Patients with NAXE-related mitochondrial encephalopathy exhibit developmental delay, cognitive regression, altered consciousness, abnormalities in eye movement (including nystagmus), muscle weakness, respiratory failure, seizure, ataxia, and gait disturbance at the age of 1 to 2 years. The disease is characterized by fluctuating symptoms over time, often exacerbated by febrile illness; it is progressive and fatal in the long term¹.

Prevalence

Single proband found in Japanese cohort¹.

Age of Onset

Single repeat expansion case had onset at 13 months, while NAXE-related mitochondrial encephalopathy more generally has predominately infantile onset, extending to 20y or older¹.

HPO Terms

HP:0000473 Torticollis HP:0000486 Strabismus HP:0000511 Vertical supranuclear gaze palsy HP:0000639 Nystagmus HP:0000711 Restlessness HP:0000737 Irritability HP:0001250 Seizure HP:0001251 Ataxia HP:0001252 Hypotonia HP:0001259 Coma HP:0001260 Dysarthria HP:0001263 Global developmental delay HP:0001298 Encephalopathy HP:0001337 Tremor HP:0002063 Rigidity HP:0002119 Ventriculomegaly HP:0002151 Increased circulating lactate concentration HP:0002181 Cerebral edema HP:0002196 Myelopathy HP:0002273 Tetraparesis HP:0002283 Global brain atrophy HP:0002318 Cervical myelopathy HP:0002352 Leukoencephalopathy HP:0002376 Developmental regression HP:0002490 Increased CSF lactate HP:0002878 Respiratory failure HP:0003128 Lactic acidosis HP:0006897 Abducens palsy HP:0011922 Abnormal activity of mitochondrial respiratory chain HP:0012378 Fatigue HP:0012444 Brain atrophy HP:0012706 Elevated brain choline level by MRS HP:0012762 Cerebral white matter atrophy HP:0030915 Cerebellar edema HP:0032794 Myoclonic seizure HP:0046507 Bradypnea HP:0200041 Skin erosion

Association

Mendelian

Locus

hg19 chr1:156561557-156561575

hg38 chr1:156591765-156591783

t2t chr1:155728131-155728159

Details

Benign range (2-7) alleles established by 484 control alleles and validated with orthogonal databases, while a single proband had expansion of ~200 repeats inherited from mother via uniparental disomy¹. While the repeat expansion is newly reported, other variants in the NAXE gene have previously been associated with mitochondrial encephalopathy.

Mechanism

LoF

Reduced NAXE expression from expansion in promoter; hypermethylation was detected at and downstream of the repeat sequence in the proband as well as the maternal copy of the expanded allele, which was not present in the maternal normal range allele nor in the controls¹.

Detection

Year

2024¹

Location in Gene

5' UTR

Gene Strand

Alleles

Ref. Motif

GGGCC

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CCGGG

Pathogen. (gene)

CCGGG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interrup. (gene)

–

References

Direct supporting references for info on this page.

Biallelic GGGCC repeat expansion leading to NAXE-related mitochondrial encephalopathy.

Kokoro,Ozaki, Yukiko,Yatsuka, Yoshinobu,Oyazato, Atsushi,Nishiyama, Kazuhiro R,Nitta, Yoshihito,Kishita, Takuya,Fushimi, Masaru,Shimura, Shohei,Noma, Yohei,Sugiyama, Michihira,Tagami, Moe,Fukunaga, Hiroko,Kinoshita, Tomoko,Hirata, Wataru,Suda, Yasuhiro,Murakawa, Piero,Carninci, Akira,Ohtake, Kei,Murayama, Yasushi,Okazaki

NPJ genomic medicine · 2024-10-25

pmid:39455596

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

AIBP-LRP2-mediated HDL uptake restricts CXCR4

Lingping,Zhu, Minghong,Chen, Kechuan,Lin, Can,Du, Meilian,Yao, Jing,Chen, Jian,Zhang, Xunjie,Cheng, Dan,Wang, Yu,Liu, Lisha,Liu, Junyu,Chen, Yamei,Liu, Xin,Luo, Guogang,Zhang, Chuanchang,Li, Longhou,Fang, Yongping,Bai

Science advances · 2025-10-15

pmid:41091881

Locus NME NAXE

Disease

Locus

Alleles

References

Additional Literature