Long-chain fatty acid oxidation disorders: Pathophysiology, - - PowerPoint PPT Presentation

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Long-chain fatty acid oxidation disorders: Pathophysiology, - - PowerPoint PPT Presentation

Dec 12, 2023 281 likes •363 views

Long-chain fatty acid oxidation disorders: Pathophysiology, diagnosis and management What are the signs and symptoms of LC-FAOD and how are they diagnosed? Prof. Dr. Ute Spiekerktter Chair and Medical Director, Department of Pediatrics and

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Long-chain fatty acid oxidation disorders: Pathophysiology, diagnosis and management

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  • Prof. Dr. Ute Spiekerkötter

Chair and Medical Director, Department of Pediatrics and Adolescent Medicine, University Children’s Hospital, Freiburg, Germany

What are the signs and symptoms of LC-FAOD and how are they diagnosed?

LC-FAOD, long-chain fatty acid oxidation disorders.

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  • Hypoglycaemia
  • Hypoketosis
  • Hepatic dysfunction
  • Elevated transaminases,

ammonia and creatinine kinase

  • Metabolic acidosis

Presenting symptoms of LC-FAOD can vary with age and stressors1–3

LC-FAOD, long-chain fatty acid oxidation disorders.

  • 1. Merritt JL II, et al. Ann Transl Med. 2018;6:473. 2. Knottnerus SJG, et al. Rev Endocr Metab Disord. 2018;19:93–106.
  • 3. Spiekerkoetter U. J Inherit Metab Dis. 2010;33:527–32.
  • Skeletal myopathy

‒ Myalgia ‒ Muscle weakness ‒ Exercise intolerance ‒ Elevated CK

  • Myoglobinuria

‒ Recurrent rhabdomyolysis

  • Peripheral neuropathy/

retinopathy (for defined defects)

  • Fasting
  • Exercise
  • Concurrent illness

Stressors

  • Cardiomyopathy

‒ Left ventricular hypertrophy

  • Reye-like symptoms
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Heterogenous phenotypes in LC-FAOD1–3

LC-FAOD, long-chain fatty acid oxidation disorders.

  • 1. Merritt JL II, et al. Ann Transl Med. 2018;6:473. 2. Knottnerus SJG, et al. Rev Endocr Metab Disord. 2018;19:93–106.
  • 3. Spiekerkoetter U. J Inherit Metab Dis. 2010;33:527–32.

Asymptomatic disease Reye-like symptoms Hypoglycaemia (Reversible) cardiomyopathy (Reversible) hepatopathy and hepatic steatosis Myopathy and rhabdomyolysis Retinopathy Peripheral neuropathy

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Diagnostic process for symptomatic patients with LC-FAOD1–4

CPK, creatinine phosphokinase; LC-FAOD, long-chain fatty acid oxidation disorders; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

  • 1. Spiekerkoetter U, et al. J Inherit Metab Dis. 2009;32:488–97. 2. Arnold GL, et al. Mol Genet Metab. 2009;96:85–90.
  • 3. Hesse J, et al. J Inherit Metab Dis. 2018;41:1169–78. 4. Ruiz M, et al. Am J Physiol Heart Circ Physiol. 2017;313:H768–H81.

Cardiac evaluation for LC-FAOD

  • Echocardiogram
  • Electrocardiogram
  • (Chest radiography)

Routine laboratory studies

  • Plasma acylcarnitine profile, total and free carnitine

(urine acylglycine or organic acids)

  • Mutation analysis, gene panel, or measurement of

specific enzyme activity

  • Transaminases, liver function, CPK, NT-proBNP,

lactate, ammonia, full blood count

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Newborn screening and diagnosis of FAOD1-6

FAOD, fatty acid oxidation disorders.

  • 1. Andresen BS, et al. Am J Hum Genet. 1999;64:479–94. 2. Spiekerkoetter U, et al. J Pediatr. 2003;143:335–42. 3. Sturm M, et al. PLoS One. 2012;7:e45110;
  • 4. Diekman EF, et al. Genet Med. 2015;17:989–94. 5. Hesse J, et al. J Inherit Metab Dis. 2018;41:1169–78.
  • 6. Knottnerus SJG, et al. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165725.
  • Inclusion of different FAODs in standard newborn screening

(national decisions)

  • Positive screening result does not confirm disease
  • Confirmed disease after positive screening is not necessarily

indicative of symptomatic disease or related to disease severity Confirmation of diagnosis after positive screen

  • Enzyme and mutational analysis

(also identification of heterozygotes)

Prediction of disease severity

  • No consistent genotype–phenotype correlation
  • Wide spectrum of mutations
  • Correlation of residual enzyme activity and phenotype
  • Correlation with fatty acid oxidation flux in cultured

skin fibroblasts

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Optimal management of asymptomatic LC-FAOD1–3

FAOD, fatty acid oxidation disorders; LC-FAOD, long-chain fatty acid oxidation disorders.

  • 1. Spiekerkoetter U, et al. J Pediatr. 2003;143:335–42. 2. Kang E, et al. BMC Pediatrics. 2018;18:103. 3. Merritt JL II, et al. Ann Transl Med. 2018;6:473.

Risk assessment of patients identified through newborn screening Molecular and enzymatic characterization Many initially asymptomatic patients have later onset

  • f symptoms (often myopathic), stressors may induce

various symptoms, which can be life-threatening Patient may remain asymptomatic

  • Lifelong observation is warranted in all patients

with FAOD Appropriate management

  • Are dietary management and

exercise restriction necessary?