Onset features and time to diagnosis in Friedreich's Ataxia

Abstract Background: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich´s Ataxia (FRDA), a genetic disorder caused by homozygous GAA-repeat expansions.Methods: 611 genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov-Identifier NCT02069509). Age and symptoms at onset as well as age at suspicion of FRDA were collected retrospectively at the baseline visit.Results: In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n=57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR=2-9) years and it improved significantly after the introduction of genetic testing (2(IQR=1-5) years, p <0.001). Still after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI[5.5,7.9] vs 4.5, [4.2,5] years, p =0.001) as well as in b) patients with late-onset (3(IQR=1-7) vs 2(IQR=1-5) years compared to early onset <25 years of age, p =0.03). Age at onset significantly correlated with GAA-repeat length in case of neurological onset (r=-0,6; p <0,0001), but not in patients with non-neurological presentation (r=-0,1; p =0,4). Across 54 siblings’ pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r=-0,14, p =0,3).Conclusions: In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA and disease milestones are not valid in case of atypical presentations or positive family history.

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Onset features and time to diagnosis in Friedreich´s Ataxia

10.21203/rs.3.rs-18562/v2 ◽

2020 ◽

Author(s):

Elisabetta Indelicato ◽

Wolfgang Nachbauer ◽

Andreas Eigentler ◽

Matthias Amprosi ◽

Raffaella Matteucci Gothe ◽

...

Keyword(s):

Late Onset ◽

Genetic Disorder ◽

Age At Onset ◽

Positive Family History ◽

Diagnostic Delay ◽

Repeat Length ◽

Presenting Symptoms ◽

Time To Diagnosis ◽

Neurological Presentation ◽

Neurological Features

Abstract Background: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich´s Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions. Methods: 611 genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov-Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit. Results: In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n=57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR=2-9) years and it improved significantly after the introduction of genetic testing (2(IQR=1-5) years, p<0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI[5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p=0.001) as well as in b) patients with late-onset (3(IQR=1-7) vs 2(IQR=1-5) years compared to typical onset <25 years of age, p=0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r=-0,6; p<0,0001), but not in patients with non-neurological presentation (r=-0,1; p=0,4). Across 54 siblings’ pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r=-0,14, p=0,3).Conclusions: In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.

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Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry

European Heart Journal ◽

10.1093/eurheartj/ehz311 ◽

2019 ◽

Vol 40 (35) ◽

pp. 2964-2975 ◽

Cited By ~ 25

Author(s):

Lia Crotti ◽

Carla Spazzolini ◽

David J Tester ◽

Alice Ghidoni ◽

Alban-Elouen Baruteau ◽

...

Keyword(s):

Age Of Onset ◽

Late Onset ◽

Age At Onset ◽

Poor Response ◽

Response To Therapy ◽

Polymorphic Ventricular Tachycardia ◽

High Prevalence ◽

Neurological Phenotype ◽

Life Threatening ◽

Neurological Features

Abstract Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

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Time to Diagnosis in Young Onset Alzheimer’s Disease: A Population-Based Study from Central Norway

Journal of Alzheimer s Disease ◽

10.3233/jad-210090 ◽

2021 ◽

pp. 1-10

Author(s):

Marte Kvello-Alme ◽

Geir Bråthen ◽

Linda R. White ◽

Sigrid Botne Sando

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Public Awareness ◽

Diagnostic Delay ◽

Healthcare Services ◽

University Hospital ◽

Time Lags ◽

Young Onset ◽

Time To Diagnosis

Background: Young onset dementia is associated with a longer time to diagnosis compared to late onset dementia. Earlier publications have indicated that atypical presentation is a key contributing factor to the diagnostic delay. Our hypothesis was that even the most common presentation of Alzheimer’s disease is associated with a substantial diagnostic delay in patients < 65 years. Objective: To determine the time to diagnosis, and time lags in the diagnostic pathway in typical young onset Alzheimer’s disease in central Norway. Methods: The main sources of patients were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav’s Hospital), and Department of Psychiatry, Levanger Hospital. Other sources included key persons in the communities, collaborating hospital departments examining patients with suspected cognitive impairment, and review of hospital records of all three hospitals in the area. Information on the time lags, and the clinical assessment, including the use of biomarkers, was collected from hospital notes. Caregivers were interviewed by telephone. Results: Time from first symptom to diagnosis in typical young onset Alzheimer’s disease was 5.5 years (n = 223, SD 2.8). Time from onset to contact with healthcare services (usually a general practitioner) was 3.4 years (SD 2.3). Time from contact with healthcare services to the first visit at a hospital was 10.3 months (SD 15.5). Time from first visit at a hospital to diagnosis was 14.8 months (SD 22.6). The analysis of cerebrospinal fluid core biomarkers was performed after 8.3 months (SD 20.9). Conclusion: Typical Alzheimer’s disease is associated with a substantial diagnostic delay in younger patients. Raising public awareness, and education of healthcare professionals on the aspects of young onset Alzheimer’s disease is warranted. CSF core biomarkers should be performed earlier in the hospital evaluation process.

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Effect of Age at Onset on Disease Characteristics in Vitiligo

Journal of Cutaneous Medicine and Surgery ◽

10.2310/7750.2013.12075 ◽

2013 ◽

Vol 17 (4) ◽

pp. 253-258 ◽

Cited By ~ 7

Author(s):

Amrinder J. Kanwar ◽

Rahul Mahajan ◽

Davinder Parsad

Keyword(s):

Early Onset ◽

Late Onset ◽

Statistical Significance ◽

Age At Onset ◽

Positive Family History ◽

Disease Onset ◽

Disease Characteristics ◽

The Difference ◽

Trauma Stress ◽

Distinguishing Features

Background: Vitiligo is a multifactorial disease in which genetic, immunologic, and environmental factors play an important part. Late-onset vitiligo is a poorly defined entity. Materials and Methods: Case records of patients who attended the pigmentary clinic at our institute from January 2001 to December 2010 were reviewed. Patients with a diagnosis of vitiligo were analyzed with respect to their demographic characteristics with special reference to their age at onset. Results: Patients with disease onset after 30 years had a significantly higher association with precipitating factors such as trauma, stress, and drugs in comparison with early-onset vitiligo ( p < .004). However, the difference did not reach statistical significance when these factors were analyzed individually. There was a significantly higher association with other nonautoimmune diseases ( p = .05), a higher incidence of positive family history ( p < .0001), and a higher association with leukotrichia ( p < .002) in late-onset disease. Early-onset nonsegmental vitiligo was associated with a higher incidence of photosensitivity and pruritus compared to early-onset segmental vitiligo. Conclusion: Late-onset vitiligo has certain distinguishing features compared to early-onset vitiligo.

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Time to diagnosis in younger-onset dementia and the impact of a specialist diagnostic service

International Psychogeriatrics ◽

10.1017/s1041610220001489 ◽

2020 ◽

pp. 1-9

Author(s):

Samantha M. Loi ◽

Anita M.Y. Goh ◽

Ramon Mocellin ◽

Charles B. Malpas ◽

Shaun Parker ◽

...

Keyword(s):

Age At Onset ◽

Diagnostic Delay ◽

Cross Sectional Study ◽

Linear Modeling ◽

Cross Sectional ◽

Younger Age ◽

Time To Diagnosis ◽

Diagnostic Delays ◽

The Impact ◽

Mean Time

ABSTRACT Objectives: While early diagnosis of younger-onset dementia (YOD) is crucial in terms of accessing appropriate services and future planning, diagnostic delays are common. This study aims to identify predictors of delay to diagnosis in a large sample of people with YOD and to investigate the impact of a specialist YOD service on this time to diagnosis. Design: A retrospective cross-sectional study. Setting: The inpatient unit of a tertiary neuropsychiatry service in metropolitan Victoria, Australia. Participants: People diagnosed with a YOD. Measurements and methods: We investigated the following predictors using general linear modeling: demographics including sex and location, age at onset, dementia type, cognition, psychiatric diagnosis, and number of services consulted with prior to diagnosis. Results: A total of 242 inpatients were included. The mean time to diagnosis was 3.4 years. Significant predictors of delay included younger age at onset, dementia type other than Alzheimer’s disease (AD) and behavioral-variant frontotemporal dementia (bvFTD), and increased number of services consulted. These predictors individually led to an increased diagnostic delay of approximately 19 days, 5 months, and 6 months, respectively. A specialized YOD service reduced time to diagnosis by 12 months. Conclusion: We found that younger age at onset, having a dementia which was not the most commonly occurring AD or bvFTD, and increasing number of services were significant predictors of diagnostic delay. A novel result was that a specialist YOD service may decrease diagnostic delay, highlighting the importance of such as service in reducing time to diagnosis as well as providing post-diagnostic support.

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Time to diagnosis in young-onset dementia as compared with late-onset dementia

Psychological Medicine ◽

10.1017/s0033291712001122 ◽

2012 ◽

Vol 43 (2) ◽

pp. 423-432 ◽

Cited By ~ 74

Author(s):

D. van Vliet ◽

M. E. de Vugt ◽

C. Bakker ◽

Y. A. L. Pijnenburg ◽

M. J. F. J. Vernooij-Dassen ◽

...

Keyword(s):

Symptom Onset ◽

Late Onset ◽

Linear Regression Analysis ◽

Age At Onset ◽

Multiple Linear Regression Analysis ◽

Living Situation ◽

Young Onset ◽

Time To Diagnosis ◽

Young Onset Dementia ◽

Late Onset Dementia

BackgroundThe extent to which specific factors influence diagnostic delays in dementia is unclear. Therefore, the aim of the present study was to compare duration from symptom onset to diagnosis for young-onset dementia (YOD) and late-onset dementia (LOD) and to assess the effect of age at onset, type of dementia, gender, living situation, education and family history of dementia on this duration.MethodData on 235 YOD and 167 LOD patients collected from caregivers from two prospective cohort studies were used. Multiple linear regression analysis was performed.ResultsThe duration between symptom onset and the diagnosis of YOD exceeded that of LOD by an average of 1.6 years (2.8 v. 4.4 years). Young age and being diagnosed with frontotemporal dementia were related to increases in the time to diagnosis. Subjects with vascular dementia experienced shorter time to diagnosis.ConclusionsThere is a need to raise special awareness of YOD to facilitate a timely diagnosis.

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An in Depth Analysis of Factors Contributing to Diagnostic Delay in Myeloma: A Retrospective UK Study of Patients Journey from Primary Care to Specialist Secondary Care

Blood ◽

10.1182/blood-2021-150848 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3007-3007

Author(s):

Md Imran Hossain ◽

Peter Hampson ◽

Craig Nowell ◽

Shamshad Khan ◽

Ranjoy Sen ◽

...

Keyword(s):

Primary Care ◽

Secondary Care ◽

Blood Test ◽

Diagnostic Delay ◽

Initial Presentation ◽

Test Results ◽

Presenting Symptoms ◽

Blood Tests ◽

Time To Diagnosis ◽

Gp Visits

Abstract Introduction Patients with Multiple Myeloma (MM) often have a significant delay between onset of symptoms and diagnosis of disease. As a result, a significant number of patients present via emergency routes with severe co-morbidities which affect survival rates. Timely diagnosis relies on the early recognition of symptoms and blood test results which may indicate disease. Methods We examined the medical records of 142 newly diagnosed MM patients (121 intact immunoglobulin and 21 light chains) across 2 UK Hospitals. Patients included had not previously been diagnosed with a plasma cell dyscrasia, including Monoclonal Gammopathy of Undetermined Significance (MGUS). Clinical symptoms and blood test results were examined from the time of initial presentation to the healthcare system with symptoms indicative of MM, to the point of diagnosis in order to highlight patterns of symptoms and blood tests results which may give an early indication of disease. Blood tests results recorded included globulin, calcium, creatinine, erythroid sedimentation rate and haemoglobin. Time to diagnosis from presentation with symptoms indicative of MM was also measured as well as the patient pathway from the point of presentation to the point of diagnosis. Results The median time to diagnosis from initial presentation was 77 days (range 0 - 12,986). Initial presentation was most commonly via primary care (58.1%). Urgent secondary care presentation was documented in 28.5% which included acute medical unit (15.6%), the emergency department (7.1%), and other secondary care specialities (5.7%) respectively. Multiple GP visits were common prior to haematology referral with a median of 3 visits (range 1 - 40). Initial presenting symptoms varied, but of those with data recorded (n=107) back/bone pain was the most common (58.2%) followed by anaemia (18.7%), fracture (7.5%), recurrent infection (7.5%) and renal impairment (3.7%) respectively. Interestingly, analysis of evaluable blood test results revealed a raised globulin was most often evident prior to diagnosis with 58% of patients recording an abnormal globulin a median of 140 days (range 3 - 4297) prior to diagnosis of disease. Conclusions Multiple GP visits prior to establishing a diagnosis of myeloma is very common. Inclusion of abnormal globulin to reflex electrophoresis request and serum free light chain assay may serve as a useful trigger for investigation when interpreted alongside presenting symptoms and other blood test results. Increased awareness of myeloma warning signs in primary care may reduce diagnostic delay and avoid presentation with severe co-morbidities in emergency settings. Disclosures No relevant conflicts of interest to declare.

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Mutational analysis in familial Alzheimer’s disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile

Scientific Reports ◽

10.1038/s41598-020-76794-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yung-Shuan Lin ◽

Chih-Ya Cheng ◽

Yi-Chu Liao ◽

Chen-Jee Hong ◽

Jong-Ling Fuh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mutational Analysis ◽

Age At Onset ◽

Positive Family History ◽

Han Chinese ◽

White Matter Hyperintensity ◽

Brain White Matter ◽

Initial Symptoms ◽

Neurological Features

AbstractMutations in PSEN1, PSEN2, or APP genes are known to be causative for autosomal dominant Alzheimer’s disease (ADAD). While more than 400 mutations were reported worldwide, predominantly PSEN1, over 40 mutations have been reported in Han Chinese and were associated with earlier onset and more affected family members. Between 2002 and 2018, 77 patients in the neurological clinic of Taipei Veterans General Hospital with a history suggestive of ADAD were referred for mutational analysis. We retrospectively collected demographics, initial symptoms, neurological features and inheritance. We identified 16 patients with PSEN1 and 1 with APP mutation. Among the mutations identified, PSEN1 p.Pro117Leu, p.Met146Ile, p.Gly206Asp, p.Gly209Glu, p.Glu280Lys and p.Leu286Val and APP p.Asp678His were known pathogenic mutations; PSEN1 p.His131Arg and p.Arg157Ser were classified as likely pathogenic and variance of unknown significance respectively. The mean age at onset was 46.2 ± 6.2 years in patients with mutation found. PSEN1 p.Met146Ile, occurred in 56.2% (9/16) of patients with PSEN1 mutations, was the most frequent mutation in the cohort. The additional neurological features occurring in 9 PSEN1 p.Met146Ile index patients were similar with the literature. We found patients with genetic diagnoses were more likely to have positive family history, younger age at onset and less brain white matter hyperintensity.

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Time to Diagnosis of Early-Onset vs. “Late-Onset” Colorectal Cancer: Is there a difference?

Proceedings of IMPRS ◽

10.18060/22673 ◽

2018 ◽

Vol 1 (1) ◽

Author(s):

Kayla L. Chin ◽

Laura E. Myers ◽

Jessica M. Coffing ◽

Jason Larson ◽

Thomas F. Imperiale

Keyword(s):

Colorectal Cancer ◽

Early Onset ◽

Late Onset ◽

Initial Presentation ◽

Published Data ◽

Advanced Stage ◽

Factors Affecting ◽

Presenting Symptoms ◽

Incidence And Mortality ◽

Time To Diagnosis

BACKGROUND Colorectal cancer (CRC) incidence and mortality is increasing in persons ˂ 50 years old. Intervals between symptom onset and initial presentation (presentation interval [PI]) and between initial presentation and diagnosis (diagnosis interval [DI]) are not well-quantified. OBJECTIVE Compare PI and DI between early-onset CRC (EOCRC) and persons >50, and identify factors affecting these intervals. METHODS In this retrospective VA-based case-control study, we identified EOCRC cases from an ongoing study and compared them to controls (CRC patients aged ≥ 50 years). We abstracted demographics, clinical features, CRC location and stage, PI, and DI. Mann-Whitney tests compared mean and median PI and DI. RESULTS Advanced stage (III-IV) CRC was more common among the 240 EOCRC patients (mean age: 45.2, 60.8% White) than in the 234 controls (mean age: 63.8, 71.8% White): 55.4% vs 43.5%; P= 0.015. PIs and DIs, respectively, were present for 153(63.8%) and 222(92.5%) of cases and for 74(31.6%) 222(94.9%) of controls. No difference was found between median PI in EOCRC and late-onset CRC patients (42 vs 60 days, P= 0.68). The EOCRC cases had a significantly shorter median DI (41 [IQR = 16-83] vs 71 days [IQR = 32-145], P<0.0001). CONCLUSIONS In this retrospective study, younger patients had more advanced stage CRC at diagnosis than their older counterparts. However, contrary to published data, median time to diagnosis was shorter in those < 50 years. Factors associated with the DI are forthcoming. Candidate factors include race, diagnosis year, presenting symptoms, type of initial provider, CRC stage, and CRC location.

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LINC-43. FACTORS LEADING TO DIAGNOSTIC DELAY FOR CHILDREN WITH PRIMARY TUMORS OF CENTRAL NERVOUS SYSTEM (CNS) IN QATAR

Neuro-Oncology ◽

10.1093/neuonc/noaa222.476 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii386-iii386

Author(s):

Tayseer Yousif ◽

Ayman Saleh ◽

Ata Maaz

Keyword(s):

Early Recognition ◽

Diagnostic Delay ◽

Cns Tumors ◽

Low Grade ◽

Sex Distribution ◽

Primary Tumors ◽

Delay In Diagnosis ◽

Presenting Symptoms ◽

Significant Difference ◽

Time To Diagnosis

Abstract INTRODUCTION Median time to diagnosis for primary CNS tumors for children in Qatar has been reported to be 28 days. However, a wide variation in diagnostic times is seen. This study was undertaken to analyze the factors leading to delay in diagnosis. METHODS Data were retrospectively analyzed for children who had diagnostic delay (more than 28 days) from September 2006 to February 2020. Presenting symptoms, number and type of healthcare contacts and presenting symptom interval (PSI) were reviewed. Parental delay (PSI-1) was defined as the date of onset of first symptom to the date of first healthcare contact. Healthcare delay (PSI-2) was defined as date of first healthcare contact to the date of diagnostic scan. RESULTS Twenty-four patients were identified with diagnostic delay. Median age at diagnosis was 48.2 (range 5.4–171.6) months with an equal sex distribution. Fifteen (62.5%) patients were older than 3 years, 13(54%) patients had low grade glioma, 16 (66.7%) had supratentorial tumors and 12 (50%) presented with raised intracranial pressure. Diagnosis was made after a median 3 (range 1–8) healthcare contacts. Nineteen (79%) patients presented to primary care. Median PSI was 132 (31–783) days. Parental delay (PSI-1) was 35 (0–496) days, while healthcare delay (PSI-2) was 41 (0–562) days. Endocrine (241 days) and oculo-visual (184 days) symptoms were associated with the longest PSI. CONCLUSIONS There was no significant difference between parental and healthcare delay. Endocrine and oculo-visual symptoms were associated with longest PSI. Increased awareness is required for early recognition of signs suggestive of CNS tumors.

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