Atypical Motor Neuron Disease Research Articles

Duropathy as a rare motor neuron disease mimic: from bibrachial amyotrophy to infratentorial superficial siderosis

BackgroundBibrachial amyotrophy associated with an extradural CSF collection and infratentorial superficial siderosis (SS) are rare conditions that may occasionally mimic ALS. Both disorders are assumed to be due to dural tears.Case presentationA 53-year-old man presented with a 7-year history of slowly progressive asymmetric bibrachial amyotrophy. Initially, a diagnosis of atypical motor neuron disease (MND) was made. At re-evaluation 11 years later, upper limb wasting and weakness had further progressed and were accompanied by sensorineural hearing loss. MRI of the brain and spine demonstrated extensive supra- and infratentorial SS (including the surface of the whole spinal cord) as well as a ventral longitudinal intraspinal fluid collection (VLISFC) extending along almost the entire thoracic spine. Osteodegenerative changes were observed at C5-C7 level, with osteophytes protruding posteriorly. The bony spurs at C6-C7 level were hypothesized to have lesioned the dura, causing a CSF leak and thus a VLISFC. Review of the MRI acquired at first evaluation showed that the VLISFC was already present at that time (actually beginning at C7 level), whereas the SS was not. 19 years after the onset of upper limb weakness, the patient additionally developed parkinsonism. Response to levodopa, brain scintigraphy with 123I-ioflupane and brain MRI with nigrosome 1 evaluation were consistent with idiopathic Parkinson’s disease (PD). On the latest follow-up 21 years after symptom onset, the VLISFC was unchanged, as were upper arm weakness and wasting.ConclusionsBased on the long-term follow-up, we could establish that, while the evidence of the VLISFC was concomitant with the clinical presentation of upper limb amyotrophy and weakness, the radiological signs of SS appeared later. This suggests that SS was not per se the cause of the ALS-like clinical picture, but rather a long-term sequela of a dural leak. The latter was instead the causative lesion, giving rise to a VLISFC which compressed the cervical motor roots. Dural tears can actually cause several symptoms, and further studies are needed to elucidate the pathophysiological correlates of “duropathies”. Finally, as iron metabolism has been implicated in PD, the co-occurrence of PD with SS deserves further investigation.

Atypical motor neuron disease variant: facial-onset sensory and motor neuronopathy syndrome (FOSMN)

BackgroundFacial-onset sensory and motor neuronopathy (FOSMN) is a rare disease whose cardinal features are initial asymmetrical facial sensory deficits slowly evolving and followed by bulbar symptoms and spreading of sensory and motor deficits from face to scalp, neck, and extremities.Case presentationWe described a 70-year-old man who presented with 6-month history of facial numbness on the left side, and gradual worsening of symptoms. Over several months, facial muscle weakness, dysarthria, and fasciculation had progressed. NCS, needle EMG and blink reflex responses suggested the diagnosis of FOSMN. The ganglioside panel (anti-GM1 and Gd1b) was positive. Considering the FOSMN autoimmune pathology hypothesis, IVIG treatment was given.ConclusionIn this case, we aimed to highlight the key clinical aspects of FOSMN and how to differentiate it from motor neuron disease and bring FOSMN to the attention of neurologists as a recently recognized and distinctive disorder.

Atypical motor neuron disease with bent spine clinical onset and long survival carrying C9orf72 expansion

Atypical motor neuron disease with bent spine clinical onset and long survival carrying C9orf72 expansion

O'Sullivan–McLeod syndrome: Unmasking a rare atypical motor neuron disease

Atypical motor neuron disease represents a rare heterogeneous group of neurodegenerative disorders with clinical, genetic and neuroimaging features distinct from those of the classic spinal or bulbar-onset amyotrophic lateral sclerosis (ALS). O'Sullivan–McLeod syndrome represents an extremely rare lower motor neuronopathy with early adult-onset distal amyotrophy and weakness in the upper limbs with asymmetrical involvement. To add to the few case series and epidemiological and genetic studies describing this variant syndrome, our team here presents a series of seven unrelated Brazilian patients with O'Sullivan–McLeod syndrome in a detailed review of their clinical, neuroimaging, laboratory and neurophysiological findings. A male-to-female ratio of 2.5 to 1 and a mean age at onset of 34.3years was observed, with a mean time delay of 6.6years between symptom-onset and a definitive diagnosis. A positive family history was observed in one case, yet whole-exome sequencing results were negative. Neuroimaging studies were unremarkable. All cases presented with chronic denervation restricted to cervical myotomes and normal sensory nerve conduction studies. This case series, one of the largest groups of patients with O'Sullivan–McLeod syndrome reported in the literature, confirms the sporadic nature of the condition and the difficulties faced in arriving at a definite diagnosis, and also expands the age limit in late adult-onset cases.

P.129 - The recessive SOD1 mutation p.A90V may cause atypical motor neuron disease by oligogenic mechanisms

SOD1 mutations are the second most common cause of familial amyotrophic lateral sclerosis worldwide after the C9orf72 hexanucleotide expansion mutation. Some SOD1 mutations cause atypical phenotypes with slow progression, reduced penetrance or a purely lower motor neuron disease. Most mutations show autosomal dominant inheritance, but recessive inheritance has also been described and indeed the atypical ALS caused by homozygous p.D91A mutations is the most common form of SOD1 ALS in Finland. The phenotype caused by the SOD1 mutation p.A90V has only been reported in a few individuals thus far. A previously reported pedigree carrying the p.A90V mutation showed autosomal dominant inheritance but with reduced penetrance. We describe four Finnish patients with atypically slowly progressive ALS or lower motor neuron disease carrying the SOD1 p.A90V mutation. Three patients were found to carry a second additional mutation in SOD1 or in other known ALS genes, indicating recessive compound heterozygosity or oligogenic disease mechanisms associated with this particular SOD1 mutation, which may also explain the incomplete penetrance observed in the previously reported pedigrees. These findings provide further support for oligogenic pathomechanisms in the pathogenesis of ALS and other motor neuron disorders.

Clinical course of primary progressive aphasia: clinical and FDG-PET patterns.

Primary progressive aphasia (PPA) may be the onset of several neurodegenerative diseases. This study evaluates a cohort of patients with PPA to assess their progression to different clinical syndromes, associated factors that modulate this progression, and patterns of cerebral metabolism linked to different clinical evolutionary forms. Thirty-five patients meeting PPA criteria underwent a clinical and neuroimaging (18)F-Fluorodeoxyglucose PET evaluation. Survival analysis was performed using time from clinical onset to the development of a non-language symptom or deficit (PPA-plus). Cerebral metabolism was analyzed using Statistical Parametric Mapping. Patients classified into three PPA variants evolved to atypical parkinsonism, behavioral disorder and motor neuron disease in the agrammatic variant; to behavioral disorder in the semantic; and to memory impairment in the logopenic. Median time from the onset of symptoms to PPA-plus was 36 months (31-40, 95 % confidence interval). Right laterality, and years of education were associated to a lower risk of progression, while logopenic variant to a higher risk. Different regions of hypometabolism were identified in agrammatic PPA with parkinsonism, motor neuron disease and logopenic PPA-plus. Clinical course of PPA differs according to each variant. Left anterior temporal and frontal medial hypometabolism in agrammatic variant is linked to motor neuron disease and atypical parkinsonism, respectively. PPA variant, laterality and education may be associated to the risk of progression. These results suggest the possibility that clinical and imaging data could help to predict the clinical course of PPA.

Familial Amyloid Polyneuropathy Presenting As Atypical Lower Motor Neuron Disease: A Case Report (P4.091)

Familial Amyloid Polyneuropathy Presenting As Atypical Lower Motor Neuron Disease: A Case Report (P4.091)

Serum anti-neuronal antibodies in amyotrophic lateral sclerosis

We aimed to investigate various anti-neuronal antibodies in sera of amyotrophic lateral sclerosis (ALS) patients to detect possible autoimmune encephalitis patients imitating ALS findings and to delineate the validity of routine screening of well-characterized anti-neuronal antibodies in ALS. The patients fulfilling the revised El Escorial diagnostic criteria for definite ALS were included. Their serum samples were investigated for antiganglioside (IgM/IgG) and onconeural (IgG) antibodies by immunoblotting, for ion channel antibodies (IgG) by a cell-based assay and for IgG binding patterns to the rat brain by indirect immunohistochemistry. Thirty-five patients with definite ALS and 30 healthy individuals were included. Ganglioside antibodies were detected in 2 out of 35 (5.7%) patients with ALS. The onconeural and ion channel antibodies were negative in our series. Varied serum IgG binding patterns were identified in eight (22.9%) patients. Although autoimmune encephalitis patients may occasionally present with atypical motor neuron disease findings, definite ALS patients do not appear to exhibit onconeural or ion channel antibodies, suggesting that routine analysis of these antibodies in typical ALS is not mandatory. By contrast, some ALS patients display anti-neuronal antibodies against undetermined target antigens, prompting investigation of these novel antibodies with more advanced methods.

Association of UBQLN1 mutation with Brown–Vialetto–Van Laere syndrome but not typical ALS

Genetic variants in UBQLN1 gene have been linked to neurodegeneration and mutations in UBQLN2 have recently been identified as a rare cause of amyotrophic lateral sclerosis (ALS). ObjectiveTo test if genetic variants in UBQLN1 are involved in ALS. Methods102 and 94 unrelated patients with familial and sporadic forms of ALS were screened for UBQLN1 gene mutations. Single nucleotide variants were further screened in a larger set of sporadic ALS (SALS) patients and unrelated control subjects using high-throughput Taqman genotyping; variants were further assessed for novelty using the 1000Genomes and NHLBI databases. In vitro studies tested the effect of UBQLN1 variants on the ubiquitin–proteasome system (UPS). ResultsOnly two UBQLN1 coding variants were detected in the familial and sporadic ALS DNA set; one, the missense mutation p.E54D, was identified in a single patient with atypical motor neuron disease consistent with Brown–Vialetto–Van Laere syndrome (BVVLS), for whom c20orf54 mutations had been excluded. Functional studies revealed that UBQLN1E54D protein forms cytosolic aggregates that contain mislocalized TDP-43 and impairs degradation of ubiquitinated proteins through the proteasome. ConclusionsGenetic variants in UBQLN1 are not commonly associated with ALS. A novel UBQLN1 mutation (E45D) detected in a patient with BVVLS altered nuclear TDP-43 localization in vitro, suggesting that UPS dysfunction may also underlie the pathogenesis of this condition.

Genetic Contributors to Frontotemporal Lobar Degeneration: Beyond Monogenic Disease

Frontotemporal Lobar Degeneration (FTLD) is a genetically and pathologically heterogeneous disorder characterized by behavioral change, executive dysfunction and language impairment associated with frontal and temporal lobe degeneration. Three major clinical subtypes have been identified so far, namely behaviour variant Frontotemporal dementia (bvFTD), Semantic Dementia (SD) and Progressive Non-Fluent Aphasia (PNFA). FTLD might also overlap with atypical parkinsonisms or motor neuron disease. Several pathogenetic mutations have been associated with specific pathological and clinical correlates. FTLD associated with either Microtuble Associated Protein Tau (MAPT) or Progranulin (PGRN) mutations is recognised as the most common form of autosomal dominant inherited disorder. However, monogenic mutations account for only about one third of all FTLD cases. Several studies have evaluated the contribution of genetic background in non-monogenic forms of FTLD, with the attempt to establish its role in increasing disease risk and in modulating clinical phenotypes. Specific MAPT and PGRN polymorphisms have been demonstrated to affect disease onset, clinical features and prognosis of FTLD, and genetic variations within other genes appear to play a role in influencing disease risk and clinical expression of FTLD. The aim of the present review is to discuss the impact and the role of genetic background in non-monogenic forms of FTLD, to highlight new potential pathogenetic and therapeutic targets.

Immunohistochemical identification of messenger RNA-related proteins in basophilic inclusions of adult-onset atypical motor neuron disease

This report concerns an immunohistochemical investigation on RNA-related proteins in the basophilic inclusions (BIs) from patients with adult-onset atypical motor neuron disease. Formalin-fixed, paraffin-embedded sections of the motor cortex and the lumbar spinal cord were examined. The BIs appeared blue in color with H&E and Nissl stain, and pink with methylgreen-pyronin stain. Ribonuclease pretreatment abolished the methylgreen-pyronin staining, suggesting that the BIs contained RNA. Immunohistochemically, the BIs were distinctly labeled with the antibodies against poly(A)-binding protein 1, T cell intracellular antigen 1, and ribosomal protein S6. These proteins are essential constituents of stress granules. In contrast, the BIs were not immunoreactive for ribosomal protein L28 and decapping enzyme 1, which are core components of transport ribonucleoprotein particles and processing bodies, respectively. Moreover, the BIs were not immunopositive for TDP-43. Our results imply that translation attenuation could be involved in the processes of BI formation in this disorder.

Atypical motor neuron disease with supranuclear vertical gaze palsy and slow saccades

In amyotrophic lateral sclerosis (ALS), eye movements are usually preserved even after the long-term use of respirators. The present study evaluated a 57-year-old male patient who showed clinical findings compatible with ALS but exhibited disorders of eye movements before he needed to be on an artificial respiration system. The patient had noted clumsiness and weakness in all extremities 5 years before presentation of abnormal eye movements. The results of electromyography and muscle biopsy were compatible with ALS. However, supranuclear vertical gaze palsy and slow saccades are seen. The present case might be representative of a distinct clinical entity, motor neuron disease with disorders of eye movement.

Investigation of the mitochondrial genome in patients with atypical motor neuron disease

The molecular aetiology of many patients with motor neuron disease (MND) remains unknown. Recent evidence of mitochondrial dysfunction, in particular the finding of histochemical abnormalities and pathogenic mitochondrial DNA (mtDNA) mutations, has prompted us to investigate further the role of mtDNA abnormalities in a cohort of thirteen patients with atypical MND presentations by whole mitochondrial genome sequencing. No pathogenic mutations were detected suggesting that inherited mtDNA mutations are not a common cause of atypical MND presentations.

A misdiagnosis of multifocal motor neuropathy

A 60-year-old man had progressive asymmetric weakness in his arms and legs for 11 years. The weakness first appeared in the distal muscles and progressed to involve the proximal muscles in the left leg. 5 years into the illness the patient developed distal weakness in his left hand, which spread to involve his left forearm, arm, and shoulder girdle muscles. 8 years after the onset of motor symptoms he developed weakness in his right hand, which gradually affected his right arm, shoulder, and leg muscles over 3 years. He also noticed progressive wasting of muscles, especially in his left arm and both legs. He also complained of frequent fasciculation over all the affected muscles. There were no cranial nerve, sensory, or autonomic symptoms. He was diagnosed with atypical motor-neuron disease in 1993. The diagnosis was confirmed by doctors at another institution in 1994. We first saw the patient in Jan, 2001. His higher mental functions and cranial nerves were intact. We detected hypotonia in the left arm and legs, and winging of the left scapula. Fasciculation was observed in both arms and the left thigh. All deep tendon jerks were hypoactive. There were neither sensory deficits nor incoordination of the limbs. Muscle strength—as assessed by use of the Medical Research Council (MRC) rating scale in ten of the most affected arm and leg muscles (total 20 muscles, maximal score=100)—was 23/100. The baseline modified Rankin disability scale was grade 4. The functional impairment scale for arms and legs was grade 4. The clinical differential diagnosis was progressive spinal muscular atrophy and multifocal motor neuropathy with conduction block. We did nerve conduction studies using a Nicolet Viking IV-D (Madison, WI, USA) and a Cadwell Excel EMG/EP system (Kennewick, WA, USA). The skin temperature was maintained at 34 C. Bilateral median, ulnar, radial, peroneal, and tibial motor nerves were studied. The stimulation sites were at the wrist, elbow, proximal part of the upper arm, and Erb’s point in the upper limb. The peroneal nerve was stimulated at the ankle, and above and below the fibular head in the popliteal fossa. Ankle and popliteal fossa were the stimulation sites for the tibial nerve. The intensity and the duration of the current were raised to the highest levels to ensure supramaximal stimulation. Negative-peak amplitude, area, and duration were measured for the compound muscle action potential obtained from each stimulation site. Distal motor latency, conduction velocity, and F-wave latency were recorded. Antidromic sensory conduction was investigated in the median, ulnar, radial, and sural nerves. Conduction block was detected by use of electrodiagnostic criteria for multifocal motor neuropathy with conduction block. We did the tests with both the electromyography machines, as well as on a healthy volunteer in order to exclude technical artefacts. Conduction block was seen in axilla-to-Erb’s segment in the left median and right radial nerves. In the elbow-to-axilla segment, definite conduction block was observed in the right ulnar and median nerves. In the right median nerve there was definite conduction block in the long segment of wristto-elbow (figure). The F-wave latency was 130% of the normal upper limit in the right tibial nerve. The motor conduction velocity was reduced in the right median nerve. Electromyography showed neurogenic changes in the muscles sampled. CSF examination did not reveal any cells; the protein was 0·6mmol/L (0·15–0·40 mmol/L) with normal sugar. The IgM anti-GM1 ganglioside antibody titre was less than 1 in 600 (Ranbaxy Laboratories, Mumbai, India). MRI of brachial and lumbosacral plexus was normal. Haemogram, blood sugar, renal, and liver function tests were normal. Serum and urine protein electrophoresis were normal. HIV and CSF venereal disease research laboratory serology were non-reactive. A chest x-ray and abdomen ultrasonogram were normal. We started the patient on intravenous immunoglobulins (IVIg) 400 mg/kg/day for 5 days, which were followed by oral cyclophosphamide 1–2 mg/kg. The patient had improved remarkably by the first follow-up examination at 1 month. The total MRC score had increased from 23/100 to 56/100. The modified Rankin disability score increased from grade 4 to grade 2. The functional impairment scale was grade 2. The patient was given IVIg for 2 days (400 mg/kg/day) every 3 months, for 1 year. Recently, IVIg therapy has been spaced to 6 months and his neurological findings are stable without any further worsening of symptoms. We did a repeat electrodiagnostic study after 18 months of IVIg therapy; there was probable conduction block in the right ulnar nerve and both median nerves in the elbow-toaxilla segment. There was pronounced improvement in the distal compound muscle action potential amplitudes compared with the previous study. The patient fulfilled the clinical, laboratory, and electrodiagnostic criteria for definite multifocal motor neuropathy with conduction block. Our patient was initially diagnosed with atypical motor-neuron disease (progressive spinal muscular atrophy) at another hospital.

Calpainopathy: how broad is the spectrum of clinical variability?

Five affected siblings were referred with a probable diagnosis of proximal adult-type spinal muscular atrophy (SMA) based on lower motor neuron signs (muscle weakness and atrophy, hypotony, hypoactive or absent reflexes, and fasciculations), normal or borderline serum creatine kinase levels, and a neurogenic pattern on electromyography, compatible with motor neuron disease, in one patient. No exon 7-8 deletion in the survival motor neuron (SMN) gene was found. Linkage analysis excluded the SMN and all known autosomal recessive limb girdle muscular dystrophy loci, with the exception of LGMD-2A. A homozygous R769Q mutation in the calpain-3 gene and absence of muscle calpain-3 protein confirmed a calpainopathy. This family suggests that the clinical spectrum of calpainopathy might be broader and that this diagnosis might be considered in patients with an atypical motor neuron disease.

Inclusion body myositis mimicking motor neuron disease.

To describe the clinical and electrophysiologic features of patients with inclusion body myositis that was misinterpreted as motor neuron disease. We retrospectively retrieved the medical records of 70 patients with a pathologic diagnosis of inclusion body myositis. From this group, we selected those who had been first diagnosed as having motor neuron disease or amyotrophic lateral sclerosis. We reviewed the clinical, electrophysiologic, laboratory, and morphologic studies. Nine (13%) of 70 patients with inclusion body myositis had been diagnosed as having motor neuron disease. Six of the 9 patients had asymmetric weakness; in 4 the distal arm muscles were affected. Eight patients had finger flexor weakness. Tendon reflexes were preserved in weak limbs in 6, hyperactive in 2, and absent in 1. Four patients had dysphagia. Fasciculation was seen in 2 patients. None had definite upper motor neuron signs or muscle cramps. Routine electromyographic studies showed fibrillation potentials and positive sharp waves in all 9. Fasciculation potentials were seen in 7 and long-duration polyphasic motor unit potentials were seen in 8. There was no evidence of a myogenic disorder in these 9 patients. Muscle biopsy was done because of slow progression or prominent weakness of the finger flexors and was diagnostic of inclusion body myositis. A quantitative electromyogram was myopathic in 4 of the 5 patients studied. Inclusion body myositis may mimic motor neuron disease. Muscle biopsy and quantitative electromyographic analysis are indicated in patients with atypical motor neuron disease, especially those with slow progression or early and disproportionate weakness of the finger flexors.

Atypical motor neuron disease and related motor syndromes.

There is an imperative need for the early diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) in the current era of emerging treatments. When evaluating the patient with ALS/MND, the neurologist must consider a number of other motor neuron disorders and related motor syndromes that may have clinical features resembling ALS/MND. The revised Airlie House-El Escorial diagnostic criteria have been established through the consensus of experts meeting at workshops. However, by definition, using these criteria a patient is likely to have fairly advanced disease at the time of a definitive ALS/MND diagnosis. The reasons for the difficulty in making an early ALS/MND diagnosis are several. No surrogate diagnostic marker currently exists for ALS/MND. ALS/MND at its onset is heterogeneous in clinical presentation, its clinical course is variable, and several clinical variants are recognized. In addition, certain motor syndromes, such as monomelic amyotrophy, postpolio muscular atrophy, and multifocal motor neuropathy, can clinically mimic ALS/MND. Therefore, not only may the diagnosis of ALS/MND be clinically missed in the early stages, but worse, the patient may be wrongly labeled as having ALS/MND. The diagnosis of ALS/MND requires a combination of upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Motor syndromes in which the deficit is restricted to the UMN or LMN through the entire course of the disease are described as atypical MND in this review. Approximately 5% of patients with ALS/MND have overt dementia with a characteristic frontal affect. ALS/MND with parkinsonism and dementia is rare outside the western Pacific region. The clinical course of motor disorder in these overlap syndromes does not differ from that in typical ALS/MND.

An Autopsy Case of Atypical Motor Neuron Disease with Bunina Bodies in the Lower Motor and Subthalamic Neurons

We report a 37-year-old male without any family history of neurological disease who suffered progressive muscular atrophy and sensory impairment of 4 years' duration. Autopsy revealed neuronal loss in the anterior horns of the spinal cord and in the hypoglossal and facial nuclei of the brain stem. The corticospinal tracts of the spinal cord showed only mild degeneration. In addition, there were obvious degenerative lesions manifested by loss of neurons, myelin and axons in the spinal posterior columns, Clarke's column, spinocerebellar tracts and dorsal root ganglia as well as in the subthalamic nucleus, globus pallidus, substantia nigra and cerebellar dentate nucleus. Furthermore, we frequently encountered Bunina bodies not only in the lower motor neurons but also in the subthalamic neurons. We consider this case to be an atypical example of motor neuron disease with features of multisystem degeneration. The fact that Bunina bodies were observed in both lower motor and subthalamic neurons in this case suggests a common etiology of neuronal degeneration in these two different systems.