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Journal of Inherited Metabolic Disease

, Volume 38, Issue 6, pp 1085–1092 | Cite as

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS

  • Jillian P. Casey
  • Suzanne Slattery
  • Melanie Cotter
  • A. A. Monavari
  • Ina Knerr
  • Joanne Hughes
  • Eileen P. Treacy
  • Deirdre Devaney
  • Michael McDermott
  • Eoghan Laffan
  • Derek Wong
  • Sally Ann Lynch
  • Billy Bourke
  • Ellen Crushell
Original Article

Abstract

Background

Recessive LARS mutations were recently reported to cause a novel syndrome, infantile liver failure syndrome type 1 (ILFS1), in six Irish Travellers. We have since identified four additional patients, including one of Ashkenazi origin, representing the largest ILFS1 cohort to date. Our study aims to define the ILFS1 clinical phenotype to help guide diagnosis and patient management.

Methods

We clinically evaluated and reviewed the medical records of ten ILFS1 patients. Clinical features, histopathology and natural histories were compared and patient management strategies reviewed.

Results

Early failure to thrive, recurrent liver dysfunction, anemia, hypoalbuminemia and seizures were present in all patients. Most patients (90 %) had developmental delay. Encephalopathic episodes triggered by febrile illness have occurred in 80 % and were fatal in two children. Two patients are currently >28 years old and clinically well. Leucine supplementation had no appreciable impact on patient well-being. However, we suggest that the traditional management of reducing/stopping protein intake in patients with metabolic hepatopathies may not be appropriate for ILFS1. We currently recommend ensuring sufficient natural protein intake when unwell.

Conclusions

We report the first non-Irish ILFS1 patient, suggesting ILFS1 may be more extensive than anticipated. Low birth weight, early failure to thrive, anemia and hypoalbuminemia are amongst the first presenting features, with liver dysfunction before age 1. Episodic hepatic dysfunction is typically triggered by febrile illness, and becomes less severe with increasing age. While difficult to anticipate, two patients are currently >28 years old, suggesting that survival beyond childhood may be associated with a favourable long-term prognosis.

Keywords

Acute Liver Failure Aminoacyl tRNA Synthetase Microcytic Anemia Leucine Supplement Leigh Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We sincerely thank the patients and their families who have contributed to this study and helped our understanding of childhood liver disease. We would also like to thank Prof. David Wilson (Professor of Paediatric Gastroenterology and Nutrition at the University of Edinburgh) for his insightful discussions on albuminemia and amino acid homeostasis and Dr Seamus Hussey and Dr Annemarie Broderick for stimulating discussions on mechanisms of liver disease.

Funding

The genetic studies were supported by The Children's Fund for Health, Temple Street Children's University Hospital, Dublin, Ireland (PAC 09131). Jillian Casey is supported by a Medical Research Charities Group (MRCG) grant from the Health Research Board (HRB) and the Children’s Fund for Health, Temple Street Children’s University Hospital (MRCG/2013/02).

Compliance with Ethics Guidelines

Conflict of interest

None.

Supplementary material

10545_2015_9849_MOESM1_ESM.docx (25 kb)
ESM 1 (DOCX 25 kb)

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Copyright information

© SSIEM 2015

Authors and Affiliations

  • Jillian P. Casey
    • 1
    • 2
  • Suzanne Slattery
    • 3
  • Melanie Cotter
    • 4
  • A. A. Monavari
    • 3
  • Ina Knerr
    • 3
  • Joanne Hughes
    • 3
  • Eileen P. Treacy
    • 3
  • Deirdre Devaney
    • 5
  • Michael McDermott
    • 6
  • Eoghan Laffan
    • 7
  • Derek Wong
    • 8
  • Sally Ann Lynch
    • 1
    • 2
    • 9
  • Billy Bourke
    • 10
  • Ellen Crushell
    • 2
    • 3
    • 10
  1. 1.Genetics DepartmentTemple Street Children’s University HospitalDublin 1Ireland
  2. 2.UCD Academic Centre on Rare Diseases, School of Medicine and Medical ScienceUniversity College DublinDublin 4Ireland
  3. 3.National Centre for Inherited Metabolic DisordersTemple Street Children’s University HospitalDublin 1Ireland
  4. 4.Department of HaematologyTemple Street Children’s University HospitalDublin 1Ireland
  5. 5.Histopathology DepartmentTemple Street Children’s University HospitalDublin 1Ireland
  6. 6.Pathology DepartmentOur Lady’s Children’s HospitalDublin 12Ireland
  7. 7.Department of RadiologyTemple Street Children’s University HospitalDublin 1Ireland
  8. 8.Department of Pediatrics, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA
  9. 9.National Centre for Medical GeneticsOur Lady’s Children’s HospitalDublin 12Ireland
  10. 10.Our Lady’s Children’s HospitalDublin 12Ireland

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