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NARP syndrome

MedGen UID:
231285
Concept ID:
C1328349
Disease or Syndrome
Synonym: Neuropathy ataxia retinitis pigmentosa syndrome
SNOMED CT: Neurogenic muscle weakness, ataxia and retinitis pigmentosa (237984008); NARP (neurogenic muscle weakness, ataxia, retinitis pigmentosa) syndrome (237984008); NARP syndrome (237984008)
Modes of inheritance:
Mitochondrial inheritance
MedGen UID:
165802
Concept ID:
C0887941
Genetic Function
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on the mitochondrial genome. Because the mitochondrial genome is essentially always maternally inherited, a mitochondrial condition can only be transmitted by females, although the condition can affect both sexes. The proportion of mutant mitochondria can vary (heteroplasmy).
 
Gene (location): MT-ATP6
 
Monarch Initiative: MONDO:0010794
OMIM®: 551500
Orphanet: ORPHA644

Definition

Mitochondrial DNA (mtDNA)-associated Leigh syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) are part of a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation. Leigh syndrome (or subacute necrotizing encephalomyelopathy) is characterized by onset of symptoms typically between ages three and 12 months, often following a viral infection. Decompensation (often with elevated lactate levels in blood and/or CSF) during an intercurrent illness is typically associated with psychomotor retardation or regression. Neurologic features include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Extraneurologic manifestations may include hypertrophic cardiomyopathy. About 50% of affected individuals die by age three years, most often as a result of respiratory or cardiac failure. NARP is characterized by proximal neurogenic muscle weakness with sensory neuropathy, ataxia, and pigmentary retinopathy. Onset of symptoms, particularly ataxia and learning difficulties, is often in early childhood. Individuals with NARP can be relatively stable for many years, but may suffer episodic deterioration, often in association with viral illnesses. [from GeneReviews]

Additional description

From MedlinePlus Genetics
Neuropathy, ataxia, and retinitis pigmentosa (NARP) is a condition that causes a variety of signs and symptoms that mainly affect the nervous system. The condition typically begins in childhood or early adulthood, and the signs and symptoms usually worsen over time. Most people with NARP experience numbness, tingling, or pain in the arms and legs (sensory neuropathy); muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have vision loss caused by changes in the light-sensitive tissue that lines the back of the eye (the retina). In some cases, the vision loss results from a condition called retinitis pigmentosa. This eye disease causes the light-sensing cells of the retina gradually to deteriorate.

Learning disabilities and developmental delays are often seen in children with NARP, and older individuals with this condition may experience a loss of intellectual function (dementia). Other features of NARP include seizures, hearing loss, and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). These signs and symptoms vary among affected individuals.  https://medlineplus.gov/genetics/condition/neuropathy-ataxia-and-retinitis-pigmentosa

Clinical features

From HPO
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Sensory neuropathy
MedGen UID:
101791
Concept ID:
C0151313
Disease or Syndrome
Peripheral neuropathy affecting the sensory nerves.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Corticospinal tract atrophy
MedGen UID:
325533
Concept ID:
C1838868
Finding
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Inborn mitochondrial myopathy
MedGen UID:
56484
Concept ID:
C0162670
Disease or Syndrome
A type of myopathy associated with mitochondrial disease and characterized by findings on biopsy such as ragged red muscle fibers.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Retinal disorder
MedGen UID:
11209
Concept ID:
C0035309
Disease or Syndrome
Any noninflammatory disease of the retina. This nonspecific term is retained here because of its wide use in the literature, but if possible new annotations should indicate the precise type of retinal abnormality.
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Disease or Syndrome
Blindness is the condition of lacking visual perception defined as a profound reduction in visual perception. On the 6m visual acuity scale, blindness is defined as less than 3/60. On the 20ft visual acuity scale, blindness is defined as less than 20/400. On the decimal visual acuity scale, blindness is defined as less than 0.05. Blindness is typically characterized by a visual field of no greater than 10 degrees in radius around central fixation.
Retinal pigment epithelial mottling
MedGen UID:
347513
Concept ID:
C1857644
Finding
Mottling (spots or blotches with different shades) of the retinal pigment epithelium, i.e., localized or generalized fundal pigment granularity associated with processes at the level of the retinal pigment epithelium.
Rod-cone dystrophy
MedGen UID:
1632921
Concept ID:
C4551714
Disease or Syndrome
An inherited retinal disease subtype in which the rod photoreceptors appear to be more severely affected than the cone photoreceptors. Typical presentation is with nyctalopia (due to rod dysfunction) followed by loss of mid-peripheral field of vision, which gradually extends and leaves many patients with a small central island of vision due to the preservation of macular cones.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for NARP syndrome in Orphanet.

Professional guidelines

PubMed

Steffann J, Gigarel N, Corcos J, Bonnière M, Encha-Razavi F, Sinico M, Prevot S, Dumez Y, Yamgnane A, Frydman R, Munnich A, Bonnefont JP
J Med Genet 2007 Oct;44(10):664-9. Epub 2007 Jun 1 doi: 10.1136/jmg.2006.048553. PMID: 17545557Free PMC Article

Recent clinical studies

Etiology

Birtel J, von Landenberg C, Gliem M, Gliem C, Reimann J, Kunz WS, Herrmann P, Betz C, Caswell R, Nesbitt V, Kornblum C, Charbel Issa P
Ophthalmol Retina 2022 Jan;6(1):65-79. Epub 2021 Jul 10 doi: 10.1016/j.oret.2021.02.017. PMID: 34257060
Lemoine S, Panaye M, Rabeyrin M, Errazuriz-Cerda E, Mousson de Camaret B, Petiot P, Juillard L, Guebre-Egziabher F
Am J Kidney Dis 2018 May;71(5):754-757. Epub 2017 Dec 8 doi: 10.1053/j.ajkd.2017.09.020. PMID: 29224958
Blanco-Grau A, Bonaventura-Ibars I, Coll-Cantí J, Melià MJ, Martinez R, Martínez-Gallo M, Andreu AL, Pinós T, García-Arumí E
Genes Brain Behav 2013 Nov;12(8):812-20. Epub 2013 Oct 25 doi: 10.1111/gbb.12089. PMID: 24118886
Debray FG, Lambert M, Lortie A, Vanasse M, Mitchell GA
Am J Med Genet A 2007 Sep 1;143A(17):2046-51. doi: 10.1002/ajmg.a.31880. PMID: 17663470
Lodi R, Montagna P, Iotti S, Zaniol P, Barboni P, Puddu P, Barbiroli B
J Neurol Neurosurg Psychiatry 1994 Dec;57(12):1492-6. doi: 10.1136/jnnp.57.12.1492. PMID: 7798979Free PMC Article

Diagnosis

Birtel J, von Landenberg C, Gliem M, Gliem C, Reimann J, Kunz WS, Herrmann P, Betz C, Caswell R, Nesbitt V, Kornblum C, Charbel Issa P
Ophthalmol Retina 2022 Jan;6(1):65-79. Epub 2021 Jul 10 doi: 10.1016/j.oret.2021.02.017. PMID: 34257060
Wojewoda M, Duszyński J, Szczepanowska J
Int J Biochem Cell Biol 2011 Aug;43(8):1178-86. Epub 2011 Apr 28 doi: 10.1016/j.biocel.2011.04.011. PMID: 21550418
Finsterer J
J Neurol Sci 2011 May 15;304(1-2):9-16. Epub 2011 Mar 13 doi: 10.1016/j.jns.2011.02.012. PMID: 21402391
Debray FG, Lambert M, Lortie A, Vanasse M, Mitchell GA
Am J Med Genet A 2007 Sep 1;143A(17):2046-51. doi: 10.1002/ajmg.a.31880. PMID: 17663470
Keränen T, Kuusisto H
Epileptic Disord 2006 Sep;8(3):200-3. PMID: 16987741

Therapy

Wojewoda M, Duszyński J, Szczepanowska J
Int J Biochem Cell Biol 2011 Aug;43(8):1178-86. Epub 2011 Apr 28 doi: 10.1016/j.biocel.2011.04.011. PMID: 21550418
Lodi R, Montagna P, Iotti S, Zaniol P, Barboni P, Puddu P, Barbiroli B
J Neurol Neurosurg Psychiatry 1994 Dec;57(12):1492-6. doi: 10.1136/jnnp.57.12.1492. PMID: 7798979Free PMC Article

Prognosis

Rabinovich M, Zambrowski O, Miere A, Bhouri R, Souied E
Ophthalmic Genet 2024 Apr;45(2):193-200. Epub 2023 Sep 6 doi: 10.1080/13816810.2023.2253905. PMID: 37671548
Lemoine S, Panaye M, Rabeyrin M, Errazuriz-Cerda E, Mousson de Camaret B, Petiot P, Juillard L, Guebre-Egziabher F
Am J Kidney Dis 2018 May;71(5):754-757. Epub 2017 Dec 8 doi: 10.1053/j.ajkd.2017.09.020. PMID: 29224958
Blanco-Grau A, Bonaventura-Ibars I, Coll-Cantí J, Melià MJ, Martinez R, Martínez-Gallo M, Andreu AL, Pinós T, García-Arumí E
Genes Brain Behav 2013 Nov;12(8):812-20. Epub 2013 Oct 25 doi: 10.1111/gbb.12089. PMID: 24118886
Debray FG, Lambert M, Lortie A, Vanasse M, Mitchell GA
Am J Med Genet A 2007 Sep 1;143A(17):2046-51. doi: 10.1002/ajmg.a.31880. PMID: 17663470
Lodi R, Montagna P, Iotti S, Zaniol P, Barboni P, Puddu P, Barbiroli B
J Neurol Neurosurg Psychiatry 1994 Dec;57(12):1492-6. doi: 10.1136/jnnp.57.12.1492. PMID: 7798979Free PMC Article

Clinical prediction guides

Sala D, Marchet S, Nanetti L, Legati A, Mariotti C, Lamantea E, Ghezzi D, Catania A, Lamperti C
Orphanet J Rare Dis 2024 May 16;19(1):200. doi: 10.1186/s13023-024-03212-y. PMID: 38755691Free PMC Article
Blanco-Grau A, Bonaventura-Ibars I, Coll-Cantí J, Melià MJ, Martinez R, Martínez-Gallo M, Andreu AL, Pinós T, García-Arumí E
Genes Brain Behav 2013 Nov;12(8):812-20. Epub 2013 Oct 25 doi: 10.1111/gbb.12089. PMID: 24118886
Martín-Jiménez R, Martín-Hernández E, Cabello A, García-Silva MT, Arenas J, Campos Y
Mitochondrion 2012 Mar;12(2):288-93. Epub 2011 Nov 7 doi: 10.1016/j.mito.2011.10.004. PMID: 22094595
Yoon MK, Roorda A, Zhang Y, Nakanishi C, Wong LJ, Zhang Q, Gillum L, Green A, Duncan JL
Invest Ophthalmol Vis Sci 2009 Apr;50(4):1838-47. Epub 2008 Nov 7 doi: 10.1167/iovs.08-2029. PMID: 18997096Free PMC Article
Debray FG, Lambert M, Lortie A, Vanasse M, Mitchell GA
Am J Med Genet A 2007 Sep 1;143A(17):2046-51. doi: 10.1002/ajmg.a.31880. PMID: 17663470

Recent systematic reviews

Finsterer J
J Clin Neuromuscul Dis 2023 Mar 1;24(3):140-146. doi: 10.1097/CND.0000000000000422. PMID: 36809201

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