy) become clearer later. PMC+1

3) Neuro-predominant form.
Progressive ataxia and neuropathy with milder or less frequent liver episodes; MRI shows cerebellar atrophy. PMC

4) Episodic vs. chronic course.
Some children have distinct, infection-triggered crises separated by recovery; others show a more steady, chronic pattern with gradual liver fibrosis and neurologic progression. PMC

These “types” are descriptive, not separate diseases. All are caused by SCYL1 variants. PMC

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Causes

1) Pathogenic variants in SCYL1.
The root cause. SCYL1 encodes a protein that helps move cargo from the Golgi back to the endoplasmic reticulum (COPI-mediated retrograde trafficking). Faulty trafficking stresses cells—especially Purkinje cells and peripheral nerves—and also harms liver cells. PMCOAText

2) Autosomal recessive inheritance.
A child is affected when both parents carry one altered SCYL1 copy and the child inherits both altered copies. NCBI

3) Purkinje cell vulnerability.
Cerebellar Purkinje neurons are highly sensitive to trafficking stress, leading to ataxia and cerebellar atrophy. (Inference from disease pattern and MRI.) PMC

4) Peripheral axonal degeneration.
Long motor and sensory nerves degenerate, producing distal weakness, numbness, and reduced reflexes. Nerve studies show axonal neuropathy. PMC

5) Hepatocyte cholestasis with low GGT.
Bile flow is impaired at a cellular level, but GGT stays low—this pattern helps point to CALFAN. PMC

6) Recurrent febrile infections.
Fevers and viral illnesses are common triggers for acute liver episodes (“attacks”). PMC

7) Catabolic stress (fasting/dehydration).
Periods of limited intake or dehydration can stress the liver and may worsen attacks (general trigger pattern in pediatric liver crises; often noted clinically alongside infections). PMC

8) Certain vaccinations or intercurrent illnesses.
Any strong immune activation may coincide with an episode in some reports (rare). The link is temporal, not causal. PMC

9) Oxidative and ER stress.
Defective trafficking can overwhelm protein handling, leading to unfolded-protein responses that harm neurons and hepatocytes. (Mechanistic inference consistent with SCYL1 biology.) OAText

10) Inadequate recovery between episodes.
Repeated inflammation and cholestasis may leave residual scarring and functional decline in the liver over years. PMC

11) Growth and developmental demand.
Rapid growth phases increase cellular stress in vulnerable tissues, unmasking deficits in trafficking. (Rationale based on pediatric onset.) PMC

12) Genetic background / modifier genes.
Different families show variable severity even with SCYL1 variants—suggesting background genes shape expression. PMC

13) Specific SCYL1 variant class.
Truncating vs. missense variants may correlate with earlier or more severe disease, although numbers are small. PMC

14) Mitochondrial vulnerability during illness.
Acute illness can transiently worsen cellular energy balance in liver and nerves. (Clinical inference in pediatric acute liver failure more broadly.) PMC

15) Nutritional deficits during prolonged illness.
Poor intake during febrile episodes may intensify cholestasis and coagulopathy. (General pediatric ALF principle.) PMC

16) Recurrent coagulopathy.
Each liver failure episode strains clotting factor production, raising bleeding risks and clinical severity. PMC

17) Secondary infections during hospitalization.
Intercurrent infections can complicate recovery from an acute episode. (General ALF risk.) PMC

18) Delayed recognition of low-GGT pattern.
If the characteristic lab pattern is missed, supportive steps can be delayed, increasing risk in an attack. PMC

19) Chronic fibrosis from repeated attacks.
Over years, scarring can accumulate and reduce liver reserve. MalaCards

20) Limited access to genetic testing.
Without confirmation of SCYL1, families may not receive precise counseling about triggers and recurrence risk. NCBI

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Symptoms

1) Gait unsteadiness (ataxia).
Children stumble, widen their stance, and have trouble turning or running because the cerebellum cannot finely control movement. PMC

2) Poor coordination of hands.
Tasks like drawing, buttoning, or touching finger-to-nose are clumsy (dysmetria and intention tremor). PMC

3) Slurred or scanning speech.
Words may sound choppy because the muscles that shape speech need precise cerebellar timing. PMC

4) Eye movement problems.
Nystagmus or slow saccades can appear, making tracking lines of text or fast objects hard. PMC

5) Distal weakness and wasting.
Hands and feet may look thinner over time due to peripheral nerve damage. Grip strength falls. PMC

6) Numbness and tingling.
Loss of vibration and position sense in the feet, with pins-and-needles sensations. Reflexes are often reduced. PMC

7) Recurrent jaundice.
During a liver attack, the eyes and skin turn yellow as bilirubin builds up. PMC

8) Itching (pruritus) with low-GGT cholestasis.
Poor bile flow causes itching; GGT is characteristically low for the degree of cholestasis. PMC

9) Abdominal pain and enlarged liver.
Tenderness or hepatomegaly may appear during flares. PMC

10) Easy bruising or bleeding.
The sick liver cannot make enough clotting factors, so bleeding risk rises in severe episodes. PMC

11) Extreme tiredness.
Fatigue is common in liver crises and with chronic neurologic effort. PMC

12) Confusion or sleepiness in severe attacks.
High ammonia or other toxins can affect the brain (hepatic encephalopathy). PMC

13) Delayed motor milestones / learning difficulties.
Some children walk late, and some develop mild learning challenges later in school years. PMC

14) Growth slowdown.
Repeated illness and poor intake during episodes can lower weight gain or height velocity. PMC

15) Tremor or shaky movements.
Hands may shake when trying to do precise tasks, reflecting cerebellar dysfunction. PMC

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Diagnostic tests

Doctors combine the story, exam, labs, imaging, nerve tests, and genetics to make the diagnosis and to rule out other causes of pediatric acute liver failure and childhood ataxia.

A) Physical examination

1) Full neurologic exam.
Checks gait, stance, heel-to-toe walking, finger-to-nose, heel-to-shin, speech, eye movements, tone, and reflexes. Cerebellar signs (ataxia, dysmetria), distal weakness, and reduced reflexes point toward SCAR21. PMC

2) Liver exam.
Looks for jaundice, scratch marks from itching, bruises, tender or enlarged liver, fluid in the abdomen, and mental status changes during attacks. PMC

3) Developmental assessment.
Milestones, school progress, and fine-motor skills are reviewed because coordination and learning can be affected. PMC

4) Nutritional and hydration status.
Illness-triggered attacks are worse with dehydration and poor intake, so weight, mucous membranes, and vital signs are checked closely. PMC

5) Family pedigree.
Looking for siblings with similar features and consanguinity helps support autosomal recessive inheritance. NCBI

B) Manual bedside tests

6) Tandem gait and Romberg.
Heel-to-toe walking stresses balance; Romberg tests position sense. Cerebellar disease often causes wide-based gait and instability. PMC

7) Finger-to-nose and heel-to-shin.
Reveal intention tremor and limb dysmetria typical of cerebellar ataxia. PMC

8) Rapid alternating movements.
Dysdiadochokinesia (slow, irregular hand flips) is a classic cerebellar sign. PMC

9) Manual muscle testing.
Graded strength testing uncovers distal weakness from axonal neuropathy. PMC

10) Vibration and joint-position with a tuning fork.
Loss at the toes supports large-fiber sensory neuropathy. PMC

C) Lab and pathological tests

11) Liver panel with GGT.
Shows cholestasis with low GGT, a hallmark clue to CALFAN during flares; bilirubin, ALT/AST, ALP, and GGT are tracked across episodes. PMC

12) Synthetic function and ammonia.
INR/PT, albumin, and blood ammonia assess severity and the risk of encephalopathy during acute liver failure. PMC

13) Infection workup during episodes.
Respiratory and GI viral panels help document febrile triggers and rule out primary infectious hepatitis. PMC

14) Metabolic and autoimmune screens (exclusion tests).
Used to exclude other causes of pediatric liver failure (e.g., Wilson disease, fatty acid oxidation defects, autoimmune hepatitis) because treatment paths differ. (General ALF practice.) PMC

15) Genetic testing for SCYL1.
Targeted sequencing or exome/genome testing confirms biallelic SCYL1 pathogenic variants and secures the diagnosis for the family. NCBI

16) Liver biopsy (select cases).
When safe, it may show cholestasis and variable fibrosis; it is not always needed if genetics are definitive. MalaCards

D) Electrodiagnostic tests

17) Nerve conduction studies and EMG.
Typically show an axonal sensorimotor neuropathy, supporting the “peripheral sensory-motor neuropathy” part of the syndrome. PMC

18) EEG during encephalopathy or seizures.
Assesses brain function and helps guide supportive care during severe liver attacks. (General ALF care.) PMC

E) Imaging tests

19) Brain MRI.
Shows cerebellar atrophy (shrinking of the cerebellum) that matches the clinical ataxia. MRI also helps rule out other structural causes. PMC

20) Abdominal ultrasound and elastography (FibroScan).
Tracks liver size, texture, bile ducts, and scarring; MRCP can be used if the biliary tree needs closer inspection. PMC

Non-pharmacological treatments

Physiotherapy-focused items

1. Postural and trunk control training
   Description: Guided exercises to keep the body upright and steady while sitting and standing; uses physio cues, wedges, and stability balls. Purpose: Reduce trunk sway and improve sitting/standing endurance. Mechanism: Repeated activation of core and paraspinal muscles builds postural reflexes and cerebellar compensation. Benefits: Better balance, fewer falls, easier transfers.

2. Gait and balance retraining
   Description: Step-by-step walking practice with parallel bars, body-weight support treadmills, or over-ground harnesses. Purpose: Safer walking. Mechanism: Task-specific repetition improves stride timing and foot placement. Benefits: More stable walking, greater distance, confidence.

3. Coordination (ataxia) drills
   Description: Frenkel-style slow, precise limb movements with visual fixation; finger-to-nose, heel-to-shin. Purpose: Improve limb accuracy. Mechanism: Visual/vestibular feedback helps cerebellar circuits recalibrate. Benefits: Smoother, more targeted reach and step.

4. Vestibular rehab
   Description: Habituation, gaze-stabilization, and balance tasks. Purpose: Reduce dizziness and oscillopsia. Mechanism: Promotes central compensation for vestibular mismatch. Benefits: Less dizziness, steadier head/eye control.

5. Strength training (low-to-moderate)
   Description: Resistance bands and closed-chain exercises. Purpose: Support joints and mobility. Mechanism: Hypertrophy and motor unit recruitment increase stability. Benefits: Easier transfers, stair climbing, and daily tasks.

6. Task-specific reaching and grasping
   Description: Repeated practice of real-life tasks (cup lifting, buttoning). Purpose: Improve hand function. Mechanism: Motor learning with error correction. Benefits: Faster dressing, feeding, writing.

7. Tremor management strategies
   Description: Weighted utensils, wrist weights, proximal stabilization. Purpose: Reduce action tremor impact. Mechanism: Damps high-frequency oscillations and stabilizes proximal joints. Benefits: Cleaner handwriting, steadier eating.

8. Spasticity and tone management stretching
   Description: Daily passive stretches, splints, serial casting if needed. Purpose: Maintain range of motion. Mechanism: Lengthens muscle-tendon units; reduces contracture risk. Benefits: Easier hygiene, positioning, and gait.

9. Neuropathy-aware foot care and orthotics
   Description: Custom insoles/ankle-foot orthoses; skin checks. Purpose: Safer stance and foot clearance. Mechanism: Mechanical alignment and sensory protection. Benefits: Fewer trips, skin breakdown prevention.

10. Endurance/aerobic conditioning (safe heart-rate zone)
    Description: Recumbent bike, aquatic therapy, or over-ground walking. Purpose: Reduce fatigue. Mechanism: Cardiometabolic conditioning raises VO₂ and mitochondrial efficiency. Benefits: More daily energy.

11. Energy conservation & pacing
    Description: Break tasks into short, planned blocks with rests. Purpose: Prevent over-fatigue and falls. Mechanism: Matches activity to physiologic reserve. Benefits: More tasks completed without crash.

12. Breathing and cough support
    Description: Incentive spirometry, assisted coughing when weak. Purpose: Lower infection risk. Mechanism: Improves lung expansion and secretion clearance. Benefits: Fewer chest infections that could trigger liver crises.

13. Swallowing safety strategies (with SLP)
    Description: Texture modification, chin-tuck, paced sips. Purpose: Reduce aspiration. Mechanism: Compensatory swallowing postures/protocols. Benefits: Safer nutrition, fewer pneumonias.

14. Home safety and fall-proofing
    Description: Rails, non-slip flooring, lighting, shower chairs. Purpose: Injury prevention. Mechanism: Hazard reduction. Benefits: Fewer fractures and ER visits.

15. Assistive technology training
    Description: Use of canes, walkers, wheelchairs, communication devices. Purpose: Preserve independence. Mechanism: Compensates for gait and coordination limits. Benefits: Longer community participation.

Mind-body, “gene-informed,” and educational therapies

16. Fever-response plan and early antipyretic/fluids protocol
    Description: Written steps for treating fevers fast at home and at the ER (antipyretics as prescribed, oral/IV glucose and fluids early). Purpose: Reduce risk of fever-triggered liver crises. Mechanism: Limits catabolic stress on hepatocytes seen in SCYL1/NBAS-like disorders. Benefits: Fewer or milder crises. Frontiers

17. Vaccination optimization
    Description: Follow routine vaccine schedule; add annual influenza and consider RSV/COVID per clinician. Purpose: Fewer infections, fewer liver crises. Mechanism: Lowers febrile illness burden. Benefits: Crisis prevention. NASPGHAN

18. Mindfulness-based stress reduction and breathing practice
    Description: Short, daily guided breathing and mindfulness. Purpose: Lower anxiety, steady motor control. Mechanism: Parasympathetic activation can reduce tremor amplitude and muscle co-contraction. Benefits: Calmer movement.

19. Cognitive-behavioral strategies for fatigue and pacing
    Description: Goal setting, graded activity, rest scheduling. Purpose: Sustain school/work. Mechanism: Behavioral energy budgeting. Benefits: Better attendance and participation.

20. Nutrition therapy with liver-smart routines
    Description: Small, frequent meals; sick-day plan for carbs/fluids; fat-soluble vitamin monitoring. Purpose: Maintain energy and prevent hypoglycemia during illness. Mechanism: Stabilizes glucose and bile flow. Benefits: More stable days. PMC

21. Gene-informed care & genetic counseling
    Description: Family counseling on autosomal-recessive inheritance; carrier testing for parents/siblings; prenatal/preimplantation options if desired. Purpose: Family planning and early detection. Mechanism: Identifies carriers/affected early. Benefits: Informed decisions. NCBI

22. Clinical-trial/registry readiness
    Description: Keep genetic report, imaging, and crisis summaries organized; join rare-disease registries. Purpose: Access future trials quickly. Mechanism: Streamlines eligibility checks. Benefits: Earlier opportunities when available.

23. School IEP / 504 accommodations
    Description: Extra time, note-takers, elevator access, rest breaks, PE modifications. Purpose: Educational success. Mechanism: Removes barriers from ataxia/fatigue. Benefits: Better grades, less stress.

24. Occupational therapy for ADLs
    Description: Task simplification, adaptive tools (button hooks, built-up pens). Purpose: Independence at home and school. Mechanism: Motor learning plus device support. Benefits: Faster self-care, writing.

25. Speech-language therapy & AAC as needed
    Description: Work on dysarthria and clear speech; introduce communication apps if necessary. Purpose: Reliable communication. Mechanism: Repetition and compensatory techniques. Benefits: Social participation and safety.

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Drug treatments

Important: Doses and choices must be individualized by your clinicians, especially in infants/children and during liver dysfunction. The drugs below are used according to standard PALF/cholestasis/neurology guidance; there is no SCYL1-specific approved drug yet. PMCaasld.org

1. N-Acetylcysteine (NAC)
   Class: Antioxidant/glutathione precursor. Typical dosing/time: PALF protocols often use IV loading then infusion; oral forms exist—follow center protocol. Purpose: Supportive therapy in acute liver failure while etiology is clarified. Mechanism: Replenishes hepatic glutathione, reduces oxidative injury. Side effects: Nausea, rare anaphylactoid reactions; monitor closely. PMC

2. Ursodeoxycholic acid (UDCA)
   Class: Bile acid. Dose: Commonly 10–15 mg/kg/day in divided doses. Purpose: Improve cholestasis symptoms and labs. Mechanism: Replaces toxic bile acids, improves bile flow. Side effects: Diarrhea, rare liver enzyme rise—monitor. jogc.com

3. Cholestyramine
   Class: Bile acid sequestrant. Dose: Split doses before/after meals; separate from other medicines. Purpose: First-line for cholestatic pruritus. Mechanism: Binds bile acids in the gut to reduce itch. Side effects: Constipation, fat-soluble vitamin loss. aasld.org

4. Rifampin (Rifampicin)
   Class: Enzyme inducer antibiotic. Dose: Often 150–300 mg/day in older children/adults; monitor LFTs. Purpose: Second-line for pruritus not relieved by cholestyramine/UDCA. Mechanism: Induces detox pathways that reduce pruritogens. Side effects: Hepatotoxicity, drug interactions, orange fluids. PMC

5. Naltrexone
   Class: Opioid antagonist. Dose: Often 25–50 mg/day titrated. Purpose: Third-line for cholestatic itch. Mechanism: Blocks endogenous opioids thought to drive pruritus. Side effects: Nausea, withdrawal-like symptoms initially. PMC

6. Sertraline
   Class: SSRI. Dose: 50–100 mg/day in older patients per guidance. Purpose: Fourth-line for itch and mood. Mechanism: Central serotonergic modulation reduces itch perception. Side effects: GI upset, sleep changes. PMC

7. Vitamin K
   Class: Hemostatic vitamin. Dose: Per protocol (oral/IV). Purpose: Correct coagulopathy in liver dysfunction. Mechanism: Restores clotting factor activation. Side effects: Rare reactions with IV; monitor INR. PMC

8. Fat-soluble vitamins (A, D, E, K) and mineral repletion
   Class: Nutritional supplements under medical supervision. Purpose: Prevent deficiency during cholestasis. Mechanism: Replaces malabsorbed vitamins. Side effects: Risk of toxicity if overdosed—monitor levels. PMC

9. Lactulose (± Rifaximin)
   Class: Non-absorbable disaccharide (± non-absorbable antibiotic). Purpose: Treat hepatic encephalopathy if present. Mechanism: Traps ammonia in the gut; rifaximin reduces ammonia-producing bacteria. Side effects: Bloating/diarrhea (lactulose). PMC

10. Proton pump inhibitor or H2 blocker
    Class: Acid suppression. Purpose: GI bleed prophylaxis during PALF/PICU care. Mechanism: Reduces gastric acid and stress ulcers. Side effects: GI and infection risks with long use. aasld.org

11. Antipyretics (e.g., Acetaminophen at safe doses per weight)
    Purpose: Rapid fever control to lower crisis risk. Mechanism: Central COX inhibition lowers temperature. Caution: In liver dysfunction, use only with hepatology guidance. Frontiers

12. Gabapentin or Pregabalin
    Class: Neuropathic pain modulators. Purpose: Treat painful peripheral neuropathy. Mechanism: α2δ subunit binding reduces excitatory neurotransmission. Side effects: Drowsiness, dizziness.

13. Baclofen or Tizanidine
    Class: Antispastic agents. Purpose: Treat troublesome spasticity/stiffness. Mechanism: GABA-B agonism (baclofen) or α2-agonism (tizanidine) reduces muscle tone. Side effects: Sedation, weakness; baclofen requires cautious use if liver involvement.

14. Propranolol (for action tremor)
    Class: β-blocker. Purpose: Reduce disabling tremor. Mechanism: Dampens peripheral tremor oscillations. Side effects: Bradycardia, fatigue; avoid if contraindicated (asthma, etc.).

15. Antiemetics and supportive IV glucose/lipids during crises
    Class: Supportive care set. Purpose: Maintain hydration and calories; control vomiting. Mechanism: Prevents catabolism and hypoglycemia that can worsen liver stress. Side effects: Drug-specific (e.g., QT risk with some antiemetics). PMC

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Dietary molecular supplements

Evidence for supplements in SCYL1 disease is limited; choices are extrapolated from cholestasis, neuropathy, or liver-support literature. Monitor levels and interactions.

1. Omega-3 fatty acids (EPA/DHA)
   Dose: Commonly 1–2 g/day EPA+DHA in older teens/adults (pediatric per weight). Function/mechanism: Anti-inflammatory effects and membrane stabilization; may help pruritus and triglycerides in cholestasis. Note: Bleeding risk on high doses.

2. Vitamin D3
   Dose: As per deficiency and monitoring. Function: Bone and immune support; cholestasis often lowers vitamin D. Mechanism: Replenishes fat-soluble vitamin stores. Note: Avoid overdose; monitor 25-OH D.

3. Vitamin E (natural d-alpha-tocopherol or water-miscible forms)
   Dose: Per weight and labs. Function: Antioxidant; prevents neurologic damage in fat-malabsorption. Mechanism: Protects neuronal membranes from oxidative stress.

4. Coenzyme Q10 (Ubiquinone/Ubiquinol)
   Dose: Often 100–300 mg/day in older patients. Function: Mitochondrial electron transport support; may aid fatigue. Mechanism: Improves cellular energy production.

5. Alpha-lipoic acid
   Dose: 300–600 mg/day in older patients. Function: Antioxidant; sometimes used in neuropathy. Mechanism: Regenerates other antioxidants; may reduce oxidative stress in nerves.

6. S-adenosyl-L-methionine (SAMe)
   Dose: Follow clinician guidance. Function: Methyl-donor that may support cholestatic symptoms in adults. Mechanism: Enhances bile flow and hepatocyte methylation. Note: Evidence varies.

7. Branched-chain amino acids (BCAA)
   Dose: As medical nutrition under supervision. Function: Support in hepatic encephalopathy and muscle loss. Mechanism: Competes with aromatic AAs; supports muscle protein. Note: Use only when indicated in liver failure care pathways. PMC

8. Choline or phosphatidylcholine
   Dose: Per dietitian plan. Function: Membrane and bile composition support. Mechanism: Supplies phospholipids for bile.

9. Taurine
   Dose: Diet-guided. Function: Conjugates bile acids and supports membrane stability. Mechanism: May assist bile flow in some cholestatic states.

10. Probiotics (strain-specific, e.g., Lactobacillus/Bifidobacterium)
    Function: Gut barrier health; may reduce ammonia production if encephalopathy is an issue. Mechanism: Alters microbiome toward lower toxin generation. Note: Evidence varies; use medically supervised.

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Immunity-booster / regenerative / stem-cell” drugs or approaches

1. Intravenous immunoglobulin (IVIG)
   Use: Not standard for SCYL1 disease itself, but may be used if an autoimmune trigger is proven during a crisis. Mechanism: Immune modulation. Dose: Protocol-based. Status: Case-by-case only.

2. Granulocyte-colony stimulating factor (G-CSF)
   Use: Not routine; considered only if documented neutropenia with infections. Mechanism: Boosts neutrophils. Status: Off-label/rare.

3. Hepatocyte transplantation (cell therapy)
   Use: Investigational bridge in pediatric liver failure at some centers. Mechanism: Donor hepatocytes provide temporary function. Status: Research/selected cases; not standard everywhere. PMC

4. Mesenchymal stromal cell infusions
   Use: Experimental in liver failure/fibrosis. Mechanism: Immunomodulation and trophic support. Status: Clinical trials only.

5. Neuro-regenerative rehab with robotic exoskeletons
   Use: Device-assisted gait training to drive neuroplasticity. Mechanism: High-repetition, task-specific stepping. Status: Rehab technology; not a drug but regenerative-aimed.

6. Future gene therapy concepts for SCYL1
   Use: No approved gene therapy today. Mechanism: In principle, AAV-based or other vectors could restore SCYL1; still preclinical/aspirational. Status: Keep genetic records to be trial-ready. Nature

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Surgeries

1. Liver transplantation
   Procedure: Replace failing liver with donor organ. Why: For irreversible acute liver failure or end-stage liver disease when medical care fails. Note: Definitive life-saving option in PALF across etiologies. PMC

2. Gastrostomy tube placement
   Procedure: Feeding tube to stomach. Why: Poor weight gain, unsafe swallow, or high energy needs.

3. Orthopedic procedures (e.g., tendon lengthening, scoliosis correction)
   Why: Fixed contractures or spinal curves that limit mobility or breathing despite therapy.

4. Intrathecal baclofen pump
   Procedure: Programmable pump delivers baclofen to spinal fluid. Why: Refractory spasticity with oral side effects.

5. Deep brain stimulation (DBS)
   Procedure: Electrodes in thalamus or GPi. Why: Severe, medication-resistant tremor or dystonia impacting function; selected cases only.

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Prevention strategies

1. Treat fevers early per plan; seek medical review for any febrile illness. Frontiers

2. Keep vaccines up to date (including flu); reduce infections. NASPGHAN

3. Avoid known hepatotoxic drugs/herbals unless essential; always check with hepatology. aasld.org

4. Have a sick-day plan: hydration, carbs, monitoring, and low threshold for ER. PMC

5. Regular monitoring of growth, nutrition, and fat-soluble vitamins in cholestasis. PMC

6. Fall-proof home; use appropriate mobility aids.

7. Foot care routines to prevent neuropathic injury.

8. Consistent sleep and energy-pacing schedule.

9. Written emergency letter explaining SCYL1 disease for ER teams. PMC

10. Genetic counseling for family planning and early diagnosis in siblings. NCBI

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When to see a doctor now

• Fever with new jaundice, dark urine, pale stools, vomiting, confusion, or bleeding.

• Fast worsening unsteady gait, falls, or new weakness/numbness.

• Severe itch, poor feeding, or dehydration in a child.

• Any episode where you suspect acute liver failure signs (sleepiness, confusion, bruising)—go to an emergency department that can contact a pediatric liver transplant center. aasld.org

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What to eat and what to avoid

Good to eat (examples):

1. Small, frequent meals with complex carbs (rice, oats, potatoes).

2. Lean proteins in moderate portions (eggs, poultry, fish); adjust only if encephalopathy under clinician guidance. PMC

3. Fruits/vegetables for fiber and micronutrients.

4. Healthy fats (olive oil, nuts; omega-3-rich fish).

5. Adequate fluids; oral rehydration during illness.

Best to avoid or limit:

1. Alcohol (if age-relevant) and vaping/smoking—liver and nerve protection.
2. High-dose vitamin A or niacin supplements (hepatotoxic risk) unless prescribed.
3. Raw/undercooked shellfish (infection risk).
4. Herbal products with liver toxicity risk (e.g., kava, chaparral, comfrey).
5. Extreme high-fat or fad diets that worsen cholestasis symptoms. aasld.org

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Frequently Asked Questions

1. Is there a cure?
   No approved cure yet. Care aims to prevent/limit liver crises and support movement and nerves. Gene therapy is a future hope. Nature

2. Will liver crises stop with age?
   They often become less frequent as children grow, but each person is different. Nature

3. Why do fevers trigger liver problems?
   Fever and illness stress the liver’s cell-traffic system that is already fragile in SCYL1 disease. Wiley Online Library

4. What tests confirm the diagnosis?
   Genetic testing showing disease-causing variants in SCYL1, plus clinical history and imaging (cerebellar atrophy), support the diagnosis. NCBI

5. What does “low GGT” mean here?
   During crises, GGT can be low/normal despite cholestasis; this pattern helps doctors think of CALFAN. Nature

6. Could my other children have it?
   Each sibling has a 25% chance if both parents are carriers; genetic counseling can help. NCBI

7. When is transplant considered?
   When the liver fails and does not recover with medical care or there is advanced scarring and complications. PMC

8. Does ataxia always get worse?
   It varies. Rehab can improve function. Neuropathy may appear later; regular follow-up helps.

9. Are there special labs during illness?
   Yes. Liver enzymes, bilirubin, INR, ammonia, glucose, and electrolytes—often repeatedly—to guide care. PMC

10. What about school and sports?
    With an IEP/504 plan and safe activity choices, most children can attend school and participate. Balance high-energy days with rest.

11. Can pruritus (itch) be treated?
    Yes—stepwise approach: cholestyramine first, then rifampin, naltrexone, or sertraline if needed. aasld.org

12. Is there a special diet?
    No single “SCYL1 diet.” Balanced meals, vitamins if low, and a sick-day plan are key. PMC

13. What hospitals should we use?
    Centers with pediatric hepatology and access to transplant and neuro-rehab are ideal in crises. aasld.org

14. Are there related disorders?
    NBAS and RINT1 defects also cause fever-triggered recurrent acute liver failure. Wiley Online Library

15. Where can clinicians read more?
    Papers describing SCYL1/CALFAN and cholestasis/PALF guidance: Lenz 2018; Schmidt 2015; recent reviews and society guidelines listed in citations. NaturePMC+1aasld.org

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Last Updated: September 06, 2025.

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