Saraswati Nashi

Fatty acid oxidation defects presenting as primary myopathy and prominent dropped head syndrome

Fatty acid oxidation disorders presenting as primary myopathy is relatively rare and also diagnostically challenging. Its association with dropped head syndrome is reported till date in single cases of carnitine deficiency and multiple acyl CoA dehydrogenase deficiency (MADD).We studied nineteen cases of primary progressive myopathy confirmed to have fatty acid oxidation defects by Tandem Mass Spectrometry. The detailed clinical, muscle histopathology, tandem mass spectrometry and muscle magnetic resonance imaging (MRI) findings are presented here. The fatty acid oxidation defects identified were sub-grouped into: medium chain acyl CoA dehydrogenase deficiency (MCAD)u2009=u20094; very long chain acyl CoA dehydrogenase deficiency (VLCAD)u2009=u20097; MADDu2009=u20096; carnitine uptake defect and short chain acyl CoA dehydrogenase (SCAD) deficiencyu2009=u20091 each. The age at onset for MCAD, VLCAD and MADD ranged from 11.5 to 15, 8 to 17 and 10 to 38 years respectively. The patients with carnitine uptake defect and SCAD had onset at 29 and 15 years of age. The dominant symptoms were exertion induced myalgia and progressive proximal limb weakness in all. 12/19 (63.2%) had classical dropped head syndrome. Ptosis and bulbar weakness were present in a few cases. This study emphasizes that fatty acid oxidation disorders presenting as primary myopathy are probably under diagnosed and should be entertained in the differential diagnosis of acute or chronic limb girdle syndromes. Hitherto, unreported we describe dropped head syndrome as a prominent phenomenon in MCAD and VLCAD. The presence of ptosis and bulbar weakness in fatty acid oxidation defects expands the clinical spectrum.

Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness

Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK‐CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742Tu2009>u2009A; p.I581N found in homozygosis, and c.1634Tu2009>u2009C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta‐analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK‐related CMS.

Natural history of a cohort of Duchenne muscular dystrophy children seen between 1998 and 2014: An observational study from South India

Background: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. There are no large studies describing its natural course from India. Materials and Methods: Immunohistochemically/genetically confirmed DMD patients diagnosed between 1998 and 2014 were ambispectively included. The main aim was to study the natural course of motor milestones, i.e., age at onset of wheelchair status, bedbound state, and age at death, which were considered as primary outcome measures. We also correlated the DMD genotype with the motor milestones and other phenotypic features. Results: A total of 500 DMD patients were included and 275 participated in the study. The mean age at symptom onset was 3.7 ± 1.9 years, mean age at presentation was 8.1 ± 2.5 years, and mean duration of illness was 4.4 ± 2.6 years. On following them over 15 years, 155 (56.4%) had attained at least one of the primary outcome measures. Wheelchair status was attained in 124 (45.1%) [mean age: 10.4 ± 1.6 years] and bedbound state in 24 (8.7%; mean age: 11.8 ± 2.2 years) patients. Seven patients (2.6%) died during the follow-up period (mean age: 15.2 ± 2.4 years). There was no significant impact of the genotypic or phenotypic features on the primary outcome. Conclusion: The pattern of major motor milestones (primary outcome measures) in this large cohort is comparable with that of the Western population despite variability in medical care. The genotypic pattern was also similar to other large studies, which suggests that DMD is a more homogeneous disorder with limited ethnic variability in its geno-phenotypic expression.

S160. Retinal involvement by optical coherence tomography and its correlation with disease severity in amyotrophic lateral sclerosis

Introduction Non motor involvement in Amyotrophic lateral sclerosis is being increasingly recognized and studies on involvement of retina have conflicting results. Optical coherence tomography (OCT) as a tool for analysis of retinal neurons and axons has been used in various neurodegenerative disorders. Our aim was to study the involvement of retina by measuring the retinal nerve fiber layer and macular thickness in ALS and correlate with disease severity. Methods Prospective cross sectional comparative study in patients diagnosed with ALS based on revised El-Escorial criteria. 50 subjects (25 cases; 25 age and gender matched controls) were recruited for the study. The disease severity was assessed using “Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS)” – Revised scale. Retinal nerve fiber layer thickness (RNFL) and macular thickness was measured using SD-OCT (Spectralis; Heidelberg Engineering). Results The mean age was 51.43u202f±u202f11.2u202fyears in cases, 48.8u202f±u202f11.9u202fyears in controls. There was no significant difference between the two groups and were comparable. The mean ALSFRS score was 31.96u202f±u202f5.99. 24% had bulbar onset and the reminder had limb onset ALS. Mean duration of illness was 14.07u202f±u202f7.8u202fmonths. Mean RNFL in cases was 102.2u202f±u202f9.7u202fμm and in controls was 100.7u202f±u202f7.2u202fμm which was not statistically significant. Average macular thickness in cases was 304.3u202f±u202f12.7u202fμm in cases and 304.5u202f±u202f11.2u202fμm in controls. Central foveal thickness was 253.5u202f±u202f21.4u202fμm in cases and 256.2u202f±u202f23.6u202fμm in controls. There was no positive/ negative correlation between ALSFRS and RNFL/ macular thickness. Mean RNFL, six sector RNFL, average macular thickness and nine segment Early Treatment Diabetic Retinopathy Study (ETDRS) grid macular thickness done in 25 patients (50 eyes) and 25 controls (50 eyes) did not show difference in thickness and there is no correlation between disease severity and retinal thickness. There was no difference in retinal thickness between bulbar onset or limb onset ALS. Conclusion Retina is the window to the brain and our study attempted to look for possibility for any changes though retinal involvement may not be a part of ALS. Previous studies on OCT had shown conflicting evidence. Our study shows that retinal thinning may not be part of the non-motor involvement in ALS. Further studies may be required to validate on a large cohort.

T130. Quantitative sudomotor axon reflex testing in anterior horn cell disorders

Introduction Autonomic disturbances in the form of hyperhidrosis, stiffness of fingers and aggravation of motor weakness on exposure to cold(Cold paresis) has been reported in anterior horn cell disorders like early stages of Amyotrophic lateral sclerosis (ALS), Brachial Monomelic Amyotrophy (BMMA) and Distal Bimelic Amyotrophy (DBMA). Quantitative sudomotor axon reflex test (QSART) was done to assess the functional integrity of postganglionic sympathetic sudomotor axons. Methods 25 patients of BMMA, 10 patients with DBMA divided into two groups based on age (Group1: 20–30u202fyears and Group2: 30–40u202fyears) and 10 patients with ALS where recruited for the study and compared with equal cohort of age matched controls. General physical examination and anthropometric measurements were taken before recording. Sudomotor function of the study participants were evaluated by using Q-Sweat device manufactured by WR Medical Electronics. Resting sweat rate was recorded 5u202fmin followed by iontophoretic stimulation. Baseline sweat volume, Total sweat volume and latency time from start of iontophoretic stimulation [acetylcholine-2u202fmA current strength for 5u202fmin] to sweat response from 4 recording sites were measured. Results The variances in parameters like age, body weight, both height of both control and disease group were not significantly different and hence comparable. The mean age of BMMA patients: [Group1: 22.8u202f±u202f3.8 and Group2: 33.8u202f±u202f3.2u202fyears] age matched controls - [Group1: 25.4u202f±u202f2.7 and Group2: 35.1u202f±u202f2.8u202fyears]. There was no significant difference in baseline line sweat rate, latency and total sweat volume between controls and patients at four sites viz. Forearm, Proximal leg, Distal leg and Foot in both affected and unaffected limb. There was no significant difference between affected and unaffected limbs in above parameters in patients with BMMA. Similar results were obtained for patients in early stages of ALS (mean age 46.8u202f±u202f3.2u202fyears) and DBMA [Group1: 23.3u202f±u202f4.8 and Group2: 38.0u202f±u202f2.9u202fyears]. Conclusion Our findings suggests normal functioning of post ganglionic sudomotor fibers in BMMA and DBMA. The highly prevalent autonomic symptoms probably arise due to pre-ganglionic autonomic dysfunction and possibly in the cervical cord.

Anti-AChR, MuSK, and LRP4 antibodies coexistence: A rare and distinct subtype of myasthenia gravis from Indian subcontinent

BACKGROUNDnMyasthenia gravis is B-cell mediated autoimmune disease and is associated with antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4) in the postsynaptic membrane at the neuromuscular junction. There are few studies on the concurrent presence of two positive antibodies in the sera of patients with myasthenia gravis.nnnCASE DESCRIPTIONnA 32-year male admitted to the hospital with progressive neuromuscular weakness. He was diagnosed with Myasthenia gravis disorder mimicking Amyotrophic Lateral Sclerosis. We herein report a rare co-existence of three antibodies (anti-AChR, MuSK, and LRP4 antibodies) in the patients serum.nnnCONCLUSIONnWe present a detailed clinical and laboratory analysis of the patient. This case report will emphasize the importance of evaluating anti-MuSK and anti-LRP4 antibodies even in patients with anti-AChR antibodies.

Intrafamilial phenotypic variations in familial cases of cervical flexion induced myelopathy/Hirayama disease

Abstract Hirayama disease is generally considered to be a sporadic disorder, except for a few reports of familial occurrence. In this study, we describe eight patients from four families with cervical flexion induced myelopathy (CFIM)/Hirayama disease (HD) and intra-familial phenotypic variations. All underwent clinical and electrophysiological evaluation, while seven of them had contrast MR imaging of cervical spine in flexion. There was significant intra-familial variability: distal bimelic form in four patients, classical monomelic form in three and proximo-distal form in one. Irrespective of the clinical phenotype, MRI showed characteristic dynamic changes of posterior dural detachment with prominent epidural enhancement extending variably from C3 vertebral level to dorsal spine in six patients. One patient with 28 years of illness, had only lower cervical cord atrophy without dynamic changes while another patient demonstrated forward dural displacement with epidural enhancement even after 38 years of disease duration.

Caregiver burden and quality of life of patients with amyotrophic lateral sclerosis in India

Abstract Aim: Amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) is a progressive degenerative disorder that can have significant debilitating impact. Few studies have explored living with ALS in the developing countries. The study aims to understand the relationship between functionality, quality of life, and caregiver burden in ALS in the sociocultural scenario in India. Methods: A cross-sectional descriptive study was performed among 30 persons with ALS and their caregivers (menu2009=u200919; womenu2009=u200911) receiving treatment from a national quaternary referral care center for Neurological disorders in Southern India. All patients were diagnosed as Definite ALS according to El Escorial Criteria. The mean age at onset of illness was 51.6 years and mean duration of illness at presenting to hospital was 11 months. The caregivers were spouses, offspring, or siblings. Variables were assessed with ALS Functional Rating Scale Revised (ALSFRS- R), ALS Specific Quality of Life Scale (ALSSQOL-R) with the patients and Zarit Burden Interview (ZBI) with the caregiver. Results: Functionality and quality of life negatively correlated with caregiver burden. Caregiver burden was negatively associated with “negative emotional state” and “interaction of the patient with family and environment”, sub domains in ALSQOL scale. No significant association was noted between caregiver burden and intimacy, religiosity as well as physical symptoms domains of quality of life. Conclusion: ALS patients and caregivers would benefit from structured care plan that is sensitive to the impact of the illness on the specific domains of quality of life as well as the deterioration in the neurological functioning.

Case Report: Neurobrucellosis with Plastered Spinal Arachnoiditis: A Magnetic Resonance Imaging–Based Report

Diffuse spinal arachnoiditis in neurobrucellosis is a rare manifestation. We report a boy aged 17, presenting with hearing impairment and recurrent vomiting for 18 months, weight loss for 12 months, dysphagia, dysarthria, hypophonia for 6 months, and gait unsteadiness for 5 months. He had bilateral 5th (motor) to 12th cranial nerve palsy, wasting and weakness of limbs, fasciculations, absent tendon reflexes, and positive Babinskis sign. Cerebrospinal fluid (CSF) showed raised protein and pleocytosis. Magnetic resonance imaging (MRI) showed extensive enhancing exudates in cisterns and post-contrast enhancement of bilateral 5th, 6th, 7th, and 8th nerves. Spine showed clumping with contrast enhancement of the cauda equina roots and encasement of the cord with exudates. Serum and CSF were positive for anti-Brucella antibodies. He showed significant improvement with antibiotics. At 4 months follow-up, MRI demonstrated near complete resolution of cranial and spinal arachnoiditis. It is important to recognize such rare atypical presentations of neurobrucellosis.

CARASIL families from India with 3 novel null mutations in theHTRA1gene

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (MIM 600142) is linked to homozygous mutations in the high-temperature requirement A serine peptidase 1 gene (HTRA1).1 The triad includes alopecia, spondylosis deformans, and young-adult onset dementia following leukoaraiosis caused by cerebral small-vessel disease (CSVD).2 Although CARASIL originally was considered to be a recessive disorder and monoethnic, restricted to Japan, there are several reports of genetically confirmed cases and a few manifest heterozygotes in other ethnicities, thus expanding the CARASIL paradigm.3–6 In this study, we describe 3 CARASIL families carrying novel null HTRA1 mutations and also the notable phenotypes among the heterozygotes.