Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life¹.

Prevalence

2.7-7.4/100,000 for all cases of ALS, NIPA1 + C9orf72 is 0.37% of ALS patients; frequency of NIPA1 expansion in controls is 3.74%². The NIPA1 expansion is associated with disease globally³, but likely unassociated in African probands⁴.

Age of Onset

Typical: 44-60⁵; Range: 25⁶- 77⁵.

HPO Terms

HP:0000217 Xerostomia HP:0000708 Atypical behavior HP:0000712 Emotional lability HP:0000716 Depression HP:0000739 Anxiety HP:0001257 Spasticity HP:0001260 Dysarthria HP:0001308 Tongue fasciculations HP:0001324 Muscle weakness HP:0001347 Hyperreflexia HP:0001618 Dysphonia HP:0001824 Weight loss HP:0002015 Dysphagia HP:0002094 Dyspnea HP:0002145 Frontotemporal dementia HP:0002180 Neurodegeneration HP:0002307 Drooling HP:0002313 Spastic paraparesis HP:0002314 Degeneration of the lateral corticospinal tracts HP:0002360 Sleep disturbance HP:0002380 Fasciculations HP:0002398 Degeneration of anterior horn cells HP:0002463 Language impairment HP:0002878 Respiratory failure HP:0003202 Skeletal muscle atrophy HP:0003324 Generalized muscle weakness HP:0003376 Steppage gait HP:0003394 Muscle spasm HP:0003470 Paralysis HP:0003484 Upper limb muscle weakness HP:0003487 Babinski sign HP:0003693 Distal amyotrophy HP:0004326 Cachexia HP:0007024 Pseudobulbar paralysis HP:0007340 Lower limb muscle weakness HP:0007354 Amyotrophic lateral sclerosis HP:0007373 Motor neuron atrophy HP:0008955 Progressive distal muscular atrophy HP:0009027 Foot dorsiflexor weakness HP:0010535 Sleep apnea HP:0012378 Fatigue HP:0012473 Tongue atrophy HP:0012531 Pain HP:0012764 Orthopnea HP:0030192 Fatigable weakness of bulbar muscles HP:0030195 Fatigable weakness of swallowing muscles HP:0030196 Fatigable weakness of respiratory muscles HP:0030878 Abnormality on pulmonary function testing HP:0031993 Hoffmann sign HP:0033683 Jaw hyperreflexia HP:0100543 Cognitive impairment

Association

Modifier

Locus

hg19chr15:23086363-23086389

hg38chr15:22786677-22786703

t2tchr15:20458510-20458536

Details

Allelic ranges taken from STRipy based on primary literature⁷. Currently proposed as a modifier for ALS². Note: the motif for this locus is CGG in hg38 and T2T reference genomes, while in hg19, the motif is the reverse complement CCG because it is on the negative strand. GCA, GCT, and GCC interruptions have been reported⁸. However, this association is disputed: a Project MinE case-control analysis found expanded alleles at similar frequencies in ALS cases and controls (4.6% each), with no significant ALS susceptibility association and only a nominal survival effect². See the criTRia curation for full evidence details.

Mechanism

Detection

Year

2019³

Location in Gene

Coding Exon 1/Intron 1 depending on transcript

Gene Strand

Alleles

Ref. Motif

CGG

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CGG

Pathogen. (gene)

CGG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

CAG, CTG, CCG

Interrup. (gene)

CAG, CTG, CCG

References

Direct supporting references for info on this page.

1omim:105400

Analysis of the GCG repeat length in NIPA1 gene in C9orf72-mediated ALS in a large Italian ALS cohort.

Lucia,Corrado, Maura,Brunetti, Alice,Di Pierro, Marco,Barberis, Roberta,Croce, Enrica,Bersano, Fabiola,De Marchi, Miriam,Zuccalà, Nadia,Barizzone, Andrea,Calvo, Cristina,Moglia, Letizia,Mazzini, Adriano,Chiò, Sandra,D'Alfonso

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2019-07-09

pmid:31286297

Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort.

Gijs H P,Tazelaar, Annelot M,Dekker, Joke J F A,van Vugt, Rick A,van der Spek, Henk-Jan,Westeneng, Lindy J B G,Kool, Kevin P,Kenna, Wouter,van Rheenen, Sara L,Pulit, Russell L,McLaughlin, William,Sproviero, Alfredo,Iacoangeli, Annemarie,Hübers, David,Brenner, Karen E,Morrison, Pamela J,Shaw, Christopher E,Shaw, Monica Povedano,Panadés, Jesus S,Mora Pardina, Jonathan D,Glass, Orla,Hardiman, Ammar,Al-Chalabi, Philip,van Damme, Wim,Robberecht, John E,Landers, Albert C,Ludolph, Jochen H,Weishaupt, Leonard H,van den Berg, Jan H,Veldink, Michael A,van Es

Neurobiology of aging · 2018-09-22

pmid:30342764

Repeats expansions in

Melissa,Nel, Thandeka,Mavundla, Kayleigh,Gultig, Gerrit,Botha, Nicola,Mulder, Michael,Benatar, Joanne,Wuu, Anne,Cooley, Jason,Myers, Evadnie,Rampersaud, Gang,Wu, Jeannine M,Heckmann

IBRO neuroscience reports · 2021-02-10

pmid:34179866

Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers.

Annelot M,Dekker, Meinie,Seelen, Perry T C,van Doormaal, Wouter,van Rheenen, Reinoud J P,Bothof, Tim,van Riessen, William J,Brands, Anneke J,van der Kooi, Marianne,de Visser, Nicol C,Voermans, R Jeroen,Pasterkamp, Jan H,Veldink, Leonard H,van den Berg, Michael A,van Es

Neurobiology of aging · 2015-12-29

pmid:26777436

NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis.

Hylke M,Blauw, Wouter,van Rheenen, Max,Koppers, Philip,Van Damme, Stefan,Waibel, Robin,Lemmens, Paul W J,van Vught, Thomas,Meyer, Claudia,Schulte, Thomas,Gasser, Edwin,Cuppen, R Jeroen,Pasterkamp, Wim,Robberecht, Albert C,Ludolph, Jan H,Veldink, Leonard H,van den Berg

Human molecular genetics · 2012-02-28

pmid:22378146

STRipy - STRs database (NIPA1 locus)

stripy:NIPA1

Reanalysis of Next-Generation Sequencing Data to Detect Tandem Repeat Expansions in 1,106 Czech Probands With Neurologic Disease.

Alena,Musilova, Petra,Lassuthova, Anna,Uhrova Meszarosova, Barbora,Straka, Jana,Krejcikova, Anna,Berounska, Marketa,Vlckova, Zuzana,Musova, Dana,Safka Brozkova

Neurology. Genetics · 2025-06-25

pmid:40585427

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)

The role of disease-associated short tandem repeats in amyotrophic lateral sclerosis.

Joke J F A,van Vugt, Ramona A J,Zwamborn, Egor,Dolzhenko, Michael A,Eberle, Ben,Weisburd, Erwin,Bekema, Maarten,Kooyman, Bi-Nan,Wang, Erik-Jan,Kamsteeg, Monique,Losekoot, Frank,Baas, Camilla,Novy, Helle,Høyer, Ruben P A,van Eijk, Michael A,van Es, Wouter,van Rheenen, Ammar,Al-Chalabi, Leonard H,van den Berg, Jan H,Veldink

Brain communications · 2025-12-09

pmid:41426430

Investigating Repeat Expansions in

Paola,Ruffo, Francesca,De Amicis, Vincenzo,La Bella, Francesca Luisa,Conforti

Cells · 2024-04-14

pmid:38667292

Genetic variability in sporadic amyotrophic lateral sclerosis.

Sien Hilde,Van Daele, Matthieu,Moisse, Joke J F A,van Vugt, Ramona A J,Zwamborn, Rick,van der Spek, Wouter,van Rheenen, Kristel,Van Eijk, Kevin,Kenna, Philippe,Corcia, Patrick,Vourc'h, Philippe,Couratier, Orla,Hardiman, Russell,McLaughin, Marc,Gotkine, Vivian,Drory, Nicola,Ticozzi, Vincenzo,Silani, Antonia,Ratti, Mamede,de Carvalho, Jesús S,Mora Pardina, Monica,Povedano, Peter M,Andersen, Markus,Weber, Nazli A,Başak, Chris,Shaw, Pamela J,Shaw, Karen E,Morrison, John E,Landers, Jonathan D,Glass, Michael A,van Es, Leonard H,van den Berg, Ammar,Al-Chalabi, Jan,Veldink, Philip,Van Damme

Brain : a journal of neurology · 2023-09-01

pmid:37043475

Amyotrophic lateral sclerosis and cerebellum.

Renata,Kabiljo, Alfredo,Iacoangeli, Ammar,Al-Chalabi, Ivana,Rosenzweig

Scientific reports · 2022-07-22

pmid:35869263

Genetic analysis of ALS cases in the isolated island population of Malta.

Rebecca,Borg, Maia,Farrugia Wismayer, Karl,Bonavia, Andrew,Farrugia Wismayer, Malcolm,Vella, Joke J F A,van Vugt, Brendan J,Kenna, Kevin P,Kenna, Neville,Vassallo, Jan H,Veldink, Ruben J,Cauchi

European journal of human genetics : EJHG · 2021-01-07

pmid:33414559

Gijs H P,Tazelaar, Steven,Boeynaems, Mathias,De Decker, Joke J F A,van Vugt, Lindy,Kool, H Stephan,Goedee, Russell L,McLaughlin, William,Sproviero, Alfredo,Iacoangeli, Matthieu,Moisse, Maarten,Jacquemyn, Dirk,Daelemans, Annelot M,Dekker, Rick A,van der Spek, Henk-Jan,Westeneng, Kevin P,Kenna, Abdelilah,Assialioui, Nica,Da Silva, Mónica,Povedano, Jesus S Mora,Pardina, Orla,Hardiman, François,Salachas, Stéphanie,Millecamps, Patrick,Vourc'h, Philippe,Corcia, Philippe,Couratier, Karen E,Morrison, Pamela J,Shaw, Christopher E,Shaw, R Jeroen,Pasterkamp, John E,Landers, Ludo,Van Den Bosch, Wim,Robberecht, Ammar,Al-Chalabi, Leonard H,van den Berg, Philip,Van Damme, Jan H,Veldink, Michael A,van Es

Brain communications · 2020-05-19

pmid:32954321

Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers.

Marka,van Blitterswijk, Bianca,Mullen, Michael G,Heckman, Matthew C,Baker, Mariely,DeJesus-Hernandez, Patricia H,Brown, Melissa E,Murray, Ging-Yuek R,Hsiung, Heather,Stewart, Anna M,Karydas, Elizabeth,Finger, Andrew,Kertesz, Eileen H,Bigio, Sandra,Weintraub, Marsel,Mesulam, Kimmo J,Hatanpaa, Charles L,White, Manuela,Neumann, Michael J,Strong, Thomas G,Beach, Zbigniew K,Wszolek, Carol,Lippa, Richard,Caselli, Leonard,Petrucelli, Keith A,Josephs, Joseph E,Parisi, David S,Knopman, Ronald C,Petersen, Ian R,Mackenzie, William W,Seeley, Lea T,Grinberg, Bruce L,Miller, Kevin B,Boylan, Neill R,Graff-Radford, Bradley F,Boeve, Dennis W,Dickson, Rosa,Rademakers

Neurobiology of aging · 2014-05-02

pmid:24866401

Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1.

Juan,Du, Ya-Cen,Hu, Bei-Sha,Tang, Chong,Chen, Ying-Ying,Luo, Zi-Xiong,Zhan, Guo-Hua,Zhao, Hong,Jiang, Kun,Xia, Lu,Shen

Clinical neurology and neurosurgery · 2011-03-17

pmid:21419568

Spastic paraplegia, ataxia, mental retardation (SPAR): a novel genetic disorder.

P,Hedera, S,Rainier, X P,Zhao, M,Schalling, K,Lindblad, Q-P,Yuan, T,Ikeuchi, J,Trobe, J J,Wald, O P,Eldevik, K,Kluin, J K,Fink

Neurology · 2002-02-12

pmid:11839840

Locus ALS NIPA1

Disease

Locus

Alleles

References

Additional Literature