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PubMed This is a summary of 9 peer-reviewed journal articles Updated
Genetics

Diagnostic Testing: Making Sense of Your Results

At a Glance

NARP syndrome is diagnosed using whole mitochondrial genome sequencing to detect mutations in the MT-ATP6 gene. A complete diagnostic report should include the gene name, the specific variant, and the heteroplasmy percentage (the amount of mutated mitochondrial DNA) to confirm the diagnosis.

Getting a clear diagnosis for NARP syndrome involves a “multimodal” approach—a combination of genetic testing, high-tech imaging, and specialized exams of the nerves and eyes [1].

Genetic Testing: The Definitive Step

Genetic testing is the most important tool for confirming NARP. However, standard Whole Exome Sequencing (WES) focuses on the nucleus of the cell and famously misses mutations in the mitochondrial DNA [2].

Instead, doctors must order Whole Mitochondrial Genome Sequencing (mtDNA sequencing) or specific Targeted Mitochondrial Panels that look at the MT-ATP6 gene [3].

Reading Your Genetic Report

A “complete” genetic report for NARP should include three specific pieces of information:

  1. Gene Name: This should be MT-ATP6 [4].
  2. Specific Variant: This identifies the exact “typo” in the DNA (e.g., m.8993T>G or m.8993T>C) [5].
  3. Heteroplasmy Load: This is the percentage of mutated mitochondrial DNA found in your sample (e.g., “80% heteroplasmy”) [6].

Note: Because the “dose” of the mutation can vary, your doctor may sometimes need to test different tissues—such as skin cells or urine—if blood tests are inconclusive [7].

Clinical and Biochemical Exams

  • ERG (Electroretinogram): Measures the electrical response of your retina, essential for detecting early Retinitis Pigmentosa [3].
  • MRI (Brain Imaging): Used primarily to distinguish NARP from Leigh Syndrome (MILS), which causes distinct lesions in the brainstem and basal ganglia [8][9].
  • Lactate and Lactic Acidosis: High levels of lactate in the blood or Cerebrospinal Fluid (CSF) indicate that your cells are relying on emergency backup systems to create energy [8]. This can lead to lactic acidosis, a state where the blood becomes too acidic, which is a common hallmark of mitochondrial stress [9].

Checklist: Is Your Report Complete?

  • [ ] Does the report specify the MT-ATP6 gene?
  • [ ] Is the specific mutation (the variant) listed (e.g., m.8993T>G)?
  • [ ] Is the Heteroplasmy Percentage clearly stated?
  • [ ] Does the report indicate which tissue (blood, saliva, etc.) was tested?

Once diagnosed, the next step is building your care team. See Standard of Care and Treatment.

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Common questions in this guide

What is the best genetic test for NARP syndrome?
The most accurate test is Whole Mitochondrial Genome Sequencing or a targeted mitochondrial panel. Standard whole exome sequencing often misses the mutations in mitochondrial DNA responsible for NARP.
What does heteroplasmy mean on my NARP genetic report?
Heteroplasmy load is the percentage of mutated mitochondrial DNA found in your sample. Because this percentage can vary between different cells in your body, doctors sometimes test multiple tissues like blood, skin, or urine to get an accurate reading.
Why do I need an MRI if I have NARP?
Brain imaging with an MRI helps doctors evaluate your condition and distinguish NARP from a related condition called Leigh Syndrome. Leigh Syndrome typically causes distinct lesions in specific areas of the brain that aren't present in typical NARP cases.
Why is lactate measured when diagnosing NARP?
High lactate levels in the blood or spinal fluid indicate that your cells are struggling to produce energy normally and are relying on backup systems. This leads to lactic acidosis, which is a common sign of mitochondrial stress.
What specific information should be on my NARP genetic lab report?
Your genetic report should explicitly list the MT-ATP6 gene and detail the exact DNA variant, such as m.8993T>G. It should also clearly state the heteroplasmy percentage and note exactly which tissue type was tested.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Was my genetic test performed using Next-Generation Sequencing (NGS) to look specifically at the mitochondrial genome rather than just the nuclear exome?
  2. 2.What was the exact heteroplasmy percentage found in my test, and in which tissue was it measured?
  3. 3.If my blood lactate levels were normal, should we consider a CSF (spinal fluid) lactate test or a metabolic screen?

Questions For You

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References

References (9)
  1. 1

    Neuropathy, ataxia, retinitis pigmentosa: a case of a mother and two siblings.

    Rabinovich M, Zambrowski O, Miere A, et al.

    Ophthalmic genetics 2024; (45(2)):193-200 doi:10.1080/13816810.2023.2253905.

    PMID: 37671548
  2. 2

    Generation of two mother-child pairs of iPSCs from maternally inherited Leigh syndrome patients with m.8993 T > G and m.9176 T > G MT-ATP6 mutations.

    Henke MT, Zink A, Diecke S, et al.

    Stem cell research 2023; (67()):103030 doi:10.1016/j.scr.2023.103030.

    PMID: 36669241
  3. 3

    Mitochondrial Retinopathy.

    Birtel J, von Landenberg C, Gliem M, et al.

    Ophthalmology. Retina 2022; (6(1)):65-79 doi:10.1016/j.oret.2021.02.017.

    PMID: 34257060
  4. 4

    Neuropathy, Ataxia, and Retinitis Pigmentosa Syndrome.

    Finsterer J

    Journal of clinical neuromuscular disease 2023; (24(3)):140-146 doi:10.1097/CND.0000000000000422.

    PMID: 36809201
  5. 5

    A 2 bp deletion in the mitochondrial ATP 6 gene responsible for the NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome.

    Mordel P, Schaeffer S, Dupas Q, et al.

    Biochemical and biophysical research communications 2017; (494(1-2)):133-137 doi:10.1016/j.bbrc.2017.10.066.

    PMID: 29054413
  6. 6

    Epilepsy in MT-ATP6 - related mils/NARP: correlation of elettroclinical features with heteroplasmy.

    Licchetta L, Ferri L, La Morgia C, et al.

    Annals of clinical and translational neurology 2021; (8(3)):704-710 doi:10.1002/acn3.51259.

    PMID: 33476484
  7. 7

    Novel genetic and neuropathological insights in neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP).

    Claeys KG, Abicht A, Häusler M, et al.

    Muscle & nerve 2016; (54(2)):328-33 doi:10.1002/mus.25125.

    PMID: 27015314
  8. 8

    Clinical, Neuroimaging, and Pathological Analyses of 13 Chinese Leigh Syndrome Patients with Mitochondrial DNA Mutations.

    Yu XL, Yan CZ, Ji KQ, et al.

    Chinese medical journal 2018; (131(22)):2705-2712 doi:10.4103/0366-6999.245265.

    PMID: 30425197
  9. 9

    Homoplasmy of the m. 8993 T>G variant in a patient without MRI findings of Leigh syndrome, ataxia or retinal abnormalities.

    Saneto RP, Patrick KE, Perez FA

    Mitochondrion 2021; (59()):58-62 doi:10.1016/j.mito.2021.04.010.

    PMID: 33894360

This page explains NARP syndrome diagnostic testing for educational purposes. Your geneticist and neurologist are the best sources for interpreting your specific genetic test results and imaging reports.

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