Brain, Vol. 123, No. 4, 718-723,
April 2000
© 2000 Oxford University Press
The natural history of hereditary neuralgic amyotrophy in the Dutch population
Two distinct types?
1 Neuromuscular Centre Nijmegen, Institute of Neurology and 2 Department of Human Genetics, University Hospital Nijmegen, The Netherlands
Correspondence to:
B. G. M. van Engelen, MD, Neuromuscular Centre Nijmegen, Institute of Neurology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands E-mail: B.vanEngelen{at}czzoneu.azn.nl
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Abstract |
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On investigation of 101 attacks in 24 patients with hereditary neuralgic amyotrophy (HNA) from nine different families, we found that HNA can run two distinct courses: a `classic' relapsing–remitting and a chronic undulating type with exacerbations. Only one type occurred per family, suggesting genetic heterogeneity. This is supported by the finding that only in a family with `classic type' HNA are data of linkage analysis compatible with linkage to the 17q24–q25 interval which harbours a locus for the disease. The average number of attacks per patient during a follow-up of 26 years was four in the classic form of HNA and five in the chronic undulating type. All patients suffered from residual symptoms on follow-up, with a median Rankin score of 2 in both groups, showing that long-term prognosis is less favourable than previously reported.
hereditary neuralgic amyotrophy; pain; paresis; plexopathy; genetics
HNA = hereditary neuralgic amyotrophy
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Introduction |
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Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disease characterized by recurring attacks of acute severe pain followed by paresis and sometimes sensory deficits, with a gradual recovery over the next months to years. Recently, a locus for HNA was detected on chromosome 17q24–q25 (Pellegrino et al., 1996
; Stögbauer et al., 1997; Wehnert et al., 1997). Mildly dysmorphic features such as hypotelorism have been reported in affected family members (Windebank, 1993). HNA predominantly involves the brachial plexus, but the lumbosacral plexus, lower cranial nerves, phrenic nerve, autonomic nervous system or a combination of these may also be involved (Taylor, 1960; Jacob et al., 1961; Dunn et al., 1978; Arts et al., 1983; Windebank, 1993). The condition is also known as hereditary brachial plexus neuropathy, but this term is inaccurate since the lesion is not restricted to the brachial plexus (Geiger et al., 1974). The age of onset usually lies in the first or second decade of life. HNA is a rare disease; so far only ~200 patients from 35 families have been reported in the literature (Ross and Bury, 1893; Gardner and Maloney, 1968; Chance et al., 1994; Serrano-Castro et al., 1995). Our clinical experience suggested the presence of different phenotypes of HNA and we also doubted the favourable prognosis reported in the literature. To clarify further the natural history of this disease, we studied 24 patients from nine Dutch families with HNA. |
Subjects and methods |
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Clinical studies
In our study, we included 24 (17 male and seven female) patients from nine Dutch families. One of these families has been described in part by Arts and colleagues. (Arts et al., 1983
). Patients were evaluated by the same person (N.v.A) by standardized, structured (familial) history, including a review of their medical history concerning HNA and a standardized neurological examination. All patients gave their informed consent to the investigations, which were part of their normal care. An attack of HNA was defined as any distinct clinical episode not related to any other cause, consisting of pain and paresis, and sometimes sensory and autonomic disturbances, distributed in the brachial or lumbosacral plexus, lower cranial nerves or other peripheral nerves. Separate attacks were defined as an onset of symptoms in different areas more than 4 weeks apart. The duration of follow-up was defined as the time between the time of onset and the time of investigation. We investigated epidemiologic features, symptoms of motor, sensory and autonomic nervous system involvement, the nature, severity and treatment of pain, dysmorphic features, precipitating events and recovery. Patients' present functional impairments were assessed using Rankin scores (van Swieten et al., 1988).
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Genetic analysis |
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DNA was isolated from peripheral blood according to the method of Miller and colleagues (Miller et al., 1988
). DNA markers were typed as described by Kremer and colleagues (Kremer et al., 1994). Two-point lod scores were calculated using the subroutine Mlink of the linkage program (version 5.1) (Lathrop et al., 1986). A frequency of the mutated allele of 0.0001 and a penetrance of 80% were assumed. DNA analysis also served to exclude deletions in the 17p11.2 region and the hereditary neuropathy with liability to pressure palsies genotype in all our families. |
Results |
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Epidemiology
The average age of onset of HNA was 24 years (range 3–59, median 20 years). The average duration of our retrospective follow-up was 26 years (range 1–50). The distribution of right- versus left-handedness was the same as for the general population (22 : 2). Characteristics of patients with HNA in the present study compared with those reported in the literature are given in Table 1
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The predominant features of HNA are pain and motor symptoms. Lower limb plexopathy has similar clinical features to brachial plexus involvement, and occurred in 12% of the attacks, either in isolation or combined with brachial plexopathy (Table 1
). Comparing this with the 7% of attacks reported in the literature suggests that a more extensive examination could reveal a higher incidence of such involvement. Features of autonomic nervous system involvement in HNA are that it is mainly sympathetic, and that it occurs in 9% of the attacks (Jacob et al., 1961; Windebank, 1993; Pellegrino et al., 1996). Thus far, there are no indications that the parasympathetic nervous system is affected in HNA.
Patterns in clinical course
We found two distinct patterns in the clinical course of the disease, which we designate as a `classic' and a `chronic' type of HNA. The classic type represents HNA as it is usually described, with severe attacks of pain followed by paresis and a relatively symptom-free interval in between. The chronic type is characterized by the interictal persistence of pain and paresis. There was only one type of course per family.
In 12 patients (50%) from five families, the disease ran a classic, relapsing–remitting course (Fig. 1A). There were attacks with an acute onset of severe pain lasting from 4 days to 3 weeks, and in many cases paresis ensued when the pain diminished. However, there was also one patient who first developed acute pareses, followed by intense pain a few hours later. Sometimes the attacks were accompanied by sensory disturbances and (or) autonomic disturbances. Recovery of strength began after a few weeks, progressing slowly over a period of months to years. Attacks recurred after an interval of ~8 years (average number of attacks was four per 26 years; median 4). During this interval, the patients were free of pain and had only slight residual paresis; however, after each subsequent attack, recovery was less complete.
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In the other 12 patients (50%) from four families, the disease followed a chronic undulating course with gradual appearance of symptoms such as painful muscles over a period of 6 weeks to 2 years, until the onset of the first real attack (Fig. 1B
). From then on, paresis remained nearly unchanged. The pain would remit to a lower level and exacerbations occurred at this clinical `baseline', sometimes consisting only of worsening of pain for a few days (`abortive attacks') (Geiger et al., 1974), but at other times manifesting as new attacks which would lead to a more permanent loss of function in the affected area. The average number of attacks in this group was five during 26 years (median 4).
Motor symptoms
We were able to record data on motor symptoms in 101 attacks of HNA. Fifty-six per cent of the attacks involving the brachial plexus were right-sided, 24% left-sided and 20% bilateral. Lumbosacral plexus involvement was evenly distributed (33% each). Isolated attacks involving the lumbosacral plexus only occurred in the chronic undulating type of HNA, whereas attacks affecting both the brachial and lumbosacral plexus occurred in both classic and chronic types. Apart from this feature, there was no significant difference in distribution of the attacks between the classic and chronic type.
Pain and pain treatment
In our study, pain in the acute stage of an attack scored an average of 8 out of 10 (range 5–10) on a Visual Analogue Scale (Chapman et al., 1985). It could be aggravated by movement of the affected limb, exposure to cold and physical or emotional stress. The best therapeutic results in terms of pain relief were obtained by a trial of analgesics, starting with opiates combined with an NSAID (non-steroidal anti-inflammatory drug) in acute situations, and with an NSAID combined with amitriptyline or benzodiazepines in chronic pain, and supportive physical therapy including the use of a transcutaneous electrical neurostimulation (TENS) apparatus.
Sensory involvement
Sensory involvement was not prominent in HNA patients, so a reliable history on its extent could not be obtained after a long follow-up period. On follow-up, 58% of the patients had vital hypaesthesia of some part of their skin, 33% also had gnostic hypaesthesia, 29% dysaesthesia and 42% paraesthesias.
Autonomic nervous system involvement
In eight attacks, vasomotor changes of the skin and appendages were reported. One patient suffered a persisting left-sided Horner's syndrome combined with brachial plexus dysfunction. On follow-up, we found 11 patients with changes in perfusion and perspiration of skin, and (or) growth of hair and nails, which was not always confined to areas affected in the attacks.
Dysmorphic features
We measured a median interpupillary distance of 57 mm for both male and female Caucasian patients (ranges 48–63 and 53–63, respectively). The average interpupillary distance is very stable among races and normally measures 63 ± 3 mm (Bogren et al., 1986; Murphy and Laskin, 1990). If hypotelorism is defined as an interpupillary distance of <60 mm, then 16 patients (67%) with HNA met this criterion. Other dysmorphic features found included bilateral pes cavus in five patients.
Preceding events
In 73% of the attacks, no preceding event was found. Twenty-seven per cent of the attacks followed non-specific events such as strenuous exercise of the affected limb (11 times), upper respiratory tract infection (five times), childbirth (four times), cold weather (four times), trauma to the affected upper limb (twice) and surgery with general anaesthaesia (once). We found that strenuous exercise, direct trauma and weather influences were followed by an attack in a matter of hours, and that infections or childbirth preceded an attack by days to weeks. There was no difference in preceding events between the classic and chronic type of HNA.
Recovery
Only 28 out of 101 episodes (28%) were followed by complete functional recovery; 57% of these episodes was either a first or second attack. At present, all 24 patients have residual symptoms (Table 2). Two patients have suffered a subluxation of the shoulder joint as a complication of an attack of HNA, another two have persistent hoarseness due to recurrent nerve dysfunction. In terms of the International Classification of Impairments, Disabilities and Handicaps (World Health Organization), 14 out of 24 patients have functional impairments. Eight of these are handicapped by HNA, and because of this permanently are unable to work; six of these suffer from chronic undulating HNA. On a modified Rankin scale ranging from 0 (no symptoms) to 5 (severe symptoms causing total dependence day and night), the median score for both types was 2 (range 1–3).
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Genetic studies
In only two families, each with a different phenotype of HNA, were enough members available for linkage analysis to be performed. In the first pedigree, with classic type HNA, there were four known affected members, with a total of eight individuals available for linkage analysis. In the second pedigree, with chronic undulating type HNA, 13 members were available for linkage analysis, including eight known affected individuals. Linkage analysis was carried out using microsatellite markers derived from the 17q24–q25 interval, harbouring a gene involved in HNA. In the first family (classic type), the markers D17S949, D17S801, D17S802, D17S836, D17S1806, D17S784 and D17S928 show co-segregation with the disease (Fig. 2
). This is compatible with linkage to the ~6 cM (centiMorgan) candidate region between the markers D17S1301, located between D17S949 and D17S801, and D17S802 (Pellegrino et al., 1996; Stögbauer et al., 1997). Non-penetrance is assumed in one non-affected individual. As the number of individuals tested is small, no significant positive lod scores were found, the maximum lod score being 0.50 at 
= 0.00 with the markers D17S949 and D17S1806. In the second family (chronic type), there is recombination between the disease gene and the DNA markers derived from the candidate region in two of the patients (III-2 and III-7) (Fig. 3). The maximum lod score calculated for this family is 0.98 at = 0.1 with the marker D17S1806, which is located distal to the candidate region.
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Discussion |
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TopAbstractIntroductionSubjects and methodsGenetic analysisResultsDiscussionReferences |
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Based on the large number of patients and families and the long period of follow-up, we conclude that HNA can run two distinct clinical courses. The classical relapsing–remitting form is a very protracted disease with a low frequency of exacerbations (one per 6.5 years). Patients with the chronic undulating type also have persisting pain between attacks. In retrospect, this chronic undulating type of HNA is also found in case descriptions by other authors (Jacob et al., 1961
; Geiger et al., 1974; Arts et al., 1983; Zuazo-Zamolloa et al., 1992; Pellegrino et al., 1996). However, it is not mentioned as a separate entity in standard texts on the subject of HNA (Windebank, 1993). We found only one type of course per family, suggesting genetic heterogeneity. The widespread distribution of symptoms, including lumbosacral and cranial nerve dysfunction and Horner's syndrome, and the finding of pes cavus suggest that the underlying process is a more disseminated neuropathy rather than a brachial plexopathy only, and that HNA can indeed involve multiple peripheral nerves but has a predilection for the right-sided brachial plexus independent of the clinical type.
Twenty-seven per cent of the attacks were preceded by a non-specific event. Data from both the present study and the literature suggest that strenuous exercise, severe emotional stress and exposure to cold are followed by an attack in a matter of hours in susceptible individuals, while (respiratory) infections usually precede HNA by ~1 week, and immunizations by a few weeks to a month (Dreschfeld, 1886; Taylor, 1960; Jacob et al., 1961; Poffenbarger, 1968; Smith et al., 1971; Arts et al., 1983; Thomas and Ormerod, 1993; Windebank, 1993). The time differences could signify different pathophysiological pathways, the exact natures of which remain unsolved.
In the literature, the extent of recovery was commented on in 17 publications, 13 of which reported that prognosis of functional recovery was usually good and overall prognosis of HNA favourable (Ungley, 1933; Taylor, 1960; Jacob et al., 1961; Poffenbarger, 1968; Smith et al., 1971; Guillozet and Mercer, 1973; Erikson, 1974; Geiger et al., 1974; Wiederholt, 1974; Windebank et al., 1982; Airaksinen et al., 1985; Zuazo-Zamolloa et al., 1992; Windebank, 1993; Gouider et al., 1994; Pellegrino et al., 1996; Stögbauer et al., 1997; Wehnert et al., 1997). Only four papers concluded that clinical evolution is not always favourable and that `attacks resulted in persisting atrophy and weakness' (Ungley, 1933; Taylor, 1960; Guillozet and Mercer, 1973; Zuazo-Zamolloa et al., 1992). We found the long-term prognosis to be even less favourable; 100% of patients suffered from persisting symptoms and had a median Rankin score of 2 on follow-up, and 33% of patients were permanently unable to work due to HNA.
Linkage analysis in the two largest families showed that data in the tested family with the classic type of HNA are compatible with the involvement of a gene from the 17q24–q25 region. In the family with the chronic undulating type of HNA, linkage analysis excludes the candidate region. Our data indicate the existence of two genotypically and phenotypically different subtypes of HNA.
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Acknowledgments |
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The authors wish to thank the patients and their families participating in this study, Professor H. F. M. Busch, MD and P. A. van Doorn, MD for their kind cooperation, and P. J. L. A. Bernsen, MD for initiating the research.
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References |
|---|
|
TopAbstractIntroductionSubjects and methodsGenetic analysisResultsDiscussionReferences |
|---|
Airaksinen EM, Iivanainen M, Karli P, Sainlo K, Haltia M. Hereditary recurrent brachial plexus neuropathy with dysmorphic features. Acta Neurol Scand 1985; 71: 309–16.[Web of Science][Medline]
Arts WF, Busch HF, Brand HJ van den, Jennekens FG, Frants RR, Stefanko SZ. Hereditary neuralgic amyotrophy. Clinical, genetic, electrophysiological and histopathological studies. J Neurol Sci 1983; 62: 261–79.[Web of Science][Medline]
Bogren HG, Franti CE, Wilmarth SS. Normal variations of the position of the eye in the orbit. Ophthalmology 1986; 93: 1072–7.[Web of Science][Medline]
Chance PF, Lensch MW, Lipe H, Brown RH Sr, Brown RH Jr, Bird TD. Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: two distinct genetic disorders. Neurology 1994; 44: 2253–7.
Chapman CR, Casey KL, Dubner R, Foley KM, Gracely RH, Reading AE. Pain measurement: an overview. Pain 1985; 22: 1–31.[Web of Science][Medline]
Dreschfeld J. On some of the rarer forms of muscular atrophies. Brain 1886; 9: 178–95.
Dunn HG, Daube JR, Gomez MR. Heredofamilial brachial plexus neuropathy (hereditary neuralgic amyotrophy with brachial predilection) in childhood. Dev Med Child Neurol 1978; 20: 28–46.[Web of Science][Medline]
Erikson A. Hereditary syndrome consisting in recurrent attacks resembling brachial plexus neuritis, special facial features, and cleft palate. Acta Paediatr Scand 1974; 63: 885–8.[Web of Science][Medline]
Gardner JH, Maloney W. Hereditary brachial and cranial neuritis genetically linked with ocular hypotelorism and syndactyly. Neurology 1968; 18: 278.
Geiger LR, Mancall EL, Penn AS, Tucker SH. Familial neuralgic amyotrophy. Report of three families with review of the literature. Brain 1974; 97: 87–102.
Gouider R, LeGuern E, Emile J, Tardieu S, Cabon F, Samid M, et al. Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: two distinct clinical, electrophysiologic, and genetic entities. Neurology 1994; 44: 2250–2.
Guillozet N, Mercer RD. Hereditary recurrent brachial neuropathy. Am J Dis Child 1973; 125: 884–7.
Jacob JC, Andermann F, Robb JP. Heredofamilial neuritis with brachial predilection. Neurology 1961; 11: 1025–33.
Kremer H, Pinckers A, Helm B van den, Deutman AF, Ropers H-H, Mariman EC. Localization of the gene for dominant cystoid macular dystrophy on chromosome 7p. Hum Mol Genet 1994; 3: 299–302.
Lathrop GM, Lalouel JM, White RL. Construction of human linkage maps: likelihood calculations for multilocus linkage analysis. Genet Epidemiol 1986; 3: 39–52.[Web of Science][Medline]
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.
Murphy WK, Laskin DM. Intercanthal and interpupillary distance in the black population. Oral Surg Oral Med Oral Pathol 1990; 69: 676–80.[Web of Science][Medline]
Pellegrino JE, Rebbeck TR, Brown MJ, Bird TD, Chance PF. Mapping of hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) to distal chromosome 17q. Neurology 1996; 46: 1128–32.
Poffenbarger AL. Heredofamilial neuritis with brachial predilection. W V Med J 1968; 64: 425–9.[Medline]
Ross J, Bury JS. On peripheral neuropathies, a treatise. London: C. Griffin; 1893.
Serrano-Castro PJ, Soto-Venegas A, Arnal-Garcia C, Foronda-Bengoa J, Hernandez-Ramos FJ, et al. Hemidiaphragmatic paralysis as a manifestation of familial brachial plexus neuropathy. [Spanish]. Neurologia 1995; 10: 163–6.[Medline]
Smith BH, Ramakrishna T, Schlagenhauff RE. Familial brachial neuropathy. Neurology 1971; 21: 941–5.
Stögbauer F, Young P, Timmerman V, Spoelders P, Ringelstein EB, Van Broeckhoven C, et al. Refinement of the hereditary neuralgic amyotrophy (HNA) locus to chromosome 17q24–q25. Hum Genet 1997; 99: 685–7.[Web of Science][Medline]
Swieten JC van, Koudstaal PJ, Visser MC, Schouten HJ, Gijn J van. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19: 604–7.
Taylor RA. Heredofamilial mononeuritis multiplex with brachial predilection. Brain 1960; 83: 113–37.
Thomas PK, Ormerod IE. Hereditary neuralgic amyotrophy associated with a relapsing multifocal sensory neuropathy. J Neurol Neurosurg Psychiatry 1993; 56: 107–9.
Ungley CC. Recurrent polyneuritis in pregnancy and the puerperium affecting three members of a family. J Neurol Psychopathol 1933; 14: 15–26.
Wehnert M, Timmerman V, Spoelders P, Meuleman J, Nelis E, Van Broeckhoven C. Further evidence supporting linkage of hereditary neuralgic amyotrophy to chromosome 17q. Neurology 1997; 48: 1719–21.
Wiederholt WC. Hereditary brachial neuropathy. Report of two families. Arch Neurol 1974; 30: 252–4.
Windebank AJ, Daube JR, Dyck PJ. Inherited plexus neuropathy and inherited tendency to pressure palsy are different disorders [abstract]. Ann Neurol 1982; 12: 78–9.
Windebank AJ. Inherited recurrent focal neuropathies. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, editors. Peripheral neuropathy. 3rd edn. Philadelphia: W.B. Saunders; 1993. p. 1137–48.
Zuazo-Zamalloa E, Pomposo-Bolumburu I, Garaizar-Axpe C, Prats-Vinas JM. Recurrent familial amyotrophic neuralgia of the brachial plexus. Report of a family and review of the literature. [Review]. [Spanish]. An Esp Pediatr 1992; 37: 47–51.[Medline]
Received June 10, 1999. Revised October 1, 1999. Accepted October 8, 1999.
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