Hereditary neuralgic amyotrophy

Hereditary neuralgic amyotrophy is a disorder characterized by episodes of severe pain and muscle wasting (amyotrophy) in one or both shoulders and arms. Neuralgic pain is felt along the path of one or more nerves and often has no obvious physical cause. The network of nerves involved in hereditary neuralgic amyotrophy, called the brachial plexus, controls movement and sensation in the shoulders and arms.

People with hereditary neuralgic amyotrophy usually begin experiencing attacks in their twenties, but episodes have occurred as early as the age of 1 year in some individuals. The attacks may be spontaneous or triggered by stress such as strenuous exercise, childbirth, surgery, exposure to cold, infections, immunizations, or emotional disturbance. While the frequency of the episodes tends to decrease with age, affected individuals are often left with residual problems, such as chronic pain and impaired movement, that accumulate over time.

Typically an attack begins with severe pain on one or both sides of the body; right-sided involvement is most common. The pain may be difficult to control with medication and usually lasts about a month. Within a period of time ranging from a few hours to a couple of weeks, the muscles in the affected area begin to weaken and waste away (atrophy), and movement becomes difficult. Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a common sign known as scapular winging. Additional features of hereditary neuralgic amyotrophy may include decreased sensation (hypoesthesia) and abnormal sensations in the skin such as numbness or tingling (paresthesias). Areas other than the shoulder and arm may also be involved.

In a few affected families, individuals with hereditary neuralgic amyotrophy also have unusual physical characteristics including short stature, excess skin folds on the neck and arms, an opening in the roof of the mouth (cleft palate), a split in the soft flap of tissue that hangs from the back of the mouth (bifid uvula), and partially webbed or fused fingers or toes (partial syndactyly). They may also have distinctive facial features including eyes set close together (ocular hypotelorism), a narrow opening of the eyelids (short palpebral fissures) with a skin fold covering the inner corner of the eye (epicanthal fold), a long nasal bridge, a narrow mouth, and differences between one side of the face and the other (facial asymmetry).

Hereditary neuralgic amyotrophy is a rare disorder, but its specific prevalence is unknown. Approximately 200 families affected by the disorder have been identified worldwide.

Mutations in the SEPTIN9 gene cause hereditary neuralgic amyotrophy. The SEPTIN9 gene provides instructions for making a protein called septin-9, which is part of a group of proteins called septins. Septins are involved in a process called cytokinesis, which is the step in cell division when the fluid inside the cell (cytoplasm) divides to form two separate cells.

The SEPTIN9 gene seems to be turned on (active) in cells throughout the body. Approximately 15 slightly different versions (isoforms) of the septin-9 protein may be produced from this gene. Some types of cells make certain isoforms, while other cell types produce other isoforms. However, the specific distribution of these isoforms in the body's tissues is not well understood. Septin-9 isoforms interact with other septin proteins to perform some of their functions.

Mutations in the SEPTIN9 gene may change the sequence of protein building blocks (amino acids) in certain septin-9 isoforms in ways that interfere with their function. These mutations may also change the distribution of septin-9 isoforms and their interactions with other septin proteins in some of the body's tissues. This change in the functioning of septin proteins seems to particularly affect the brachial plexus, but the reason for this is unknown.

Because many of the triggers for hereditary neuralgic amyotrophy also affect the immune system, researchers believe that an autoimmune reaction may be involved in this disorder. However, the relation between SEPTIN9 gene mutations and immune function is unclear. Autoimmune disorders occur when the immune system malfunctions and attacks the body's own tissues and organs. An autoimmune attack on the nerves in the brachial plexus likely results in the signs and symptoms of hereditary neuralgic amyotrophy.

At least 15 percent of families affected by hereditary neuralgic amyotrophy do not have SEPTIN9 gene mutations. In these cases, the disorder is believed to be caused by mutations in a gene that has not been identified.

Genetic Testing Information

• Genetic Testing Registry: Amyotrophic neuralgia

Genetic and Rare Diseases Information Center

• Hereditary neuralgic amyotrophy

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• AMYOTROPHY, HEREDITARY NEURALGIC; HNA

Scientific Articles on PubMed

• PubMed

• Hannibal MC, Ruzzo EK, Miller LR, Betz B, Buchan JG, Knutzen DM, Barnett K, Landsverk ML, Brice A, LeGuern E, Bedford HM, Worrall BB, Lovitt S, Appel SH, Andermann E, Bird TD, Chance PF. SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy. Neurology. 2009 May 19;72(20):1755-9. doi: 10.1212/WNL.0b013e3181a609e3. Citation on PubMed or Free article on PubMed Central
• Hoque R, Schwendimann RN, Kelley RE, Bien-Willner R, Sivakumar K. Painful brachial plexopathies in SEPT9 mutations: adverse outcome related to comorbid states. J Clin Neuromuscul Dis. 2008 Jun;9(4):379-84. doi: 10.1097/CND.0b013e318166ee89. Citation on PubMed
• Klein CJ, Wu Y, Cunningham JM, Windebank AJ, Dyck PJ, Friedenberg SM, Klein DM, Dyck PJ. SEPT9 mutations and a conserved 17q25 sequence in sporadic and hereditary brachial plexus neuropathy. Arch Neurol. 2009 Feb;66(2):238-43. doi: 10.1001/archneurol.2008.585. Citation on PubMed or Free article on PubMed Central
• Kuhlenbaumer G, Hannibal MC, Nelis E, Schirmacher A, Verpoorten N, Meuleman J, Watts GD, De Vriendt E, Young P, Stogbauer F, Halfter H, Irobi J, Goossens D, Del-Favero J, Betz BG, Hor H, Kurlemann G, Bird TD, Airaksinen E, Mononen T, Serradell AP, Prats JM, Van Broeckhoven C, De Jonghe P, Timmerman V, Ringelstein EB, Chance PF. Mutations in SEPT9 cause hereditary neuralgic amyotrophy. Nat Genet. 2005 Oct;37(10):1044-6. doi: 10.1038/ng1649. Epub 2005 Sep 25. Citation on PubMed
• Laccone F, Hannibal MC, Neesen J, Grisold W, Chance PF, Rehder H. Dysmorphic syndrome of hereditary neuralgic amyotrophy associated with a SEPT9 gene mutation--a family study. Clin Genet. 2008 Sep;74(3):279-83. doi: 10.1111/j.1399-0004.2008.01022.x. Epub 2008 May 19. Citation on PubMed
• Landsverk ML, Ruzzo EK, Mefford HC, Buysse K, Buchan JG, Eichler EE, Petty EM, Peterson EA, Knutzen DM, Barnett K, Farlow MR, Caress J, Parry GJ, Quan D, Gardner KL, Hong M, Simmons Z, Bird TD, Chance PF, Hannibal MC. Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy. Hum Mol Genet. 2009 Apr 1;18(7):1200-8. doi: 10.1093/hmg/ddp014. Epub 2009 Jan 12. Citation on PubMed or Free article on PubMed Central
• McDade SS, Hall PA, Russell SE. Translational control of SEPT9 isoforms is perturbed in disease. Hum Mol Genet. 2007 Apr 1;16(7):742-52. doi: 10.1093/hmg/ddm003. Citation on PubMed
• Sudo K, Ito H, Iwamoto I, Morishita R, Asano T, Nagata K. SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling. Hum Mutat. 2007 Oct;28(10):1005-13. doi: 10.1002/humu.20554. Citation on PubMed
• van Alfen N, Hannibal MC, Chance PF, van Engelen BGM. Hereditary Neuralgic Amyotrophy - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2008 Feb 27 [updated 2012 Dec 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1395/ Citation on PubMed
• van Alfen N, van der Werf SP, van Engelen BG. Long-term pain, fatigue, and impairment in neuralgic amyotrophy. Arch Phys Med Rehabil. 2009 Mar;90(3):435-9. doi: 10.1016/j.apmr.2008.08.216. Citation on PubMed
• van Alfen N, van Engelen BG. The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain. 2006 Feb;129(Pt 2):438-50. doi: 10.1093/brain/awh722. Epub 2005 Dec 21. Citation on PubMed