Myotonic Dystrophy Type 1 (DM1): Clinical Characteristics and Disease Progression in a Large Cohort.

BACKGROUND: DM1 is a multisystem disorder caused by expansion of a CTG triplet repeat in the 3' non-coding region of DMPK. Neuropsychological consequences and sleep abnormalities are important associations in DM1. OBJECTIVE: To describe the clinical phenotype, disease progression and characterize the sleep alterations and cognitive abnormalities in a sub-set of patients. MATERIALS AND METHODS: A retrospective study on 120 genetically confirmed DM1 cases. Findings in neuropsychological assessment and multiple sleep questionnaires were compared with 14 age and sex matched healthy individuals. All 120 patients were contacted through letters/telephonic consultation/hospital visits to record their latest physical and functional disabilities. RESULTS: The mean age at symptom onset was 23.1 ± 11.4 years, M: F = 3.8:1, mean duration of illness = 14.3 ± 9.5 years. Clinically 54.2% had adult onset form, juvenile = 27.5%, infantile = 10.8%, late adult onset = 7.5%. Paternal transmission occurred more frequently. The predominant initial symptoms were myotonia (37.5%), hand weakness (21.7%), lower limb weakness (23.3%) and bulbar (10%). Twenty patients completed sleep questionnaires (SQ). Abnormal scores were noted in Epworth sleepiness scale (55%); Pittsburgh sleep quality index (45%); Berlin SQ (30%); Rapid eye movement sleep Behaviour Disorder SQ (15%); Restless leg syndrome rating scale (10%). Neuropsychological assessment of 20 patients revealed frontal executive dysfunction, attention impairment and visuospatial dysfunction. Frontal lobe was most affected (72%) followed by parietal (16%) and temporal lobe (12%). CONCLUSIONS: The current study provides a comprehensive account of the clinical characteristics in Indian patients with DM1. Hypersomnolence was most commonly seen. Excessive daytime sleepiness and Sleep disordered breathing were the most common sleep related abnormality. Cognitive impairment comprised predominantly of frontal lobe dysfunction.

An individualised psychosocial intervention program for persons with MND/ALS and their families in low resource settings.

OBJECTIVE: To develop individualised psychosocial intervention program for people with MND and their families in India. METHODS: People with MND and healthcare staff were constructively involved in co-designing the intervention program in four phases adapted from the MRC framework: 1. A detailed need assessment phase where 30 participants shared their perceptions of psychosocial needs 2. Developing the intervention module (synthesis of narrative review, identified needs); 3. Feasibility testing of the intervention program among seven participants; 4. Feedback from participants on the feasibility (acceptance, practicality adaptation). The study adopted an exploratory research design. RESULTS: Intervention program of nine sessions, addressing psychosocial challenges through the different stages of progression of the illness and ways to handle the challenges, specific to the low resource settings, was developed and was found to be feasible. People with MND and families who participated in the feasibility study shared the perceived benefit through feedback interviews. CONCLUSION: MND has changing needs and challenges. Intervention programme was found to be feasible to be implemented among larger group to establish efficacy.

Development of Guidelines for Spouses Engaged in Home-Based Care of Persons With Motor Neuron Disease From Indian Context.

Background: The caregivers of persons with motor neuron disease (MND) have several needs that are usually not voiced on any platform. Aim: To explore the lived experience of spouses of persons with MND, identify their needs and develop guidelines for better home-based care. Method: An exploratory study with 3-point in-depth interviews among 13 participants was conducted. Participants were the spouses of persons with MND under treatment at a national quaternary referral center. The interpretative phenomenological analysis identified participants' needs. These needs, with literature review synthesis, guided the drafting of guidelines, which was validated by experts. Results: The needs were emotional, social, care systems, and skills. The guidelines developed contained 2 sections (1) Information for the spouses: understanding MND, communication, symptom management, marital relationship, palliative care, and everyday life made easier. (2) Well-being of the spouse caregivers: well-being of the spouse caregivers, self-care, mental health, supporting carers in palliative care, where to find help. Conclusion: The guidelines can be developed as a manual for the caregivers and for training healthcare professionals working with neurodegenerative conditions.

Integrated Home-Based Palliative Care in Motor Neuron Disease: A Case Report from Low- Middle Income Country.

In many international care guidelines, multidisciplinary palliative care forms a key to optimum management in Motor Neuron Disease (MND). We describe the home-based palliative care interventions for a client with MND and his family from a Low and Middle-income country context. This report also discusses the advantages and challenges of the same with suggestions for sustaining the quality of care for neuro palliative conditions.

Palliative Care in Duchenne Muscular Dystrophy: A Study on Parents' Understanding.

INTRODUCTION: Duchene muscular dystrophy (DMD) is a neuromuscular disease of childhood, which has clear progression. The international standardized care guidelines for DMD suggest that palliative care is essential for the affected children. OBJECTIVE: To explore the parent's understanding of palliative care services available for children with DMD and the challenges faced by them in utilizing the same. METHODS: A cross-sectional qualitative exploratory study was conducted among six families of boys diagnosed with DMD. A semi-structured interview guide with prompts was used to conduct in-depth interviews which lasted for an average of 1 h. Thematic analysis was done to identify the pattern or themes. RESULTS: The major themes identified were "palliative care, living with DMD, Awareness about palliative care services and challenges." Awareness about palliative care services is the dominant theme identified as influencing rest of the experiences narrated by the parents of children with DMD. DISCUSSION: Integration of palliative care services from an early stage of the illness can help the child to make transition from one stage to another stage of the illness. To ensure the utilization of the available palliative care services, there is a need to create awareness about it among the general public. CONCLUSION: Introducing the concept of palliation of symptoms and ensuring quality of life of the child with DMD by accessing the available services can aid the parents to reach out for help for their child.

Comparison of The Carrier Frequency of Pathogenic Variants of DMD Gene in an Indian Cohort.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked disorder caused due to large deletions, duplications,and small pathogenic variants. This article compares the carrier frequency of different pathogenic variants in the DMD gene for the first time in an Indian cohort. METHODS: Ninety-one mothers of genetically confirmed DMD probands are included in this study. Pathogenic variants in the DMD gene in probands were detected by multiplex ligation-dependent probe amplification (MLPA) or next-generation sequencing (NGS). Maternal blood samples were evaluated either by MLPA or Sanger sequencing. The demographic and clinical details for screening of muscle weakness and cardiomyopathy were collected from the confirmed carriers. RESULTS: Out of 91 probands, large deletions and duplications were identified in 46 and 6 respectively, while 39 had small variants. Among the small variants, substitutions predicted to cause nonsense mutations were the most common (61.5%), followed by frameshift causing small insertion/deletions (25.6%) and splice affecting intronic variants (12.8%). Notably, 19 novel small variants predicted to be disease-causing were identified. Of the 91 mothers, 53 (58.7%) were confirmed to be carriers. Exonic deletions had a significantly lower carrier frequency of 47.8% as compared to small variants (64.1%). The mean age of the carriers at evaluation was 30 years. Among the carriers, two were symptomatic with onset in the 4th decade, manifesting with progressive proximal muscle weakness and dilated cardiomyopathy. CONCLUSION: Carrier frequency of small pathogenic variants differs significantly from large deletions. Small pathogenic variants are more commonly inherited, whereas large deletions arise de novo.

Altered REM sleep architecture in patients with Myotonic dystrophy type 1: is related to sleep apnea?

OBJECTIVE: To determine the sleep architecture and sleep respiratory abnormalities and to correlate with sleep symptoms in patients with Myotonic dystrophy type 1 (DM1). METHODS: We recruited a cohort of genetically confirmed patients with DM1, who attended the Neuromuscular clinic between July 2016 and December 2019. Clinical, sleep and whole night polysomnography data were collected. The analysis of sleep architecture, sleep respiratory parameters and comparison with healthy controls (HC) was performed in our sleep laboratory. RESULTS: A total of 59 patients with DM1 underwent sleep evaluation. Hypersomnolence in 42 (77.8%), ESS>10 in 23 (39%), and PSQI>5 in 18 (30.5%) were found in patients with DM1. Thirty-one (68.89%) patients with DM1 and 22 (95.65%) HC had more than 4-h of total sleep time (TST). More than 4 h of TST was taken to compare respiratory and sleep architecture parameters. Patients with DM1 had reduced sleep efficiency, reduced N2 sleep, and increase in N1 sleep, wake index, stage shift index, nocturnal sleep-onset REM periods compared to HC. AHI>15 was found in 16 (51.61%) DM1 and in 3 HC (13.64%). AHI had positive correlation with BMI, but not with age, ESS or disease progression (MIRS). All DM1 with AHI>15; 8(80%) and 1(33.33%) in AHI5to15, and AHI<5 groups, respectively had hypersomnolence. CONCLUSION: In this first study on Indian cohort, daytime hypersomnolence, poor nocturnal sleep quality, sleep architecture irregularities are identified to be common in patients with DM1. These abnormalities may be explained by sleep-related breathing disorders that are highly prevalent in these patients.

Lived Experience of Spouses of Persons with Motor Neuron Disease: Preliminary Findings through Interpretative Phenomenological Analysis.

INTRODUCTION: Motor neuron disease (MND) is a progressive neuromuscular disorder that can have significant and debilitating impact on the affected patient and families. Spouses are the primary carers for persons with MND in India, and the life of the person with MND and their spouse is never the same after the diagnosis. AIM: The objective was to explore the lived experience of spouses of persons diagnosed with MND. METHODS: A qualitative exploratory study with three-point interviews was conducted with spouse caregivers of two persons diagnosed with MND who were receiving treatment from a national tertiary referral care center for neurological disorders. All the patients were diagnosed as definite MND according to the modified El Escorial criteria. With the spouses, in-depth interviews were conducted at their home, lasting on an average of 1 hour using a semi-structured interview guide (prompts). Interpretative phenomenological analysis was used to derive themes from the interviews. RESULTS: The major themes emerged from the analysis were meaning of MND which contained the subthemes of delay in diagnosis and deterioration, psychological response across illness trajectory, relationship with the subthemes of changing roles in being acarer, marital relationship, to be seen as doing "right," and communication; adaptation with the subthemes of coping strategies and support system and life without the loved one. CONCLUSION: The changes in the lives of spouses and in strategies for caring the partner with deterioration of symptoms in the illness trajectory are explained in this study. The palliative approach in the management of MND has to take into account, the experiences and needs of carers since care happens at home.

C9orf72 hexanucleotide repeat expansion in Indian patients with ALS: a common founder and its geographical predilection.

Hexanucleotide repeat expansion in C9orf72 is defined as a major causative factor for familial amyotrophic lateral sclerosis (ALS). The mutation frequency varies dramatically among populations of different ethnicity; however, in most cases, C9orf72 mutant has been described on a common founder haplotype. We assessed its frequency in a study cohort involving 593 clinically and electrophysiologically defined ALS cases. We also investigated the presence of reported Finnish haplotype among the mutation carriers. The identified common haplotype region was further screened in 192 (carrying 2-6 G4C2 repeats) and 96 (≥7 repeats) control chromosomes. The G4C2 expansion was observed in 3.2% (19/593) of total cases where 9/19 (47.4%) positive cases belonged to the eastern region of India. Haplotype analysis revealed 11 G4C2-Ex carriers shared the common haplotype (haplo-A) background spanning a region of ∼90 kbp (rs895021-rs11789520) including rs3849942 (a well-known global at-risk loci with T allele for G4C2 expansion). The other 3 G4C2-Ex cases had a different haplotype (haplo-B) with core difference from haplo-A at G4C2-Ex flanking 31 kbp region between rs3849942 and rs11789520 SNPs (allele 'C' of rs3849942 which is a nonrisk allele). Out of other five G4C2-cases, four carried the risk allele T of rs3849942 while one harbored the non-risk allele. This study establishes the prevalence of C9orf72 expansion in Indian ALS cases providing further evidence for geographical predilection. The global core risk haplotype predominated C9orf72 expansion-positive ALS cases, yet the existence of a different haplotype suggests a second lineage (haplo B), which may have been derived from the Finnish core haplotype or may imply a unique haplotype among Asians. The association of risk haplotype with normal intermediate C9orf72 alleles reinforced its role in conferring instability to the C9orf72-G4C2 region. We thus present an effective support to interpret future burden of ALS cases in India.

Family Caregivers' Experiences with Dying and Bereavement of Individuals with Motor Neuron Disease in India.

Motor neuron disease (MND) is a progressive neurodegenerative disease. Ideal management plan in MND includes palliative care initiated from the time of diagnosis. At present, most of the neurodegenerative conditions are cared for at home. Neuropalliative care is an emerging concept in India and social workers are integral team members in this process. The primary aims of the study were to explore (a) the caregivers' experiences of the end-of-life stage, and (b) the sources of support for individuals and their caregivers with MND at the end-of-life stage. In-depth interviews were conducted with seven bereaved caregivers of individuals with MND from a national tertiary referral care center for neuropsychiatry in South India. Interviews were conducted either in person or by telephone. Thematic analysis was done using the constant comparative method. Major themes derived from the interviews were: (1) Transition from person to patient, (2) support, (3) death, and (4) impact on the caregivers. Mapping of themes identified "Support received during advanced stages" as the central theme influencing all other themes. The need for a care manager seems evident and is a role that can be effectively fulfilled by the care teams' social workers.

Mutation pattern in 606 Duchenne muscular dystrophy children with a comparison between familial and non-familial forms: a study in an Indian large single-center cohort.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is induced by a wide spectrum of mutations such as exon deletions, duplications and small mutations in the dystrophin gene. This is the first study on the mutational spectrum in a cohort of DMD children from India, with an emphasis to compare the mutations in familial and sporadic forms. RESULTS: Multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) identified 525 and 70 cases of DMD, respectively, while 11 cases showed absent dystrophin staining with no mutations detected. Families with two or more affected males contributed to 12% of the entire cohort. The mutations comprised of exonic deletions in 492/606 (81.2%), duplications in 33/606 (5.4%) and small mutations (point mutations and INDELs) in 70/606 (11.5%) cases. MLPA identified significantly more larger mutations in sporadic (88.2%) than in familial cases (75.3%). The mutations in NGS were: [nonsense = 40 (57.1%); frameshift = 17 (24.3%); splice variant = 12 (17.1%)]. Nonsense mutations were more common in familial than in sporadic cases: 17.8% vs 10.7%. The familial group reported an earlier onset of disease (2.8 ± 1.7 years) as compared to sporadic cases (3.8 ± 1.6 years). CONCLUSION: MLPA could identify mutations in a high percentage of our DMD children. The preponderance of small mutations was noted to be distinctly higher in the familial group. Intriguingly, the familial form of DMD formed a small percentage of the entire cohort. The reasons could be increasing awareness among parents and physicians with early identification of DMD cases, genetic counseling and prenatal testing.

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

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 (men = 19; women = 11) 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.