Welcome to PhenoDis

NARP syndrome

General Information (adopted from Orphanet):

Synonyms, Signs:	Neuropathy -ataxia -retinitis pigmentosa Neurogenic muscle weakness -ataxia -retinitis pigmentosa
Number of Symptoms	29
OrphanetNr:	644
OMIM Id:	551500
ICD-10:	G31.8
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence:	8.3
Inheritance:
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases:

Metabolic disease with pigmentary retinitis
-Rare eye disease
-Rare genetic disease
Mitochondrial disease with epilepsy
-Rare neurologic disease
Mitochondrial disease with eye involvement
-Rare eye disease
-Rare genetic disease
Mitochondrial disease with peripheral neuropathy
-Rare genetic disease
-Rare neurologic disease
Mitochondrial oxidative phosphorylation disorder due to a point mutation of mitochondrial DNA
-Rare developmental defect during embryogenesis
-Rare genetic disease
-Rare neurologic disease
Neurometabolic disease
-Rare genetic disease
-Rare neurologic disease

Comment:

A 24-year-old woman was diagnosed with NARP caused by a heteroplasmic m.T8993G mutation in the MT-ATP6 encoding subunit 6 of mitochondrial ATP synthase. Her son was diagnosed with Leigh syndrome due to a maternally inherited homoplasmic MT-ATP6-m.T8993G mutation (PMID:25240982). In Leigh syndrome the mutant load exceeds 90%; milder symptoms of neuropathy, ataxia, and retinitis pigmentosa (NARP) tend to occur at lower mutant loads (60-90%). Although many reports have emphasized the relationship between the T8993G mutant load and the clinical phenotype, several other reports indicate that this relationship is not always valid. For example, Leigh syndrome has been observed in individuals with a T8993G mutant load in blood or muscle of less than 60% and, conversely, family members with a relatively high T8993G mutant load in blood (78-98%) might be asymptomatic or have only mild symptoms (PMID:19433277). There exists a strong similarity between NARP and non-mitochondrial neurodegenerative disorders by the lack of ragged red fibres, or other histological “mitochondrial” hallmarks in muscle biopsies of patients with NARP. Lactic acidosis may be absent as well. Muscle weakness is often mild and masked by the cerebellar symptoms, and the biochemical defect associated with NARP may go undetected because ATPase activity is seldom measured in routine screening of respiratory chain defects (PMID:9221962). MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, and MT-CO3 are the mitochondrial genes in which pathogenic variants are known to cause mtDNA-associated Leigh syndrome. MT-ATP6 is the only gene in which pathogenic variants are known to cause NARP. Approximately 10% of individuals with Leigh syndrome have either the m.8993T>G or m.8993T>C MT-ATP6 pathogenic variant; approximately 10%-20% have pathogenic variants in other mitochondrial genes. The proportion of individuals with NARP who have a detectable pathogenic variant at MT-ATP6 nucleotide 8993 is unknown but likely greater than 50%; a T-to-G transversion (m.8993T>G) is most common; a T-to-C transition (m.8993T>C) has also been described (PMID:20301352).

Symptom Information: Sort by abundance

	Symptom Information	Symptom	Pubmed	Source	DB Freq
1	(HPO:0007703)	Abnormality of retinal pigmentation	23266623	IBIS	21 / 7739
2	(HPO:0011504)	Bull's eye maculopathy	10676807	IBIS	8 / 7739
3	(HPO:0000510)	Rod-cone dystrophy	25240982	IBIS	266 / 7739
4	(HPO:0007814)	Retinal pigment epithelial mottling	10676807	IBIS	5 / 7739
5	(HPO:0000639)	Nystagmus	20953793	IBIS	555 / 7739
6	(HPO:0000572)	Visual loss	23266623	IBIS	272 / 7739
7	(HPO:0003572)	Low plasma citrulline	25240982	IBIS	7 / 7739
8	(HPO:0008972)	Decreased activity of mitochondrial respiratory chain	25746071	IBIS	34 / 7739
9	(HPO:0011923)	Decreased activity of mitochondrial complex I	25746071	IBIS	35 / 7739
10	(HPO:0003323)	Progressive muscle weakness	25240982	IBIS	17 / 7739
11	(HPO:0007141)	Sensorimotor neuropathy	20953793	IBIS	27 / 7739
12	(HPO:0000763)	Sensory neuropathy	23266623	IBIS	78 / 7739
13	(HPO:0001251)	Ataxia	25240982	IBIS	413 / 7739
14	(HPO:0002066)	Gait ataxia	23266623	IBIS	327 / 7739
15	(HPO:0011098)	Speech apraxia	25240982	IBIS	9 / 7739
16	(HPO:0001263)	Global developmental delay	23266623	IBIS	853 / 7739
17	(HPO:0000716)	Depression	20953793	IBIS	99 / 7739
18	(HPO:0001250)	Seizures	20953793	IBIS	1245 / 7739
19	(HPO:0000365)	Hearing impairment	9221962	IBIS	539 / 7739
20	(HPO:0003737)	Mitochondrial myopathy	23266623	IBIS	18 / 7739
21	(HPO:0007366)	Atrophy/Degeneration affecting the brainstem	25746071	IBIS	4 / 7739
22	(HPO:0007371)	Corpus callosum atrophy	20953793	IBIS	14 / 7739
23	(HPO:0006799)	Basal ganglia cysts	20953793	IBIS	6 / 7739
24	(HPO:0012444)	Brain atrophy	20953793	IBIS	24 / 7739
25	(HPO:0007007)	Cavitation of the basal ganglia	20953793	IBIS	2 / 7739
26	(HPO:0001272)	Cerebellar atrophy	23266623	IBIS	197 / 7739
27	(OMIM)	Muscle mitochondria normal by histochemical analysis	23266623	IBIS	1 / 7739
28	(OMIM)	No histochemical evidence of mitochondrial myopathy.	23266623	IBIS	1 / 7739
29	(OMIM)	T2-weighted hyperintensities in the basal ganglia	20953793	IBIS	2 / 7739

Associated genes:

MT-ATP6;

ClinVar (via SNiPA)

Gene symbol	Variation	Clinical significance	Reference

Additional Information:

Clinical Description OMIM

Holt et al. (1990) described a family in which 4 members showed a variable combination of developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy, in a pedigree pattern consistent with maternal transmission. ... Holt et al. (1990) described a family in which 4 members showed a variable combination of developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy, in a pedigree pattern consistent with maternal transmission. There was no histochemical evidence of mitochondrial myopathy. Blood and muscle from the patients contained 2 populations of mitochondrial DNA, one of which had a previously unreported restriction site for AvaI. Sequence analysis showed that this new restriction site was the consequence of a point mutation at nucleotide 8993 of the MTATP6 gene, resulting in an amino acid change from a highly conserved leucine to arginine in mitochondrial H(+)-ATPase (8993T-G; 516060.0001). There was some correlation between clinical severity and the amount of mutant mitochondrial DNA in the patients; this was present in only small amounts in the blood of healthy elderly relatives in the same maternal line. The index case was a 47-year-old female who developed night blindness at the age of 12 years and was diagnosed as having retinitis pigmentosa. She was almost blind by the age of 30 years. At the age of 24 years, she had a generalized seizure and was treated with phenytoin. In her early thirties, she suddenly noticed unsteadiness on walking which subsequently progressed; there had been no evidence of anticonvulsant toxicity. Sensory action potentials were reduced in amplitude, indicating an axonal sensory neuropathy. Quadriceps-muscle biopsy showed mild chronic partial denervation with collateral reinnervation. The patient's sister was asymptomatic at the age of 52 years but had a few clumps of retinal pigment and proximal muscle weakness. Her daughter noticed reduced peripheral vision at the age of 25 years and was diagnosed as having retinitis pigmentosa. The daughter of this daughter was severely affected and at the age of 3 years spoke only single words, had a pigmentary retinopathy, and limb and gait ataxia. Kerrison et al. (2000) described the progression of retinopathy in NARP. Prior to the onset of visual field constriction, ophthalmoscopy revealed salt-and-pepper retinopathy. After the visual fields had become constricted, fundus examination showed diffuse peripheral bone spicule formation, optic nerve pallor, and arteriolar attenuation. The authors stressed that mild mottling of the peripheral retinal pigment epithelium (salt-and-pepper retinopathy or retinitis pigmentosa sine pigmento) does not represent a specific entity but is an early stage of the retinitis pigmentosa, whether the patient has NARP or isolated retinitis pigmentosa. Lopez-Gallardo et al. (2009) reported a 40-year-old man with NARP syndrome. He had delayed development, psychomotor retardation, and irritability in childhood, and later developed other neurologic signs, including hearing loss, blindness due to optic atrophy and retinitis pigmentosa, ataxia, and clonic spasms. Genetic analysis identified a novel truncating mutation in the MTATP6 gene (516060.0009). The mutation was heteroplasmic, present in 26% and 85% of blood and muscle, respectively.

Symptoms & Signs

	Field	Query
	Disease
	Symptom