Acute Onset of Weakness and Numbness in the Proximal Left Upper Extremity in a Swimmer

Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disease characterized by recurrent mono-neuropathies precipitated by minor trauma or compression. We present a case of 17-year-old young man who presented with sudden onset of weakness, and numbness of proximal left upper extremity which plateaued in a few weeks. His electrodiagnostic studies showed chronic bilateral multiple symptomatic and asymptomatic neuropathies. Such a presentation with multiple focal demyelinating mononeuropathies should make clinicians suspicious for the diagnosis of HNPP which can be easily proven by genetic testing. ABBREVIATIONS HNPP: Hereditary Neuropathy with Pressure Palsies; CMT: Charcot Marie Tooth disease; MRSA (methicillin resistance staphylococcus aureus); NCS: Nerve Conduction Studies, EMG: Electromyography INTRODUCTION Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disease characterized by recurrent entrapment or compressive mono-neuropathies precipitated by minor trauma or compression. HNPP has a prevalence of approximately 16/100000 [1]. CASE PRESENTATION A 17-year-old male swimmer presented to our neuromuscular clinic for evaluation of paresthesias and weakness in his left upper extremity. He reported that he woke up with numbness and tingling over his left shoulder area. After a week, he started noticing difficulty with external rotation of the arm. He noticed that the weakness progressed over four weeks and then plateaued. He started physical therapy at that point, and noticed some minimal improvement in his weakness over the next four weeks. After a few months, he again had numbness over his left biceps area. This was followed within the next day by weakness of elbow flexion which remained unchanged over time. He reported no pain at any point. He denied any other neurological symptoms. His past medical history was significant for asthma and sinus surgery as a child. His family history was significant for a 19 year old brother who has had two shoulder dislocations and prior diagnosis of ulnar neuropathy. His paternal grandfather had Parkinson’s disease. No other known neurological diseases were noted in the family. His social history was unremarkable. Pertinent neurological exam findings included decreased strength in the left spinati and biceps muscles, absent left biceps reflex, and patchy decreased pinprick sensation in the left C5/ C6 dermatomes. Rest of the physical examination was normal. Electrodiagnostic studies showed chronic bilateral ulnar neuropathies at the elbow, left suprascapular and musculocutaneous neuropathies with active denervation in the left biceps muscle (Tables 1 and 2). Lab work included unremarkable CBC, CMP, thyroid profile, autoimmune workup. Genetic testing was positive for PMP 22 gene deletion. Clinical presentation, electrodiagnostic and genetic testing confirmed the diagnosis of HNPP in this young patient. DISCUSSION HNPP is an autosomal dominant disease with high degree of penetrance. However, clinically asymptomatic obligate gene carriers are sometimes noted. It usually presents in 2nd-3rd decade of life. Clinical features include a spectrum, from asymptomatic patients to severely symptomatic and debilitating disease. In an analysis of 39 patients with HNPP from 16 unrelated pedigrees, two-thirds of patients had the typical presentation of acute mononeuropathy and the remaining subjects were thought to have features consistent with a more long-standing polyneuropathy. Furthermore, it was noted that more than 40% of affected persons were unaware of their illness and 25% of patients were essentially symptom free at the time of observation [2-4]. More recently, the spectrum of clinical and neurophysiological findings in 99 patients with HNPP was documented by. The majority of patients in this survey (70%) presented with a typical history of a single, focal episode of neuropathy, however, there were Central Kaur et al. (2014) Email: J Neurol Disord Stroke 2(2): 1038 (2014) 2/3 patients with short term or chronic sensory syndromes, as well as asymptomatic gene carriers. [5] Electrodiagnostic studies typically show generalized motor and sensory slowing usually in the demyelinating range, commonly involving superficial nerves due to being more prone to pressure/trauma. Conduction blocks are characteristic of affected segments in symptomatic nerves, especially over entrapment sites. Histological assessment of sural nerve biopsies reveals segmental deand remyelination. The presence of tomacula or “sausage”-shaped structures is the pathological feature of HNPP, however not pathognomic as they may be seen in other subtypes of CMT’s and IgM paraproteinemias. They consist of massive redundancy or overfolding of variable thickness layers in the myelin sheath [1]. The genetic locus for HNPP maps to chromosome 17p12, where it is most commonly associated with a large, 1.4 Mb (megabase pair) DNA deletion. HNPP deletions and CMT1A duplications of different sizes have been observed, although they are very rare. The PMP22 gene encodes a 160amino acid membrane-associated protein with a predicted molecular weight of 18 kDa that is increased to 22 kDa by glycosylation. The PMP22 protein is localized to the compact portion of peripheral nerve myelin contains four putative transmembrane domains, and is highly conserved in evolution. The mechanism underlying the generation of the CMT1A DNA duplication and HNPP deletion has been studied in detail. Two point mutations create an early Nerve Sensory Latency (ms) Sensory Amplitude (μV) Motor Distal Latency (ms) Motor Amplitude (μV) Motor Conduction Velocity (m/s) F Wave Latencies (ms) Median L^ 3.4(<3.5) 23.4(>20.0) 4.1(<4.1) 12.58(>6.0) 55.8(>51.0) 30.4(<31) Ulnar L^ 3.8(<3.4) 15.3(>17.0) 3.5(<3.4) 15.73(>6.0) 52.5(>47.0)* 26.0(>47.0)* 36.8(<32) Radial L** 2.3(<2.9) 16.8(>15.0) Median R 3.4(<3.5) 24.5(>20) 3.8(<4.1) 15.09(>6.0) 51.0(>51.0) 30.4(<31) Ulnar R 4.2(<3.4) 4.1(>17.0) 3.6(<4.1) 15.10(>6.0) 60.0(>47.0)* 24.4(>47.0)* 37.6(<32) Radial R 2.5(<2.9) 16.8(>15.0) Table 1: Nerve conduction studies in our patient with HNPP. Normal values given in parentheses. *Below elbow and above elbow. ^Stimulating wrist, recording digits 2 or 5 (sensory) or recording abductor pollicis brevis or abductor digiti minimi muscle (motor). **Stimulating forearm, recording anatomical snuff box Insert Activity Spontaneous and/or Volitional Activity Maximum Volitional Activity Max Volitional Activity Muscle Insert Fibs +Waves Fasc's Other Amp Dur Recruit Polys Effort 1st dorsal interosseous.R Normal None None None None Normal Normal Normal None Max. Abductor pollicis brevis.R Normal None None None None Normal Normal Normal None Max. Flexor carpi radialis.R Normal None None None None Normal Normal Normal None Max. Flexor carpi ulnaris.R Normal None None None None Incr 2+ Incr 2+ Decr 2+ None Max. Flexor digitorum profundus III & IV.R Normal None None None None Incr 2+ Incr 2+ Decr 1+ None Max. Biceps brachii.R Normal None None None None Normal Normal Normal None Max. Triceps brachii.R Normal None None None None Normal Normal Normal None Max. 1st dorsal interosseous.L Normal None None None None Normal Normal Normal None Max. Abductor pollicis brevis.L Normal None None None None Normal Normal Normal None Max. Flexor carpi radialis.L Normal None None None None Normal Normal Normal None Max. Biceps brachii.L Incr 3+ 3+ None None Incr 3+ Incr 3+ Decr 3+ None Max. Triceps brachii.L Normal None None None None Normal Normal Normal None Max. Flexor digitorum profundus III & IV.L Normal None None None None Incr 2+ Incr 2+ Decr 2+ None Max. Flexor carpi ulnaris.L Normal None None None None Incr 2+ Incr 2+ Decr 1+ None Max. Deltoid.L (anterior) Normal None None None None Normal Normal Normal None Max. Deltoid (posterior).L Normal None None None None Normal Normal Normal None Max. Infraspinatus.L Normal None None None None Incr 2+ Incr 2+ Normal 1+ Max. Supraspinatus.L Normal None None None None Incr 2+ Incr 2+ Decr 1+ None Max. Rhomboid major.L Normal None None None None Normal Normal Normal None Max. Cervical paraspinals.L Normal None None None None Normal Normal Normal None Max. Cervical paraspinals.R Normal None None None None Normal Normal Normal None Max. Table 2: Electromyography data in our patient with HNPP. Central Kaur et al. (2014) Email: J Neurol Disord Stroke 2(2): 1038 (2014)3/3Kaur D, Ahmed A (2014) Acute Onset of Weakness and Numbness in the Proximal Left Upper Extremity in a Swimmer. J Neurol Disord Stroke 2(2): 1038.Cite this articlestop codon, leading to a truncated protein. Two splice mutationsare predicted to cause exon skipping, also resulting in an altered,nonfunctional protein. The pathogenic mechanism of thesePMP22 mutations is hypothesized to be that they either mimic thedosage effect of the HNPP deletion by creation of a null allele, ordominant negatively interfere with the function of the remainingnormal PMP22 protein [2].HNPP should be considered as a possible diagnosis in youngpatients presenting with focal demyelinating neuropathies.When palsies occur, they may be debilitating in that they may lastfor days to weeks and may require installation of a lower limbbrace or ankle foot orthosis in the cases of prolonged peronealpalsies [1]. There is no specific treatment for HNPP. The currenttherapy consists of conservative management and symptom-easing measures. Excessive force or repetitive movementsshould be reduced to a minimum and extreme, awkward, orstatic joint positions should be avoided. Chemotherapeuticagents known to affect peripheral nerves should be used withgreat caution in patients with inherited neuropathies, and inthe case of vincristine, total avoidance is strongly advised [2].Genetic therapy is currently being investigated, but will probablytake years before safe and effective gene therapy is available.Therefore to conclude, early diagnosis with electrophysiologictesting is important in order to prevent recurrent palsy episodesespecially in situations that imply prolonged immobilization suchas plaster splints or prolonged anesthesia. Similarly, in our case,competitive swimming would require repetitive movementsof the shoulder girdles that could potentially cause long termpermanent damage to nerves involved in those regions.REFERENCES 1. Chance PF. Inherited demyelinating neuropathy: Charcot Marie Toothdiease and related disorders. The molecular and genetic basis ofneurological disease. 1996; 807-816. 2. Chance PF. Inherited focal, episodic neuropathies: hereditaryneuropathy with liability to pressure palsies and hereditary neuralgicamyotrophy. Neuromolecular Med. 2006; 8: 159-174. 3. Adlkofer K, Martini R, Aguzzi A, Zielasek J, Toyka KV, Suter U.Hypermyelination and demyelinating peripheral neuropathy inPmp22-deficient mice. Nat Genet. 1995; 11: 274-280. 4. Pareyson D, Scaioli V, Taroni F, Botti S, Lorenzetti D, Solari A, et al.Phenotypic heterogeneity in hereditary neuropathy with liability topressure palsies associated with chromosome 17p11.2-12 deletion.Neurology. 1996; 46: 1133-1137. 5. Mouton P, Tardieu S, Gouider R, Birouk N, Maisonobe T, Dubourg O,et al. Spectrum of clinical and electrophysiologic features in HNPPpatients with the 17p11.2 deletion. Neurology. 1999; 52: 1440-1446.