Adult Onset Research Articles

Latent factors underlying the symptoms of adult-onset myotonic dystrophy type 1 during the clinical course

BackgroundMyotonic dystrophy type 1 (DM1) is a multisystem genetic disorder that classically presents with symptoms associated with myotonia, early onset cataracts, and muscular weakness, although the presentation and pattern of disease progression is quite varied. Presenting symptoms are well documented among adults with DM1. However, less is known about the co-occurrence of symptoms over time. We aimed to use factor analysis to explore the correlation pattern of signs and symptoms (S/S) that emerged during the clinical course.ResultsClinical records of 228 individuals with adult onset DM1 were abstracted using the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from a six-site cohort in the United States during an eight-year study period. Factor analysis was used to group the correlated S/S into latent factors. Three factors were identified. Group 1: ‘Facial Weakness/Myotonia’ includes the two most common S/S, as indicated by its name. Group 2: ‘Skeletal Muscle Weakness’ includes eight muscular S/S and is more frequently reported by males and those with older age at onset. Group 3: ‘Gastrointestinal distress/Sleepiness’ includes four non-muscular S/S and hand stiffness. The abstracted medical records reported that over 63% of individuals had S/S from all three groups. Associations of covariates with factor scores were also examined using linear regression. CTG repeat length was significantly positively associated with higher factor scores for all three factors.ConclusionsThis study identified three latent factors of S/S which accumulated during the clinical course of adult onset DM1.

Asymptomatic, slowly progressing erythematous papules with adult onset.

A 35 year old woman presented with sudden onset of multiple asymptomatic erythematous papules on her dorsal feet followed by a 2 year period of additional lesions appearing on ankles, right forearm and right superior eyelid.

Delirium and risk of incident cardiovascular events in elderly: data from a global health research network

Abstract Introduction Delirium is a common complication of acute medical disorders. A strong association between cardiovascular events and the occurrence of delirium has been recorded. Thus far, no data are available regarding the risk of incident cardiovascular events after delirium onset in older adults. Methods Using data from TriNetX, a global health federated research network, we performed a propensity score matched (PSM) analysis of older adults (age ≥65 years) admitted to the emergency department (ED) reporting delirium within two weeks, who were compared with those without delirium. We evaluated the occurrence of a composite outcome of cardiovascular events (myocardial infarction, ischemic stroke, heart failure, intracranial haemorrhage, ventricular arrhythmias, takotsubo syndrome, and atrial fibrillation) at 30 days and 1 and 3 years of follow-up. Results 4,480,229 patients were retrieved for the analysis, and 82,693 (1.8%) reported delirium. Before PSM, patients reporting delirium were older, with more prevalent comorbidities. After PSM, a total of 165,386 patients were included in the analysis (mean (SD) age 76.6 (9.0) years, 51.1% females). Throughout the entire follow-up period, the cumulative composite cardiovascular events outcome was significantly higher in patients which reported delirium [Red Line, Figure 1]. Delirium was associated with cardiovascular events at 30 days (HR 1.96, 95% CI 1.92-2.00) ,1 year (HR 1.75, 95% CI 1.72-1.78) and 3 years (HR 1.67, 95% CI 1.64-1.69) of follow-up, as well as for each of its components (Table 1). The presence of delirium was also associated with a higher risk of all-cause death and hospital access (Table 1), evaluated as secondary outcomes. In patients with delirium associated with the occurrence of incident cardiovascular events, there was a higher risk of recurrent cardiovascular events at 1 year (HR 3.11, 95% CI 2.92-3.31) and 3 years (HR 2.84, 95% CI 2.67-3.01) of follow-up. Conclusions In a large, unselected cohort of older adults admitted to ED, occurrence of delirium was associated with a higher risk of cardiovascular events, both in the short and long-term follow-up.Figure 1:Delirium and CV EventsTable 1:Cox Regression Analysis

Who should be prioritized for screening for adult onset dilated cardiomyopathy among first degree relatives?

Abstract Introduction Familial genetic and cardiovascular screening is highly recommended to detect dilated cardiomyopathy (DCM) in first-degree relatives (FDRs). Consequently, questions arise regarding the prioritization of screening among FDRs especially in Asian populations. Purpose To investigate prevalence and proportion of FDRs of DCM patients presenting with DCM. Methods Patients with DCM and their FDRs who underwent genetic counseling between April 2017 and March 2023 at a single tertiary center were retrospectively enrolled. The study collected baseline demographics and conducted sequential echocardiograms, along with genetic cascade sequencing for 36 genes clinically relevant to DCM. A positive DCM phenotype in FDRs was determined based on the presence of a decreased left ventricular ejection fraction (LVEF) with left ventricular enlargement, with a full phenotype containing both criteria and a partial phenotype containing either of them. Results A total of 122 probands (median age 59 years) and 241 FDRs (median age 43 years) participated in the study. Out of 72 FDRs (29.9%) with P/LP proband variants, only 18.6% of FDRs showed a positive DCM-phenotype. Overall, 29 individuals (15.5%) exhibited a positive DCM-phenotype, with 2.7% displaying a full DCM-phenotype and 12.8% displaying a partial DCM-phenotype. Among them, 69% exhibited heart failure (HF) with preserved EF, 20.7% had HF with mildly reduced EF, and 10.3% had HF with reduced EF. Siblings tended to be older compared to offspring (52.1 years vs. 35.5 years), aligning with the tendency shown in the more fulminant manifestation of the positive phenotype. Accordingly, a higher prevalence was observed among siblings (n=4, 80%) with a full phenotype and in those with a partial phenotype. Conclusion This study demonstrated higher prevalence of phenotype-positive DCM among siblings of probands. Given disease’s manifestation in adulthood, it is essential to prioritize the screening of all FDRs with emphasis on the siblings.

Adult Onset Acute Disseminated Encephalomyelitis: A Case Report

Adult Onset Acute Disseminated Encephalomyelitis: A Case Report

Intravenous anakinra for treating macrophage activation syndrome in adult onset still’s disease

Intravenous anakinra for treating macrophage activation syndrome in adult onset still’s disease

Role of vitamin D in prevention of type 2 diabetes mellitus: A systematic review and meta‑analysis.

The escalating prevalence of diabetes mellitus, projected to affect over 700 million by 2045, underscores the urgent need for effective management and prevention strategies, with type 2 diabetes mellitus (T2DM) constituting over 90% of these cases globally. The present meta-analysis aims to rigorously evaluate the potential of vitamin D supplementation in mitigating the onset of T2DM, amidst the backdrop of its biological plausibility yet inconclusive evidence regarding its efficacy in reducing new incidences of the disease. A comprehensive literature search up to December 2023 in MEDLINE, EMBASE and the Cochrane Library, employing a strategy focused on diabetes and vitamin D, identified randomized controlled trials (RCTs) that explore the impact of vitamin D supplementation on T2DM onset in adults with impaired glucose regulation, incorporating quality assessment via the Cochrane ROB2 tool and utilizing meta-analysis with RevMan Web to evaluate effect magnitude and heterogeneity. In a meta-analysis of 11 RCTs with 5,221 prediabetic patients, vitamin D supplementation was associated with a 10% reduction in the progression to T2DM [RR, 0.90; 95% CI, (0.81-0.99)] and a significant increase in regression to normoglycemia [RR, 1.24; 95% CI, (1.08-1.43)], with no significant heterogeneity or publication bias observed. This meta-analysis of 11 RCTs shows that vitamin D supplementation in prediabetic patients lowers the risk of T2DM and promotes regression to normoglycemia, with no significant differences in subgroup analyses or interaction with baseline vitamin D levels, ethnicity, or body mass index (BMI). Despite indications from some trials that baseline vitamin D status may influence outcomes, the present comprehensive analysis found benefits of vitamin D across diverse populations, including non-obese individuals, without conclusive evidence linking supplementation to changes in BMI or age-specific advantages.

A meta-analysis of the prevalence of neuropsychiatric disorders and their association with disease onset in myotonic dystrophy.

There is a high prevalence of neuropsychiatric disorders in myotonic dystrophy types 1 and 2 (DM1 and DM2), including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in DM1, and depression and anxiety in both DMs. The aim of this systematic review and meta-analysis was to estimate the prevalence of ASD, ADHD, depression and anxiety in the population with DM, and their association with disease onset. A systematic search of Medline, Scopus, Web of Science, and the Cochrane Library was conducted from inception to November 2023. Observational studies estimating the prevalence of these disorders in DM1 or DM2 were included. A meta-analysis of the prevalence of these disorders and an association study with disease onset by prevalence ratio meta-analysis were performed. Thirty-eight studies were included. In DM1, the prevalence of ASD was 14%, with congenital onset being 79% more common than juvenile onset, while the prevalence of ADHD was 21%, with no difference between congenital and juvenile onset, and the prevalence of depression and anxiety were 14% and 16%. Depression was more common in the adult onset. Finally, the prevalence of depression in DM2 was 16%. A higher prevalence of neuropsychiatric disorders is observed in individuals with DM1 and DM2 than in the general population. Therefore, actively screening for congenital and juvenile neurodevelopmental disorders in DM1 and emotional disorders in DM1 and DM2 may improve the quality of life of those affected.

Resolving Phenotypic Variability in Mitochondrial Diseases: Preliminary Findings of a Proteomic Approach

The introduction of new sequencing approaches into clinical practice has radically changed the diagnostic approach to mitochondrial diseases, significantly improving the molecular definition rate in this group of neurogenetic disorders. At the same time, there have been no equal successes in the area of in-depth understanding of disease mechanisms and few innovative therapeutic approaches have been proposed recently. In this regard, the identification of the molecular basis of phenotypic variability in primary mitochondrial disorders represents a key aspect for deciphering disease mechanisms with important therapeutic implications. In this study, we present data from proteomic investigations in two subjects affected by mitochondrial disease characterized by a different clinical severity and associated with the same variant in the TWNK gene, encoding the mitochondrial DNA and RNA helicase with a specific role in the mtDNA replisome. Heterozygous pathogenic variants in this gene are associated with progressive external ophthalmoplegia and ptosis, usually with adult onset. The overall results suggest an imbalance in glucose metabolism and ROS production/regulation, with possible consequences on the phenotypic manifestations of the enrolled subjects. Although the data will need to be validated in a large cohort, proteomic investigations have proven to be a valid approach for a deep understanding of these neurometabolic disorders.

Rare Yet Relevant: Adult Onset Cervical Lymphangioma - Our Experience and Comprehensive Review.

Cervical lymphangiomas are anomalies that arise from lymphatic vessels, characterized by gradual and painless growth. While predominantly located in the neck, they may also manifest in the axilla, mediastinum, groin, and abdominal organs. Cervical lymphangioma usually occurs in children and is relatively rare in adults. The purpose of this study was to investigate the characteristics of cervical lymphangiomas in adults. We reviewed the medical records and analysed clinical data obtained from fifteen adult patients who suffered from cervical lymphangioma and were operated from January 2021 to January 2023. Out of 15 cases, 73.3% were females and 26.7% were males. All tumours were unilaterally located. Five patients had prior history of associated dyspnoea / dysphagia. All 15 cervical lymphangiomas (100%) were adjacent to the carotid sheath .Tumour size ranged from 6cm to 15cm, with the maximum diameter of ≥ 15cm in two cases, between 6cm and 10cm in eight cases and less than 6cm in five cases. Further, in this study all cervical lymphangiomas were surgically excised. Postoperative courses were uneventful, and histo-pathological examinations confirmed all cases to be cystic lymphangiomas. A 6 -month follow-up in all 15 cases showed no recurrences. Overall, this study underscores the importance of a multidisciplinary approach involving clinicians, radiologists, and surgeons in the management of adult cervical lymphangiomas, with an emphasis on accurate diagnosis, appropriate classification, and tailored treatment strategies to optimize patient outcomes and minimize complications.

Naproxen-induced liver injury in a case of adult-onset Still's disease.

We present the case of a young female with fever, rash, and joint pain without any other history of connective tissue disorder, who was found on evaluation to have neutrophilic leucocytosis, elevated inflammatory markers and lymphadenopathy with hepatosplenomegaly. After extensive workup, the possibility of adult onset Still's disease was suggested by Yamaguchi criteria. She was started on naproxen, but later on developed drug-induced liver injury. She already had central serous retinopathy due to steroid use, and it was difficult to treat the adult-onset Stills disease due to the liver injury in view of contraindication to use of anti-inflammatory drugs but her illness was monocyclic and did not require further immunosuppression.

PFAPA syndrome: a case report

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a complex autoinflammatory disease characterized by recurrent episodes of fever and systemic inflammatory features. It is usually a disease of children but adult onset has also been reported. The common clinical features are aphthous stomatitis, cervical lymphadenitis, pharyngitis etc with exclusion of upper respiratory tract infection and cyclic neutropenia. The patient remains completely asymptomatic between the episodes of these clinical features with normal growth and development. Here we report a case of 20-year-old male who presented with features suggestive of PFAPA syndrome and well responded with a single dose of high dose prednisolone. BIRDEM Med J 2024; 14(3): 161-165

Adult‐onset neuronal ceroid lipofuscinosis in a smooth‐haired dachshund

AbstractA 5‐year‐old, smooth‐haired miniature dachshund exhibited a progressive history of frequent episodes of aggression towards objects, head pressing, circling and intermittent pelvic limb ataxia over a period of 2 weeks. Visual impairment was also noticed several months prior. Neurolocalisation was consistent with forebrain disease. Blood and urine analysis, magnetic resonance imaging of the brain and cerebrospinal fluid analysis were all unremarkable. The patient was euthanased due to disease progression, and postmortem histopathological analysis and electronic microscopy identified the accumulation of intracellular granular material in a number of neurons, mainly located in the thalamus and hypothalamus. This supported a diagnosis of neuronal ceroid lipofuscinosis. Genetic testing showed no mutations in the causative genes reported for this breed. This case reports the occurrence of a potentially novel subtype of neuronal ceroid lipofuscinosis, due to a currently unidentified genetic mutation, leading to an adult onset of clinical signs in the dachshund.

Sjögren disease, new name, new guidelines: Key messages for primary care

Sjögren’s syndrome is increasingly renamed Sjögren disease, as in the recent British Society of Rheumatology guidelines. These guidelines provide evidence-based recommendations for the management of adult and juvenile onset Sjögren disease. Sjögren disease is the second most common autoimmune rheumatic disease (after rheumatoid arthritis), affecting approximately 0.6% of adults, over 90% of whom are women. Sjögren disease can occur as a stand-alone autoimmune disease or overlap with other conditions such as rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis. This article aims to highlight the salient features of the guidelines for primary care physicians to improve the early diagnosis of Sjögren disease and inform the day-to-day management of established cases. The two clinical case scenarios featured in this article should help to highlight the importance of early diagnostic pick up whilst minimising false positive diagnosis and to highlight key messages from the new guidelines. A summary sheet of these guidelines is included in the supplementary material.

ITPR3-associated neuropathy: Report of a further family with adult onset intermediate Charcot-Marie-Tooth disease.

ITPR3 encodes type 3 inositol-tri-phosphate receptor (IP3R3), a protein expressed in Schwann cells, predominantly in the paranodal region, and involved in the regulation of Ca2+ release from the endoplasmic reticulum. Dominant variants in ITPR3 have recently been recognized as a rare cause of intermediate Charcot-Marie-Tooth disease (CMT). We collected the clinical data of a family with autosomal dominant neuropathy whose proband was diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) for many years. The genetic diagnosis was achieved by whole exome sequencing. The proband developed symmetrical sensory-motor neuropathy with demyelinating features at 32 years old. He was diagnosed with CIDP and received numerous immunomodulatory treatments. However, his condition progressed, leading to severe proximal leg and hand atrophy that confined him to a wheelchair at 60 years. The patient's two sons began to exhibit symptoms suggestive of neuropathy shortly after age 30 years, and the condition was reoriented as inherited. Exome sequencing identified a heterozygous c.4271C > T variant in the ITPR3 gene segregating with the disease. Nerve conduction studies showed a combination of demyelinating and axonal features that vary by nerve, disease duration, and patient. A uniform thickening of the nerves was identified on nerve echography, as was distal symmetric fatty infiltration in lower limb muscle imaging. The c.4271C > T ITPR3 variant causes a late onset CMT that can be considered an intermediate CMT. Considering the electrophysiological findings and the distribution of IP3R3, we hypothesize that this variant could start as nodal dysfunction that progresses to widespread nerve degeneration.

Prevalence of hypopituitarism in survivors of adult onset, primary, non-pituitary, brain tumours treated with intensity-modulated radiotherapy

Prevalence of hypopituitarism in survivors of adult onset, primary, non-pituitary, brain tumours treated with intensity-modulated radiotherapy

Proposed criteria for the O'Sullivan McLeod syndrome: Case series and literature review

AbstractWe aimed to summarize the clinical characteristics of the O'Sullivan McLeod syndrome and propose the diagnostic criteria of the syndrome. We reviewed our database to identify patients with the O'Sullivan McLeod syndrome. Online databases including PubMed, EMBASE, and OVID were also searched for relevant cases. We identified a total of 24 cases, including 3 cases from our database and 21 ones from online searching. A predominance of male was observed [17 (73.9%)] with median onset age of 31 (range: 15–56) years old. The median (range) disease duration was 9 (0.5–28) years at the time of the visit. All patients showed involvement of hands and ~1/3 patients reported weakness and atrophy of right/left forearm. The upper arm was scarcely affected (8.7%). Needle electromyography suggested chronic denervation in C7‐T1 among the majority of involved cases (over 78%). Cervical magnetic resonance imaging showed longitudinal T2‐hypertenssive signals among 5/14 (35.7%) patients, which confined to the anterior horn area. No patients showed responsiveness to immunotherapy. Ten patients remained clinical stable during follow‐up, nine ones manifested chronic progressive course. The O'Sullivan and McLeod syndrome, characterized by progressive weakness and atrophy in upper limbs, might be an incurable disorder of lower motor neuron. Onset in early adulthood, the plateau period of over 12 months and years of chronic progression in clinical manifestations might be supportive indicators for the diagnosis of the syndrome. The prognosis is relatively good with no effective treatment.

Adult Stuttering Prevalence II: Recalculation, Subgrouping and Estimate of Stuttering Community Engagement

PurposeEpidemiological research of stuttering has frequently focused on children, with a relative paucity of population level data specific to adults. Prevalence data for adults are reassessed here, including a breakdown of whether stuttering is overt or covert, and whether onset was in childhood or adulthood. The engagement of adults who stutter with stuttering communities is also estimated. MethodsPrevalence calculations were based on data from studies having the strongest designs, following the systematic review of Gattie, Lieven & Kluk (2024, this issue). Original data for engagement with stuttering communities were gathered from English language internet stuttering support groups, a national stuttering charity in the UK and a regional stuttering support group in Manchester, UK. ResultsAdult stuttering prevalence was estimated at 0.96% (95% CI 0.65, 1.44). This can be broken down to 0.63% overt stuttering (95% CI 0.46, 0.79) comprising 0.53% childhood onset and 0.10% adult onset; and 0.33% covert stuttering (95% CI 0.19, 0.58) comprising 0.28% childhood onset and 0.05% adult onset. Covert stuttering will have been overestimated, and may often be very mild. Engagement with stuttering communities was estimated at 0.99% internationally, 0.63% nationally and 1.01% regionally. Actual engagement will have been lower due to attrition and overcounting. ConclusionThe adult stuttering prevalence estimate of 0.96% is consistent with the widely-cited all ages stuttering prevalence estimate of 1%. Of adults who stutter, fewer than 1% engage with stuttering communities.

RNF213 Mutation Associated with the Progression from Middle Cerebral Artery Steno-Occlusive Disease to Moyamoya Disease.

Middle cerebral artery steno-occlusive disease (MCAD) has been recognized as a different clinical entity from moyamoya disease (MMD). Although MCAD can progress to MMD, the extent to which patients actually progress and the risk factors for this progression have not been fully elucidated. We retrospectively reviewed patients with MCAD who underwent RNF213 genotyping. Demographic features, RNF213 p.R4810K mutation, medical history, and longitudinal changes in angiography were analyzed. Sixty patients with 81 affected hemispheres were enrolled. During the follow-up period, 17 patients developed MMD, and the RNF213 p.R4810K mutation was the only factor significantly associated with progression to MMD (odds ratio, 16.1; 95% CI, 2.13-731; P = 0.001). The log-rank test demonstrated that patients with the mutation had a higher risk of progression to MMD (P = 0.007), stenosis progression (P = 0.010), and symptomatic cerebral infarction or hemorrhage (P = 0.026). In Cox regression analysis the p.R4810K mutation remained a significant factor after adjusting for age group (childhood or adult onset) at diagnosis (hazard ratio, 8.42; 95% CI, 1.10-64.4). Hemisphere-based analysis also showed that the mutation was associated with a higher risk of progression to the MMD hemisphere (P = 0.002), stenosis progression (P = 0.005), and cerebral infarction or hemorrhage (P = 0.012). The RNF213 p.R4810K mutation was identified as a risk factor for progression from MCAD to MMD. Genotyping for this mutation may contribute to risk stratification in MCAD.

Clinical and neuroradiological spectrum of biallelic variants in NOTCH3

NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. The Wellcome Trust, the MRC.