Skip to main content
SpringerLink
Log in
Book cover

JIMD Reports, Volume 28 pp 75–84Cite as

Neuropsychological Development in Patients with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency

  • Research Report
  • Chapter
  • First Online:

Part of the book series: JIMD Reports ((JIMD,volume 28))

Abstract

Background: Reports on cognitive outcomes in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) are scarce. We present results from neuropsychological assessments of eight patients diagnosed with LCHADD prior to newborn screening with regard to clinical disease severity.

Methods: Intellectual ability and adaptive and executive functions were assessed using age-appropriate Wechsler Scales, Adaptive Behavior Assessment Scales (ABAS), and Behavior Rating Inventory of Executive Function (BRIEF).

Results: Five patients performed in the normal range on IQ tests but with lower scores on verbal working memory. In addition, they had lower parent-rated adaptive and executive functions.

Three patients had intellectual disabilities with IQs below normal and/or autism spectrum disorders. In addition, they had low results on parent-rated adaptive functions. (Two of these patients had epilepsy.)

Conclusions: Patients with LCHADD seem to have a specific cognitive pattern, with presentation as intellectual disability and specific autistic deficiencies or a normal IQ with weaknesses in auditive verbal memory and adaptive and executive functions. Future studies are warranted to investigate whether newborn screening programs and early treatment may promote improved neuropsychological development and outcomes.

Competing interests: None declared

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

ABAS:

Adaptive Behavior Assessment System®

ASD:

Autism spectrum disorder

BRIEF:

Behavior Rating Inventory of Executive Function®

DHA:

Docosahexaenoic acid

FAOD:

Fatty acid oxidation defect

GAC:

General Adaptive Composite

GEF:

Global executive function

LCHADD:

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

LCT:

Long-chain triglyceride

MCT:

Medium-chain triglyceride

MTP:

Mitochondrial trifunctional protein

References

  • Angelidou A, Asadi S, Alysandratos KD, Karagkouni A, Kourembanas S, Theoharides TC (2012) Perinatal stress, brain inflammation and risk of autism – review and proposal. BMC Pediatr 12:89

    Article  PubMed  PubMed Central  Google Scholar 

  • APA DSM IV (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Baddeley A (1992) Working memory. Science 255:556–559

    Article  CAS  PubMed  Google Scholar 

  • Bakermans AJ, Geraedts TR, Van Weeghel M et al (2011) Fasting-induced myocardial lipid accumulation in long-chain acyl-CoA dehydrogenase knockout mice is accompanied by impaired left ventricular function. Circ Cardiovasc Imaging 4:558–565

    Article  PubMed  Google Scholar 

  • Brown A, Crowe L, Andresen BS, Anderson V, Boneh A (2014) Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening. Mol Genet Metab 113:278–282

    Article  CAS  PubMed  Google Scholar 

  • Carver JD, Benford VJ, Han B, Cantor AB (2001) The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects. Brain Res Bull 56:79–85

    Google Scholar 

  • Chaste P, Leboyer M (2012) Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci 14:281–292

    PubMed  PubMed Central  Google Scholar 

  • Clark-Taylor T, Clark-Taylor BE (2004) Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial beta-oxidation by long chain acyl-CoA dehydrogenase. Med Hypotheses 62:970–975

    Article  CAS  PubMed  Google Scholar 

  • Cox GF, Souri M, Aoyama T et al (1998) Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr 133:247–253

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13:701–712

    Article  CAS  PubMed  Google Scholar 

  • De Urquiza AM, Liu SY, Sjoberg M et al (2000) Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290:2140–2144

    Article  PubMed  Google Scholar 

  • Den Boer ME, Wanders RJ, Morris AA, Ijlst L, Heymans HS, Wijburg FA (2002) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics 109:99–104

    Article  Google Scholar 

  • Fahnehjelm KT, Holmstrom G, Ying L et al (2008) Ocular characteristics in 10 children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a cross-sectional study with long-term follow-up. Acta Ophthalmol 86:329–337

    Article  PubMed  Google Scholar 

  • Fletcher AL, Pennesi ME, Harding CO, Weleber RG, Gillingham MB (2012) Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies. Mol Genet Metab 106:18–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fliesler SJ, Anderson RE (1983) Chemistry and metabolism of lipids in the vertebrate retina. Prog Lipid Res 22:79–131

    Article  CAS  PubMed  Google Scholar 

  • German OL, Monaco S, Agnolazza DL, Rotstein NP, Politi LE (2013) Retinoid X receptor activation is essential for docosahexaenoic acid protection of retina photoreceptors. J Lipid Res 54:2236–2246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillingham MB, Weleber RG, Neuringer M et al (2005) Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency. Mol Genet Metab 86:124–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gioia GA, Isquith PK, Guy SC, Kenworthy L (2000) Behavior rating inventory of executive function. Psychological Assessment Resources, Odessa

    Google Scholar 

  • Haglind CB, Halldin MU, Ask S et al (2013) Growth in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. JIMD Rep 8:81–90

    Article  PubMed  Google Scholar 

  • Harding CO, Gillingham MB, Van Calcar SC, Wolff JA, Verhoeve JN, Mills MD (1999) Docosahexaenoic acid and retinal function in children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 22:276–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harrison PL, Oakland T (2003) Swedish version (2008) Adaptive behavior assessment system – ABAS-II. Harcourt Assessment, Stockholm Pearson Assessment, San Antonio

    Google Scholar 

  • Heaton AE, Meldrum SJ, Foster JK, Prescott SL, Simmer K (2013) Does docosahexaenoic acid supplementation in term infants enhance neurocognitive functioning in infancy? Front Hum Neurosci 7:1–12

    Article  Google Scholar 

  • Hsu HW, Zytkovicz TH, Comeau AM et al (2008) Spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by newborn screening. Pediatrics 121:e1108–e1114

    Article  PubMed  Google Scholar 

  • Iafolla AK, Thompson RJ Jr, Roe CR (1994) Medium-chain acyl-coenzyme A dehydrogenase deficiency: clinical course in 120 affected children. J Pediatr 124:409–415

    Article  CAS  PubMed  Google Scholar 

  • Joy P, Black C, Rocca A, Haas M, Wilcken B (2009) Neuropsychological functioning in children with medium chain acyl coenzyme a dehydrogenase deficiency (MCADD): the impact of early diagnosis and screening on outcome. Child Neuropsychol 15:8–20

    Article  PubMed  Google Scholar 

  • Kayser MA (2008) Inherited metabolic diseases in neurodevelopmental and neurobehavioral disorders. Semin Pediatr Neurol 15:127–131

    Article  PubMed  Google Scholar 

  • Manzi B, Loizzo AL, Giana G, Curatolo P (2008) Autism and metabolic diseases. J Child Neurol 23:307–314

    Article  PubMed  Google Scholar 

  • Olpin SE, Clark S, Andresen BS et al (2005) Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency. J Inherit Metab Dis 28:533–544

    Article  CAS  PubMed  Google Scholar 

  • Rossignol DA, Frye RE (2012) Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 17:290–314

    Article  CAS  PubMed  Google Scholar 

  • Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A (2014) The familial risk of autism. JAMA 311:1770–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saudubray JM, Martin D, De Lonlay P et al (1999) Recognition and management of fatty acid oxidation defects: a series of 107 patients. J Inherit Metab Dis 22:488–502

    Article  CAS  PubMed  Google Scholar 

  • Svennerholm L (1968) Distribution and fatty acid composition of phosphoglycerides in normal human brain. J Lipid Res 9:570–579

    CAS  PubMed  Google Scholar 

  • Waisbren SE, Landau Y, Wilson J, Vockley J (2013) Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. Dev Disabil Res Rev 17:260–268

    Article  PubMed  PubMed Central  Google Scholar 

  • Walterfang M, Bonnot O, Mocellin R, Velakoulis D (2013) The neuropsychiatry of inborn errors of metabolism. J Inherit Metab Dis 36:687–702

    Article  CAS  PubMed  Google Scholar 

  • Wechsler D (1997) Swedish version (2003) WAIS-III: Wechsler adult intelligence scale, 3rd edn. The Psychological Corporation, San Antonio

    Google Scholar 

  • Wechsler D (2002) Swedish version (2005) WPPSI-III: Wechsler preschool and primary scale of intelligence, 3rd edn. Psychological Corporation, San Antonio

    Google Scholar 

  • Wechsler D (2004) Swedish version (2007) WISC-IV: the Wechsler intelligence scale for children, 4th edn. Pearson Assessment, London

    Google Scholar 

  • Wechsler D (2008) Swedish version (2010) WAIS-IV: Wechsler adult intelligence scale, 4th edn. Pearson Assessment, London

    Google Scholar 

  • Wechsler D, Naglieri JA (2006) Swedish version (2007). WNV: Wechsler nonverbal scale of ability. Harcourt Assessment, Stockholm

    Google Scholar 

Download references

Acknowledgments

We are greatly indebted to all the families who participated in the study and to all our collaborators at the Center for Inherited Metabolic Diseases for skillful laboratory knowledge. The study was supported by grants from the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institute and Uppsala County and Uppsala University, the Swedish Order of Freemasons (Frimurare Barnhuset), HRH Crown Princess Lovisa’s Association for Child Medical Care (HKH Kronprinsessan Lovisas förening för barnasjukvård), and the Swedish Neuropsychological Society.

Author information

Authors and Affiliations

  1. Department of Women and Children’s Health, Karolinska Institutet, 171 76, Stockholm, Sweden

    A. Strandqvist, C. Bieneck Haglind & A. Nordenström

  2. Department of Psychology, Karolinska University Hospital, Stockholm, Sweden

    A. Strandqvist

  3. Department of Pediatrics, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden

    C. Bieneck Haglind

  4. Departments of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    R. H. Zetterström

  5. Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

    R. H. Zetterström & U. von Döbeln

  6. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

    A. Nemeth

  7. Department of Pediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital, Stockholm, Sweden

    A. Nemeth

  8. Department of Laboratory Medicine, Division for Metabolic Diseases, Karolinska Institutet, Stockholm, Sweden

    U. von Döbeln

  9. Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden

    M. Halldin Stenlid

  10. Department of Pediatric Endocrinology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden

    A. Nordenström

Authors
  1. A. Strandqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Bieneck Haglind
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. H. Zetterström
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Nemeth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U. von Döbeln
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Halldin Stenlid
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Nordenström
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Bieneck Haglind .

Editor information

Editors and Affiliations

  1. Tulane University Medical School , New Orleans, Louisiana, USA

    Eva Morava

  2. Division of Metabolism and Children’s Research Centre, University Children's Hospital Zurich, Zurich, Switzerland

    Matthias Baumgartner

  3. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  4. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK

    Shamima Rahman

  5. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Jerry Vockley, M.D., Ph.D.

Appendices

Synopsis

Patients with LCHADD seem to have a specific cognitive pattern, with presentation as intellectual disability and specific autistic deficiencies or a normal IQ with weaknesses in auditive verbal memory and adaptive and executive functions.

Compliance with Ethics Guidelines

Conflict of Interest

Anna Bengtsson Strandqvist, Charlotte Bieneck Haglind, Rolf. H. Zetterström, Antal Nemeth, Ulrika von Döbeln, Maria Halldin Stenlid, and Anna Nordenström declare that they have no conflict of interest. The study was supported by research grants. Anna Bengtsson Strandqvist, Charlotte Bieneck Haglind, Rolf. H. Zetterström Antal Nemeth, Ulrika von Döbeln, Maria Halldin Stenlid, and Anna Nordenström confirm that the content of the article has not been influenced by the grants.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Ethics Committee of Uppsala University, Sweden, decision number 2006/005, 2009-09-30) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all families for being included in the study. This article does not contain any studies with animal subjects.

Anna Bengtsson Strandqvist, Charlotte Bieneck Haglind, Rolf H Zetterström Antal Nemeth, Ulrika von Döbeln, Maria Halldin Stenlid, and Anna Nordenström have seen the final version of the manuscript and confirm that the data has not been published elsewhere. An abstract for a poster presentation, based on the same data, has been submitted to SSIEM 2015. All authors agree with submission.

Anna Bengtsson Strandqvist performed and analyzed all cognitive tests and contributed to the conception, design, analysis and interpretation of data, and drafting the article and is the guarantor for the cognitive tests.

Charlotte Bieneck Haglind contributed to the conception and design, analysis and interpretation of data, and drafting the article and is the guarantor for the work.

Anna Bengtsson Strandqvist and Charlotte Bieneck Haglind share the first authorship as Anna Bengtsson Strandqvist has been responsible for performing neurocognitive tests and Charlotte Bieneck Haglind has been responsible for writing and editing the manuscript. They have equally contributed to the design, analysis, and interpretation of data.

Rolf H Zetterström has been involved in analysis and interpretation of data, as well as drafting and critically revising the manuscript for intellectual content.

Antal Nemeth has been involved in critical revision.

Ulrika von Döbeln contributed to the analysis and interpretation of data and has been critically revising the article for intellectual content. She has also been responsible for many of the laboratory analyses.

Maria Halldin Stenlid has been involved in design and interpretation of data and critically revising the article for intellectual content.

Anna Nordenström has been involved in conception and design, analysis, and interpretation of data, drafting the article, and critically revising it for intellectual content.

Rights and permissions

Reprints and permissions

Copyright information

© 2015 SSIEM and Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Strandqvist, A. et al. (2015). Neuropsychological Development in Patients with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 28. JIMD Reports, vol 28. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_505

Download citation

  • DOI: https://doi.org/10.1007/8904_2015_505

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-52846-4

  • Online ISBN: 978-3-662-52847-1

  • eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)

Publish with us

Policies and ethics

Search

Navigation