Clinical, morphological and genetic features of a cohort of late onset GSD II patients: typical and atypical presentations

Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in FOXP3 gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features (e.g., atrophic gastritis, interstitial lung disease, nephropathy etc.). Several atypical presentations have recently been reported, suggesting that IPEX incidence might be underestimated. Immunosuppression (IS) treatment strategies can control the disease, however at the moment allogeneic hematopoietic stem cell transplantation (HSCT) is the only available definitive cure, therefore it is important to achieve a prompt diagnosis. This review aims to describe unusual clinical phenotypes, beyond classical IPEX. Overall, our analysis contributes to increase awareness and finally improve diagnosis and treatment intervention in IPEX in order to ensure a good quality of life.

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A challenging diagnosis of MPO-C-ANCA EGPA

BMJ Case Reports ◽

10.1136/bcr-2018-228621 ◽

2019 ◽

Vol 12 (7) ◽

pp. e228621

Author(s):

Gareth Lim ◽

Sheryl Lim ◽

Shang-Ian Tee ◽

Chai Yiing Ling

Keyword(s):

Nasopharyngeal Carcinoma ◽

Rare Case ◽

Granulomatosis With Polyangiitis ◽

Late Onset ◽

Rare Condition ◽

Eosinophilic Granulomatosis With Polyangiitis ◽

Mononeuritis Multiplex ◽

Atypical Presentations ◽

Eosinophilic Granulomatosis ◽

Proximal Myopathy

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic small-vessel vasculitic disease that can present with positive MPO-P-ANCA (myeloperoxidase–perinuclear–anti-neutrophil cytoplasmic antibody). It is a rare condition that is difficult to diagnose. We present the case of a 64-year-old man with late-onset adult asthma and treated nasopharyngeal carcinoma who initially presented to us with proximal myopathy. Thereafter, he developed a constellation of fleeting symptoms which included rhinosinusitis, mononeuritis multiplex, skin vasculitis and arthritis. Blood investigations showed that he had eosinophilia, and skin biopsy demonstrated dermal vasculitis with eosinophils. He was found to be MPO-C-ANCA positive, and although initially thought to have granulomatosis with polyangiitis, the diagnosis was later revised to EGPA. This case highlights the diagnostic challenges with atypical presentations of EGPA and also presents a rare case of positive MPO-C-ANCA that has never been described in EGPA before.

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A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine

Neurology ◽

10.1212/wnl.0000000000005862 ◽

2018 ◽

Vol 91 (4) ◽

pp. e339-e348 ◽

Cited By ~ 5

Author(s):

Macarena Cabrera-Serrano ◽

Fabiola Mavillard ◽

Valerie Biancalana ◽

Eloy Rivas ◽

Bharti Morar ◽

...

Keyword(s):

Neuromuscular Disease ◽

Haplotype Analysis ◽

Founder Mutation ◽

Late Onset ◽

Compound Heterozygous ◽

Centronuclear Myopathy ◽

Limb Weakness ◽

Roma Population ◽

Paravertebral Muscles ◽

Genetic Features

ObjectiveTo describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified.MethodsPatients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed.ResultsEighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma.ConclusionWe have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.

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Characterization of the initial complaint and care pathways prior to diagnosis in very young sporadic Alzheimer’s disease

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00829-0 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Pauline Olivieri ◽

Lorraine Hamelin ◽

Julien Lagarde ◽

Valérie Hahn ◽

Elodie Guichart-Gomez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Late Onset ◽

Young Patients ◽

Care Pathways ◽

Severe Stage ◽

Atypical Presentations ◽

New Treatments ◽

Negative Controls

Abstract Background Very-early-onset Alzheimer’s disease (young-AD) differentiates from late-onset AD (old-AD) by a predominant involvement of the parietal neocortex leading to atypical presentations. The diagnosis of AD is often not the first to be mentioned in such young patients. Methods We retrospectively reviewed the initial complaint and care pathways of 66 sporadic young-AD (age < 62) and 30 old-AD patients (age > 65) and compared their neuropsychological profiles at the time of diagnosis (based on clinical-biological criteria) with 44 amyloid-negative controls. Results The initial complaint of young-AD was non-cognitive and mimicked a burnout in 32% of cases. Their main cognitive complaints were memory (38% vs 87% in old-AD) and language (17% vs 13%) impairment. The referral to a psychiatrist prior to AD diagnosis was more frequent in young-AD than in old-AD (26% vs 0%). At the time of diagnosis, young-AD were at a more severe stage of dementia than old-AD (24% vs 10% with CDR ≥ 1) but had less anosognosia. Conclusions Better identifying the initial signs of very-early-onset AD is crucial to improve the early diagnosis and develop new treatments.

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Clinical and genetic features of Epstein‐Barr virus‐triggered late‐onset primary hemophagocytic lymphohistiocytosis: Ten pedigrees study

Clinical and Translational Medicine ◽

10.1002/ctm2.393 ◽

2021 ◽

Vol 11 (6) ◽

Author(s):

Lili Gao ◽

Li Yang ◽

Liang Huang ◽

Yi Xiao ◽

Jinniu Deng ◽

...

Keyword(s):

Hemophagocytic Lymphohistiocytosis ◽

Epstein Barr Virus ◽

Late Onset ◽

Barr Virus ◽

Genetic Features ◽

Epstein Barr

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Atypical presentations of non-familial anterior megalophthalmos: a rare disease

BMJ Case Reports ◽

10.1136/bcr-2021-244350 ◽

2021 ◽

Vol 14 (10) ◽

pp. e244350

Author(s):

Aparna Rao ◽

Rakhi P Dcruz

Keyword(s):

Family History ◽

Late Onset ◽

Positive Family History ◽

Late Presentation ◽

Optic Nerve Damage ◽

Atypical Features ◽

The Family ◽

Anterior Megalophthalmos ◽

Advanced Glaucoma ◽

Atypical Presentations

Anterior megalophthalmos usually presents early in life with megalocornea, deep anterior chamber, raised intraocular pressure, glaucomatous optic nerve damage and iridodonesis/stromal thinning with positive family history. We report atypical features and presentations in two patients (four eyes) with non-familial megalophthalmos. While the first patient, a male, presented at 51 years of age with megalocornea, cataract, phacodonesis, normal pupillary dilatation/normal iris and advanced glaucoma, the second patient presented with iridodonesis with stromal thinning, aphakia and advanced glaucoma. The family history was negative in both patients. The vitreous index was unusually high, >70% in all four eyes, owing to aphakia in the second patient and possible late presentation/variant phenotype in the first patient. Thus, atypical features such as greater vitreous length, absent iris involvement and late-onset adult presentation are common in non-familial anterior megalophthalmos. Clinical surprises due to varied phenotypes should be kept in mind in such cases.

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Differential clinicopathologic and genetic features of late-onset amnestic dementias

Acta Neuropathologica ◽

10.1007/s00401-014-1302-2 ◽

2014 ◽

Vol 128 (3) ◽

pp. 411-421 ◽

Cited By ~ 76

Author(s):

Melissa E. Murray ◽

Ashley Cannon ◽

Neill R. Graff-Radford ◽

Amanda M. Liesinger ◽

Nicola J. Rutherford ◽

...

Keyword(s):

Late Onset ◽

Genetic Features

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Enlarged vestibular aqueduct and Mondini Malformation: audiological, clinical, radiologic and genetic features

European Archives of Oto-Rhino-Laryngology ◽

10.1007/s00405-020-06333-9 ◽

2020 ◽

Author(s):

F. Forli ◽

F. Lazzerini ◽

G. Auletta ◽

L. Bruschini ◽

S. Berrettini

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Late Onset ◽

Pure Tone Audiometry ◽

Enlarged Vestibular Aqueduct ◽

Vestibular Aqueduct ◽

Genetic Features ◽

Ear Malformations ◽

Caucasian Patients ◽

Genetic Assessment

Abstract Purpose When referring to enlarged vestibular aqueduct (EVA) we should differentiate between nonsyndromic enlarged vestibular aqueduct (NSEVA) and Pendred Syndrome (PDS), a disease continuum associated with pathogenic sequence variants of Pendrin’s Gene (SLC26A4) in about half of the cases. The study was aimed to analyse the clinical and audiological features of a monocentric cohort of Caucasian patients with NSEVA/PDS, their genetic assessment and morphological inner ear features. Methods We retrospectively reviewed the audiologic, genetic and anamnestic data of 66 patients with NSEVA/PDS followed by our audiology service. Results SLC26A4 mutations was significantly correlated with the presence of PDS rather than NSEVA (p < 0.019), with the expression of inner ear malformations (p < 0.001) and with different severity of hearing loss (p = 0.001). Furthermore, patients with PDS showed significantly worse pure tone audiometry (PTA) than patients with NSEVA (p = 0.001). Anatomically normal ears presented significantly better PTA than ears associated with Mondini Malformation or isolated EVA (p < 0.001), but no statistically significative differences have been observed in PTA between patients with Mondini Malformation and isolated EVA. Conclusion NSEVA/PDS must be investigated in all the congenital hearing loss, but also in progressive, late onset, stepwise forms. Even mixed or fluctuating hearing loss may constitute a sign of a NSEVA/PDS pathology. Our findings can confirm the important role of SLC26A4 mutations in determining the phenotype of isolated EVA/PDS, both for the type/degree of the malformation, the hearing impairment and the association with thyroid dysfunction.

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Innate immune genes distinguish the immune microenvironment of early onset colorectal cancer

10.1101/2020.06.26.20141143 ◽

2020 ◽

Author(s):

Ivy H. Gardner ◽

Ragavan Siddharthan ◽

Katherine Watson ◽

Elizabeth Dewey ◽

Rebecca Ruhl ◽

...

Keyword(s):

Colorectal Cancer ◽

Early Onset ◽

Late Onset ◽

Progression Free Survival ◽

Tumor Location ◽

Immune Microenvironment ◽

Immune Genes ◽

Genetic Features ◽

Innate Immune Genes ◽

Early Onset Colorectal Cancer

AbstractDespite a decrease in the incidence of colorectal cancer (CRC) over the last 40 years, the incidence of CRC in people under 50 years old is increasing around the globe. Early onset (≤50 years old) and late onset (≥65 years old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression. We used Nanostring immune profiling to analyze mRNA expression of immune genes in FFPE surgical specimens from patients with early (N=40) and late onset (N=39) CRC. We found three genes, SAA1, C7, and CFD, have increased expression in early onset colorectal cancer and distinct immune signatures based on the tumor location. After adjusting for clinicopathological features, increased expression of CFD and SAA1 were associated with worse progression free survival and increased expression of C7 was associated with worse overall survival. Our data demonstrate that the immune microenvironment in early onset CRC is unique, location dependent, and associated with worse outcomes.

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