Developmental, Cognitive, Ocular Motor, and Neuroimaging Findings Related to SUFU Haploinsufficiency: Unraveling Subtle and Highly Variable Phenotypes.

BACKGROUND: Biallelic SUFU variants have originally been linked to Joubert syndrome, comprising cerebellar abnormalities, dysmorphism, and polydactyly. In contrast, heterozygous truncating variants have recently been associated with developmental delay and ocular motor apraxia, but only a limited number of patients have been reported. Here, we aim to delineate further the mild end of the phenotypic spectrum related to SUFU haploinsufficiency. METHODS: Nine individuals (from three unrelated families) harboring truncating SUFU variants were investigated, including two previously reported individuals (from one family). We provide results from a comprehensive assessment comprising neuroimaging, neuropsychology, video-oculography, and genetic testing. RESULTS: We identified three inherited or de novo truncating variants in SUFU (NM_016169.4): c.895C>T p.(Arg299∗), c.71dup p.(Ala25Glyfs∗23), and c.71del p.(Pro24Argfs∗72). The phenotypic expression showed high variability both between and within families. Clinical features include motor developmental delay (seven of nine), axial hypotonia (five of nine), ocular motor apraxia (three of nine), and cerebellar signs (three of nine). Four of the six reported children had macrocephaly. Neuropsychological and developmental assessments revealed mildly delayed language development in the youngest children, whereas general cognition was normal in all variant carriers. Subtle but characteristic SUFU-related neuroimaging abnormalities (including superior cerebellar dysplasia, abnormalities of the superior cerebellar peduncles, rostrally displaced fastigium, and vermis hypoplasia) were observed in seven of nine individuals. CONCLUSIONS: Our data shed further light on the mild but recognizable features of SUFU haploinsufficiency and underline its marked phenotypic variability, even within families. Notably, neurodevelopmental and behavioral abnormalities are mild compared with Joubert syndrome and seem to be well compensated over time.

Neuro-ophthalmic challenges and multi-morbidity in vasculitis among the older adults.

INTRODUCTION: Vasculitides are a heterogeneous group of disorders producing inflammation of blood vessels (e.g. arteries or veins). All major vasculitides potentially have ophthalmological symptoms and signs including visual loss. Co-morbidity, multimorbidity, polypharmacy, and geriatric syndromes all play important roles in patient outcomes for these rheumatic conditions in the elderly. This monograph reviews the NCBI PubMed database (Feb 2023) literature on the neuro-ophthalmic and geriatric considerations in vasculitis. AREAS COVERED: Cogan Syndrome, Granulomatosis with Polyangiitis, Giant Cell Arteritis, Polyarteritis Nodosa, Takayasu Arteritis, Vasculitis epidemiology, and neuro-ophthalmological symptoms. EXPERT OPINION: Geriatric patient care for vasculitis with neuro-ophthalmological manifestations can be complicated by the interplay of multiple co-morbidities, polypharmacy, and specific geriatric syndromes. The valuation and treatment of vasculitis and the complications associated with the disease can negatively impact patient care. Advances in noninvasive imaging and updates in diagnostic criteria have enabled increased identification of patients at earlier stages with less severe disease burden. Novel therapeutic agents can be glucocorticoid sparing and might reduce the adverse effects of chronic steroid use. Holistic care models like the 5 M geriatric care model (mind, mobility, medications, multicomplexity, and matters most) allow patients' needs to be in the forefront with biopsychosocial aspects of a patient being addressed.

Potential causal association between leisure sedentary behaviors and osteoporosis: A two-sample Mendelian randomization analysis.

Previous observational studies have observed a correlation between sedentary behavior and osteoporosis. However, conclusions from these studies have been contradictory. To explore the potential causal relationship between sedentary behavior and osteoporosis, we conducted a Mendelian randomization analysis. A two-sample Mendelian randomization was adopted to explore the causal relationship of leisure sedentary behavior with osteoporosis. We employed 5 methods to estimate the causal associations between leisure sedentary behavior and osteoporosis. Univariable Mendelian randomization results provided evidence for the causal relationship of the time spent on computer-use with the bone mineral density estimated by heel quantitative ultrasound (eBMD) (inverse variance weighted [IVW]: ß (95% confidence interval [CI]) - 0.150 (-0.270 to -0.031), P = .013; weighted median: ß (95%CI) - 0.195 (-0.336 to -0.055), P = .006). Similar associations were observed in the driving forearm bone mineral density (FABMD) (IVW: ß (95%CI) - 0.933 (-1.860 to -0.007), P = .048) and driving lumbar spine bone mineral density (IVW: ß (95%CI) - 0.649 (-1.175 to -0.124), P = .015). However, we did not find a significant causal relationship between the time spent on watching TV and bone mineral density. Research showed that there was a causal relationship between the time spent on computer use and driving time and eBMD, FABMD, and lumbar spine bone mineral density.

Heterozygous APTX mutation associated with atypical multiple system atrophy-like phenotype: A case report.

We describe here a 73-year-old patient presenting with atypical MSA-P-like phenotype carrying a monoallelic p. W279X mutation in the APTX gene, which causes ataxia with oculomotor apraxia type 1 (AOA1) when in homozygous state. We hypothesize that rare monoallelic APTX variants could modulate MSA risk and phenotype.

Atypical Cogan's syndrome: A case report.

Cogan's syndrome is a rare autoimmune inflammatory disease, characterized by interstitial keratitis and audio-vestibular signs. The syndrome was first described in 1945 by David G. Cogan. Then, it was only in 1980 when Haynes et al. proposed diagnostic criteria for patients with other symptoms and was qualified as atypical form of Cogan's syndrome. Herein, we report a case of a 28-year-old woman with atypical Cogan's syndrome. The patient was treated with corticosteroids and received a cochlear implant.

Clinical outcomes of epithelial basement membrane dystrophy after keratorefractive lenticule extraction.

PURPOSE: To determine the clinical outcomes of keratorefractive lenticule extraction (KLEx) in eyes with epithelial basement membrane dystrophy (EBMD) that developed after surgery. SETTING: Onnuri Smile Eye Clinic, Seoul, South Korea. DESIGN: Retrospective single-center study. METHODS: This study reviewed the medical records of 26 eyes of 16 patients who exhibited signs of EBMD after KLEx. Postoperatively, corneal findings and visual outcomes were evaluated. Statistical analyses were also performed on eyes without corneal complications after KLEx. RESULTS: Signs of EBMD were first observed within 1 week postoperatively in 22 eyes (84.6%): 6 eyes (23.1%) showed epithelial defects, 10 eyes (38.5%) showed subepithelial corneal opacity, 5 eyes (19.2%) showed diffuse lamellar keratitis, and 1 eye (3.9%) showed epithelial ingrowth. Symptoms such as pain, while corneal lesions were present, occurred in 21 eyes (80.8%). At 3 months postoperatively, 21 eyes (80.8%) showed no specific findings on slitlamp microscopy after medical treatment, 2 eyes (7.7%) showed subepithelial corneal opacity, 2 eyes (7.7%) showed corneal scar, and 1 eye (3.9%) showed epithelial ingrowth. Uncorrected distance visual acuity was 20/25 or better in 24 eyes (92.3%), and spherical equivalent was within ±1.0 D in 20 eyes (76.9%). The efficacy index of the EBMD group did not significantly differ from the control group, while the safety index was significantly lower. CONCLUSIONS: Manifestations of EBMD can occur after KLEx and can affect clinical outcomes. Most cases showed favorable results with appropriate nonsurgical treatment; however, some cases had long-term complications such as corneal scarring.

[Behçet's and Cogan's syndromes - The Variable Vessel Vasculitides]. / Behçet- und Cogan-Syndrom.

Behçet's syndrome and Cogan's syndrome constitute the group of variable vessel vasculitides in the Chapel-Hill Nomenclature. They involve arteries and veins of all sizes. As reflected in the name "syndrome", both diseases can manifest with different individual symptoms. Both formally are rare diseases, but the Cogan syndrome is much rarer than Behçet`s. For the latter, there are diagnosis and classification criteria as well as European (EULAR, European Alliance of Associations for Rheumatology) treatment recommendations. The symptomatology, diagnostic measures and treatment as well as some considerations about pathogenesis will be discussed in this article.

Cogan syndrome: a case report and review of the literature.

Cogan syndrome is a rare disease whose etiology is still undetermined. It typically affects men and women between the second and fourth decade of life. We report a case of Cogan syndrome with ocular and audio-vestibular involvement as a systemic manifestation in a 31-year-old woman.

Paediatric Cogan Syndrome masquerading as IgA vasculitis.

Paediatric Cogan Syndrome is a rare and underrecognised autoimmune vasculitis characterised by ocular inflammation and sensorineural hearing loss. Its etiopathogenesis, diagnosis, and management are not well defined. We report a 12-year-old girl who initially presented with symptoms of IgA vasculitis formerly called Henoch Schoenlein Purpura (HSP) and eventually developed anterior uveitis and bilateral sensorineural hearing loss leading to the diagnosis of atypical Cogan Syndrome. The workup for infectious etiologies and other systemic rheumatologic disorders was negative. The management was multidisciplinary involving Rheumatology, Ophthalmology, Otorhinolaryngology, and Audiology. The anterior uveitis responded well to systemic glucocorticoids and Methotrexate, but the hearing loss was grossly progressive warranting a cochlear implant. We are not aware of Paediatric Cogan Syndrome being reported as a mimicker of IgA vasculitis previously in the literature. It is an important finding as IgA vasculitis is prevalent in the paediatric age group and new-onset ocular or vestibular symptoms after IgA vasculitis should alert the clinician to the possibility of Cogan Syndrome. In the absence of well-defined diagnostic criteria, it is crucial to recognise the clinical symptoms of Paediatric Cogan Syndrome for early diagnosis and treatment since the delay in diagnosis can lead to permanent disability.

The atypical sphingolipid SPB 18:1(14Z);O2 is a biomarker for DEGS1 related hypomyelinating leukodystrophy.

Sphingolipids (SL) represent a structurally diverse class of lipids that are central to cellular physiology and neuronal development and function. Defects in the sphingolipid metabolism are typically associated with nervous system disorders. The C4-dihydroceramide desaturase (DEGS1) catalyzes the conversion of dihydroceramide to ceramide, the final step in the SL de-novo synthesis. Loss of function mutations in DEGS1 cause a hypomyelinating leukodystrophy, which is associated with increased plasma dihydrosphingolipids (dhSL) and with the formation of an atypical SPB 18:1(14Z);O2 metabolite. Here, we characterize two novel DEGS1 variants of unknown significance (VUS), provide a structural model with a predicted substrate binding site, and propose a regulatory link between DEGS1 and fatty acid desaturase 3 (FADS3). Both VUS involve single amino acid substitutions near the C-terminus within conserved regions of the enzyme. Patient 1 (p.R311K variant) shows severe progressive tetraspasticity, intellectual disability, and epilepsy in combination with brain magnetic resonance imaging (MRI) findings, typical for DEGS1-related leukodystrophy. Patient 2 (p.G270E variant) presents with delayed psychomotor development, oculomotor apraxia, and a normal brain MRI. Plasma from the p.R311K carrier showed a significantly elevated dhSL species and the presence of SPB 18:1(14Z);O2, while the plasma SL profile for the p.G270E variant was not altered. This suggests the p.R331K variant is pathogenic, while the p.G270E appears benign. As an increase in dihydroSL species is also seen in other pathological disorders of the SL metabolism, the SPB 18:1(14Z);O2 seems to be a more specific biomarker to discriminate between pathogenic and benign DEGS1 variants.

Cogan Syndrome: A Case Study and Review of the Literature.

Cogan syndrome is an autoimmune disease characterized by vestibular symptoms, bilateral sensorineural hearing loss, and inflammatory ocular manifestations, which may be accompanied by systemic vasculitis. We herein present the case of a patient with bilateral sensorineural hearing loss who presented with pain over her cochlear implantation incision site. She was later found to have evidence of ocular disease and underlying vasculitis leading to a diagnosis of Cogan syndrome.

Speech reception after cochlear implantation for Cogan's syndrome: Case series following CARE guidelines.

INTRODUCTION: Cogan's syndrome is a rare form of vasculitis mainly affecting young subjects of whatever gender, associating cochleovestibular and ophthalmological damage. Despite medical treatment, auditory prognosis is uncertain, with 50-60% of patients showing irreversible severe to profound hearing loss, thus being candidates for cochlear implantation. Following CARE guidelines, we report 10 cases of cochlear implantation in Cogan's syndrome, with assessment of speech reception threshold and maximum intelligibility after a minimum 1 year's experience with the implant. CASE SERIES: Ten patients from 4 centers received cochlear implants (14 implants) for Cogan's syndrome between 2005 and 2020. After 1 year's experience, there was significant improvement in speech reception threshold (P=0.0002) and maximum intelligibility (P=0.0002). CONCLUSION-DISCUSSION: Audiovestibular signs associated with ophthalmological manifestations should suggest Cogan's syndrome. Hearing impairment is usually irreversible. Cochlear implantation may be necessary and improves hearing performance.

Paediatric Cogan´s syndrome - review of literature, case report and practical approach to diagnosis and management.

BACKGROUND: Cogan´s syndrome is a rare, presumed autoimmune vasculitis of various vessels characterized by interstitial keratitis and vestibular impairment accompanied by sensorineural hearing loss. Due to the rarity of Cogan´s syndrome in children, therapeutic decision making may be challenging. Therefore, a literature search was performed to collect all published paediatric Cogan´s syndrome cases with their clinical characteristics, disease course, treatment modalities used and their outcome. The cohort was supplemented with our own patient. MAIN TEXT: Altogether, 55 paediatric Cogan´s syndrome patients aged median 12 years have been reported so far. These were identified in PubMed with the keywords "Cogan´s syndrome" and "children" or "childhood". All patients suffered from inflammatory ocular and vestibulo-auditory symptoms. In addition, 32/55 (58%) manifested systemic symptoms with musculoskeletal involvement being the most common with a prevalence of 45%, followed by neurological and skin manifestations. Aortitis was detected in 9/55 (16%). Regarding prognosis, remission in ocular symptoms was attained in 69%, whereas only 32% achieved a significant improvement in auditory function. Mortality was 2/55. Our patient was an 8 year old girl who presented with bilateral uveitis and a history of long standing hearing deficit. She also complained of intermittent vertigo, subfebrile temperatures, abdominal pain with diarrhoea, fatigue and recurrent epistaxis. The diagnosis was supported by bilateral labyrinthitis seen on contrast-enhanced magnetic resonance imaging. Treatment with topical and systemic steroids was started immediately. As the effect on auditory function was only transient, infliximab was added early in the disease course. This led to a remission of ocular and systemic symptoms and a normalization of hearing in the right ear. Her left ear remained deaf and the girl is currently evaluated for a unilateral cochlear implantation. CONCLUSIONS: This study presents an analysis of the largest cohort of paediatric Cogan´s syndrome patients. Based on the collected data, the first practical guide to a diagnostic work-up and treatment in children with Cogan´s syndrome is provided.

Cogan's syndrome is more than just keratitis: a case-based literature review.

BACKGROUND: Cogan's syndrome (CS) is a rare autoimmune disorder characterized by non-syphilitic interstitial keratitis (IK) and Menière-like cochlear vestibular symptoms, which may also have systemic effects. Corticosteroids are first-line treatment. DMARDs and biologics have been used to treat ocular and systemic symptoms of CS. CASE PRESENTATION: This is a case of a 35-year-old female who reported hearing loss, eye redness and photophobia. Her condition progressed to a sudden sensorineural hearing loss, tinnitus, and constant vertigo accompanied by cephalea. CS was diagnosed after excluding other diseases. The patient still developed bilateral sensorineural hearing loss after receiving hormone, methotrexate, cyclophosphamide, and a variety of biological agents. Joint symptoms were relieved after treatment with a JAK inhibitor (tofacitinib), and hearing did not deteriorate further. CONCLUSIONS: CS should be involved in the differential diagnosis of keratitis. Early identification and intervention of this autoimmune disease can minimize disability and irreversible damage.

[Epithelial basement membrane corneal dystrophy: A case report]. / Distrofia de membrana basal epitelial corneal: a propósito de un caso.

Epithelial basement membrane corneal dystrophy is a rare entity, characterized by recurrent corneal erosions secondary to a disorder in the attachment of the corneal epithelium to the basement membrane. To date, mainly the ophthalmological aspect of cases has been reported, with little emphasis on the pathology of this lesion. Here we aim to describe the microscopy and discuss the clinical and therapeutic aspects of a case.