• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Hereditary Neuralgic Amyotrophy

Synonyms: Hereditary Brachial Plexus Neuropathy, Neuritis with Brachial Predilection

, MD, PhD, , MD, PhD, , MD, and , MD, PhD.

Author Information
, MD, PhD
Department of Neurology and Clinical Neurophysiology
Radboud University Nijmegen Medical Center
Nijmegen, Netherlands
, MD, PhD
Division of Genetics
Department of Pediatrics and Communicable Diseases
University of Michigan Medical School
Ann Arbor, Michigan
, MD
Division of Genetics and Developmental Medicine
Department of Pediatrics
Children’s Hospital and Regional Medical Center
University of Washington
Seattle, Washington
, MD, PhD
Department of Neurology and Clinical Neurophysiology
Radboud University Nijmegen Medical Center
Nijmegen, Netherlands

Initial Posting: ; Last Update: December 6, 2012.

Summary

Disease characteristics. Hereditary neuralgic amyotrophy (HNA) is characterized by sudden onset of severe, non-abating pain in the shoulder girdle and/or the upper limb and amyotrophy (muscle wasting or atrophy) that typically develops within two weeks of the onset of severe pain. Other sites may also be involved in an attack; sensory symptoms, present in the majority of affected individuals, can include hypoesthesia (decreased sensation) and paresthesias. Onset is typically in the second or third decade (median age 28 years). Although attacks appear to become less frequent with age, residual deficits accumulate with subsequent attacks. In some families, non-neurologic findings (characteristic craniofacial features, bifid uvula or cleft palate, short stature, and/or partial syndactyly of the fingers or toes) are present.

Diagnosis/testing. The diagnosis of HNA is based on clinical findings. SEPT9 is the only gene in which mutations are known to cause HNA; however, genetic heterogeneity exists.

Management. Treatment of manifestations: Pain management is the primary goal of therapy and varies between acute and chronic stages. Corticosteroids have been used in the acute phase to shorten the duration of pain and improve recovery. Consultation with a physiatrist is recommended for chronic pain and persisting paresis. Patients with phrenic nerve palsy need specialized respiratory consultation and can benefit from noninvasive nocturnal positive pressure ventilation. Cleft palate is managed by standard protocols.

Surveillance: Follow up every six to 12 months after the initial diagnosis to identify chronic pain resulting from altered biomechanics of the shoulder or arm.

Agents/circumstances to avoid: Overexertion of a limb with persistent weakness, especially if the scapula is unstable.

Genetic counseling. Hereditary neuralgic amyotrophy is inherited in an autosomal dominant manner. Most individuals diagnosed with HNA have an affected parent; the proportion of cases caused by a de novo mutation is unknown. Each child of an individual with HNA has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

Hereditary neuralgic amyotrophy (HNA) is an episodic disorder diagnosed clinically using criteria developed by the European CMT Consortium; see modified criteria (Table 1) and Kuhlenbäumer et al [2000].

Sensory and motor nerves are typically affected; occasionally autonomic nerve injury also occurs.

HNA is characterized in 95% of cases by the following:

  • Sudden onset of severe, non-abating pain in the shoulder girdle and/or the upper limb. The pain may be unusually debilitating and, in some cases, even refractory to narcotic medications. The intense pain typically lasts for up to several weeks and may give way to a chronic aching pain in the limb persisting for months [van Alfen & van Engelen 2006].
  • Amyotrophy (muscle wasting or atrophy) that typically develops within two weeks of the onset of severe pain [van Alfen & van Engelen 2006]

Table 1. HNA Diagnostic Criteria

FeatureInclusion CriteriaCompatible Criteria
Age of onset  • Second or third decade of life (median: 28 years)  • Earlier or later onset
Clinical manifestations  • Acute, uni- or bilateral brachial plexopathy
 • Severe pain preceding the onset of weakness by days to a few weeks
 • Predominantly motor deficits
 • Number of episodes variable (1-20)
 • Precipitating factors: infections, immunizations, surgery, parturition, unusually strenuous exercise of the affected limb, exposure to cold
 • Attack recurrence (75%)
 • Sensory symptoms (70%)
 • Lumbar plexus (33%) and/or phrenic nerve (14%) involved
 • Cranial nerve involved 1
 • Dysmorphic features 2
 • Abortive attacks (pain is not followed by weakness)
 • Weakness preceding the onset of pain by days to weeks
 • Long intervals between attacks (up to many years)
 • No pain during an attack (5%)
Family history  • Autosomal dominant inheritance  • Simplex case (i.e., single occurrence in a family)
Clinical examination 3 • Patchy or multifocal distribution of abnormalities  • More prominent motor loss than sensory loss
 • Sensory abnormalities (80%)
 • Autonomic symptoms (15%) 4
 • Mononeuropathy 5
 • Absent or diminished tendon reflexes in affected limbs
 • Muscle weakness and atrophy
Course and severity 6 • Relapsing/remitting course with symptom-free intervals
 • Recovery incomplete; persisting neurologic deficit especially after repeated attacks in the same limb
 • Complete recovery without residual deficit between attacks
 • Chronic undulating course without completely symptom-free intervals
Electrophysiologic findings 7 • Signs of denervation or reinnervation in clinically weak muscles seen on electromyogram (EEG) • Reduced amplitude of compound muscle action potential (CMAP) in muscles innervated by affected nerves
 • Reduced amplitudes of sensory nerve action potentials in affected nerves
Molecular genetics 8 • Identification of a presumed pathologic mutation or duplication in SEPT9
 • Linkage to the SEPT9 locus on chromosome 17q25
 • Absence of linkage to the SEPT9 locus on chromosome 17q25

Modified from Kuhlenbäumer et al [2000]

1. Most commonly recurrent laryngeal nerve (19%) or facial nerve

2. Most commonly ocular hypotelorism, epicanthal folds, cleft palate, bifid uvula, excessive neck or arm skin folds

3. Exclusion criterion: Signs of generalized neuropathy

4. Such as abnormal sweating in affected arm or, rarely, Horner syndrome

5. Most commonly long thoracic, anterior interosseus, or phrenic nerve

6. Exclusion criterion: Slow progression of motor impairment over >3 months

7. Exclusion criterion: Electrophysiologic signs of systemic generalized neuropathy

8. Exclusion criteria: PMP22 deletion or mutation (chromosome 17p11.2) that is diagnostic of hereditary neuropathy with liability to pressure palsies (HNPP)

Molecular Genetic Testing

Gene. SEPT9 is the only gene in which mutations are known to cause HNA.

Evidence for locus heterogeneity. In at least five reported families, markers flanking the SEPT9 locus do not segregate with the HNA phenotype, suggesting the involvement of another as-yet unknown gene(s) [van Alfen et al 2000, Kuhlenbäumer et al 2001, Watts et al 2001].

  • The percentage of families in the US who appear not to be genetically linked to the SEPT9 locus is estimated at 15%.
  • The percentage of families in other countries (e.g., the Netherlands) who appear not to be genetically linked to the SEPT9 locus may be much higher [unpublished/preliminary data].

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in Hereditary Neuralgic Amyotrophy

Gene SymbolProportion of HNA Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
SEPT9 ~55% 2Sequence analysis Sequence variants 3See footnote 4
Deletion / duplication analysis 5Exonic, multiexonic, or whole-gene duplication 6See footnote 7
Unknown~45%Unknown

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. The proportion may be higher or lower depending on country or region of origin [van Alfen 2011].

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. In families with HNA linked to SEPT9, sequence analysis identified a sequence variant in 8/42 families [Hannibal et al 2009] a roughly 20% mutation detection rate.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Both a founder duplication and nonrecurrent duplications (with unique breakpoints) have been reported [Landsverk et al 2009, Collie et al 2010]. See Molecular Genetics.

7. In families with HNA linked to SEPT9, CMA identified the founder haplotype duplication in 12/55 families [Landsverk et al 2009] and a tandem duplication in 6/55 families [Collie et al 2010], a roughly 33% mutation detection rate.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Neuralgic amyotrophy attacks. Typically, onset of painful attacks in hereditary neuralgic amyotrophy (HNA) occurs in the second or third decade of life (median age of onset 28 years), but children as young as age one year have had attacks. The male to female ratio is 2:1.

The attacks comprise severe aching, burning, or stabbing pains, most often in the shoulders, neck, and/or arm region, followed by multifocal atrophy and paresis. Usually the brachial plexus is involved. In one third of cases, the involvement is bilateral, although severity is usually asymmetric. Attacks appear to become less frequent with age.

The most comprehensive review of attack features in both HNA and sporadic idiopathic neuralgic amyotrophy (see Differential Diagnosis) was reported by van Alfen & van Engelen [2006]. The pain lasts an average of four weeks. Weakness most often begins in the periscapular or perihumeral muscles (see Figure 1) between one and two weeks after the onset of pain. In some instances the onset of weakness may follow within 24 hours of the onset of pain.

Figure 1

Figure

Figure 1. Different presentations of upper-extremity atrophy and paresis

A. On the left: atrophy of supraspinatus and infraspinatus muscles and rhomboid muscles (white arrow); on the right: scapular tilting and rotation caused by serratus (more...)

The long thoracic and suprascapular nerves are affected in about 70% of cases. Other frequently involved nerves are the axillary, musculocutanous, radial, and anterior interosseus. Lower plexus involvement (median motor and ulnar distribution) occurs in about 5% [van Alfen 2011].

In many cases the muscle weakness may go unnoticed, especially if it only affects the periscapular muscles such as the serratus anterior, rhomboids or subscapularis. Functionally, however, the resulting scapular instability often causes pain, limitation of movement, and exercise intolerance of the affected limb that can persist for months to years.

Sensory symptoms, present in the majority of affected individuals, are often overlooked. They can include the following:

  • Hypoesthesia (decreased sensation) located anywhere from the shoulder to the fingertips; found in 85% of individuals
  • Paresthesias; reported in more than 50% of attacks
  • Vasomotor changes in the arm; reported in 15% of attacks. This autonomic dysfunction of the cervical sympathetic nerves can result in hand edema or vasomotor instability [van Alfen 2007].

While the shoulder and arm are primarily affected by attacks in HNA, other sites that may also be involved in an attack include the following:

  • Lumbosacral plexus in ~33% of attacks
  • Phrenic nerve palsy in 14% of attacks; may cause orthopnea, respiratory distress and sleep disturbance
  • Recurrent laryngeal nerve in 3% of attacks; may cause vocal cord paresis resulting in hoarseness and hypophonia
  • Facial nerve or other cranial nerves (rarely)

Two patterns of HNA attacks are described:

  • Common. Classic remitting/relapsing type, characterized by rapid onset of attacks accompanied by complete or substantial slow recovery
  • Rare. Chronic undulating type, characterized by slower onset of persistent pain with a protracted fluctuating but unremitting course of attacks resulting in severe residual neurologic deficits [van Alfen et al 2000]

The prognosis for eventual recovery of neurologic function in neuralgic amyotrophy is guarded, with residual deficits accumulating with additional attacks.

Characteristic physical features. In some families, HNA is associated with non-neurologic physical features that allow assessment of the risk for HNA before attacks appear. Typically, these non-neurologic findings include short stature; partial syndactyly of the fingers or toes; characteristic craniofacial features with relatively closely spaced eyes, short palpebral fissures, and epicanthus; and cleft (bifid) uvula or cleft palate [Jeannet et al 2001]. The ocular hypotelorism in some families is striking, with interpupillary distance typically between -1 to -2 standard deviations. As pointed out by several authors, the facial features of persons with HNA resemble portraits painted by the artist Amedeo Modigliani [Dunn et al 1978].

Excessive partial circumferential skin folds of the neck and arms are also characteristic features [Jeannet et al 2001].

Pathophysiology. Attacks may be triggered by periods of physical, immunologic, or emotional stress. Females appear to have a predilection for attacks after childbirth. This, and association of attacks following immunizations and recent viral or bacterial infections, raise a possible role of an immune system trigger. Prior strenuous usage of the upper limbs has also been reported to precipitate attacks suggesting that local trauma or ischemia of the brachial plexus resulting from compression between muscle groups may underlay the plexopathy, making it more susceptible to (auto-) immune damage.

Biopsy of sural or superficial radial nerves is rarely performed in this disorder. The only finding described in the majority of biopsies is focal decreases in myelinated fibers within individual nerve fascicles [van Alfen et al 2005]. In one report, multiple epineural perivascular mononuclear infiltrates without necrosis were seen in three of four upper-extremity nerve biopsies, obtained three weeks, three months, and seven months after onset of an attack [Klein et al 2002]. These infiltrates were accompanied by active axonal degeneration.

Genotype-Phenotype Correlations

In families with SEPT9 mutations, non-neurologic features may or may not be observed. In many cases these dysmorphisms are related to the SEPT9 mutation p.Arg88Trp [van Alfen 2011]. Generally, non-neurologic features are rarely observed in Dutch individuals, which could indicate that the p.Arg88Trp mutation is rare in this population.

In one family that appears to have HNA but does not segregate with markers flanking SEPT9, affected individuals show the chronic undulating phenotype: slowly increasing pain before the onset of the first severe attack followed by an undulating course without complete recovery or cessation of symptoms [van Alfen et al 2000]. Whether other families with the chronic undulating phenotype are also not genetically linked to SEPT9 is unknown.

Penetrance

Studies based on clinical criteria suggest that the penetrance is between 80% and greater than 90% for all individuals with HNA, not taking into account the underlying cause of the disorder [Kuhlenbäumer et al 2000, van Alfen 2007].

Data regarding penetrance in relation to SEPT9 mutation status have not yet been published.

Nomenclature

Out-of-date terms previously used for hereditary neuralgic amyotrophy include the following:

  • Familial brachial plexus neuritis
  • Heredofamilial neuritis with brachial plexus predilection

Prevalence

The prevalence of HNA is unknown. About 300 families are known worldwide.

The prevalence of HNA is estimated to be about an order of magnitude less than that of idiopathic neuralgic amyotrophy (Parsonage-Turner syndrome), which has an estimated incidence of 1.64:100,000/year to 3:100,000/year [Beghi et al 1985, MacDonald et al 2000].

Prevalence of any brachial neuritis was estimated to be 3:10,000 in the London (UK) area [MacDonald et al 2000].

The actual prevalence of these disorders is likely to be higher because of underdiagnosis. Sixty percent of individuals with neuralgic amyotrophy seen at the Nijmegen clinical center were first diagnosed with a different disorder [van Alfen & van Engelen 2006].

Differential Diagnosis

Acute pain in the shoulder and upper arm region may be caused by neurologic or non-neurologic disorders.

  • If all the pain, paresis, and sensory symptoms are in the same cervical root distribution, a degenerative or acute disk rupture cervical radiculopathy must be considered.
  • Cervical spondylosis may have referred arm pain that is position- or activity-dependent, with no focal deficits and a fluctuating course. Imaging studies such as MRI or CT scan may exclude vertebral or space-occupying causes. The focus, however, should be on the clinical picture, as approximately 50% of affected adults usually show degenerative changes on cervical spine MRI.
  • Complex regional pain syndrome involving the shoulder or arm has predominantly vasomotor symptoms, with subacute onset of diffuse pain and weakness with progression.
  • Other rare neurologic disorders could include mononeuritis multiplex (peripheral nervous system vasculitis), multifocal motor neuropathy, or brachial amyotrophic diplegia, but these tend to have subacute onset and the latter two disorders are usually painless. Electromyography (EMG) and nerve conduction studies help to distinguish radiculopathies; examination of unaffected limbs excludes generalized peripheral neuropathies.
  • In extremely rare cases, an acute painful brachial plexopathy is found as the only sign of an underlying hereditary neuropathy with liability to pressure palsies (HNPP). HNPP is an autosomal dominant disorder caused by the deletion or mutation of PMP22. Usually there is a family history of nerve damage resulting from minor stretch or compressive trauma.
  • Shoulder joint pathology (e.g., bursitis, calcifying tendonitis) or rotator cuff injury may cause pain that is exacerbated by joint movement and relieved by rest or passive immobilization.

Brachial plexopathy may also be caused by trauma, surgery, or prior irradiation:

  • Lower plexus lesions may be seen in the case of a Pancoast tumor or true neurogenic thoracic outlet syndrome.
  • A peripheral nerve or nerve sheath tumor may involve the plexus, as could direct peripheral nervous system infections such as neuroborreliosis or HIV.

The main differential diagnosis in an individual presenting with an acute-onset, painful, multifocal, brachial plexopathy is neuralgic amyotrophy in either its hereditary or idiopathic form. HNA is clinically similar to its sporadic counterpart, idiopathic neuralgic amyotrophy (INA). The disorders share the same precipitating factors, signs, and symptoms. INA, also called brachial neuritis or Parsonage-Turner syndrome, is estimated to be about ten times more common than HNA. HNA is distinguished from INA by its familial recurrence, earlier average age of onset, more severe pain in the acute stage, more frequent involvement of nerves outside of the brachial plexus, higher rate of recurrence, and greater eventual disability. However, no single feature in a given individual can distinguish hereditary from sporadic neuralgic amyotrophy; this distinction is based on a positive family history and/or the presence of the typical dysmorphic features.

Excluding the holoprosencephaly syndromes, a couple of syndromes known to share some of the craniofacial features of HNA are autosomal dominant Schilbach-Rott syndrome [OMIM 164220] and Michelin tire baby syndrome [OMIM 156610].

  • Like HNA, Schilbach-Rott syndrome is characterized by short stature, cutaneous syndactyly, ocular hypotelorism, and cleft palate [Joss et al 2002]. The families reported do not have neuralgic amyotrophy.
  • A subset of individuals with Michelin tire baby syndrome (with what now may be known as “circumferential skin creases, Kunze type”) also may share the following with HNA: craniofacial features (including relatively closely spaced eyes and short palpebral fissures), cleft palate, and circumferential skin folds [Wouters et al 2011].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with hereditary neuralgic amyotrophy, the following evaluations are recommended:

  • Comprehensive neuromuscular evaluation
  • Needle EMG to identify the severity and extent of denervation and reinnervation
  • Evaluation of phrenic nerve involvement by chest x-ray, ultrasound/fluoroscopic evaluation of diaphragm movement, and pulmonary function tests in seated and supine positions
  • Medical genetics consultation

For a practical overview of the physical examination and the value of additional investigations in neuralgic amyotrophy see pn.bmj.com.

Treatment of Manifestations

Currently, no effective therapy is proven to abort or shorten an HNA attack.

Treatment of acute episodes of pain and weakness with corticosteroids has been proposed based on retrospective analysis of cases [van Alfen et al 2009, van Eijk et al 2009]. These reports summarize retrospective, anecdotal evidence that corticosteroids can have a favorable effect on pain and recovery. Additional immunomodulatory treatments with such agents as corticosteroids and immune globulin may be considered, but no prospective trials have been performed [van Alfen et al 2009, Johnson et al 2011].

Pain management is the primary goal of therapy:

  • In the acute stage, a combination of a long-acting nonsteroidal anti-inflammatory drug (NSAID) such as ketorolac and a narcotic such as controlled-release morphine are used.
  • In the second phase of chronic pain resulting from damaged, hypersensitive nerves, co-analgesics such as gabapentin, carbamazepine, and amitryptiline may be used.
  • In the third chronic phase, persistent pain in the neck and shoulder region usually points to strain of the paretic or compensating muscles or to a complication in the glenohumeral joint, such as rotator cuff pathology. As the weakness has to recover by itself, therapy focuses on arm support in a sling, rest, physical therapy, range of motion stretching, and modification of activities. This rehabilitation and prevention of further injury is best managed by a physiatrist.

For persistent paresis, physical therapy is recommended to maintain exercise tolerance and prevent joint or ligament contractures. Care must be taken to avoid post-exercise pain in the affected area, as this is often a sign of strain. In this case, exercise should be temporarily deferred, or at least be without extra added weights and with fewer repetitions per set. The patient must find his or her personal level of exercise tolerance; in practice, this is often much lower than estimated (or desired) by the patient or therapist.

For severe paresis of the serratus anterior muscle persisting more than one year, corrective surgery can be considered to increase scapular stability, for example by a split pectoralis major muscle transfer.

Patients with phrenic nerve palsy need consultation with a respiratory specialist and can benefit from noninvasive nocturnal positive pressure ventilation.

For a clinical overview of neurologic and rehabilitative management, see van Alfen [2007]. For a comprehensive information brochure for patients and caregivers see www.umcn.nl.

Cleft palate is best managed by a local craniofacial team.

Surveillance

As chronic pain resulting from altered biomechanics of the shoulder or upper extremity tends to develop during the first one to two years, follow up every six to 12 months after the initial diagnosis is recommended.

Agents/Circumstances to Avoid

Although immunizations have been known to precede and possibly trigger attacks, it is still recommended that they be given on the usual recommended schedule because the risk of immunization precipitating an attack is probably low [based on expert opinion].

Patients with persistent weakness and especially scapular instability should be cautioned to avoid overexerting the affected limb.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with HNA should be monitored in the post-partum interval for the development of symptoms. Prompt treatment with corticosteroids or similar agents may ameliorate an HNA attack.

Therapies Under Investigation

In an open-label study of oral prednisone in adults with INA or HNA (60 mg/day for one week, followed by a one week taper by 10 mg/day with a last dose of 5 mg) the only statistically significant finding was a reduction in the time for paresis recovery [van Alfen & van Engelen 2006]. Other variables showed no statistical difference from an untreated group of persons with neuralgic amyotrophy; variables included the duration of the initial pain, maximum present Numerical Rating Scale score and use of analgesics, the occurrence of a chronic pain syndrome, maximum Medical Research Council level of strength recovery, complications such as frozen shoulder or shoulder dislocation, and Rankin score.

An additional review of the Dutch experience revealed the following:

  • Relative to the untreated patients, a significantly higher proportion of the patients receiving oral prednisolone recovered early from their pareses;
  • Taken in the first month, prednisolone tended to decrease the average duration of the initial pain, although this finding was not statistically significant;
  • Functional recovery set in earlier, with significantly more treated patients achieving full recovery within a year or reporting a ‘‘good’’ outcome within six months;
  • Side effects occurred in 20% of patients, but did not result in discontinuation of treatment [van Eijk et al 2009].

A randomized placebo-controlled trial of oral prednisone conducted in the Netherlands was terminated after three years because of insufficient recruitment within the specified time frame. No treatment effect could be demonstrated in the 13 persons in the primary treatment and placebo arm; however, the small number of participants precluded any definite conclusions.

Experimental immunosuppressive therapies that have been used in other inflammatory polyneuropathies, but for which there are limited data available for treatment of attacks in HNA, include the following:

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary neuralgic amyotrophy is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with hereditary neuralgic amyotrophy have an affected parent.
  • A proband with hereditary neuralgic amyotrophy may have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations is unknown.
  • If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for parents of a proband with an apparent de novo mutation include a clinical evaluation for findings of HNA. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with hereditary neuralgic amyotrophy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with hereditary neuralgic amyotrophy has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation in either SEPT9 or another as-yet unknown gene. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic adults. Although uncommonly requested, testing of at-risk asymptomatic adults for hereditary neuralgic amyotrophy is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity and type of symptoms, or rate of disease progression in asymptomatic individuals will be. When testing at-risk individuals for hereditary neuralgic amyotrophy, an affected family member must be tested first to confirm the molecular diagnosis in the family.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of hereditary neuralgic amyotrophy, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.

Molecular genetic testing of asymptomatic individuals younger than age 18 years. Because no proven preventive or ameliorating treatment is available, individuals younger than age 18 years who are at risk of having inherited and developing HNA are typically not offered testing during childhood. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications.

Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like hereditary neuralgic amyotrophy) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • ISNO: Dutch Neuromuscular Research Centre
    Postbus 85810
    Den Hague 2508 CM
    Netherlands
    Phone: +31 70 3029722
    Fax: +31 70 3648450
    Email: isno@isno.nl
  • Hereditary Neuropathy Foundation, Inc.
    1751 2nd Avenue
    Suite 103
    New York NY 10128
    Phone: 877-463-1287 (toll-free); 212-722-8396
    Email: info@hnf-cure.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • Neuralgic Amyotrophy: Idiopathic and Hereditary Form
    UMC St Radboud
    Neuromuscular Centrum Nijmegen
    Netherlands

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Hereditary Neuralgic Amyotrophy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hereditary Neuralgic Amyotrophy (View All in OMIM)

162100AMYOTROPHY, HEREDITARY NEURALGIC; HNA
604061SEPTIN 9; SEPT9

Normal allelic variants. SEPT9 and septin-9 protein have numerous published aliases, including MSF, SepD1, Ov/Br septin, and PNUTL4. At least 17 exons spanning 213 kilobases are used to generate alternatively spliced transcripts (see Table A, Gene Symbol). In the seven most abundant transcripts, variation in splicing occurs in the alternate use of 5' exons to include 10-12 exons that generate polypeptides ranging from 586 to 335 amino acids. The three transcripts that encode the longest proteins encode short, distinct N-terminal polypeptides of 25 amino acids (septin-9 isoform a, NM_001113491.1), 18 amino acids (septin-9 isoform b, NM_001113493.1), and seven amino acids (septin-9 isoform c, NM_006640.4).

Pathologic allelic variants. Three small intragenic mutations have been reported: a non-coding 5'-untranslated region mutation and two missense mutations, p.Arg88Trp and p.Ser93Phe [Kuhlenbäumer et al 2005, Hannibal et al 2009]. Both missense mutations occur within a 645-bp exon of SEPT9 (hg18 chr17:72,909,736-72,910,380). p.Arg88Trp is a recurrent missense mutation and is located at a presumably hypermutable CG dinucleotide [Kuhlenbäumer et al 2005, Hannibal et al 2009, Klein et al 2009, Ueda et al 2010]. See Table 3.

Six intragenic duplications and one whole-gene duplication have been identified in families with HNA [Landsverk et al 2009, Collie et al 2010]. Each of these minimally duplicates a 7,592-bp genomic region containing a 645-bp exon within SEPT9 (hg18 coordinates chr17:72,904,532-72,912,123). A larger SEPT9 protein is produced from some of the intragenic duplication alleles.

Note: Human Mar. 2006 (NCBI36/hg18) Browser Sequences are available at genome.ucsc.edu.

Table 3. Selected SEPT9 Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.-134G>C
(SEPT9_v3 5'-UTR-131G>C)
--NM_006640​.4
NP_006631​.2
c.262C>Tp.Arg88Trp
(SEPT9_v3 R88W)
c.278C>Tp.Ser93Phe
(SEPT9_v3 S93F)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

For more information, see Table A.

Normal gene product. SEPT9 appears to be ubiquitously expressed, but studies of the distribution of septin-9 protein isoforms in normal tissues are limited. Septin-9 is thought to play a role in cytokinesis and tumorigenesis. The long isoforms of septin-9 have unique N-terminal polypeptides with a proline-rich domain. Only the septin proteins encoded by SEPT4 also have a nonhomologous proline-rich domain. Septin-9 shares a polybasic and GTP-binding domain with all septins, but lacks a C-terminal coiled-coil domain found in all septins, except those encoded by SEPT9, SEPT3, and SEPT12. Septin-9 has been shown to be localized with other septins to intermediate filaments that associate with actin microfilaments and microtubules.

Abnormal gene product. Several hypotheses have arisen regarding the functional consequences of SEPT9 mutations. One report suggests that the mutations alter a putative internal ribosome entry site in the mRNA transcript that controls the choice of the initiating ATG codon for protein translation [McDade et al 2007]. Another paper proposes that the mutations alter the interaction of septin-9 with septin-4 and perturb the regulation of septin-9-containing filaments by Rho/Rhotekin signaling [Sudo et al 2007]. The limited range of mutations seen to date (i.e., two missense mutations with the 645-bp exon and SEPT9 duplications that produce a larger protein product containing two tandem copies of the peptide encoded by the 645-bp exon) suggest that a novel gain-of-function mechanism may account for SEPT9 pathogenesis.

References

Literature Cited

  1. Ardolino G, Barbieri S, Priori A. High dose intravenous immune globulin in the treatment of hereditary recurrent brachial plexus neuropathy. J Neurol Neurosurg Psychiatry. 2003;74:550. [PMC free article: PMC1738363] [PubMed: 12640095]
  2. Beghi E, Kurland LT, Mulder DW, Nicolosi A. Brachial plexus neuropathy in the population of Rochester, Minnesota, 1970-1981. Ann Neurol. 1985;18:320–3. [PubMed: 2996415]
  3. Collie AM, Landsverk ML, Ruzzo E, Mefford HC, Buysse K, Adkins JR, Knutzen DM, Barnett K, Brown RH, Parry GJ, Yum SW, Simpson DA, Olney RK, Chinnery PF, Eichler EE, Chance PF, Hannibal MC. Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy. J Med Genet. 2010;47:601–7. [PubMed: 19939853]
  4. Dunn HG, Daube JR, Gomez MR. Heredofamilial branchial plexus neuropathy (hereditary neuralgic amyotrophy with branchial predilection) in childhood. Dev Med Child Neurol. 1978;20:28–46. [PubMed: 205473]
  5. 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;72:1755–9. [PMC free article: PMC2683739] [PubMed: 19451530]
  6. Jeannet PY, Watts GD, Bird TD, Chance PF. Craniofacial and cutaneous findings expand the phenotype of hereditary neuralgic amyotrophy. Neurology. 2001;57:1963–8. [PubMed: 11739810]
  7. Johnson NE, Petraglia AL, Huang JH, Logigian EL. Rapid resolution of severe neuralgic amyotrophy after treatment with corticosteroids and intravenous immunoglobulin. Muscle Nerve. 2011;44:304–5. [PubMed: 21717467]
  8. Joss SK, Paterson W, Donaldson MD, Tolmie JL. Cleft palate, hypotelorism, and hypospadias: Schilbach-Rott syndrome. Am J Med Genet. 2002;113:105–7. [PubMed: 12400075]
  9. Klein CJ, Dyck PJ, Friedenberg SM, Burns TM, Windebank AJ, Dyck PJ. Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy. J Neurol Neurosurg Psychiatry. 2002;73:45–50. [PMC free article: PMC1757294] [PubMed: 12082044]
  10. 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;66:238–43. [PMC free article: PMC2770426] [PubMed: 19204161]
  11. Kuhlenbäumer G, Hannibal MC, Nelis E, Schirmacher A, Verpoorten N, Meuleman J, Watts GD, De Vriendt E, Young P, Stögbauer 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;37:1044–6. [PubMed: 16186812]
  12. Kuhlenbäumer G, Meuleman J, De Jonghe P, Falck B, Young P, Hunermund G, Van Broeckhoven C, Timmerman V, Stogbauer F. Hereditary Neuralgic Amyotrophy (HNA) is genetically heterogeneous. J Neurol. 2001;248:861–5. [PubMed: 11697522]
  13. Kuhlenbäumer G, Stogbauer F, Timmerman V, De Jonghe P. Diagnostic guidelines for hereditary neuralgic amyotrophy or heredofamilial neuritis with brachial plexus predilection. On behalf of the European CMT Consortium. Neuromuscul Disord. 2000;10:515–7. [PubMed: 10996784]
  14. 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;18:1200–8. [PMC free article: PMC2722193] [PubMed: 19139049]
  15. MacDonald BK, Cockerell OC, Sander JW, Shorvon SD. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain. 2000;123:665–76. [PubMed: 10733998]
  16. McDade SS, Hall PA, Russell SE. Translational control of SEPT9 isoforms is perturbed in disease. Hum Mol Genet. 2007;16:742–52. [PubMed: 17468182]
  17. Moriguchi K, Miyamoto K, Takada K, Kusunoki S. Four cases of anti-ganglioside antibody-positive neuralgic amyotrophy with good response to intravenous immunoglobulin infusion therapy. J Neuroimmunol. 2011;238:107–9. [PubMed: 21872943]
  18. Nakajima M, Fujioka S, Ohno H, Iwamoto K. Partial but rapid recovery from paralysis after immunomodulation during early stage of neuralgic amyotrophy. Eur Neurol. 2006;55:227–9. [PubMed: 16778440]
  19. 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;28:1005–13. [PubMed: 17546647]
  20. Ueda M, Kawamura N, Tateishi T, Sakae N, Motomura K, Ohyagi Y, Kira JI. Phenotypic spectrum of hereditary neuralgic amyotrophy caused by the SEPT9 R88W mutation. J Neurol Neurosurg Psychiatry. 2010;81:94–6. [PubMed: 20019224]
  21. van Alfen N. The neuralgic amyotrophy consultation. J Neurol. 2007;254:695–704. [PMC free article: PMC2780663] [PubMed: 17446996]
  22. van Alfen N. Clinical and pathophysiological concepts of neuralgic amyotrophy. Nat Rev Neurol. 2011;7:315–22. [PubMed: 21556032]
  23. van Alfen N, Gabreels-Festen AA, Ter Laak HJ, Arts WF, Gabreels FJ, van Engelen BG. Histology of hereditary neuralgic amyotrophy. J Neurol Neurosurg Psychiatry. 2005;76:445–7. [PMC free article: PMC1739556] [PubMed: 15716548]
  24. van Alfen N, van Engelen BG. The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain. 2006;129:438–50. [PubMed: 16371410]
  25. van Alfen N, van Engelen BG, Hughes RA. Treatment for idiopathic and hereditary neuralgic amyotrophy (brachial neuritis). Cochrane Database Syst Rev. 2009;(3):CD006976. [PubMed: 19588414]
  26. van Alfen N, van Engelen BG, Reinders JW, Kremer H, Gabreels FJ. The natural history of hereditary neuralgic amyotrophy in the Dutch population: two distinct types? Brain. 2000;123:718–23. [PubMed: 10734003]
  27. van Eijk JJ, van Alfen N, Berrevoets M, van der Wilt GJ, Pillen S, van Engelen BG. Evaluation of prednisolone treatment in the acute phase of neuralgic amyotrophy: an observational study. J Neurol Neurosurg Psychiatry. 2009;80:1120–4. [PubMed: 19321467]
  28. Watts GD, O'Briant KC, Borreson TE, Windebank AJ, Chance PF. Evidence for genetic heterogeneity in hereditary neuralgic amyotrophy. Neurology. 2001;56:675–8. [PubMed: 11245726]
  29. Wouters L, Rodriguez Rodriguez CM, Dapena EP, Poorten VV, Devriendt K, Van Esch H. Circumferential skin creases, cleft palate, typical face, intellectual disability and growth delay: "circumferential skin creases Kunze type. Eur J Med Genet. 2011;54:236–40. [PubMed: 21262397]

Suggested Reading

  1. van Alfen N, Schuuring J, van Engelen BG, Rotteveel JJ, Gabreels FJ. Idiopathic neuralgic amyotrophy in children. A distinct phenotype compared to the adult form. Neuropediatrics. 2000;31:328–32. [PubMed: 11508556]

Chapter Notes

Revision History

  • 6 December 2012 (me) Comprehensive update posted live
  • 27 February 2008 (me) Review posted to live Web site
  • 11 June 2007 (mch) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1395PMID: 20301569
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...