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PubMed This is a summary of 7 peer-reviewed journal articles Updated
Medical Genetics

The Biology of NARP: Energy and Genetics

At a Glance

NARP syndrome is a mitochondrial disease caused by mutations in the MT-ATP6 gene, which creates a cellular energy shortage. Disease severity depends on heteroplasmy—the percentage of mutated DNA. NARP typically occurs at 70-90% mutation, while over 90% leads to the more severe condition MILS.

To understand NARP, you must look inside the cell at the “power plants” known as mitochondria. Unlike most of your DNA, which is kept in the cell’s nucleus, mitochondria have their own small set of instructions. When these instructions are flawed, the result is an “energy crisis” that affects the entire body.

The Biological “Gatekeeper”: MT-ATP6

The MT-ATP6 gene is responsible for building a critical part of a machine called ATP synthase [1]. Think of this machine as a waterwheel that turns to generate electricity. The ATP6 protein acts as a gate that allows ions to flow through the wheel, providing the power to create ATP—the molecule your body uses for energy [1][2].

In NARP, a mutation in this gene breaks the gate. This makes the “waterwheel” spin inefficiently or stop altogether, leading to a severe shortage of energy [3]. Because your brain, nerves, and eyes are “energy-hungry” organs, they are the first to suffer when the power goes out [4].

The Mix of Healthy and Mutated: Heteroplasmy

One of the most unique aspects of mitochondrial disease is that you don’t just have “good” or “bad” DNA; you often have a mix of both. This mix is called heteroplasmy [5].

Imagine having 100 power plants in a city. If only 10 are broken, the city runs fine. If 80 are broken, the lights start to flicker—this is the NARP range. If 95 are broken, the entire grid collapses—this is the MILS range.

The NARP-MILS Spectrum

Doctors view NARP and Maternally Inherited Leigh Syndrome (MILS) not as two entirely different diseases, but as two points on the same sliding scale based on that mutation load [6][5].

  • NARP (70% to 90% mutated): Usually results in the classic triad of nerve damage, balance issues, and vision loss [7].
  • MILS (>90% mutated): Leads to a more severe condition which involves early-onset brain lesions, severe developmental challenges, and more rapid progression [5][7].

Because this ratio can change from one tissue to another, a definitive diagnosis requires specialized testing. Learn more in Diagnostic Testing.

Return to Home

Common questions in this guide

What causes NARP syndrome?
NARP is caused by a genetic mutation in the MT-ATP6 gene inside the mitochondria. This mutation breaks the biological machinery that creates cellular energy, causing a severe energy crisis that primarily affects the brain, nerves, and eyes.
What does heteroplasmy mean in mitochondrial disease?
Heteroplasmy refers to having a mixture of both healthy and mutated mitochondrial DNA in your cells. In mitochondrial diseases like NARP, the percentage of mutated DNA (the mutation load) determines how severe your symptoms will be.
What is the difference between NARP and Maternally Inherited Leigh Syndrome (MILS)?
NARP and MILS are considered two points on the same disease spectrum based on your mutation load. NARP usually occurs when 70% to 90% of the mitochondria are mutated, while MILS is a more severe condition that occurs when more than 90% are mutated.
Can an MRI help determine if I have NARP or MILS?
Doctors use MRI scans to look for specific patterns of brain damage. The presence of lesions in the brainstem or basal ganglia often suggests a diagnosis of the more severe MILS rather than NARP.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What is my (or my child's) specific heteroplasmy level, and how does that influence our expectations for the future?
  2. 2.Does this diagnosis shift toward Maternally Inherited Leigh Syndrome (MILS), or are we firmly in the NARP range?
  3. 3.Do my MRI results show any brainstem or basal ganglia lesions that would suggest a diagnosis of MILS rather than NARP?

Questions For You

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References

References (7)
  1. 1

    A histidine-rich extension of the mitochondrial F0 subunit ATP6 from the ice worm Mesenchytraeus solifugus increases ATP synthase activity in bacteria.

    Dunkley T, Shain DH, Klein EA

    FEBS letters 2025; (599(8)):1113-1121 doi:10.1002/1873-3468.15100.

    PMID: 39821116
  2. 2

    Co segregation of the m.1555A>G mutation in the MT-RNR1 gene and mutations in MT-ATP6 gene in a family with dilated mitochondrial cardiomyopathy and hearing loss: A whole mitochondrial genome screening.

    Alila-Fersi O, Chamkha I, Majdoub I, et al.

    Biochemical and biophysical research communications 2017; (484(1)):71-78 doi:10.1016/j.bbrc.2017.01.070.

    PMID: 28104394
  3. 3

    Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase.

    Ding Q, Kucharczyk R, Zhao W, et al.

    Life (Basel, Switzerland) 2020; (10(9)) doi:10.3390/life10090215.

    PMID: 32971864
  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

    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
  6. 6

    Pathogenic variants in MT-ATP6: A United Kingdom-based mitochondrial disease cohort study.

    Ng YS, Martikainen MH, Gorman GS, et al.

    Annals of neurology 2019; (86(2)):310-315 doi:10.1002/ana.25525.

    PMID: 31187502
  7. 7

    The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability.

    Strasser L, Doja A, Davila J, et al.

    American journal of medical genetics. Part A 2023; (191(12)):2890-2897 doi:10.1002/ajmg.a.63378.

    PMID: 37654102

This page explains the biology and genetics of NARP syndrome for educational purposes only. Always discuss your specific heteroplasmy levels, MRI results, and genetic testing with your neurologist or medical geneticist.

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