No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy.

Inclusion body myopathy (IBM) associated with Paget disease of the bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), sometimes called IBMPFD/ALS or multi system proteinopathy, is a rare, autosomal dominant disorder characterized by progressive degeneration of muscle, brain, motor neurons, and bone with prominent TDP-43 pathology. Recently, 2 novel genes for multi system proteinopathy were discovered; heterogenous nuclear ribonucleoprotein (hnRNP) A1 and A2B1. Subsequently, a mutation in hnRNPA1 was also identified in a pedigree with autosomal dominant familial ALS. The genetic evidence for ALS and other neurodegenerative diseases is still insufficient. We therefore sequenced the prion-like domain of these genes in 135 familial ALS, 1084 sporadic ALS, 68 familial FTD, 74 sporadic FTD, and 31 sporadic IBM patients in a Dutch population. We did not identify any mutations in these genes in our cohorts. Mutations in hnRNPA1 and hnRNPA2B1 prove to be a rare cause of ALS, FTD, and IBM in the Netherlands.

Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation.

Increasing evidence suggests a role for the immune system in amyotrophic lateral sclerosis (ALS). To determine the extent of the immune activation in ALS we analyzed the expression and cellular distribution of components of innate and adaptive immunity in spinal cord (SC) and motor cortex (MCx) from patients with rapid and slow sporadic ALS and controls. High levels of mRNA and protein of classical complement pathway, C1q and C4, as well as the downstream complement components C3 and C5b-9 were found in all ALS samples. Furthermore, we found higher numbers of activated microglia, reactive astrocytes, dendritic cells (DCs) and CD8(+) T-cells in ALS than in control tissue. Rapid ALS cases had more dendritic cells than slow ALS cases, whereas slow ALS cases had more activated microglia than rapid cases. Our findings demonstrate a persistent and prominent activation of both innate and adaptive immunity in ALS. We propose a complement-driven immune response which may contribute to the progression of the inflammation and ultimately lead to even more motor neuron injury.

MR spectroscopy findings in early stages of motor neuron disease.

BACKGROUND AND PURPOSE: Upper motor neuron degeneration varies in different phenotypes of MND. We used single-voxel MR spectroscopy of the primary motor cortex to detect corticomotoneuron degeneration and glial hyperactivity in different phenotypes of MND with a relatively short disease duration, contributing to further delineation of the phenotypes. MATERIALS AND METHODS: We prospectively included patients with ALS-B, ALS-L, and PMA and compared their data with those of patients with PLS and healthy controls. Each cohort consisted of 12 individuals. Disease duration was <1 year in ALS and PMA, but longer in PLS by definition. Follow-up examination was at 6 months. We measured ALSFRS-R, finger- and foot-tapping speed, and levels of the following: 1) NAAx, 2) mIns, and 3) Glx in the primary motor cortex. RESULTS: At baseline, we found significantly decreased NAAx levels and increased mIns levels in PLS. Levels of NAAx and mIns in patients with ALS-L and ALS-B were not significantly different from those in controls, but NAAx levels were significantly lower compared with those in PMA. At follow-up, only in PMA was a decrease of NAAx demonstrated. Glx levels varied widely in all groups. Levels of NAAx and mIns correlated well with clinical variables. CONCLUSIONS: Metabolite changes suggest neuronal dysfunction and active glial involvement in PLS. The corticomotoneuron is affected in early ALS-B and ALS-L, but at a later stage also in PMA. MR spectroscopy data are useful to obtain insight into the disease process at the level of the upper motor neuron in various phenotypes of MND.

Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: a clinical and brain imaging review.

There is an ongoing discussion whether ALS is primarily a disease of upper motor neurons or lower motor neurons. We undertook a review to assess how new insights have contributed to solve this controversy. For this purpose we selected relevant publications from 1995 onwards focussing on (1) primary targets and disease progression in ALS and variants of ALS, (2) brain imaging markers for upper motor neuron lesion, and (3) evidence for ALS being a multisystem disorder. Clinically, upper motor and lower motor neuron symptoms can occur in any order over time. Brain imaging markers show upper motor neuron involvement in early disease. Overlap syndromes of ALS and dementia, and involvement of autonomic and sensory nerves occur frequently. PET/SPECT scans, functional MRI and voxel based morphometry studies clearly show abnormalities in extra-motor areas of the brain. Pathologically, the 43 kDa TAR DNA-binding protein (TDP-43) provides a clue to these overlapping disorders. In conclusion, evidence accumulates that ALS is a multisystem disorder rather than a pure lower and/or upper motor neuron disorder.

Interpretation of electrodiagnostic findings in sporadic progressive muscular atrophy.

OBJECTIVE: We present the electrophysiologic data at baseline of 37 patients who were included in our prospective study on sporadic adult-onset progressive muscular atrophy (PMA). The aim was to correlate electrophysiological signs of lower motor neuron (LMN) loss with clinical signs of LMN loss, and to determine the prognostic value of the distribution of electrophysiological abnormalities in patients who presented clinically with only lower motor neuron signs. METHODS: Thirty-seven patients, who met our inclusion criteria for a prospective study on sporadic adult-onset PMA, underwent extensive standardized electrophysiological examination at baseline, consisting of concentric needle EMG in three regions (cervical, thoracic and lumbosacral) and standardized nerve conduction studies. RESULTS: Denervation on needle EMG was found in 88 % of clinically affected and in 40 % of clinically unaffected limb regions. All patients with a segmental or distal phenotype at baseline who developed generalized weakness had denervation in the thoracic region. Motor nerve conduction abnormalities were found in a substantial number of nerves and included reduced CMAP amplitude, increased distal motor latency, decreased motor conduction velocity, and F-wave abnormalities. Signs of demyelination and sensory nerve conduction abnormalities were rare. CONCLUSIONS: Our electrophysiological data in patients recently diagnosed with sporadic progressive muscular atrophy are consistent with widespread LMN loss. Progression in patients with a segmental or distal onset of PMA may be likely if denervation is found in clinically unaffected regions, including the thoracic region.

Lack of association between VEGF polymorphisms and ALS in a Dutch population.

Sequence alterations in the promoter region of the vascular endothelial growth factor (VEGF) gene have been implicated in increasing the risk of developing ALS. VEGF promoter haplotypes were determined in 373 patients with sporadic ALS and 615 matched healthy controls in The Netherlands. No significant association between the previously reported at-risk haplotypes and ALS was found. Pooling our results with the previously studied population still showed a significant association with the AAG haplotype.

Immunohistochemical localization of vascular endothelial growth factor receptors-1, -2 and -3 in human spinal cord: altered expression in amyotrophic lateral sclerosis.

Vascular endothelial growth factor (VEGF) has recently been implicated in several neurological disorders. Apart from its prominent role in angiogenesis, VEGF has been shown to have direct effects on neuronal and glial cells through activation of different VEGF receptor (VEGFR) types. In the present study the expression patterns of VEGFR-1, -2 and -3 were investigated in the spinal cord of control and both sporadic and familial amyotrophic lateral sclerosis (ALS) patients. Immunocytochemical analysis of control human spinal cord demonstrated that VEGFR-1, but not VEGFR-2 or -3 was found to be present in blood vessels of both white and grey matter. All three VGEFRs were not detectable in resting glial cells of control tissue. Diffuse neuropil staining was observed in the control spinal cord grey matter for VEGFR-3. Regional differences in VEGFRs immunoreactivity (IR) were apparent in ALS compared to controls. In particular, VEGFR-1 expression was increased in reactive astroglial cells in both grey (ventral horn) and white matter of ALS spinal cord. In addition to the astroglial labelling, increased expression of VEGFR-1 and, to a less extent also of VEGFR-2, was observed in blood vessels of the ALS spinal cord. No changes in VEGFR-3 IR were detected in blood vessels or reactive astroglial cells, whereas VEGFR-3 neuropil expression was reduced and paralleled the distribution of neuronal loss in the ventral horn of ALS spinal cord. These findings indicate that VEGFRs have specific distribution patterns, suggesting different physiological functions in human spinal cord. Moreover, the altered expression observed in ALS supports a role for these receptors in the complex reactive processes that are associated with the progression of spinal cord damage.

Comparison of maximal voluntary isometric contraction and hand-held dynamometry in measuring muscle strength of patients with progressive lower motor neuron syndrome.

Context. Maximal voluntary isometric contraction, a method quantitatively assessing muscle strength, has proven to be reliable, accurate and sensitive in amyotrophic lateral sclerosis. Hand-held dynamometry is less expensive and more quickly applicable than maximal voluntary isometric contraction. Objective. To investigate if hand-held dynamometry is as reliable and valid as maximal voluntary isometric contraction in measuring muscle strength in patients with an adult-onset, non-hereditary progressive lower motor neuron syndrome. Design. Two testers performed maximal voluntary isometric contraction and hand-held dynamometry measurements in six muscle groups bilaterally in patients with progressive lower motor neuron syndrome to assess reliability and validity of both the methods. Setting. Outpatient units of an academic medical center. Patients. A consecutive sample of 19 patients with non-hereditary progressive lower motor neuron syndrome (median disease duration 32.5 months, range 10-84) was tested. Outcome measures. Comparison between maximal voluntary strength contractions as measured by hand-held dynamometry and maximal voluntary isometric contraction. Results. Low intra- and interrater variation in all muscle groups were found, intraclass correlation coefficients vary between 0.86 and 0.99 for both methods. Both methods correlated well in all muscle groups with Pearson's correlation coefficients ranged between 0.78 and 0.98. Scatter plots indicated a trend to under-estimate muscle strength above 250 N by hand-held dynamometry as compared with maximal voluntary isometric contraction. Conclusions. For longitudinal evaluation of muscle strength in patients with progressive lower motor neuron syndrome (i.e. between 0 and 250 N), muscle strength can be accurate quantified with both hand-held dynamometry and maximal voluntary isometric contraction. Hand-held dynamometry has the advantage of being cheap and quickly applicable. However, our results indicate that hand-held dynamometry is less sensitive than maximal voluntary isometric contraction in detecting subnormal muscle strength in strong muscle groups (i.e. >250 N), due to limited strength of the tester.

Sporadic lower motor neuron disease with adult onset: classification of subtypes.

The discovery of the genetic basis of hereditary lower motor neuron disease (LMND) and the recognition of multifocal motor neuropathy as a distinct clinical entity necessitate a new classification of LMND. To this end, we studied the clinical and electrophysiological features of 49 patients with sporadic adult-onset LMND in a cross-sectional study. Disease duration was more than 4 years to exclude the majority of patients with amyotrophic lateral sclerosis. Based on the pattern of weakness, we identified three groups: 13 patients with generalized weakness (group 1); eight patients with symmetrical, distal muscle weakness (group 2); and 28 patients with non-generalized asymmetrical weakness of the arms in most patients (group 3). Group 3 could be subdivided into patients with weakness in predominantly the distal (group 3a) or the proximal (group 3b) muscle groups, both with disease progression to adjacent spinal cord segments. Distinctive features of group 1 were an older age at onset, more severe weakness and muscle atrophy, lower reflexes, greater functional impairment, more widespread abnormalities on concentric needle EMG, respiratory insufficiency and serum M-protein. In groups 2 and 3, concentric needle EMG findings also suggested a more widespread disease process. Retrospectively, the prognosis of sporadic adult-onset LMND appears to be favourable, because clinical abnormalities were still confined to one limb in most patients after a median disease duration of 12 years. We propose to classify the patients in the different subgroups as slowly progressive spinal muscular atrophy (group 1), distal spinal muscular atrophy (group 2), segmental distal spinal muscular atrophy (group 3a) and segmental proximal spinal muscular atrophy (group 3b). The described clinical phenotypes may help to distinguish between different LMND forms.

Mimic syndromes in sporadic cases of progressive spinal muscular atrophy.

Described are patients initially diagnosed with progressive spinal muscular atrophy (PSMA), in whom further evaluation established another diagnosis. The authors prospectively investigated incident and prevalent cases of PSMA. Seventeen of 89 patients, after initial registration, were later excluded because reassessment revealed a diagnosis other than PSMA. In 11 of the 17 patients with a revised diagnosis, a potential treatment was available: multifocal motor neuropathy (7), chronic inflammatory demyelinating polyneuropathy (2), inflammatory myopathy (1), and MG (1). Other misdiagnoses included myopathy, syringomyelia, ALS, idiopathic chronic axonal polyneuropathy, and idiopathic brachial plexus neuropathy. One patient with a possible herniated lumbar disk recovered spontaneously.