Clinical spectrum, biochemical profile and disease progression of Kennedy disease in an Indian cohort.

BACKGROUND: Kennedy disease (KD) is a slowly progressive lower motor neuron degenerative disease. The prevalence of KD is unknown in India. AIM: To describe the phenotypic and laboratory features of an Indian cohort of KD patients. METHODS: A retrospective study was done on seven genetically confirmed KD patients based on demographic, clinical and laboratory details. RESULTS: Mean age at onset and presentation was 37 ± 11.9 and 44.6 ± 13.5 years respectively. Progressive asymmetric proximal and distal limb weakness was the commonest symptom (57.1%). All patients had motor symptoms along with non-specific symptoms such as cramps from the onset. Easy fatigability, decremental response along with ptosis were noted in two patients, which was a novel finding. Gynaecomastia and tongue wasting with fasciculations were universal findings. All five patients with nerve conduction studies showed sensorimotor neuropathy. Magnetic resonance imaging muscle done in two patients showed a prominent moth-eaten appearance in the thigh and posterior leg compartment in one patient. The mean cytosine-adenine-guanine repeats were 44 ± 3.7, and there was no association between age of onset or severity with repeat length. Only one patient required an assistive device for ambulation after 15 years of symptom onset. CONCLUSIONS: This study showed phenotypic heterogeneity in the Indian cohort. The age of onset was earlier with a slowly progressive indolent course as compared with other ethnic cohorts. This highlights the importance of considering the KD diagnosis in patients with the indolent course and suspected ALS diagnosis even with ptosis and fatigability in an appropriate clinical context.

Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5' splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.

A large series of immunohistochemically confirmed cases of congenital muscular dystrophy seen over a period of one decade.

BACKGROUND: Although congenital muscular dystrophies (CMD) is a common condition among primary muscle disorders, there are only a few small series reported from India. AIMS, SETTINGS, AND DESIGN: Retrospective analysis to characterize histopathologically and/or immunohistochemically confirmed cases of CMD. MATERIALS AND METHODS: Patients were identified retrospectively from the archived muscle biopsy reports between 1997 and 2007 at the Department of Neuropathology of the institute. Medical records were scrutinized for all details. RESULTS: There were 102 cases which were characterized by clinical phenotype and histopathology. Among these 56 had immunohistochemical staining and were included in the final analysis. Merosin staining performed in 53 samples identified nine patients with merosin negative CMD. The male to female ratio (M:F) was 2:1 and the mean age at presentation was 69.7 ± 62.2 months. All had grossly delayed motor milestones. There were 13 cases of Ullrich CMD confirmed by absent staining for collagen 6A1 in muscle. Mean age at diagnosis was 63.7 ± 27.9 months. Onset of symptoms was in infancy in 12 patients. All had significant delay in motor milestones and had classical features of proximal contractures, distal hyperextensibility, prominent calcaneum, velvety palms and soles with absent palmar creases. Mean creatine kinase (CK) value was 259.1 ± 109.4 IU/l. Alpha-dystroglycan (α-DG) deficiency was identified in three cases. Illness onset was in infancy. Classical magnetic resonance imaging (MRI) features were seen in all. Large group of 31 cases of merosin positive CMD had clinical findings of early onset limb weakness, hypotonia, and contractures; with histopathological evidence of dystrophy, and normal staining pattern of merosin, collagen 6A1 and α-DG. Mean age at evaluation was 58.61 ± 48.4 months. Majority (87.1%) had onset of symptom in infancy with delay in motor milestones. CONCLUSIONS: This study provides a significant data on one of the largest cohort of patients with CMDs from India. Immunohistochemistry (IHC) has definitely helped us to categorize 56 patients into specific subtypes of CMDs. This is essential for directing genetic analysis which is imperative for definitive diagnosis and also prenatal diagnosis.

Audiovestibular Dysfunction in Siblings with Charcot-Marie-Tooth Disease 4F: A Case Series.

BACKGROUND: Charcot-Marie-Tooth disease type 4F (CMT4F) is an autosomal recessive disorder with symptoms presenting in early adulthood. This clinical case series demonstrates atypical findings in cervical and ocular vestibular evoked myogenic potentials (VEMP) in siblings with CMT4F. PURPOSE: The aim of this study was to highlight the audiovestibular test findings in CMT4F. RESEARCH DESIGN: Case series study sample: 4 siblings, 3 of whom diagnosed with CMT4F. DATA COLLECTION AND ANALYSIS: Audiological test battery and electrophysiological tests comprising auditory brainstem response (ABR) and VEMP (both cervical and ocular) were performed in our patient population. RESULTS: Older siblings, in whom the hearing loss was present, manifested prolonged peak V latencies in ABR. Three out of four siblings with CMT4F showed prolongation of latencies on cervical and ocular VEMP. CONCLUSIONS: In many neurodegenerative conditions, prolongation of ABR peak latencies has often been reported in the literature. There have also been a few reports of prolonged VEMP peak latencies. This article reports prolongation of only VEMP peak latencies (in both cervical and ocular recordings). The youngest sibling had prolongation of VEMP latencies, with ABR peak latencies being normal. The assumption we put forth that CMT4F may affect the vestibular pathway first requires to be tested on a larger sample and by longitudinally studying the individuals with disease condition.

Utility of Immunohistochemistry and Western Blot in Profiling Clinically Suspected Cases of Congenital Muscular Dystrophy.

OBJECTIVE: Immunocharacterization of congenital muscular dystrophy (CMD) to determine the frequency of various subtypes in a large Indian Cohort. MATERIALS AND METHODS: This retrospective (2014-2017) study was carried on muscle biopsies of clinically suspected cases of CMD with histological evidence of dystrophy/myopathic features. Immunohistochemistry (IHC) to antibodies against laminin (α2, α5,ß1,γ1), Collagen-VI (A1,2,3), and Western blot (WB) for α-dystroglycan and POMT1 was performed. RESULTS: The study included 57 cases, of which 15 cases (26.3%) had mean age at presentation of 3.5 years, M: F = 1.5:1, elevated creatinine kinase (CK) (mean 1657 U/L), global developmental delay, multiple contractures, abnormal facies, white matter hyperintensities and showed laminin-α2 deficiency (Merosin deficient CMD). In addition, secondary reduction in laminin-ß1, over-expression of laminin-α5, and preserved laminin-γ1 was noted. Ullrich CMD constituted 11/57 cases (19.2%) with mean age at presentation of 5.3 years, M: F = 1.2:1 and normal CK. They presented with proximal muscle weakness, soft velvety palms and soles, contractures, and joint hyperextensibility. Collagen-VI (A1,2,3) showed either complete (n = 3) or sarcolemmal specific (n = 8) loss of staining. Out of the remaining 31 cases, WB for α-dystroglycan was performed in 17 cases which showed deficiency in seven (12.3%). Three of these in addition revealed secondary partial loss of laminin-α2. WB for POMT1 showed deficiency in a single case clinically diagnosed Walker-Warburg syndrome, who presented with seizures and classical features of pachygyria, lissencephaly, and cerebellar cyst on MRI. Twenty-four cases (42.2%) remained uncharacterized and need genetic evaluation. CONCLUSION: The study helped in characterizing 57.8% of the proband. Immunotyping helps to direct mutational analysis for targeted genes and offers a potential route for prenatal diagnosis.

Lead Encephalopathy with Distinctive Brain Magnetic Resonance Imaging Findings.

Lead poisoning is a multisystem disorder, more commonly affecting children. Occupational exposure, traditional medicines, and contaminated alcohol have been associated with lead encephalopathy in adults. Herein, we report a patient of lead toxicity presenting to the emergency services as acute encephalopathy with symptomatic hyponatremia and chronic recurrent abdominal colic and vomiting. This 50-year-old battery mechanic had multisystem involvement with anemia, basophilic stippling, lead line on the gums, and chronic hypertension. The blood lead level was more than 65 mcg/dL. Computed tomography of the brain showed intracranial calcifications and the MRI brain showed bilateral symmetric involvement of the thalamus, basal ganglia, brainstem, and external capsule. His sensorium improved rapidly after the correction of hyponatremia, however, apathy and psychomotor slowing persisted. This case highlights the importance of recognizing clinical markers and characteristic imaging findings, which can provide clues to an early diagnosis of this otherwise rare clinical condition, and prompt chelation therapy and avoid further lead exposure.

Anti-N-methyl-D-aspartate-receptor Encephalitis as a Harbinger of Pediatric HIV Infection.

Anti-N-methyl-D-aspartate-receptor (A-NMDAR) encephalitis is the most common type of autoimmune encephalitis in the pediatric age group. It is known to be triggered by viral infections such as herpes simplex infections. However, A-NMDAR encephalitis with HIV infection is a very rare event, with cases reported mostly in adults. The current report is of a previously healthy child who presented with recurrent vomiting, irritability, visual impairment, and new onset complex partial seizures and right somatosensory seizures with generalization occurring in clusters. Over a period of 3 weeks, he developed rapidly progressive bilateral painless visual loss, visual hallucinations, and behavioral changes. Brain magnetic resonance imaging (MRI) showed predominantly cortical symmetrical T2/FLAIR hyperintense signal change in parieto-occipito-temporal regions. The serum and cerebrospinal fluid were strongly positive for anti-NMDAR antibodies, and he also tested positive for HIV-1 antibodies acquired by vertical transmission. The patient and mother tested positive for HIV antibodies for the first time. Repeat MRI revealed gliosis in the parieto-occipito-temporal regions, and hippocampi showed volume loss and T2/FLAIR hyperintense signal change in the posterior thalami with patchy hyperintensities in the right putamen. The seizures subsided with immunomodulation along with anti-epileptic drugs, but he had residual cortical visual impairment on follow-up. This is the first report of A-NMDAR encephalitis presenting as a harbinger of HIV infection in a child. This calls for testing for A-NMDAR antibodies in children with HIV infection presenting with neurological or neuropsychiatric manifestations.

A Dominant C150Y Mutation in FHL1 Induces Structural Alterations in LIM2 Domain Causing Protein Aggregation In Human and Drosophila Indirect Flight Muscles.

FHL1-related myopathies are rare X-linked dominant myopathies. Though clinically classified into several subgroups, spinal and scapuloperoneal muscle involvement are common to all. In this study, we identified c.449G > A, p.C150Y mutation by clinical exome sequencing in two patients from same family (son and mother) of Indian origin who presented with multiple contractures. Muscle biopsy showed numerous intracytoplasmic aggregates intensely stained on HE and MGT. The strong reactions to M-NBT revealed aggregates to be reducing bodies and positively labeled to anti-FHL1 antibody. Ultrastructurally, Z-band streaming and granular and granulofilamentous material were seen. Further, the translational evidence of mutant peptide was confirmed using mass spectrometric analysis. To establish p.C150Y as the cause for protein aggregation, in vivo studies were carried out using transgenic Drosophila model which highlighted Z-band abnormalities and protein aggregates in indirect flight muscles with compromised physiological function. Thus, recapitulating the X-linked human disease phenotype. Additionally, the molecular dynamics simulation analysis unraveled the drastic change in α-helix of LIM2, the region immediately next to site of C150Y mutation that could be the plausible cause for protein aggregation. To the best of our knowledge, this is the first study of p.C150Y mutation in FHL1 identified in Indian patients with in vivo and in silico analysis to establish the cause for protein aggregation in muscle.

A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein.

Desminopathies (MIM*601419) are clinically heterogeneous, manifesting with myopathy and/or cardiomyopathy and with intra-sarcoplasmic desmin-positive deposits. They have either an autosomal dominant (AD) or recessive (AR) pattern of inheritance. Desmin is a crucial intermediate filament protein regulating various cellular functions in muscle cells. Here, we report a 13-year-old girl, born of second-degree consanguineous parents, with normal developmental milestones, who presented with dilated cardiomyopathy, respiratory insufficiency and predominant distal upper limb weakness. A striking feature on muscle biopsy was the presence of a peripheral chain of nuclei in addition to myopathic features. Immunostaining showed complete lack of desmin expression, further confirmed by western blot analysis. Ultrastructurally, subsarcolemmal granular material, expanded Z-band aggregation, distortion of myofilaments, focal Z-band streaming, lobed and clustered myonuclei were observed. Next-generation sequencing revealed a novel homozygous nonsense mutation c.448C>T, p.R150X in the patient, while the parents were heterozygous carriers. Single mitochondrial DNA deletion and isolated complex IV deficiency were noted. Our findings add to the ever-expanding phenotype and molecular spectrum of desminopathies.

Tubular aggregate myopathy: a phenotypic spectrum and morphological study.

Tubular aggregates (TAs) are inclusions described in skeletal muscle in a variety of disorders. In a retrospective analysis, TAs were found in 18 (0.24%) cases and involved a spectrum of clinical phenotypes. Ultrastructurally, four distinct types of aggregates were noted. There was no correlation between the clinical phenotypes, duration of illness and types of TAs.

Palliative Care Needs and Care Giver Burden in Neurodegenerative Diseases: A Cross Sectional Study.

BACKGROUND AND AIMS: Palliative care is an important area of intervention in neurodegenerative diseases. The aim of this study is to understand the relationship between Palliative Care Needs and Caregiver Burden among persons diagnosed with neurodegenerative diseases. METHODS: A cross-sectional study design was adopted to explore the research problem. A prospective sample of 120 participants (60 Patient Caregiver dyads) of Motor Neurone Disease (MND) and Parkinson's disease (PD) were recruited for the study based on inclusion and exclusion criteria from a quaternary referral care centre for neurology in south India. Patients seeking care were recruited for the study consecutively. Palliative care outcome scale and Zarit Burden Interview scale were administered to understand the relationship. RESULTS: It was found that Palliative care outcomes score was positively correlated with caregiver burden (r = 0.597), showing that there is a bi-directional relationship between palliative care needs and caregiver burden. CONCLUSION: Irrespective of the differences in illness characteristics, the study found that palliative care needs are high among chronic neurological conditions which requires a noncategorical psychosocial approach in ensuring care.

Central motor conduction in brachial monomelic amyotrophy.

BACKGROUND: Prevalence of subclinical involvement of motor pathways in clinically diagnosed Brachial Monomelic Amyotrophy (BMMA) is unknown. AIMS: To determine the prevalence of subclinical involvement of central motor pathways in BMMA using transcranial magnetic stimulation. SETTING AND DESIGN: Prospective case-control study. MATERIALS AND METHODS: Central motor conduction time (CMCT) was determined by 'F' wave method using figure-of-eight coil attached to Magstim 200 stimulator, in 17 patients with BMMA. Motor evoked potentials were recorded from first dorsal interosseous of the affected (AFF) and unaffected upper limbs (UNAFF) at rest and during partial contraction. Comparison was made with data from 10 healthy controls (CTRL). STATISTICAL ANALYSIS: Descriptive analysis and Analysis of Variance (ANOVA). RESULTS: Compared to controls, the mean CMCT of AFF was significantly prolonged, both at rest and contraction: (a) Rest: AFF-6.68+/-1.78 ms, UNAFF-6.36+/-1.16 ms, CTRL-5.71+/-1.02 ms; Fisher's PLSD for AFF vs. CTRL: P =0.037, (b) Contraction: AFF-5.78+/-1.62 ms, UAFF - 4.86+/-1.38 ms, CTRL-4.06+/-0.80 ms; Fisher's PLSD for AFF vs. CTRL; P =0.0002, AFF vs. UNAFF- P =0.044). Prolonged CMCT (>mean+2SD of controls) was observed in 29.4% of AFF and 6.25% of UNAFF at rest, and in 47.1% and 23.5% respectively during contraction. CONCLUSIONS: Dysfunction of central motor pathways was observed in both affected and unaffected upper limbs of some patients with BMMA of upper limbs. The dysfunction was more pronounced during voluntary contraction. A larger study is needed to validate the significance of these findings.

Detection of Dysferlin Gene Pathogenic Variants in the Indian Population in Patients Predicted to have a Dysferlinopathy Using a Blood-based Monocyte Assay and Clinical Algorithm: A Model for Accurate and Cost-effective Diagnosis.

BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is the most common adult-onset class of muscular dystrophies in India, but a majority of suspected LGMDs in India remain unclassified to the genetic subtype level. The next-generation sequencing (NGS)-based approaches have allowed molecular characterization and subtype diagnosis in a majority of these patients in India. MATERIALS AND METHODS: (I) To select probable dysferlinopathy (LGMD2B) cases from other LGMD subtypes using two screening methods (i) to determine the status of dysferlin protein expression in blood (peripheral blood mononuclear cell) by monocyte assay (ii) using a predictive algorithm called automated LGMD diagnostic assistant (ALDA) to obtain possible LGMD subtypes based on clinical symptoms. (II) Identification of gene pathogenic variants by NGS for 34 genes associated with LGMD or LGMD like muscular dystrophies, in cases showing: absence of dysferlin protein by the monocyte assay and/or a typical dysferlinopathy phenotype, with medium to high predictive scores using the ALDA tool. RESULTS: Out of the 125 patients screened by NGS, 96 were confirmed with two dysferlin variants, of which 84 were homozygous. Single dysferlin pathogenic variants were seen in 4 patients, whereas 25 showed no variants in the dysferlin gene. CONCLUSION: In this study, 98.2% of patients with absence of the dysferlin protein showed one or more variants in the dysferlin gene and hence has a high predictive significance in diagnosing dysferlinopathies. However, collection of blood samples from all over India for protein analysis is expensive. Our analysis shows that the use of the "ALDA tool" could be a cost-effective alternative method. Identification of dysferlin pathogenic variants by NGS is the ultimate method for diagnosing dysferlinopathies though follow-up with the monocyte assay can be useful to understand the phenotype in relation to the dysferlin protein expression and also be a useful biomarker for future clinical trials.