Dasappaiah Ganesh Rao

Clinical features of hereditary spastic paraplegia due to spastin mutation

Background: Mutations in the spastin gene are the commonest cause of hereditary spastic paraparesis (HSP), accounting for up to 40% of autosomal dominant cases. The phenotype associated with HSP due to mutation in the spastin gene (SPG4) tends to be pure HSP. Objective: To characterize in more detail the genetic and phenotypic characteristics of SPG4 by examining a large cohort of patients with HSP. Methods: The authors identified patients who tested positive for spastin mutation using a direct sequencing approach of all exons. Results: The authors identified spastin mutations in 53 patients. Twenty-seven of the mutations identified were novel. The phenotype in the majority of patients was of pure HSP. In one individual, a complicated phenotype with progressive bulbar dysfunction and respiratory insufficiency was observed. Evidence of lower motor neuron dysfunction in a subgroup of SPG4 patients was identified. The missense changes S44L and P45Q were identified in patients with other spastin mutations and seemed to be exerting a phenotype-modifying effect. Conclusion: These findings add to the number of spastin mutations identified and demonstrate the importance of screening the whole gene, given the possibility of double mutations and intragenic modifiers. The identification of the complicated phenotypes has important implications for identifying the phenotype of patients in whom spastin screening should be considered. The presence of lower motor neuron dysfunction in a subgroup of SPG4 patients suggests that the cellular dysfunction in SPG4 extends beyond the axonal projections of upper motor neurons and ascending sensory pathways.

Myopathy associated with gluten sensitivity

Ataxia and peripheral neuropathy are the most common neurological manifestations of gluten sensitivity. Myopathy is a less common and poorly characterized additional neurological manifestation of gluten sensitivity. We present our experience with 13 patients who presented with symptoms and signs suggestive of a myopathy and in whom investigation led to the diagnosis of gluten sensitivity. Three of these patients had a neuropathy with or without ataxia in addition to the myopathy. The mean age at onset of the myopathic symptoms was 54 years. Ten patients had neurophysiological evidence of myopathy. Inflammatory myopathy was the most common finding on neuropathological examination. One patient had basophilic rimmed vacuoles suggestive of inclusion‐body myositis. Six patients received immunosuppressive treatment in addition to starting on a gluten‐free diet; five improved and one remained unchanged. Among seven patients not on immunosuppressive treatment, four showed clinical improvement of the myopathy with a gluten‐free diet. The improvement was also associated with reduction or normalization of serum creatine kinase level. The myopathy progressed in one patient who refused the gluten‐free diet. Myopathy may be another manifestation of gluten sensitivity and is likely to have an immune‐mediated pathogenesis. A gluten‐free diet may be a useful therapeutic intervention. Muscle Nerve, 2006

Sensory ganglionopathy due to gluten sensitivity

Objectives: Gluten sensitivity can engender neurologic dysfunction, one of the two commonest presentations being peripheral neuropathy. The commonest type of neuropathy seen in the context of gluten sensitivity is sensorimotor axonal. We report 17 patients with sensory ganglionopathy associated with gluten sensitivity. Methods: This is a retrospective observational case series of 17 patients with sensory ganglionopathy and gluten sensitivity. All patients had been followed up for a number of years in dedicated gluten sensitivity/neurology and neuropathy clinics. Results: Out of a total of 409 patients with different types of peripheral neuropathies, 53 (13%) had clinical and neurophysiologic evidence of sensory ganglionopathy. Out of these 53 patients, 17 (32%) had serologic evidence of gluten sensitivity. The mean age of those with gluten sensitivity was 67 years and the mean age at onset was 58 years. Seven of those with serologic evidence of gluten sensitivity had enteropathy on biopsy. Fifteen patients went on a gluten-free diet, resulting in stabilization of the neuropathy in 11. The remaining 4 had poor adherence to the diet and progressed, as did the 2 patients who did not opt for dietary treatment. Autopsy tissue from 3 patients demonstrated inflammation in the dorsal root ganglia with degeneration of the posterior columns of the spinal cord. Conclusions: Sensory ganglionopathy can be a manifestation of gluten sensitivity and may respond to a strict gluten-free diet.

Neurological Dysfunction in Coeliac Disease and Non-Coeliac Gluten Sensitivity

Objectives:Non-coeliac gluten sensitivity (NCGS) refers to patients with primarily gastrointestinal symptoms without enteropathy that symptomatically benefit from gluten-free diet (GFD). Little is known about its pathophysiology, propensity to neurological manifestations, and if these differ from patients with coeliac disease (CD). We investigated the clinical and immunological characteristics of patients presenting with neurological manifestations with CD and those with NCGS.Methods:We compared clinical, neurophysiological, and imaging data of patients with CD and NCGS presenting with neurological dysfunction assessed and followed up regularly over a period of 20 years.Results:Out of 700 patients, 562 were included. Exclusion criteria included no bowel biopsy to confirm CD, no HLA type available, and failure to adhere to GFD. All patients presented with neurological dysfunction and had circulating anti-gliadin antibodies. Out of 562 patients, 228 (41%) had evidence of enteropathy (Group 1, CD) and 334 (59%) did not (Group 2, NCGS). The most common neurological manifestations were cerebellar ataxia, peripheral neuropathy, and encephalopathy. There was a greater proportion of patients with encephalopathy in Group 1 and with a greater proportion of neuropathy in Group 2. The severity of ataxia did not differ between the two groups. Patients in Group 1 had more severe neuropathy. All patients from both groups responded to gluten-free diet. Anti-tissue transglutaminase (TG2) antibodies were found in 91% of patients in Group 1 and in 29% of patients in Group 2. Comparison between those patients in Group 2 with HLA-DQ2/DQ8 and those without as well as those with positive TG2 compared with those with negative TG2 antibodies identified no differences within these subgroups. Serological positivity for TG6 antibodies was similar in the two groups (67 and 60%).Conclusions:The neurological manifestations of CD and NCGS are similar and equally responsive to a GFD suggestive of common pathophysiological mechanisms.

Pure motor Herpes Zoster induced brachial plexopathy.

Brachial plexus neuritis in the presence of herpes zoster infection is uncommon. Motor involvement is probably due to the spreading of inflammation from the dorsal root ganglia to the ventral roots and may be more extensive than the affected dermatomes. We present a case of herpes zoster brachial plexopathy with pure motor involvement both clinically and electrophysiologically.

Transglutaminase 6 antibodies in gluten neuropathy

BACKGROUND TG6 antibodies have been shown to be a marker of gluten ataxia but their presence in the context of other neurological manifestations of gluten sensitivity has not been explored. We investigated the presence of TG6 antibodies in gluten neuropathy (GN), defined as as an otherwise idiopathic peripheral neuropathy associated with serological markers of gluten sensitivity (one or more of antigliadin IgG and/or IgA, endomysial and transglutaminase-2 antibodies). METHODS This was a cross-sectional study conducted at the Sheffield Institute of Gluten Related Diseases, Royal Hallamshire Hospital, Sheffield, UK. Blood samples were collected whilst the patients were on a gluten containing diet. Duodenal biopsies were performed to establish the presence of enteropathy. RESULTS Twenty-eight patients were recruited (mean age 62.5±13.7 years). Fifteen (53.6%) had sensory ganglionopathy, 12 (42.9%) had symmetrical axonal neuropathy and 1 had mononeuritis multiplex. The prevalence of TG6 antibodies was 14 of 28 (50%) compared to 4% in the healthy population. TG6 antibodies were found in 5/15 (33.3%) patients with sensory ganglionopathy and in 8/12 (66.7%) with symmetrical axonal neuropathy. Twenty-four patients underwent duodenal biopsy 11 (45.8%) of which had enteropathy. The prevalence of TG6 was not significantly different when comparing those with or without enteropathy. CONCLUSIONS We found a high prevalence of antibodies against TG6 in patients with GN. This suggests that TG6 involvement is not confined to the central nervous system. The role of transglutaminase 6 in peripheral nerve function remains to be determined but TG6 antibodies may be helpful in the diagnosis of GN.

Cerebellar ataxia and sensory ganglionopathy associated with light-chain myeloma.

BackgroundCerebellar ataxia with sensory ganglionopathy is a rare neurological combination that can occur in some hereditary ataxias including mitochondrial diseases and in gluten sensitivity. Individually each condition can be a classic paraneoplastic neurological syndrome. We report a patient with this combination who was diagnosed with light-chain myeloma ten years after initial presentation.Case presentationA 65-year-old Caucasian lady was referred to our Ataxia Clinic because of a 6-year history of progressive unsteadiness and a 2-year history of slurred speech. Past medical history included arterial hypertension. The patient was a non-smoker was not consuming alcohol excessively. There was no family history of ataxia.Neurological examination revealed prominent gaze-evoked nystagmus, heel to shin ataxia, gait ataxia, reduced reflexes and loss of vibration sensation in the legs.Cerebellar ataxia was confirmed using magnetic resonance spectroscopy of the cerebellum and sensory ganglionopathy using neurophysiological assessments including blink reflex study. A muscle biopsy that was arranged to explore the possibility of mitochondrial disease revealed amyloidosis. Urinalysis confirmed the presence of light chains. A bone marrow biopsy confirmed the diagnosis of light chain multiple myeloma.ConclusionsWhilst it could be argued that this could simply be a coincidence, the rarity of these conditions and the absence of an alternative aetiology for the neurological dysfunction argue in favour of a paraneoplastic phenomenon.

Rapid neurophysiological screening for sensory ganglionopathy: A novel approach

Pure sensory neuropathies involving the dorsal root ganglia are commonly referred to as sensory ganglionopathies (SG). Causes of SG can be inherited (as seen in Friedreichs ataxia) or acquired (e.g. immune‐mediated or paraneoplastic). Diagnostic criteria for confirming SG have been published and consist of a combination of clinical and neurophysiological parameters. The aim of our study was to develop a neurophysiological method for rapid screening for diagnosis of SG.

A prospective pilot study measuring muscle volumetric change in amyotrophic lateral sclerosis

Abstract Our objective was to investigate the potential of muscle volume, measured with magnetic resonance (MR), as a biomarker to quantify disease progression in patients with amyotrophic lateral sclerosis (ALS). In this longitudinal pilot study, we first sought to determine the stability of volumetric muscle MR measurements in 11 control subjects at two time-points. We assessed feasibility of detecting atrophy in four patients with ALS, followed at three-month intervals for 12 months. Muscle power and MR volume were measured in thenar eminence (TEm), first dorsal interosseous (1DIO), tibialis anterior (TA) and tongue. Changes over time were assessed using linear regression models and t-tests. Results demonstrated that, in controls, no volumetric MR changes were seen (mean volume variation in all muscles < 5%, p > 0.1). In patients, between-subject heterogeneity was identified. Trends for volume loss were found in TEm (mean, − 26.84%, p = 0.056) and TA (− 8.29%, p = 0.077), but not in 1DIO (− 18.47%, p = 0.121) or tongue (< 5%, p = 0.367). In conclusion, volumetric muscle MR appears a stable measure in controls, and progressive volume loss was demonstrable in individuals with ALS in whom clinical weakness progressed. In this small study, subclinical atrophy was not demonstrable using muscle MR. Clinico-radiological discordance between muscle weakness and MR atrophy could reflect a contribution of upper motor neuron pathology.

Quality of Life in Patients with Gluten Neuropathy: A Case-Controlled Study

Background: Gluten neuropathy (GN) is defined as an otherwise idiopathic peripheral neuropathy in the presence of serological evidence of gluten sensitivity (positive native gliadin antibodies and/or transglutaminase or endomysium antibodies). We aimed to compare the quality of life (QoL) of GN patients with that of control subjects and to investigate the effects of a gluten-free diet (GFD) on the QoL. Methods: All consecutive patients with GN attending a specialist neuropathy clinic were invited to participate. The Overall Neuropathy Limitations Scale (ONLS) was used to assess the severity of the neuropathy. The 36-Item Short Form Survey (SF-36) questionnaire was used to measure participants’ QoL. A strict GFD was defined as effectively being able to eliminate all circulating gluten sensitivity-related antibodies. Results: Fifty-three patients with GN and 53 age- and gender-matched controls were recruited. Compared to controls, GN patients showed significantly worse scores in the physical functioning, role limitations due to physical health, energy/fatigue, and general health subdomains of the SF-36. After adjusting for age, gender, and disease severity, being on a strict GFD correlated with better SF-36 scores in the pain domain of the SF-36 (beta 0.317, p = 0.019) and in the overall health change domain of the SF-36 (beta 0.306, p = 0.017). Conclusion: In GN patients, physical dysfunctioning is the major determinant of poor QoL compared to controls. Routine checking of the elimination of gluten sensitivity-related antibodies that results from a strict GFD should be encouraged, as such elimination ameliorates the overall pain and health scores, indicating a better QoL.