Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant form of recurrent focal neuropathy characterized clinically by acute, recurrent episodes of brachial plexus neuropathy with muscle weakness and atrophy preceded by severe pain in the affected arm.
Kuhlenbaumer et al. (2000) presented diagnostic guidelines for HNA, as reported on behalf of the European CMT Consortium. Pertinent exclusion criteria are absence of pain before or during attacks, signs of a generalized neuropathy, and presence of mutations ... Kuhlenbaumer et al. (2000) presented diagnostic guidelines for HNA, as reported on behalf of the European CMT Consortium. Pertinent exclusion criteria are absence of pain before or during attacks, signs of a generalized neuropathy, and presence of mutations in the PMP22 gene.
Taylor (1960) studied a family in which 5 generations were affected by single or recurrent attacks of mononeuritis with a particular predilection for proximal brachial localization. The trait behaved as an autosomal dominant with high penetrance. Clinically, the ... Taylor (1960) studied a family in which 5 generations were affected by single or recurrent attacks of mononeuritis with a particular predilection for proximal brachial localization. The trait behaved as an autosomal dominant with high penetrance. Clinically, the picture closely resembled serum neuritis, suggesting that the fundamental defect might be a genetic susceptibility to 'hyperergic reactions.' The authors noted that episodes may be triggered by periods of physical or emotional stress and pregnancy. In 7 patients from 2 unrelated families, Jacob et al. (1961) observed 14 similar episodes of recurrent brachial neuritis or mononeuritis multiplex. Attacks were featured by incapacitating pain, weakness, wasting, depression of reflexes, and sensory loss. The legs were involved only in instances of severe arm involvement. Narrow face with close-set eyes was a feature. Gardner and Maloney (1968) emphasized ocular hypotelorism and reported associated syndactyly in this disorder. Guillozet and Mercer (1973) described 4 cases of recurrent brachial neuropathy in 3 generations of a family. These patients showed recurrent attacks of pain, weakness, and sometimes muscle-wasting in the arms and hands. These attacks generally were known to remit gradually, sometimes leaving residual weakness or muscular atrophy. Although the brachial plexus is primarily involved in this condition, the lower cranial nerves and the sympathetic nervous system may also be affected. Airaksinen et al. (1985) reported a Finnish pedigree in which 13 members in 3 generations were affected with recurrent brachial plexus neuropathy. The first episode usually occurred in childhood after a mild infection. Affected patients had hypotelorism, small palpebral fissures, and a small mouth. Despite limitation of symptoms to the upper limbs, sural nerve biopsy in 1 patient showed tomaculous neuropathy. The authors interpreted this finding as indicating a generalized abnormality of Schwann cells predisposing the patients to recurrent palsies precipitated by exogenous factors. Phillips (1986) pointed out that isolated long thoracic nerve palsy causing weakness of the serratus anterior muscle and winging of the scapula, while usually traumatic in origin, can be a major manifestation of familial brachial plexus neuropathy. He studied the disorder in 4 persons in 3 generations of a family. There was male-to-male transmission. In 1 person, facial paresis was also present. Thomas and Ormerod (1993) described a family in which 4 members over 2 generations were affected by neuralgic amyotrophy. A brother and sister were described in detail; another brother and the father were described briefly and not examined. At 19 years of age, the sister had developed pain around her right shoulder which lasted for about 2 days and was followed by difficulty in elevating the right arm and winging of the right scapula. This resolved over the following 5 months. At the age of 20 years, she began to suffer from episodes of pain, usually in the limbs, which lasted for a few days and were followed by areas of sensory loss. At the age of 31, toward the end of a pregnancy, she developed severe pain over the outer aspect of the right upper thigh which she maintained was worse than her subsequent labor pains. This was followed by cutaneous sensory loss in the same area. A brother developed painful winged scapula at age 25 with subsequent recovery. The father of the 3 sibs experienced a painful winged scapula which developed 2 weeks after an injection of antitetanus serum. Although the pain subsided, muscle strength was recovered only partially. There were no dysmorphic features in the family. Thomas and Ormerod (1993) pointed out similarities to the migrant sensory neuritis of Wartenberg (Matthews and Esiri, 1983). Stogbauer et al. (1997) noted that the disorder is characterized clinically by episodes of brachial plexus neuropathy with muscle weakness and atrophy, as well as sensory disturbances. In almost all cases, the onset of muscle weakness is preceded by severe pain in the affected arm. The age of onset of the disease is in the second and third decade of life, although children in the first decade may be affected. Recovery is usually complete and begins weeks to months after the onset of symptoms. Recurrent episodes affect the same as well as the opposite arm. From electrophysiologic studies there is no evidence for a generalized neuropathy in HNA. Histologically, minor signs of axonal degeneration distal to the affected brachial plexus have been described. Several minor dysmorphic features are associated with HNA, including short stature, hypotelorism, epicanthal folds, and cleft palate, but clear segregation of the dysmorphism with the neuropathy has not been proved. In the hereditary form, as in the sporadic form, individual episodes of symptoms may be preceded by infections or immunization (Jacob et al., 1961; Taylor, 1960; Tsairis et al., 1972). Orstavik et al. (1997) described a mother and son with recurrent episodes of brachial plexus neuropathy. They suggested that the hereditary form of this disorder is usually associated with dysmorphic features (Airaksinen et al., 1985), such as hypotelorism, small palpebral fissures, and a small mouth. Although their patients had only very slight dysmorphic features, they concluded that they represented the inherited form. Pellegrino et al. (1997) noted that dysmorphic features, including hypotelorism, long nasal bridge, and facial asymmetry, are frequently associated with this disorder. Meuleman et al. (2001) reviewed the topic of hereditary neuralgic amyotrophy. They pointed out that 2 different clinical courses had been discerned: the classic relapsing-remitting course and a chronic undulating course, consistent with the evidence of genetic heterogeneity. Jeannet et al. (2001) cited 27 patients with hereditary neuralgic amyotrophy from 7 families. Twenty-five patients had an average of 3 attacks of brachial neuritis. The right arm was involved more frequently. Cleft palate was present in 4 individuals. Facial measurements showed significant hypotelorism in patients versus controls. Unusual skin folds and creases were observed on the necks of several individuals, as well as on the scalp of 1 man (cutis verticis gyrata). In 3 families, deep skin creases were present on the limbs of infants and toddlers who were subsequently affected by hereditary neuralgic amyotrophy. Thus, the phenotypic spectrum is wider than previously appreciated and involves nonneural tissues. Kuhlenbaumer et al. (2005) summarized the clinical features of hereditary neuralgic amyotrophy, also called neuralgic amyotrophy with predilection for brachial plexus. The disorder, an autosomal dominant recurrent neuropathy affecting the brachial plexus, is triggered by environmental factors such as infection or parturition. The clinical hallmarks are recurrent painful brachial plexus neuropathies with weakness and atrophy of arm muscles and sensory loss. Full or partial recovery occurs in most affected individuals within weeks to months. A more common sporadic form of painful brachial plexus neuropathy, called Parsonage-Turner syndrome, is clinically indistinguishable from HNA. Attacks of brachial plexus neuritis are often triggered by infections, immunizations, and strenuous use of the affected limb. Inflammatory changes in the blood and brachial plexus have been shown, suggesting involvement of the immune system. Dysmorphic features such as hypotelorism, epicanthal folds, and, rarely, cleft palate had been found in many but not all individuals with the disorder (Pellegrino et al., 1997). Laccone et al. (2008) reported a brother and sister, aged 2.5 years and 6.5 years, respectively, with HNA and dysmorphic features. Dysmorphic features included hypotelorism, upslanting palpebral fissures, very thin, downslanting eyebrows, deep-set eyes, and blepharophimosis. Both sibs also had slight ptosis, epicanthal folds, depressed nasal root, microstomia, and low-set dorsally rotated ears with very broad upper helices. The boy had cleft palate. Developmental milestones for both were normal. On history, the father and paternal grandmother reported painful episodes of brachial muscle weakness with residual wasting and paralysis, consistent with HNA. Photographs of the father and grandmother as children showed similar dysmorphic features as in the 2 sibs. Genetic analysis identified a heterozygous mutation in the SEPT9 gene (R88W; 604061.0001) in all 4 individuals. The boy was originally thought to have BPES (110100), but that was excluded by genetic analysis. His sister had experienced a painful attack in her elbow at age 2.5 years and was incorrectly diagnosed with radial head subluxation at that time. Laccone et al. (2008) emphasized that wider recognition of the characteristic dysmorphic features of HNA can facilitate clinical diagnosis of this syndrome.
Kuhlenbaumer et al. (2005) performed linkage analysis in 10 previously reported multigeneration families with the classical phenotype of what they referred to as hereditary neuralgic amyotrophy (HNA). The families were derived from different geographic areas. Segregation analysis of ... Kuhlenbaumer et al. (2005) performed linkage analysis in 10 previously reported multigeneration families with the classical phenotype of what they referred to as hereditary neuralgic amyotrophy (HNA). The families were derived from different geographic areas. Segregation analysis of short tandem repeat (STR) markers in informative recombinants of these families allowed further reduction of the HNA locus to a 600-kb interval containing only 2 known genes, SEC14L1 and SEPT9 (604061). Kuhlenbaumer et al. (2005) sequenced the coding region of SEPT9 including its untranslated regions (UTRs), multiple splice variants, and alternative first exons. In 4 families with HNA, they found a sequence variation (262C-T) in exon 2 of the SEPT9 gene. This transition caused the amino acid change R88W (604061.0001). These 4 families did not share a common disease-associated haplotype, suggestive of a mutation hotspot rather than a founder mutation. The genomic variation occurred at a potential hypermutable CG dinucleotide. In one family they detected an S93F missense mutation (604061.0002). In another family a variation was found in the 5-prime UTR of the SEPT9 alpha transcript (604061.0003). In 8 of 42 unrelated pedigrees with HNA, Hannibal et al. (2009) identified mutations in the SEPT9 gene. The R88W mutation was consistent with a founder effect. Landsverk et al. (2009) identified an intragenic 38-kb tandem duplication in the SEPT9 gene (604061.0004) that was linked to HNA in 12 North American families that shared a common founder haplotype. The duplication was identical in all pedigrees and included the 645-bp exon in which 2 previous HNA mutations had been found. Collie et al. (2010) identified heterozygous tandem duplications affecting the SEPT9 gene in affected individuals from 6 unrelated families with HNA. All of the duplications were of different sizes with unique breakpoints and ranged size from 30 to 330 kb. The smallest common region shared by all duplications encompassed the proline-rich 645-bp exon in which HNA-linked mutations had previously been identified, suggesting that this region is involved in the pathogenesis of the disorder. Five of the duplications generated larger protein products compared to the wildtype protein. The largest 330-kb duplication spanned the entire SEPT9 gene and included a portion of the adjacent gene SEC14L1 (601504); this duplication did not generate aberrant transcripts or proteins, suggesting that increased dosage of SEPT9 alone may be responsible for the disorder. There was no single mechanism responsible for the generation of these duplications. The HNA phenotype was the same as that observed for other mutations in the SEPT9 gene.
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]. ...
DiagnosisClinical DiagnosisHereditary 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 CriteriaView in own windowFeatureInclusion CriteriaCompatible CriteriaAge 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 TestingGene. 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 AmyotrophyView in own windowGene SymbolProportion of HNA Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySEPT9 ~55% 2Sequence analysis Sequence variants 3See footnote 4ClinicalDeletion / duplication analysis 5Exonic, multiexonic, or whole-gene duplication 6See footnote 7Unknown~45%UnknownNA1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 StrategyTo confirm/establish the diagnosis in a probandConfirmation of the diagnosis in persons in whom a clinical diagnosis of HNA is suspected requires molecular genetic testing to identify the SEPT9 mutation. If sequence analysis of SEPT9 does not identify a mutation, deletion/duplication analysis should be considered.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.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with germline mutations in SEPT9. The MLL oncogene may fuse with SEPT9 in somatic cells to give rise to some forms of myelodysplasia and acute myeloid leukemia (AML).Note: There is no known relationship between HNA and AML.
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. ...
Natural HistoryNeuralgic 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.FigureFigure 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.
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. ...
Genotype-Phenotype CorrelationsIn 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.
Acute pain in the shoulder and upper arm region may be caused by neurologic or non-neurologic disorders. ...
Differential DiagnosisAcute 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with hereditary neuralgic amyotrophy, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 consultationFor a practical overview of the physical examination and the value of additional investigations in neuralgic amyotrophy see pn.bmj.com. Treatment of ManifestationsCurrently, 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. SurveillanceAs 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 AvoidAlthough 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 RiskSee 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 InvestigationIn 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:Methylprednisolone, intravenous 30 mg/kg (or 1.0 g in adults) every 24 hours for three days [Klein et al 2002, Nakajima et al 2006]. Cessation or tapering of corticosteroid therapy has resulted in relapse. Intravenous immune globulin, 0.4 g/kg/day for five days [Ardolino et al 2003, Moriguchi et al 2011] Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSEPT917q25.2-q25.3Septin-9IPN Mutations, SEPT9 SEPT9 homepage - Leiden Muscular Dystrophy pagesSEPT9Data 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) View in own window 162100AMYOTROPHY, HEREDITARY NEURALGIC; HNA 604061SEPTIN 9; SEPT9Normal 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 VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Reference Sequencesc.-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)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org ). 1. Variant designation that does not conform to current naming conventionsFor 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.