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Brainstem and spinal cord motor neuron involvement with optineurin inclusions in proximal-dominant hereditary motor and sensory neuropathy
  1. Koji Fujita1,
  2. Mari Yoshida2,
  3. Wataru Sako1,
  4. Kouji Maeda1,3,
  5. Yoshio Hashizume4,
  6. Satoshi Goto1,
  7. Gen Sobue5,
  8. Yuishin Izumi1,
  9. Ryuji Kaji1
  1. 1Department of Clinical Neuroscience, The University of Tokushima Graduate School, Tokushima, Japan
  2. 2Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan
  3. 3Department of Neurology, Oka Hospital, Sanuki, Japan
  4. 4Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan
  5. 5Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  1. Correspondence to Dr Ryuji Kaji, Department of Clinical Neuroscience, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; rkaji{at}

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Proximal-dominant hereditary motor and sensory neuropathy (HMSN-P) is characterised by slowly progressive proximal-dominant atrophy and weakness with fasciculations, sensory disturbance and autosomal dominant inheritance.1 HMSN-P has been reported in Okinawa and Kansai, Japan, and the disease locus was mapped to 3q13.1.2 3

The clinical entity of HMSN-P remains controversial. Although this disease was originally described as a new HMSN, it has sometimes been referred to as a part of HMSN type 2 or axonal HMSN. On the other hand, some clinical features of HMSN-P are similar to those of familial amyotrophic lateral sclerosis (ALS).1 Here, we report an autopsy case of HMSN-P that exhibited prominent lower motor neuron (LMN) lesions in the spinal cord and in the brainstem nuclei. Furthermore, we demonstrated optineurin (OPTN)-positive inclusions, which are seen in sporadic and familial ALS,4 in the affected neurons of the present case.

Case report

The patient is the index case of Kansai-type HMSN-P (IV:25 of pedigree 1).3 A 64-year-old man was admitted to a hospital because of gradually developing muscle atrophy and weakness with fasciculations. When he was 51 years old, he had difficulty in climbing up stairs. Five years after the onset, he needed support when walking. Two years later, he was unable to stand up by himself. In a few years, he became bed-ridden. When he was at 64 years of age, he had dysphagia and started tube-feeding after hospitalisation. Neurological examination on admission showed weakness in the facial, soft palate and sternocleidomastoid muscles and tongue atrophy (figure 1A); proximal-dominant weakness and prominent fasciculations were noted; deep tendon reflexes were absent but Babinski sign was present bilaterally; vibration and position sense were severely affected in the limbs, although tactile sensation was preserved. Routine laboratory examinations including vitamin B12 level were normal except for moderately elevated creatinine kinase. Sensory nerve action potentials of the sural nerves were absent. Needle electromyography showed high amplitude and long duration motor units in the affected muscles. Central motor conduction times were within normal limits. Mutations of known genes for HMSN or familial ALS including copper–zinc superoxide dismutase (SOD1), fused in sarcoma/translated in liposarcoma and OPTN were negative. The patient died of pneumonia at the age of 67 years.

Figure 1

Clinicopathological features. (A) The tongue is atrophic. The hypoglossal nucleus shows mild neuron loss (B) compared with the control (C). (D) Severe myelin pallor of the posterior and lateral columns and atrophy of the anterior horn of the cervical cord. (E) Severe neuronal loss, atrophy of the remaining neurons (arrows) and gliosis in the anterior horn of the cervical cord. (F) Neuronal loss and gliosis of Clarke's nucleus of the thoracic cord. (G) Mild neuronal loss of Betz cell (arrow ahead) and cluster of macrophages (arrow) in the precentral gyrus. (H) Severe neurogenic atrophy of iliopsoas muscles against a background of fatty tissue. (I) Both large and small myelinated fibres are markedly decreased without onion-bulb formation in the sural nerve. (J) Ubiquitin-positive inclusions of motor neurons in the facial nucleus. (K) Optineurin (OPTN)-positive inclusion of motor neurons in the hypoglossal nucleus. Double-immunofluorescence staining for ubiquitin (L, red) and OPTN (M, green) in residual neurons in the abducens nucleus shows that ubiquitin inclusions are largely colocalised with OPTN inclusions (N). Scale bars=200 μm (B, C); 1 cm (D); 50 μm (E, F, H); 100 μm (G); 20 μm (I); 10 μm (J–N).


Autopsy was performed 12 h and 40 min after death. Macroscopically, no focal lesions were observed in the cerebrum. In the spinal cord, marked atrophy of anterior and posterior roots was found. Histologically, mild neuronal loss and gliosis were found in the hypoglossal and facial nuclei of the brainstem (figure 1B). Myelin pallor was evident in the posterior and lateral columns of the spinal cord (figure 1D). Severe neuronal loss and gliosis were evident in the spinal anterior horns (figure 1E). Bunina bodies and hyaline inclusions were not seen. The posterior column, corticospinal tract and spinocerebellar tract showed loss of myelinated fibres and gliosis. In Clarke's nucleus, neuronal loss and gliosis were found (figure 1F). Dorsal root ganglion showed mild neuronal loss with a few Nageotte's nodules. Anterior and posterior roots revealed loss of myelinated fibres. Glial bundles were abundant in the proximal portions of the anterior and posterior nerve roots of cervical and lumbosacral segments. In the precentral gyrus, mild loss of Betz cells and gliosis together with neurophagia were observed (figure 1G).

In the iliopsoas muscle, islands of isolated muscle fibres can be seen against a background of fatty tissue (figure 1H). The sural nerve showed a markedly decreased number of large and small myelinated fibres without onion-bulb formation (figure 1I).

Small infarctions were seen in the subcortical white matter, the basal ganglia, the brainstem and the cerebellum.

Immunohistochemistry revealed ubiquitin-positive inclusions in the remaining LMNs of the facial nucleus and the segments of lumbosacral cord (figure 1J). However, TAR DNA-binding protein 43 kDa-positive inclusions were not seen. On the other hand, OPTN-positive inclusions were confirmed in the hypoglossal, the facial and the abducens nuclei, and the anterior horn of the lumbar spinal cord (figure 1K). Double immunofluorescence study demonstrated that ubiquitin-positive inclusions colocalised with OPTN deposit in some affected neurons (figure 1L–N). No ubiquitin- or OPTN-positive inclusions were seen in the dorsal root ganglion.


To our knowledge, this is the first study to describe pathological evidence of motor neuron lesions in both the spinal cord and the brainstem of HMSN-P. Our results clearly demonstrate that HMSN-P differs from HMSN type 2 or other peripheral neuropathies. Instead, we have identified some common features between HMSN-P and motor neuron diseases. For instance, the LMN involvement in our case is similar to that of adult-onset autosomal dominant spinal muscular atrophy, which is characterised by proximal muscular involvement due to LMN damage. Bulbar symptoms, which are common features of HMSN-P, are also described in some cases of adult-onset spinal muscular atrophy.

Furthermore, our case with HMSN-P shares some characteristics with familial ALS, if not sporadic ALS. First, the lesion distribution is similar between our case and familial ALS; the posterior column involvement and slight or mild corticospinal involvement, in contrast to severe degeneration of the LMNs, are the hallmark of many SOD1-mutated familial ALS cases.5 A previously autopsied case with HMSN-P also showed severe neuronal loss in the anterior horn and a pronounced loss of myelinated fibres in the posterior column, although brainstem lesions were not described.1

Second, OPTN inclusions in our case provide a potential pathophysiological link between HMSN-P and ALS. OPTN staining may be associated with ALS because OPTN-positive cytoplasmic inclusions are seen in sporadic ALS and familial ALS with OPTN, SOD1 and fused in sarcoma/translated in liposarcoma mutations, but not in controls.4 6 On the other hand, however, there is a controversy concerning the relevance of OPTN to ALS.7 8 Even if OPTN positivity is not a specific marker for ALS, OPTN inclusions can indicate neurodegenerative process in the central nervous system, and thus differentiate this disease from HMSN. Meanwhile, negative immunoreactivity for TDP-43 indicates that the pathomechanisms of HMSN-P may be different from those of sporadic ALS.

In conclusion, the clinicopathological features of HMSN-P are rather similar to those of SOD1-mutated familial ALS. We propose that this disease is better classified as familial motor neuron disease with sensory neuronopathy rather than HMSN.


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  • Funding This work was supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was approved by the ethics committee of the Tokushima University Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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