A quantitative method for the assessment of intraepidermal nerve fibers in small–fiber neuropathy

OBJECTIVES: The purpose of this paper is to present an easy-to-use and reproducible morphometrical method of determining the density of intraepidermal nerve fibers (IENF) per epidermal area with the corresponding reference range of the IENF-counts. METHODS: Thirty patients and 22 controls were included in this study. The patients were divided into three groups: small-fiber (SFN), diabetic and demyelinating neuropathy. All subjects underwent punch skin biopsy. Specimens were fixed routinely in formalin and thereafter embedded in paraffin. Nerve fibers were revealed using immunoperoxidase staining with panaxonal antibody PGP 9.5. Using light microscopy, immunopositive nerves were counted morphometrically per epidermal area (NPEA) and, for comparison, per epidermal length (NPEL). RESULTS: Both the NPEA and NPEL estimates of SFN and diabetic neuropathy group differed significantly from those of control specimen (p < 0.001 and p < 0.001, Mann-Whitney test). Our method of counting, NPEA, shows a good correlation to NPEL (r = 0.945). CONCLUSIONS: IENF-counting by a new morphometric modification is reproducible and diagnostically sensitive and can easily be adopted in any laboratory familiar with the basic immunohistochemical methodology. The method is less dependent on costly technical support systems and seems to be less time consuming when compared with conventional methods for IENF-counting.     

Clinical and paraclinical features of small fiber neuropathy in Sjögren’s syndrome

Journal of Neurology - Sjögren’s syndrome is a potentially treatable cause of Small Fiber Neuropathy (SFN)—a condition that severely affects patients’ quality of life. We...     

Long-term efficacy of immunoglobulins in small fiber neuropathy related to Sjögren’s syndrome

Journal of Neurology - The most common peripheral nervous system manifestations in Sjogren’s syndrome are small fiber sensory neuropathies (SFPN) and axonal sensorimotor polyneuropathies....     

Small fiber function in drug naïve patients with idiopathic restless legs syndrome

To assess whether idiopathic restless legs syndrome (RLS) is associated with small fiber abnormalities, we evaluated somatic and autonomic small fiber function in 56 patients with idiopathic RLS and 36 age-matched and sex-matched healthy controls using quantitative sensory testing and quantitative sudomotor axon reflex tests. The warm detection thresholds (WDT) of the hands (p=0.017) and feet (p=0.008) were higher in patients with RLS than in controls. Cooling detection thresholds (CDT) were higher in the feet of patients with RLS than controls (p<0.001), but CDT in the hands did not differ between groups (p=0.161). There were no significant between-group differences in total sweat volume and sweat production in the forearms, proximal legs, distal legs, and feet (p>0.1 each). These findings suggest that abnormal sensory perception in patients with idiopathic RLS may result from impairment of central somatosensory processing rather than small fiber neuropathy.     

Structure–function analyses of tyrosine phosphatase PTP69D in giant fiber synapse formation of Drosophila

PTP69D is a receptor protein tyrosine phosphatase (RPTP) with two intracellular catalytic domains (Cat1 and Cat2) and has been shown to play a role in axon guidance of embryonic motoneurons as well as targeting of photoreceptor neurons in the visual system of Drosophila melanogaster. Here, we characterized the developmental role of PTP69D in the giant fiber (GF) neurons, two interneurons in the central nervous system (CNS) that control the escape response of the fly. Our studies revealed that PTP69D has a function in synaptic terminal growth in the CNS. We found that missense mutations in the first immunoglobulin (Ig) domain and in the Cat1 domain, present in Ptp69D¹⁰ and Ptp69D²⁰ mutants, respectively, did not affect axon guidance or targeting but resulted in stunted terminal growth of the GFs. Cell autonomous rescue experiments demonstrated a function for the Cat1 and the first Ig domain of PTP69D in the GFs but not in its postsynaptic target neurons. In addition, complementation studies and structure–function analyses revealed that for GF terminal growth Cat1 function of PTP69D requires the immunoglobulin and the Cat2 domains, but not the fibronectin III or the membrane proximal region domains. In contrast, the fibronectin III but not the immunoglobulin domains were previously shown to be essential for axon targeting of photoreceptor neurons. Thus, our studies uncover a novel role for PTP69D in synaptic terminal growth in the CNS that is mechanistically distinct from its function in photoreceptor targeting.     

Auditory function in individuals within Leber’s hereditary optic neuropathy pedigrees

The aims of this study are to investigate whether auditory dysfunction is part of the spectrum of neurological abnormalities associated with Leber’s hereditary optic neuropathy (LHON) and to determine the perceptual consequences of auditory neuropathy (AN) in affected listeners. Forty-eight subjects confirmed by genetic testing as having one of four mitochondrial mutations associated with LHON (mt11778, mtDNA14484, mtDNA14482 and mtDNA3460) participated. Thirty-two of these had lost vision, and 16 were asymptomatic at the point of data collection. While the majority of individuals showed normal sound detection, >25% (of both symptomatic and asymptomatic participants) showed electrophysiological evidence of AN with either absent or severely delayed auditory brainstem potentials. Abnormalities were observed for each of the mutations, but subjects with the mtDNA11778 type were the most affected. Auditory perception was also abnormal in both symptomatic and asymptomatic subjects, with >20% of cases showing impaired detection of auditory temporal (timing) cues and >30% showing abnormal speech perception both in quiet and in the presence of background noise. The findings of this study indicate that a relatively high proportion of individuals with the LHON genetic profile may suffer functional hearing difficulties due to neural abnormality in the central auditory pathways.     

Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers–Danlos syndromes

Background and purpose

Ehlers–Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers–Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood.

Study Purpose

To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers-Danlos Syndromes.

Methods

We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt-table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS-31 (Composite Autonomic Symptom Score 31) questionnaire.

Results

Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions.

Conclusion

These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism.     

Acute small fibre sensory neuropathy: another variant of Guillain-Barré syndrome?

Six patients who presented with acute sensory neuropathy were studied. All patients underwent detailed clinical assessment along with electrophysiological tests and relevant laboratory investigations. All patients had acute onset numbness, reaching the peak deficit within 4 weeks. Four of them had associated burning dysaesthesia. An antecedent illness was reported in four; diarrhoea in three, and urinary tract infection in one. The neurological examination disclosed normal muscle strength, symmetric glove and stocking type sensory loss for pain and temperature, normal proprioception, and vibration senses with normal or brisk tendon reflexes. Analysis of CSF demonstrated albuminocytological dissociation in all. Routine motor and sensory nerve conduction studies were normal. Sympathetic skin responses were also normal except for the lower limbs in one patient. Stool cultures for Campylobacter jejuni were negative. The outcome was favourable. Burning dysaesthesia disappeared within 4 months. Numbness and objective sensory loss tended to persist longer. The clinical features and normal routine nerve conduction studies, which assess large diameter nerve fibre function, indicate small sensory fibre dysfunction in the group. Their presentation and CSF findings would fit into the diagnosis of sensory Guillain-Barré syndrome. The current study suggests that acute small fibre sensory neuropathy (ASFSN) is another clinical entity which could perhaps be included in the heterogeneous range of Guillain-Barré syndrome.     

Olfactory function in patients with idiopathic Parkinson’s disease: effects of deep brain stimulation in the subthalamic nucleus

Summary. Decrease of olfactory function in patients with Parkinsons disease (PD) is a well-investigated fact. The present study aimed to investigate olfaction in PD patients with a specific focus on the effects of deep brain stimulation in the subthalamic nucleus. Eleven patients (age 42–67 years) participated in this study. Using the Sniffin Sticks, olfactory function was assessed based on butanol odor thresholds and the patients ability to discriminate odors. Measures were taken with the stimulator being switched ON and OFF, respectively. While deep brain stimulation had no effect on odor thresholds, in hyposmic PD patients odor discrimination was found to be significantly higher during the ON period. This may indicate that deep brain stimulation has a positive effect on the cognitive processing of olfactory information in PD patients.     

Epilepsy and sodium channel gene mutations: gain or loss of function?

Mutations in voltage-gated sodium channel genes (SCN1A, SCN2A, SCN1B) have been reported to be responsible for some epilepsies. Although studying such mutations to elucidate the disease mechanisms would be indispensable for the development of effective therapies, the functional consequences of these mutations remain controversial. Here, I propose a novel hypothesis for an epileptic disease mechanism which could drive the design of further studies to understand the molecular pathology of these diseases.     

Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy

Epilepsy is a heterogeneous neurological disease affecting approximately 50 million people worldwide. Genetic factors play an important role in both the onset and severity of the condition, with mutations in several ion-channel genes being implicated, including those encoding the GABA(A) receptor. Here, we evaluated the frequency of additional mutations in the GABA(A) receptor by direct sequencing of the complete open reading frame of the GABRA1 and GABRG2 genes from a cohort of French Canadian families with idiopathic generalized epilepsy (IGE). Using this approach, we have identified three novel mutations that were absent in over 400 control chromosomes. In GABRA1, two mutations were found, with the first being a 25-bp insertion that was associated with intron retention (i.e. K353delins18X) and the second corresponding to a single point mutation that replaced the aspartate 219 residue with an asparagine (i.e. D219N). Electrophysiological analysis revealed that K353delins18X and D219N altered GABA(A) receptor function by reducing the total surface expression of mature protein and/or by curtailing neurotransmitter effectiveness. Both defects would be expected to have a detrimental effect on inhibitory control of neuronal circuits. In contrast, the single point mutation identified in the GABRG2 gene, namely P83S, was indistinguishable from the wildtype subunit in terms of surface expression and functionality. This finding was all the more intriguing as the mutation exhibited a high degree of penetrance in three generations of one French Canadian family. Further experimentation will be required to understand how this mutation contributes to the occurrence of IGE in these individuals.     

Location matters – Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P

More than 80 genes are known to be associated with Charcot-Marie-Tooth disease (CMT). Mutations of LRSAM1 were identified as a rare cause and define the subgroup of axonal neuropathy CMT2P. We identified additional 14 patients out of 12 families. Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment. The patients harbored ten different variants in LRSAM1, seven of which were novel. Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging. The majority follows dominant inheritance, whereas recessive inheritance has been described for one variant. Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance. Our data emphasize the importance of the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein. In conclusion, CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy. ACMG (American College of Medical Genetics and genomics) criteria should be carefully applied in variant interpretation, with special attention to premature termination codon-introducing variants and their location within the gene.     

Biochemical consequences of glucocerebrosidase 1 mutations in Parkinson's disease

<正>Parkinson’s disease (PD,OMIM#168600) is a common neurodegenerative disorder with a global prevalence of approximately 8.5 million.PD is characterized by four cardinal motor symptoms:bradykinesia,rigidity,resting tremor,and subsequently by postural instability.It usually involves non-motor symptoms such as rapid eye movement sleep disorder,dementia,     

Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder – A PET study

IntroductionNoradrenergic denervation is thought to aggravate motor dysfunction in Parkinson's disease (PD). In a previous PET study with the norepinephrine transporter (NART) ligand ¹¹C-MeNER, we detected reduced NART binding in primary sensorimotor cortex (M1S1) of PD patients. Idiopathic rapid-eye-movement sleep behaviour disorder (iRBD) is a phenotype of prodromal PD. Using ¹¹C-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether ¹¹C-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with ¹⁸F-DOPA PET were correlated.Methods17 iRBD patients, 16 PD patients with (PD^RBD+) and 14 without RBD (PD^RBD−), and 25 control subjects underwent ¹¹C-MeNER PET. iRBD patients also had ¹⁸F-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed.ResultsPartial-volume corrected ¹¹C-MeNER binding potential (BP^ND) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PD^RBD+ groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PD^RBD+ P = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 ¹¹C-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal ¹⁸F-DOPA uptake and thalamic ¹¹C-MeNER binding in iRBD patients (r² = 0.343, P = 0.013).ConclusionsThis study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 ¹¹C-MeNER binding in iRBD may represent noradrenergic terminal degeneration or physiological down-regulation of NARTs in this prodromal phenotype of PD. The correlation between thalamic ¹¹C-MeNER binding and putaminal ¹⁸F-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD.     

The cause of death in idiopathic Parkinson’s disease

ObjectivesTo identify the cause of death in patients with idiopathic Parkinson’s disease (IPD)BackgroundCurrent literature provides little data relating to cause of death in IPD and much is based on the recording of IPD on death certificates.MethodsAll patients under the care of a Parkinson’s disease (PD) service who had died between 1999 and 2006 inclusive were identified and further classified into those with IPD according to the UK PD Society Brain Bank Criteria. Details were extracted from the service database and medical notes and further information obtained from the Office for National Statistics (ONS). Corrections were made for data classified using the International Classification of Diseases (ICD) 9 classification (prior to 2001) in order to compare accurately with data classified using ICD 10. Trends in cause of death were identified. Comparative data was obtained from the ONS for a control population.ResultsOf 219 patients on the database who had died, 143 were identified as having IPD. They were more likely to be classified as dying from pneumonia, and less likely as malignancy or ischaemic heart disease, than the control population. Pneumonia was a terminal event in 45%. IPD was recorded on the death certificate in only 63% of patients.ConclusionAs expected, pneumonia is very often the terminal event. As previously demonstrated, malignancy is uncommon. Death certificate documentation is inadequate in one third of certificates; this has implications for research.