Clinical features of Pompe disease with motor neuronopathy

Pompe disease with motor neuronopathy Journal Pre-proof Clinical Features of Pompe Disease with Motor Neuronopathy Li-Kai Tsai , Wuh-Liang Hwu , Ni-Chung Lee , Pei-Hsin Huang , Yin-Hsiu Chien PII: DOI: Reference: S0960-8966(19)31131-9 https://doi.org/10.1016/j.nmd.2019.09.011 NMD 3751 To appear in: Neuromuscular Disorders Received date: Revised date: Accepted date: 4 June 2019 6 August 2019 19 September 2019 Please cite this article as: Li-Kai Tsai , Wuh-Liang Hwu , Ni-Chung Lee , Pei-Hsin Huang , Yin-Hsiu Chien , Clinical Features of Pompe Disease with Motor Neuronopathy, Neuromuscular Disorders (2019), doi: https://doi.org/10.1016/j.nmd.2019.09.011 This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. 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Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. ฀฀฀฀฀฀฀฀฀ Highlights:  Pompe patients developed foot drop, distal weakness and generalized hypo/areflexia.  Pompe patients showed impersistent F waves and mixed small and giant polyphasia.  Muscular pathology features the existence of angular fingers or group atrophy.  There is coexistence of motor neuronopathy additionally to myopathy in Pompe disease. 1 ฀฀฀฀฀฀฀฀฀ Clinical Features of Pompe Disease with Motor Neuronopathy Li-Kai Tsaia, Wuh-Liang Hwub,c, Ni-Chung Leeb,c, Pei-Hsin Huangd, Yin-Hsiu Chienb,c a Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan b Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan c Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan d Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan Corresponding authors: Yin-Hsiu Chien: Department of Medical Genetics, Room 19005, 19F, Children's Hospital Building, National Taiwan University Hospital, 8 Chung-Shan South Road, Taipei 10041, Taiwan, Tel.: +886-2-23123456-71936, Fax: +886-2-23314518, E-mail: [email protected] Abbreviated title: Pompe disease with motor neuronopathy Type of manuscript: Case Report Number of words in the Abstract: 143 Number of words in the Introduction/Case Report/Discussion: 1379 Number of figure: 1 Number of Table: 2 Conflicts of Interest: no 2 ฀฀฀฀฀฀฀฀฀ Abstract Pathological studies on rodent models and patients of Pompe disease have demonstrated the accumulation of glycogen in spinal motor neurons; however, this finding has rarely been evaluated clinically in patients with Pompe disease. In this study, we analyzed seven patients (age, 7-11 years) with Pompe disease who received long-term enzyme replacement therapy. In addition to traditional myopathy-related clinical and electrophysiological features, these patients often developed bilateral foot drop, distal predominant weakness of four limbs, and hypo- or areflexia with preserved sensory function. Electrophysiological studies showed not only reduced amplitudes of compound muscle action potential, but also absent or impersistent F waves and mixed small and large/giant polyphasic motor unit action potentials with normal sensory study. Muscle biopsy usually showed the existence of angular fingers, fiber type grouping or group atrophy. Taken together, these features support the co-existence of motor neuronopathy additionally to myopathy. Key words: electromyography, motor neuronopathy, Pompe disease. 3 ฀฀฀฀฀฀฀฀฀ 1. Introduction Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an autosomal recessive glycogen storage disease, which results from deficiency of acid α-glucosidase, leading to impairment of glycogen degradation in lysosomes [1]. Subsequently, the glycogen accumulation in skeletal and cardiac muscles causes progressive myopathy and cardiomegaly with weakness and hypotonia of four limbs and heart failure. With the advent of enzyme replacement therapy (ERT), the life expectancy markedly increases from 1 year to more than decade in infantile-onset Pompe disease [2]. Patients who get early genetic diagnosis and receive ERT asymptomatically may thus show variable clinical manifestations at future disease onset. Although patients with Pompe disease usually present with progressive proximal muscle weakness, which is a typical feature of myopathy, previous pathological studies of Pompe disease also demonstrated the accumulation of glycogen in spinal motor neurons of rodent models [3-5], and patients [6-9] with abnormal neuromuscular junction [10,11]. However, there is still no clinical or electrophysiological studies focusing on the features of motor neuronopathy in patients with Pompe disease. Here we analyzed seven patients with Pompe disease who received ERT since birth or infancy 4 and showed some clinical, ฀฀฀฀฀฀฀฀฀ electrophysiological, and muscular pathological features of motor neuronopathy. 2. Case Report In the cohort of 10 patients of infantile-onset Pompe disease identified by newborn screening [12], six of them accepted to have the detailed neurological and electrophysiological assessment. They all received ERT continuously since diagnosis of Pompe disease until now. The other one patient (patient 7) developed postnatal generalized hypotonia, got diagnosis of Pompe disease at the age of 1 year, and received ERT after then. The mean age of seven patients (6 male) was 9.3±1.8 years (7-11 years old). The clinical, electrophysiological, and muscular pathological features were summarized in Tables 1 and 2, respectively. All patients had dysarthria with nasal speech and weakness of neck and four limbs symmetrically. Five (71%) of seven patients showed bilateral foot drop. Using the Medical Research Council (MRC) scale, muscle power of neck flexion was 3 to 4. Notably, four (57%) patients revealed distal predominant weakness of four limbs, with two of them showing marked discrepancy of muscle power between proximal (4to 4+) and distal (0-1) lower limbs (patients 1 and 6). The deep tendon reflex (DTR) in four limbs was absent in three patients and decreased in four. Otherwise, the examinations on sensory or cerebellar function were unremarkable. 5 ฀฀฀฀฀฀฀฀฀ The nerve conduction study showed reduced amplitudes of compound muscle action potential (CMAP) in peroneal nerves of six patients (86%) with preservation of CMAP in median nerves. The motor nerve conduction velocity and distal motor latency were all normal. The sensory studies on median, ulnar, and sural nerves were within normal limits. However, F-waves were absent or impersistent in median or peroneal nerves of six patients (86%) with normal minimal F-latency. The electromyography showed needle-induced myotonia in four patients (57%) at rest. All patients showed small brief polyphasic waves, indicating existence of myopathy; however, four of them (57%) also had large polyphasic waves or giant waves with amplitudes of motor unit action potential (MUAP) of 5 to 10 mV. All of them have received muscle biopsy of the quadriceps at the age from 1 month to 7 years and we retrospectively reviewed the muscle pathology. In addition to muscular intracytoplasmic glycogen accumulation, the existence of angular fibers, muscle fiber type grouping or group atrophy can be detected in six (86%) patients using H&E and ATPase stains (Figure 1). One patient had severe glycogen accumulation with only few scatter myocytes, impeding further analysis. 3. Discussion Pathological studies on rodent models and patients of Pompe disease have 6 ฀฀฀฀฀฀฀฀฀ demonstrated the accumulation of glycogen in spinal motor neurons [3-9]. However, this finding has rarely been evaluated clinically in patients with Pompe disease. Since ERT was not able to target central nerve system (CNS) because of the existence of blood brain barrier [13,14], the motor neuronopathy may persist despite ERT treatment. In this study, we found that patients with Pompe disease receiving long-term ERT often developed bilateral foot drop, distal predominant weakness of four limbs, and hypo- or areflexia with preserved sensory function. Electrophysiological studies showed not only reduced CMAP amplitudes, but also absent or impersistent F waves and mixed small and large/giant polyphasic waves with normal sensory study. Muscle biopsy usually showed the existence of angular fingers, muscle fiber type grouping or group atrophy. Taken together, these features support the co-existence of motor neuronopathy in addition to myopathy. The typical neurological manifestations of Pompe disease include general weakness/hypotonia of neck and four limbs and dysarthria with preservation of sensory and cerebellar function [1], which are compatible with a pathological result of myopathy. In our patients, additionally to above clinical features, we also found that about 70%, 60%, and 100% of them showed foot drop, distal predominant weakness of four limbs, and hypo- or areflexia of DTR, respectively. Patients with myopathy usually developed proximal-predominant weakness, while distal-predominant 7 ฀฀฀฀฀฀฀฀฀ weakness more likely caused from motor neuronopathy or polyneuropathy [15]. Foot drop indicates predominant weakness of tibialis anterior muscles, which is an unusual finding for myopathy but a common presentation of motor neuronopathy or polyneuropathy [15]. In addition, hyporeflexia or areflexia is a typical feature of motor neuronopathy or polyneuropathy [15]. Although severe myopathy may also show reduction of DTR, the relatively preserved muscle power (3-4+) with hyporeflexia or areflexia in upper limbs of our patients may suggest that the abnormal DTR in Pompe disease is resulted mainly from motor neuronopathy or polyneuropathy. Considering of normal sensory function, the existence of motor neuronopathy is likely. The electrophysiological findings of Pompe disease include reduction of CMAP amplitudes with preserved sensory results in nerve conduction study and existence of needle-induced myotonia and small brief MUAPs in electromyography study [16]. The above features are characteristics of myopathy, which could be detected in most of our patients. Here, we demonstrated that patients with Pompe disease may also show absent or impersistent F-waves (86%) and large or giant MUAPs (57%). The F-wave abnormality along with relatively preserved CMAP amplitude indicates problems in motor neurons or proximal motor nerves [17]. None of our patients experienced root pain and the X-ray of whole spine in all of our patients only 8 ฀฀฀฀฀฀฀฀฀ disclosed mild scoliosis, which made a diagnosis of radiculopathy less likely. The median CMAP amplitudes were quite well along with low peroneal CMAP amplitudes in general, which may indicate mild severity of motor neuronopathy and presence of a length-dependent problem in Pompe disease. Previous pathological study has also shown the accumulation of glycogen in spinal motor neuron, but not peripheral nerve [18]. Although glycogen can deposit in schwann cells [18,19], which play a role on nerve conduction, the motor and sensory nerve conduction velocity and F-latency were both within normal limits in all of our patients. The mixed small and large MUAPs can be seen in patients with chronic myopathy [17]; however, the existence of giant waves (5-10 mV in amplitude) is unusual for myopathy but common for motor neuronopathy. Therefore, the electrophysiological study also support that the coexisting motor neuronopathy is possible in Pompe disease. All of our patients had typical muscle pathology for Pompe disease featuring muscular intracytoplasmic glycogen accumulation [1]. In addition, most of them showed the existence of angular fingers, muscle fiber type grouping or group atrophy, which indicated muscular denervating changes followed by collateral reinnervation [6]. Although the above abnormalities were not severe, the coexisting motor neuronopathy in Pompe disease is still likely. In summary, this study provides the clinical, electrophysiological and muscular 9 ฀฀฀฀฀฀฀฀฀ pathological evidences of neuropathic changes in patients with Pompe disease. Considering of previous pathological findings of glycogen accumulation in spinal motor neuron [3-9], our findings thus support a diagnosis of motor neuronopathy in Pomp disease. Since ERT limits to target CNS because of the existence of blood brain barrier [13,14], further studies should also focus on CNS-specific therapy, eg. gene therapy; future clinical trials should also evaluate the treatment effects on non-muscular phenotypes, such as motor neuronopathy, assessing by DTR, F-wave study, MUNE, and electromyography. In the post-ERT era of Pompe disease, patients may present as variable atypical clinical manifestations. Carefully identifying these presentations, including motor neuronopathy, with regular follow-up will be helpful for optimization of clinical care and setup of future clinical trials in Pompe disease. 10 ฀฀฀฀฀฀฀฀฀ Acknowledgements: Nil Funding: This work was supported by the Ministry of Science and Technology [grant numbers MOST 107-2314-B-002-164-MY3]. 11 ฀฀฀฀฀฀฀฀฀ Reference [1] van der Ploeg AT, Reuser AJ. Pompe's disease. Lancet 2008;372:1342-53. [2] Chien YH1, Hwu WL, Lee NC. Pompe disease: early diagnosis and early treatment make a difference. Pediatr Neonatol 2013;54:219-27. [3] Turner SMF, Falk DJ, Byrne BJ, Fuller DD. Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology. Physiol Genomics 2016;48:785-94. [4] Lee NC, Hwu WL, Muramatsu SI, Falk DJ, Byrne BJ, Cheng CH, et al. A Neuron-specific gene therapy relieves motor deficits in Pompe disease mice. Mol Neurobiol 2018;55:5299-309. [5] Qiu K, Falk DJ, Reier PJ, Byrne BJ, Fuller DD. Spinal delivery of AAV vector restores enzyme activity and increases ventilation in Pompe mice. Mol Ther. 2012;20:21-7. [6] Thurberg BL, Lynch Maloney C, Vaccaro C, Afonso K, Tsai AC, Bossen E, et al. Characterization of pre- and post-treatment pathology after enzyme replacement therapy for Pompe disease. Lab Invest 2006;86:1208-20. [7] Teng YT1, Su WJ, Hou JW, Huang SF. Infantile-onset glycogen storage disease type II (Pompe disease): report of a case with genetic diagnosis and pathological findings. Chang Gung Med J 2004;27:379-84. [8] Martini C1, Ciana G, Benettoni A, Katouzian F, Severini GM, Bussani R, et al. Intractable fever and cortical neuronal glycogen storage in glycogenosis type 2. Neurology 2001;57:906-8. [9] eRuisseau LR, Fuller DD, Qiu K, DeRuisseau KC, Donnelly WH Jr, Mah C, et al. Neural deficits contribute to respiratory insufficiency in Pompe disease. Proc Natl Acad Sci U S A. 2009;106:9419-24. 12 ฀฀฀฀฀฀฀฀฀ [10] Todd AG, McElroy JA, Grange RW, Fuller DD, Walter GA, Byrne BJ, et al. Correcting Neuromuscular Deficits With Gene Therapy in Pompe Disease. Ann Neurol. 2015;78:222-34. [11] Falk DJ, Todd AG, Lee S, Soustek MS, ElMallah MK, Fuller DD, et al. Peripheral nerve and neuromuscular junction pathology in Pompe disease. Hum Mol Genet. 2015;24:625-36. [12] Chien YH, Lee NC, Chen CA, Tsai FJ, Tsai WH, Shieh JY, et al. Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. J Pediatr. 2015;166:985-91. [13] Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis 2004;27:385-410. [14] Fuller DD, ElMallah MK, Smith BK, Corti M, Lawson LA, Falk DJ, et al. The respiratory neuromuscular system in Pompe disease. Respir Physiol Neurobiol. 2013;189:241-9. [15] Bradley WG, Daroff RB, Fenichel GM. Neurology in Clinical Practice: Principles of Diagnosis and Management. Butterworth‐Heinemann, 2000; 2045-236. [16] Hobson-Webb LD, Dearmey S, Kishnani PS. The clinical and electrodiagnostic characteristics of Pompe disease with post-enzyme replacement therapy findings. Clin Neurophysiol 2011;122:2312-7. [17] Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders: clinical-electrophysiologic correlations. Third edition. Elsevier, 2013; 125-248. [18] Goebel HH, Lenard HG, Kohlschütter A, Pilz H. The ultrastructure of the sural nerve in Pompe’s disease. Ann Neurol 1977;2:111-5. [19] Winkel LP1, Kamphoven JH, van den Hout HJ, Severijnen LA, van Doorn PA, Reuser AJ, et al. Morphological changes in muscle tissue of patients with 13 ฀฀฀฀฀฀฀฀฀ infantile Pompe's disease receiving enzyme replacement therapy. Muscle Nerve 2003;27:743-51. 14 ฀฀฀฀฀฀฀฀฀ Figure 1. Muscle pathology in patients with Pompe disease. (A) ATPase stain (pH 9.4) of quadriceps tissue section from patient 7 at the age of 3 years shows focal grouping of the same muscle fiber type (triangle) and existence of angular fiber (arrow). Panel shows presence of angular fiber and group atrophy of muscle fibers (asterisk) by ATPase stain (pH 4.3). (B) ATPase stain (pH 4.3) of quadriceps tissue section from patient 3 at the age of 6 months shows group atrophy of muscle fibers and existence of angular fibers of both type I and type II fibers. (C) H&E stain of quadriceps tissue section from patient 5 at the age of 6 months shows group atrophy of muscle fibers (dotted line) and existence of angular fibers. Scale bar = 50 μm. 15 ฀฀฀฀฀฀฀฀฀ Table 1. Clinical neurological features of patients with Pompe disease Patient Patient Patient 3 Patient 4 Current Patient 5 Patient Patient 7 1 2 6 7/M 11/M 7/F 9/M 11/M 11/M 9/M NBS NBS NBS NBS NBS NBS 1-year-o Age/Gender Age at diagnosis Speech Weakness ld dysart dysart hria hria a distal distal predominanc dysarthri dysarthri dysarthri dysart dysarthri a a hria a generali proxima distal distal proxima zed l l e Foot drop + + + + - + - 4-/4+ 4-/4 4-/4+ 3/4- 4-/4+ 4/4+ 4/5 4+/4- 4/4- 4-/4 3/4 4+/3 4+/3 4+/5 4+/1 1/1 4-/3 3/3 4-/4- 4-/0 4/4+ hyporefl hyporefl exia exia exia ia exia Normal Normal Normal Norma Normal Muscle power: Neck (flexion/exte nsion) Upper limb (P/D)* Lower limb (P/D)* Deep tendon reflex Sensory areflex areflex ia ia Norma Norma 16 Hyporefl areflex hyporefl ฀฀฀฀฀฀฀฀฀ function l l l D indicates distal; F, female; M, male; NBS, newborn screen; P, proximal. *Shoulder abduction for proximal upper limb, finger flexion for distal upper limb, hip flexion for proximal lower limb, and ankle dorsiflexion for distal lower limb; muscle power with the worse side was recorded. 17 ฀฀฀฀฀฀฀฀฀ Table 2. Electrophysiological and muscular pathological features of patients with Pompe disease Patient Patient 2 Patient 3 1 Patient Patien 4 t5 11/NP 10.9/8 Patient 6 Patie nt 7 Nerve conduction study CMAP 6.1/NP 6.4/7.7 Median 16.8/16. 8 8/7.6 .5 9.3/9 .3 (N>5) 1.4/1 0.8/0.6 1.6/1.8 1.1/0.8 Peroneal 2.1/1. 0.2/0.3 1 3.6/2 .8 (N>2) SAP 37/NP 67/78 87/65 62/NP 82/83 54/52 Median 47/3 9 (N>10) 16/17 17/32 34/22 21/17 14/23 7/10 Sural (N>5) F-waves* Median Peroneal 14/1 4 absent/ absent/ab normal/ normal/ norma Impersist norm NP sent normal NP l/ ent/ al/ norma impersist norm l ent al absent/ impersist impersist absent/ norma absent/ab norm impersis ent/ ent/ absent l/ sent al/ tent absent normal 18 absent norm ฀฀฀฀฀฀฀฀฀ al Electromyog raphy Spontaneous Myotoni - a Myoto Myoto Myotoni - nia nia a Small, Small, Small, Mixe brief brief brief d activity Mixed Mixed Mixed Polyphasic waves Muscle biopsy Angular + + + - + + + + + + - + - + fiber Muscle type groupin g or group atrophy CMAP indicates compound muscle action potential at distal stimulation; N, normal cutoff point; NP, not performed; SAP, sensory action potential. Data were results from right/left limbs in mV. *The cut-off values of F-impersistence are 50% and 40% for median and peroneal nerves, respectively. 19