7. Wakerley BR, Uncini A, Yuki N. GBS Classification Group. GuillainBarre and Miller Fisher syndromes—new diagnostic classification. Nat Rev Neurol 2014;10:537–544. 8. Fisher, M. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med 1956;255:57–65. 9. Funakoshi K, Kuwabara S, Odaka M, Hirata K, Yuki N. Clinical predictors of mechanical ventilation in Fisher/Guillain-Barr e overlap syndrome. J Neurol Neurosurg Psychiatry 2009;80:60–64. 10. Albertı MA, Alentorn A, Martınez-Yelamos S, Martınez-Matos JA, Povedano M, Montero J, et al. Very early electrodiagnostic findings in Guillain–Barre syndrome. J Peripher Nerv Syst 2011;16:136–142. 11. Zaidman CM, Al-Lozi M, Pestronk A. Peripheral nerve size in normals and patients with polyneuropathy: an ultrasound study. Muscle Nerve 2009;40:960–966. 12. Zaidman CM, Harms MB, Pestronk A. Ultrasound of inherited vs. acquired demyelinating polyneuropathies. J Neurol 2013;260:3115–3121. 13. Gallardo E, Sedano MJ, Orizaola P, Sanchez-Juan P, Gonzalez-Suarez A, Garcıa A, et al. Spinal nerve involvement in early Guillain–Barr e syndrome: a clinico-electrophysiological, ultrasonographic and pathological study. Clin Neurophysiol 2015;126:810–819. 14. Grimm A, Decard B, Axer H. Ultrasonography of the peripheral nerve system in the early stage of Guillain–Barr e syndrome. J Periph Nerv Syst 2014;19:234–241. 15. Almeida V, Mariotti P, Veltri S, Erra C, Padua L. Nerve ultrasound follow-up in a child with Guillain Barre syndrome. Muscle Nerve 2012;46:270–275. 16. Kerasnoudis A, Pitarokoili K, Behrendt V, Gold R, Yoon MS. Correlation of nerve ultrasound, electrophysiological, and clinical findings in post Guillain-Barr e syndrome. J Peripher Nerv Syst 2013;18:232–240. 17. Grimm A, Heiling B, Schumacher U, Witte OW, Axer H. Ultrasound differentiation of axonal and demyelinating neuropathies. Muscle Nerve 2014;50:976–983. 18. Boehm J, Scheidl E, Bereczki D, Schelle T, Aranyi Z. High-resolution ultrasonography of peripheral nerves: measurements on 14 nerve seg-
19. 20.
21. 22.
23. 24.
25. 26.
27.
ments in 56 healthy subjects and reliability assessments. Ultraschall Med 2014;35:459–467. Preston D, Shapiro B. Electromyography and neuromuscular disorders, clinical–electrophysiological correlations. New York: Elsevier Saunders; 2013. 664 p. Mannil M, Solari A, Leha A, Pelayo-Negro AL, Berciano J, SchlotterWeigel B, et al. Selected items from the Charcot-Marie-Tooth (CMT) Neuropathy Score and secondary clinical outcome measures serve as sensitive clinical markers of disease severity in CMT1A patients. Neuromuscul Disord 2014;24:1003–1017. Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis. Medicine (Baltimore) 1969;48:173–215. Kerasnoudis A, Pitarokoili K, Behrendt V, Gold R, Yoon MS. Increased cerebrospinal fluid protein and motor conduction studies as prognostic markers of outcome and nerve ultrasound changes in Guillain-Barr e syndrome. J Neurol Sci 2014;340:37–43. Yuki N, Uncini A. Acute and chronic ataxic neuropathies with disialosyl antibodies: a continuous clinical spectrum and a common pathophysiological mechanism. Muscle Nerve 2014;49:629–635. Grimm A, D ecard BF, Axer H, Fuhr P. The Ultrasound Pattern Sum Score—UPSS. A new method to differentiate acute and subacute neuropathies using ultrasound of the peripheral nerves. Clin Neurophysiol (to appear). pii: S1388-2457(15)00064-4. doi: 10.1016/j.clinph.2015. 01.011. [Epub ahead of print] Fross RD, Daube JR. Neuropathy in the Miller Fisher syndrome: clinical and electrophysiologic findings. Neurology 1987;37:1493–1498. Shahrizaila N, Goh KJ, Kokubun N, Abdullah S, Yuki N. Serial nerve conduction studies provide insight into the pathophysiology of Guillain–Barr e and Fisher syndromes. J Neurol Sci 2011;309: 26–30. Sugimoto T, Ochi K, Hosomi N, Mukai T, Ueno H, Takahashi T, et al. Ultrasonographic reference sizes of the median and ulnar nerves and the cervical nerve roots in healthy Japanese adults. Ultrasound Med Biol 2013;39:1560–1570.
A CASE OF NEUROMYOTONIA AND AXONAL MOTOR NEUROPATHY: A REPORT OF A HINT1 MUTATION IN THE UNITED STATES NIVEDITA U. JERATH, MD, MICHAEL E. SHY, MD, TIFFANY GRIDER, MS, CGC, and LUDWIG GUTMANN, MD Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52246, USA Accepted 13 July 2015 ABSTRACT: Introduction: HINT1 mutations cause an autosomal recessive distal hereditary motor axonal neuropathy with neuromyotonia. This is a case report of a HINT1 mutation in the United States. Methods: A 30-year-old man of Slovenian heritage and no significant family history presented with scoliosis as a child and later developed neuromyotonia and distal weakness. Electrodiagnostic testing revealed an axonal motor neuropathy and neuromyotonic discharges. Previous diagnostic work-up, including testing for Cx32, MPZ, PMP-22, NF-L, EGR2, CLCN1, DM1, DM2, SMN exon 7/8, emerin, LMNA, MPK, SCNA4, acid maltase gene, paraneoplastic disorder, and a sural nerve biopsy, was negative. Results: Genetic testing for a HINT1 mutation was
Additional Supporting Information may be found in the online version of this article. Abbreviations: CMT, Charcot–Marie–Tooth disease; EMG, electromyography; HINT1, histidine triad nucleotide binding protein 1 Key words: EMG; hereditary neuropathy; HINT1; mutation; neurogenetics; neuromyotonia This study was supported by grants from the National Institutes of Neurological Disorders and Stroke (to M.E.S.) and Office of Rare Diseases (U54NS065712 to M.E.S.), the Muscular Dystrophy Association (to M.E.S.), and the Charcot-Marie-Tooth Association (to M.E.S.), and by a Muscular Dystrophy Association clinical research training grant and University of Iowa internal funding initiatives award (to N.U.J.). Correspondence to: N.U. Jerath; e-mail: [email protected] C 2015 Wiley Periodicals, Inc. V
Published online 16 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24774
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performed and revealed a homozygous mutation at p.Arg37Pro. Conclusion: This entity should be distinguished clinically and genetically from myotonic dystrophy and channelopathies with the clinical features of neuromyotonia and an axonal neuropathy. This case illustrates the importance of identifying the correct phenotype to avoid unnecessary and costly evaluations. Muscle Nerve 52: 1110–1113, 2015
Neuromyotonia is a relatively rare syndrome that results in spontaneous muscle contractions and delayed muscle relaxation after voluntary contraction; it is attributed to a channelopathy that produces hyperexcitable motor axons in the peripheral nervous system. Electrophysiologically, neuromyotonia is associated with spontaneous doublets, triplets, multiplets, and neuromyotonic discharges on needle electromyography (40–300 HZ). Charcot–Marie–Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of disorders that present with distal muscle weakness, wasting, and sensory loss. Type 1 is the primarily demyelinating form, and type 2 is the axonal form. MUSCLE & NERVE
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Neuromyotonia associated with axonal CMT, also known as autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM), is caused by a genetic mutation in the HINT1 (histidine triad nucleotide binding protein 1) gene. This mutation, although a tumor suppressor gene in rodents, results in an axonal neuropathy and neuromyotonia in humans.1 It remains unknown how loss-offunction mutations in HINT1 result in axonal neuropathy and neuromyotonia. We report a case of ARAN-NM from the United States. CASE REPORT
A 30-year-old man developed idiopathic thoracic scoliosis at age 11 years, requiring surgical stabilization. He was born at term with a birth weight of 3.6 kg. He walked independently at 15 months. He was evaluated at 18 months for clumsiness. He was placed in speech therapy for articulation difficulties; he was able to speak short phrases at age 2.5 years. As a child, he kept up with his peers physically, was an average runner, and had no muscle cramps or problems using his hands. He was able to ride a bicycle, roller skate, and ice skate. At age 12, he ran cross country competitively. At age 13, he first noted that he walked “crookedly” with right foot intorsion, ran slower, and had reduced endurance. He was still able to swim. After making a fist, he noted difficulty relaxing the hand muscles. His legs felt stiff. Frequent muscle sprains and ankle twists occurred. He developed a right foot drop and progressive leg weakness. At age 18, tendon transfer surgery was performed. By age 25, he was unable to run long distances. Currently, he has difficulty walking and has had multiple falls. His weakness is worse on the right side. Cramping in all his muscles has been present for years; his hands stiffen with cold temperature and anxiety, but improve when he moves them. Therapeutic trials with oxcarbazepine, phenytoin, carbamazepine, and acetazolamide have been unsuccessful. His creatine kinase levels have ranged from 1,000 to 2,000 U/L. Testing for genetic abnormalities, performed at a variety of other institutions prior to our evaluation, was negative and has included Cx32, MPZ, PMP-22, NF-L, EGR2, CLCN1, DM1, DM2, SMN exon 7/8, emerin, LMNA, MPK, SCNA4, and acid maltase gene. A paraneoplastic autoantibody profile (including antineuronal nuclear autoantibodies 1/2/3, Purkinje cell antibody 1/2/Tr, amphiphysin antibody, P/Q- and N-type calcium channel binding antibody, acetylcholine receptor binding antibody, acetylcholine receptor ganglionic neuronal antibody, striational antibody, collapsin response mediator protein 5 immunoglobulin G, voltage-gated potassium channel antibodies HINT1 mutation
and glutamic acid decarboxylase 65 antibodies) was negative. A muscle biopsy showed a neuropathic process, and a sural nerve biopsy was normal. When he was first seen in our clinic at age 30, findings included a height of 165 cm, mild delay of eye closure and opening, and high arches without shortened Achilles tendons or hammer toes. He had atrophy of the intrinsic hand muscles and calf muscles (left greater than right), and his right foot was smaller than his left. Weakness was moderate in intrinsic hand muscles, including the first dorsal interosseous, abductor digiti minimi, and abductor pollicis brevis on the right and just the first dorsal interosseous and abductor digiti minimi on the left; weakness was profound in all distal leg muscles below the knees. His feet were inverted, and he had atrophy of his legs without spasticity. Sensory examination was entirely normal. Deep tendon reflexes were absent, and plantar reflexes were flexor. He had marked difficulty releasing a forced grip that improved dramatically with repeated attempts (refer to SV1 in Supplementary Material, available online). No percussion myotonia, myokymia, or fasciculations were present. Family History. There was no family history of neurological or neuromuscular disease, including family members with similar symptoms; his maternal ethnicity is Greek and Slovenian, and his father is Slovenian. No parental consanguinity was present. Electrodiagnostic Examination. Electrodiagnostic testing revealed an axonal motor neuropathy: the compound muscle action potentials of the left ulnar and fibular nerves demonstrated reduced amplitude. The sensory nerve action potentials were normal (Table 1). After-discharges were not seen on motor nerve conduction studies. Needle electromyography (EMG) was performed on the left flexor carpi radialis, abductor pollicis brevis, first dorsal interosseous, and tibialis anterior. There was reduced recruitment in most muscles tested. Motor unit potentials were normal except for the first dorsal interosseous muscle, which had high-amplitude motor unit potentials with fibrillation potentials and positive sharp waves. The tibialis anterior muscle had decreased insertional activity. Needle EMG showed spontaneous multiplets (Fig. 1) and neuromyotonic discharges (see SV2 in Supplementary Material, available online). Genetic Testing. Given the clinical presentation, electrodiagnostic examination, and ethnicity, genetic testing for a HINT1 gene mutation was performed. This revealed a homozygous mutation at c.110G>C (p.Arg37Pro), which has been reported in most unrelated families as a cause of an axonal distal motor neuropathy with neuromyotonia. MUSCLE & NERVE
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Table 1. Nerve conduction study data showing a predominantly axonal motor neuropathy.
Motor NCS Median nerve Wrist Elbow Ulnar nerve ADM, wrist Wrist, below elbow Below elbow–above elbow Fibular nerve EDB Tibialis anterior below knee Tibialis anterior above knee Sensory NCS Median Ulnar Radial Sural
Latency
Amplitude
NCV
3.9 ms 8.1 ms
9.8 mV 9.8 mV
56 m/s
3.4 ms 7.4 ms 9.6 ms
1.9 mV 1.8 mV 1.9 mV
50 m/s 59 m/s
NR 4 ms 5.5 ms
910 lV 820 lV
47 m/s
2.3 2.1 1.7 2.5
27.4 mV 32.2 mV 35.8 mV 9.1 mV
67 57 59 40
ms ms ms ms
m/s m/s m/s m/s
Values shown in bold are abnormal. NCV, nerve conduction velocity; APB, abductor pollicis brevis; ADM, abductor digiti minimi, EDB, extensor digitorum brevis; AH, abductor hallucis; NR, not recordable; NCS, nerve conduction studies.
DISCUSSION
Clinically, patients with a HINT1 mutation are reported to have symptom onset at between 3 and 25 years of age, along with gait imbalance, distal weakness, neuromyotonia (especially in the hands) that increases with action, leg stiffness, cramps, foot deformities, and toe contractures. Patients can remain ambulatory throughout most of their adult lives, but will have gait impairment. Some reports have mentioned sensory loss.2 Our patient had no sensory loss, sensory potential alterations on nerve conduction studies, and a normal sural nerve biopsy, although his sural sensory nerve action potential amplitude could be considered mildly low for his age. Serum creatinine kinase should be normal but can be elevated into the 1,000s U/L.3 The patient presented with mild asymmetry; his left foot was smaller than the right, and electrodiagnostic testing showed that the left ulnar nerve was affected compared with median nerve. On clinical examination, the left abductor pollicis brevis was full strength, and the first dorsal interosseous and abductor digiti minimi showed Medical Research Council 4–/5 strength. Although not reported in the literature, this may be identified as a unique feature in future cases. Spontaneous doublets, multiplets, and neuromyotonic discharges are the distinct underlying electrophysiological basis for clinical neuromyotonia. Their presence is a major electrophysiological feature and likely a distinguishing phenotypic hallmark for this disorder. Abnormalities of voltage-gated K1 channels have been documented as the basis for this form of 1112
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axonal hyperexcitability in episodic ataxia 1 and autoimmune neuromyotonia/myokymia. Not all patients with HINT1 mutations will present with spontaneous repetitive and neuromyotonic discharges; because neuromyotonia is a rare phenomenon, it is not easily identified.2 In 19 patients with a HINT1 mutation from the Czech Republic, neuromyotonia was properly recognized in 3 patients before the molecular genetic diagnosis; after the genetic diagnosis, neuromyotonia was found in all but 2 patients.4 In a Portuguese girl who was diagnosed with a HINT1 mutation at age 16, neuromyotonia was recognized after 10 years of evolution.2 It is important to recognize that, in the few cases not showing neuromyotonia yet having abnormal sensory nerve conduction studies, the disease could be diagnosed as autosomal recessive CMT2. HINT1 mutations are a frequent cause of hereditary neuropathy in the Czech population; they are the fourth most commonly identified cause of hereditary neuropathy in this country and are exceeded in frequency only by mutations in the PMP22, GJB1, and MPZ genes.4 The Arg37Pro mutation located in exon 1 of the HINT1 gene is highly prevalent in the Czech population.4 Eight different HINT1 mutations have been found in 33 families.3 Previous reports have identified new sequence variations in Austrian and Belgian families involving the p.[Arg37Pro]1[Gly89Val] and p.[His51Arg]1[Cys84Arg] mutations.3 A new compound heterozygous mutation, p.[Gln62*]1[Gly93Asp], was identified in a Canadian family of Chinese ancestry.3,5 The HINT1 gene is located on chromosome 5q31.1 and encodes a histidine triad nucleotide binding protein 1.6 HINT1 protein was found to be very highly expressed in the mouse sciatic nerve, suggesting that it is an important component of peripheral nervous system function.3 Functional studies showed that HINT1 mutations were loss-of-function mutations.3 HINT1 mutations have defined a new genetic subtype as autosomal recessive axonal neuropathy with neuromyotonia, ARAN-NM.6
FIGURE 1. Spontaneous and recurrent multiplets (predominantly triplets and occasional quadruplets). MUSCLE & NERVE
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It remains unclear how loss-of-function mutations in HINT1 result in an axonal neuropathy and neuromyotonia. HINT1 knockout mice show increased susceptibility to tumor development, but it is not known whether these mice develop an axonal motor neuropathy.1 It is possible that the axonal neuropathy and neuromyotonia could be a result of toxic products in the peripheral nervous system, but the pattern of abnormality, a primarily axonal motor neuropathy with the unique feature of neuromyotonia, is likely to be important in understanding the pathogenesis of the mutation. A recent study analyzed HINT1 knockout mice; these mice appeared normal, had normal behavior and motor test results, and lacked significant electrophysiological or functional alterations.7 However, the animals moved more slowly and for a smaller fraction of time than wild-type mice; in addition, axons were smaller in these mice, thus suggesting that the mouse model could be useful for assessing the role of HINT1 in regeneration.7 ARAN-NM is a recently recognized entity and needs to be distinguished clinically and genetically from myotonic dystrophy and channelopathies causing nondystrophic myotonia.1 It is one of the only genetic disorders, along with episodic ataxia with myokymia type 1, in which hyperexcitable axons occur. The ethnicity of our patient helped significantly with the diagnosis; HINT1 mutations seem to be a frequent cause of hereditary motor neuropathy in those of Czech descent and neighboring European countries.4 This case illustrates the importance of
identifying the correct phenotype to avoid unnecessary and costly evaluations. In conclusion, neuromyotonia in patients with a HINT 1 mutation is an under-recognized phenomenon. Identification of the clinical and electrophysiological features likely predicts the presence of the correct gene mutations. Because neuromyotonia may be elusive at times, a HINT1 mutation should be considered in patients with axonal CMT or hereditary motor neuropathy without a clear family history.4 Defining the relationship of HINT1 mutations and channel regulation may provide important new insights into the pathogenesis of this disease. REFERENCES 1. Zhao H, Race V, Matthijs G, De Jonghe P, Robberecht W, Lambrechts D, et al. Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy. Eur J Hum Genet 2014;22:847–850. 2. Caetano JS, Costa C, Baets J, Zimon M, Vin^ancio M, Saraiva J, et al. Autosomal recessive axonal neuropathy with neuromyotonia: a rare entity. Pediatr Neurol 2014;50:104–107. 3. Zimon M, Baets J, Almeida-Souza L, De Vriendt E, Nikodinovic J, Parman Y, et al. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet 2012;44:1080–1083. Kr˚utova M, Neupauerova J, Haberlova J, 4. Lassuthova P, Brozkova DS, Mazanec R, et al. Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom. Neurogenetics 2015;16:43–54. 5. Hahn AF, Parkes AW, Bolton CF, Stewart SA. Neuromyotonia in hereditary motor neuropathy. J Neurol Neurosurg Psychiatry 1991;54:230– 235. 6. Aminkeng F. HINT1 mutations define a novel disease entity—autosomal recessive axonal neuropathy with neuromyotonia. Clin Genet 2013;83:31–32. 7. Seburn KL, Morelli KH, Jordanova A, Burgess RW. Lack of neuropathy-related phenotypes in hint1 knockout mice. J Neuropathol Exp Neurol 2014;73:693–701.
MYOPATHY IN A PATIENT WITH SYSTEMIC AA AMYLOIDOSIS POSSIBLY INDUCED BY PSORIASIS VULGARIS: AN AUTOPSY CASE HAJIME TANABE, MD,1 YOSHIMITSU MAKI, MD,1 SHOGO URABE, MD, PhD,2 ITSURO HIGUCHI, MD, PhD,3 KONEN OBAYASHI, MD, PhD,4 and YOUICHI HOKEZU, MD, PhD1 1 Department of Neurology, Oita Prefectural Hospital, 476 Bunyo, Oita, 870-0855, Japan 2 Department of Clinical Laboratory, Oita Prefectural Hospital, Oita, Japan 3 School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan 4 Diagnostic Unit for Amyloidosis, Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, Japan Accepted 8 July 2015
Abbreviations: AA, amyloid A; AL, amyloid light chain; BNP, brain natriuretic peptide; CK, creatine kinase; CRP, C-reactive protein; H&E, hematoxylin and eosin; HLA, human leukocyte antigen; MRC, Medical Research Council; SAA, serum amyloid A; TTR, transthyretin; TTR-FAP, transthyretin-related familial amyloidotic polyneuropathies Key words: AA amyloidosis; hypertrophic cardiomyopathy; muscle amyloid angiopathy; psoriasis vulgaris; serum amyloid A Correspondence to: H. Tanabe; e-mail: [email protected] C 2015 Wiley Periodicals, Inc. V
Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24771
Myopathy in Systemic AA Amyloidosis
ABSTRACT: Introduction: Amyloid myopathy is a rare manifestation of primary systemic amyloid light-chain (AL) amyloidosis, but it has not been reported to occur in secondary amyloid A (AA) amyloidosis. Methods: We describe a 46-year-old man with psoriasis vulgaris who presented with idiopathic upper and lower limb weakness and was eventually diagnosed with hypertrophic cardiomyopathy. Muscle biopsy findings were compatible with mild inflammatory myopathy. He died of cardiopulmonary arrest, and an autopsy was performed. Results: The autopsy revealed amyloid plaques immunopositive for AA (but not AL or transthyretin) in the perimysial, perivascular, and endomysial regions of the iliopsoas muscle. The final diagnosis was systemic AA amyloidosis with muscle amyloid angiopathy, possibly induced by psoriasis vulgaris. Conclusion: This is an extremely MUSCLE & NERVE
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19. 20.
21. 22.
23. 24.
25. 26.
27.
ments in 56 healthy subjects and reliability assessments. Ultraschall Med 2014;35:459–467. Preston D, Shapiro B. Electromyography and neuromuscular disorders, clinical–electrophysiological correlations. New York: Elsevier Saunders; 2013. 664 p. Mannil M, Solari A, Leha A, Pelayo-Negro AL, Berciano J, SchlotterWeigel B, et al. Selected items from the Charcot-Marie-Tooth (CMT) Neuropathy Score and secondary clinical outcome measures serve as sensitive clinical markers of disease severity in CMT1A patients. Neuromuscul Disord 2014;24:1003–1017. Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis. Medicine (Baltimore) 1969;48:173–215. Kerasnoudis A, Pitarokoili K, Behrendt V, Gold R, Yoon MS. Increased cerebrospinal fluid protein and motor conduction studies as prognostic markers of outcome and nerve ultrasound changes in Guillain-Barr e syndrome. J Neurol Sci 2014;340:37–43. Yuki N, Uncini A. Acute and chronic ataxic neuropathies with disialosyl antibodies: a continuous clinical spectrum and a common pathophysiological mechanism. Muscle Nerve 2014;49:629–635. Grimm A, D ecard BF, Axer H, Fuhr P. The Ultrasound Pattern Sum Score—UPSS. A new method to differentiate acute and subacute neuropathies using ultrasound of the peripheral nerves. Clin Neurophysiol (to appear). pii: S1388-2457(15)00064-4. doi: 10.1016/j.clinph.2015. 01.011. [Epub ahead of print] Fross RD, Daube JR. Neuropathy in the Miller Fisher syndrome: clinical and electrophysiologic findings. Neurology 1987;37:1493–1498. Shahrizaila N, Goh KJ, Kokubun N, Abdullah S, Yuki N. Serial nerve conduction studies provide insight into the pathophysiology of Guillain–Barr e and Fisher syndromes. J Neurol Sci 2011;309: 26–30. Sugimoto T, Ochi K, Hosomi N, Mukai T, Ueno H, Takahashi T, et al. Ultrasonographic reference sizes of the median and ulnar nerves and the cervical nerve roots in healthy Japanese adults. Ultrasound Med Biol 2013;39:1560–1570.
A CASE OF NEUROMYOTONIA AND AXONAL MOTOR NEUROPATHY: A REPORT OF A HINT1 MUTATION IN THE UNITED STATES NIVEDITA U. JERATH, MD, MICHAEL E. SHY, MD, TIFFANY GRIDER, MS, CGC, and LUDWIG GUTMANN, MD Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52246, USA Accepted 13 July 2015 ABSTRACT: Introduction: HINT1 mutations cause an autosomal recessive distal hereditary motor axonal neuropathy with neuromyotonia. This is a case report of a HINT1 mutation in the United States. Methods: A 30-year-old man of Slovenian heritage and no significant family history presented with scoliosis as a child and later developed neuromyotonia and distal weakness. Electrodiagnostic testing revealed an axonal motor neuropathy and neuromyotonic discharges. Previous diagnostic work-up, including testing for Cx32, MPZ, PMP-22, NF-L, EGR2, CLCN1, DM1, DM2, SMN exon 7/8, emerin, LMNA, MPK, SCNA4, acid maltase gene, paraneoplastic disorder, and a sural nerve biopsy, was negative. Results: Genetic testing for a HINT1 mutation was
Additional Supporting Information may be found in the online version of this article. Abbreviations: CMT, Charcot–Marie–Tooth disease; EMG, electromyography; HINT1, histidine triad nucleotide binding protein 1 Key words: EMG; hereditary neuropathy; HINT1; mutation; neurogenetics; neuromyotonia This study was supported by grants from the National Institutes of Neurological Disorders and Stroke (to M.E.S.) and Office of Rare Diseases (U54NS065712 to M.E.S.), the Muscular Dystrophy Association (to M.E.S.), and the Charcot-Marie-Tooth Association (to M.E.S.), and by a Muscular Dystrophy Association clinical research training grant and University of Iowa internal funding initiatives award (to N.U.J.). Correspondence to: N.U. Jerath; e-mail: [email protected] C 2015 Wiley Periodicals, Inc. V
Published online 16 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24774
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performed and revealed a homozygous mutation at p.Arg37Pro. Conclusion: This entity should be distinguished clinically and genetically from myotonic dystrophy and channelopathies with the clinical features of neuromyotonia and an axonal neuropathy. This case illustrates the importance of identifying the correct phenotype to avoid unnecessary and costly evaluations. Muscle Nerve 52: 1110–1113, 2015
Neuromyotonia is a relatively rare syndrome that results in spontaneous muscle contractions and delayed muscle relaxation after voluntary contraction; it is attributed to a channelopathy that produces hyperexcitable motor axons in the peripheral nervous system. Electrophysiologically, neuromyotonia is associated with spontaneous doublets, triplets, multiplets, and neuromyotonic discharges on needle electromyography (40–300 HZ). Charcot–Marie–Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of disorders that present with distal muscle weakness, wasting, and sensory loss. Type 1 is the primarily demyelinating form, and type 2 is the axonal form. MUSCLE & NERVE
December 2015
Neuromyotonia associated with axonal CMT, also known as autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM), is caused by a genetic mutation in the HINT1 (histidine triad nucleotide binding protein 1) gene. This mutation, although a tumor suppressor gene in rodents, results in an axonal neuropathy and neuromyotonia in humans.1 It remains unknown how loss-offunction mutations in HINT1 result in axonal neuropathy and neuromyotonia. We report a case of ARAN-NM from the United States. CASE REPORT
A 30-year-old man developed idiopathic thoracic scoliosis at age 11 years, requiring surgical stabilization. He was born at term with a birth weight of 3.6 kg. He walked independently at 15 months. He was evaluated at 18 months for clumsiness. He was placed in speech therapy for articulation difficulties; he was able to speak short phrases at age 2.5 years. As a child, he kept up with his peers physically, was an average runner, and had no muscle cramps or problems using his hands. He was able to ride a bicycle, roller skate, and ice skate. At age 12, he ran cross country competitively. At age 13, he first noted that he walked “crookedly” with right foot intorsion, ran slower, and had reduced endurance. He was still able to swim. After making a fist, he noted difficulty relaxing the hand muscles. His legs felt stiff. Frequent muscle sprains and ankle twists occurred. He developed a right foot drop and progressive leg weakness. At age 18, tendon transfer surgery was performed. By age 25, he was unable to run long distances. Currently, he has difficulty walking and has had multiple falls. His weakness is worse on the right side. Cramping in all his muscles has been present for years; his hands stiffen with cold temperature and anxiety, but improve when he moves them. Therapeutic trials with oxcarbazepine, phenytoin, carbamazepine, and acetazolamide have been unsuccessful. His creatine kinase levels have ranged from 1,000 to 2,000 U/L. Testing for genetic abnormalities, performed at a variety of other institutions prior to our evaluation, was negative and has included Cx32, MPZ, PMP-22, NF-L, EGR2, CLCN1, DM1, DM2, SMN exon 7/8, emerin, LMNA, MPK, SCNA4, and acid maltase gene. A paraneoplastic autoantibody profile (including antineuronal nuclear autoantibodies 1/2/3, Purkinje cell antibody 1/2/Tr, amphiphysin antibody, P/Q- and N-type calcium channel binding antibody, acetylcholine receptor binding antibody, acetylcholine receptor ganglionic neuronal antibody, striational antibody, collapsin response mediator protein 5 immunoglobulin G, voltage-gated potassium channel antibodies HINT1 mutation
and glutamic acid decarboxylase 65 antibodies) was negative. A muscle biopsy showed a neuropathic process, and a sural nerve biopsy was normal. When he was first seen in our clinic at age 30, findings included a height of 165 cm, mild delay of eye closure and opening, and high arches without shortened Achilles tendons or hammer toes. He had atrophy of the intrinsic hand muscles and calf muscles (left greater than right), and his right foot was smaller than his left. Weakness was moderate in intrinsic hand muscles, including the first dorsal interosseous, abductor digiti minimi, and abductor pollicis brevis on the right and just the first dorsal interosseous and abductor digiti minimi on the left; weakness was profound in all distal leg muscles below the knees. His feet were inverted, and he had atrophy of his legs without spasticity. Sensory examination was entirely normal. Deep tendon reflexes were absent, and plantar reflexes were flexor. He had marked difficulty releasing a forced grip that improved dramatically with repeated attempts (refer to SV1 in Supplementary Material, available online). No percussion myotonia, myokymia, or fasciculations were present. Family History. There was no family history of neurological or neuromuscular disease, including family members with similar symptoms; his maternal ethnicity is Greek and Slovenian, and his father is Slovenian. No parental consanguinity was present. Electrodiagnostic Examination. Electrodiagnostic testing revealed an axonal motor neuropathy: the compound muscle action potentials of the left ulnar and fibular nerves demonstrated reduced amplitude. The sensory nerve action potentials were normal (Table 1). After-discharges were not seen on motor nerve conduction studies. Needle electromyography (EMG) was performed on the left flexor carpi radialis, abductor pollicis brevis, first dorsal interosseous, and tibialis anterior. There was reduced recruitment in most muscles tested. Motor unit potentials were normal except for the first dorsal interosseous muscle, which had high-amplitude motor unit potentials with fibrillation potentials and positive sharp waves. The tibialis anterior muscle had decreased insertional activity. Needle EMG showed spontaneous multiplets (Fig. 1) and neuromyotonic discharges (see SV2 in Supplementary Material, available online). Genetic Testing. Given the clinical presentation, electrodiagnostic examination, and ethnicity, genetic testing for a HINT1 gene mutation was performed. This revealed a homozygous mutation at c.110G>C (p.Arg37Pro), which has been reported in most unrelated families as a cause of an axonal distal motor neuropathy with neuromyotonia. MUSCLE & NERVE
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Table 1. Nerve conduction study data showing a predominantly axonal motor neuropathy.
Motor NCS Median nerve Wrist Elbow Ulnar nerve ADM, wrist Wrist, below elbow Below elbow–above elbow Fibular nerve EDB Tibialis anterior below knee Tibialis anterior above knee Sensory NCS Median Ulnar Radial Sural
Latency
Amplitude
NCV
3.9 ms 8.1 ms
9.8 mV 9.8 mV
56 m/s
3.4 ms 7.4 ms 9.6 ms
1.9 mV 1.8 mV 1.9 mV
50 m/s 59 m/s
NR 4 ms 5.5 ms
910 lV 820 lV
47 m/s
2.3 2.1 1.7 2.5
27.4 mV 32.2 mV 35.8 mV 9.1 mV
67 57 59 40
ms ms ms ms
m/s m/s m/s m/s
Values shown in bold are abnormal. NCV, nerve conduction velocity; APB, abductor pollicis brevis; ADM, abductor digiti minimi, EDB, extensor digitorum brevis; AH, abductor hallucis; NR, not recordable; NCS, nerve conduction studies.
DISCUSSION
Clinically, patients with a HINT1 mutation are reported to have symptom onset at between 3 and 25 years of age, along with gait imbalance, distal weakness, neuromyotonia (especially in the hands) that increases with action, leg stiffness, cramps, foot deformities, and toe contractures. Patients can remain ambulatory throughout most of their adult lives, but will have gait impairment. Some reports have mentioned sensory loss.2 Our patient had no sensory loss, sensory potential alterations on nerve conduction studies, and a normal sural nerve biopsy, although his sural sensory nerve action potential amplitude could be considered mildly low for his age. Serum creatinine kinase should be normal but can be elevated into the 1,000s U/L.3 The patient presented with mild asymmetry; his left foot was smaller than the right, and electrodiagnostic testing showed that the left ulnar nerve was affected compared with median nerve. On clinical examination, the left abductor pollicis brevis was full strength, and the first dorsal interosseous and abductor digiti minimi showed Medical Research Council 4–/5 strength. Although not reported in the literature, this may be identified as a unique feature in future cases. Spontaneous doublets, multiplets, and neuromyotonic discharges are the distinct underlying electrophysiological basis for clinical neuromyotonia. Their presence is a major electrophysiological feature and likely a distinguishing phenotypic hallmark for this disorder. Abnormalities of voltage-gated K1 channels have been documented as the basis for this form of 1112
HINT1 mutation
axonal hyperexcitability in episodic ataxia 1 and autoimmune neuromyotonia/myokymia. Not all patients with HINT1 mutations will present with spontaneous repetitive and neuromyotonic discharges; because neuromyotonia is a rare phenomenon, it is not easily identified.2 In 19 patients with a HINT1 mutation from the Czech Republic, neuromyotonia was properly recognized in 3 patients before the molecular genetic diagnosis; after the genetic diagnosis, neuromyotonia was found in all but 2 patients.4 In a Portuguese girl who was diagnosed with a HINT1 mutation at age 16, neuromyotonia was recognized after 10 years of evolution.2 It is important to recognize that, in the few cases not showing neuromyotonia yet having abnormal sensory nerve conduction studies, the disease could be diagnosed as autosomal recessive CMT2. HINT1 mutations are a frequent cause of hereditary neuropathy in the Czech population; they are the fourth most commonly identified cause of hereditary neuropathy in this country and are exceeded in frequency only by mutations in the PMP22, GJB1, and MPZ genes.4 The Arg37Pro mutation located in exon 1 of the HINT1 gene is highly prevalent in the Czech population.4 Eight different HINT1 mutations have been found in 33 families.3 Previous reports have identified new sequence variations in Austrian and Belgian families involving the p.[Arg37Pro]1[Gly89Val] and p.[His51Arg]1[Cys84Arg] mutations.3 A new compound heterozygous mutation, p.[Gln62*]1[Gly93Asp], was identified in a Canadian family of Chinese ancestry.3,5 The HINT1 gene is located on chromosome 5q31.1 and encodes a histidine triad nucleotide binding protein 1.6 HINT1 protein was found to be very highly expressed in the mouse sciatic nerve, suggesting that it is an important component of peripheral nervous system function.3 Functional studies showed that HINT1 mutations were loss-of-function mutations.3 HINT1 mutations have defined a new genetic subtype as autosomal recessive axonal neuropathy with neuromyotonia, ARAN-NM.6
FIGURE 1. Spontaneous and recurrent multiplets (predominantly triplets and occasional quadruplets). MUSCLE & NERVE
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It remains unclear how loss-of-function mutations in HINT1 result in an axonal neuropathy and neuromyotonia. HINT1 knockout mice show increased susceptibility to tumor development, but it is not known whether these mice develop an axonal motor neuropathy.1 It is possible that the axonal neuropathy and neuromyotonia could be a result of toxic products in the peripheral nervous system, but the pattern of abnormality, a primarily axonal motor neuropathy with the unique feature of neuromyotonia, is likely to be important in understanding the pathogenesis of the mutation. A recent study analyzed HINT1 knockout mice; these mice appeared normal, had normal behavior and motor test results, and lacked significant electrophysiological or functional alterations.7 However, the animals moved more slowly and for a smaller fraction of time than wild-type mice; in addition, axons were smaller in these mice, thus suggesting that the mouse model could be useful for assessing the role of HINT1 in regeneration.7 ARAN-NM is a recently recognized entity and needs to be distinguished clinically and genetically from myotonic dystrophy and channelopathies causing nondystrophic myotonia.1 It is one of the only genetic disorders, along with episodic ataxia with myokymia type 1, in which hyperexcitable axons occur. The ethnicity of our patient helped significantly with the diagnosis; HINT1 mutations seem to be a frequent cause of hereditary motor neuropathy in those of Czech descent and neighboring European countries.4 This case illustrates the importance of
identifying the correct phenotype to avoid unnecessary and costly evaluations. In conclusion, neuromyotonia in patients with a HINT 1 mutation is an under-recognized phenomenon. Identification of the clinical and electrophysiological features likely predicts the presence of the correct gene mutations. Because neuromyotonia may be elusive at times, a HINT1 mutation should be considered in patients with axonal CMT or hereditary motor neuropathy without a clear family history.4 Defining the relationship of HINT1 mutations and channel regulation may provide important new insights into the pathogenesis of this disease. REFERENCES 1. Zhao H, Race V, Matthijs G, De Jonghe P, Robberecht W, Lambrechts D, et al. Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy. Eur J Hum Genet 2014;22:847–850. 2. Caetano JS, Costa C, Baets J, Zimon M, Vin^ancio M, Saraiva J, et al. Autosomal recessive axonal neuropathy with neuromyotonia: a rare entity. Pediatr Neurol 2014;50:104–107. 3. Zimon M, Baets J, Almeida-Souza L, De Vriendt E, Nikodinovic J, Parman Y, et al. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet 2012;44:1080–1083. Kr˚utova M, Neupauerova J, Haberlova J, 4. Lassuthova P, Brozkova DS, Mazanec R, et al. Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom. Neurogenetics 2015;16:43–54. 5. Hahn AF, Parkes AW, Bolton CF, Stewart SA. Neuromyotonia in hereditary motor neuropathy. J Neurol Neurosurg Psychiatry 1991;54:230– 235. 6. Aminkeng F. HINT1 mutations define a novel disease entity—autosomal recessive axonal neuropathy with neuromyotonia. Clin Genet 2013;83:31–32. 7. Seburn KL, Morelli KH, Jordanova A, Burgess RW. Lack of neuropathy-related phenotypes in hint1 knockout mice. J Neuropathol Exp Neurol 2014;73:693–701.
MYOPATHY IN A PATIENT WITH SYSTEMIC AA AMYLOIDOSIS POSSIBLY INDUCED BY PSORIASIS VULGARIS: AN AUTOPSY CASE HAJIME TANABE, MD,1 YOSHIMITSU MAKI, MD,1 SHOGO URABE, MD, PhD,2 ITSURO HIGUCHI, MD, PhD,3 KONEN OBAYASHI, MD, PhD,4 and YOUICHI HOKEZU, MD, PhD1 1 Department of Neurology, Oita Prefectural Hospital, 476 Bunyo, Oita, 870-0855, Japan 2 Department of Clinical Laboratory, Oita Prefectural Hospital, Oita, Japan 3 School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan 4 Diagnostic Unit for Amyloidosis, Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, Japan Accepted 8 July 2015
Abbreviations: AA, amyloid A; AL, amyloid light chain; BNP, brain natriuretic peptide; CK, creatine kinase; CRP, C-reactive protein; H&E, hematoxylin and eosin; HLA, human leukocyte antigen; MRC, Medical Research Council; SAA, serum amyloid A; TTR, transthyretin; TTR-FAP, transthyretin-related familial amyloidotic polyneuropathies Key words: AA amyloidosis; hypertrophic cardiomyopathy; muscle amyloid angiopathy; psoriasis vulgaris; serum amyloid A Correspondence to: H. Tanabe; e-mail: [email protected] C 2015 Wiley Periodicals, Inc. V
Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24771
Myopathy in Systemic AA Amyloidosis
ABSTRACT: Introduction: Amyloid myopathy is a rare manifestation of primary systemic amyloid light-chain (AL) amyloidosis, but it has not been reported to occur in secondary amyloid A (AA) amyloidosis. Methods: We describe a 46-year-old man with psoriasis vulgaris who presented with idiopathic upper and lower limb weakness and was eventually diagnosed with hypertrophic cardiomyopathy. Muscle biopsy findings were compatible with mild inflammatory myopathy. He died of cardiopulmonary arrest, and an autopsy was performed. Results: The autopsy revealed amyloid plaques immunopositive for AA (but not AL or transthyretin) in the perimysial, perivascular, and endomysial regions of the iliopsoas muscle. The final diagnosis was systemic AA amyloidosis with muscle amyloid angiopathy, possibly induced by psoriasis vulgaris. Conclusion: This is an extremely MUSCLE & NERVE
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