Early Onset Of Symptoms Research Articles

Diagnosis of hereditary ataxias: a real-world single center experience.

This study aims to evaluate our experience in the diagnosis of hereditary ataxias (HAs), to analyze data from a real-world scenario. This is a retrospective, cross-sectional, descriptive study conducted at a single Italian adult neurogenetic outpatient clinic, in 147 patients affected by ataxia with a suspicion of hereditary forms, recruited from November 1999 to February 2024. A stepwise approach for molecular diagnostics was applied: targeted gene panel (TP) next-generation sequencing (NGS) and/or clinical exome sequencing (CES) were performed in the case of inconclusive first-line genetic testing, such as short tandem repeat expansions (TREs) testing for most common spinocerebellar ataxias (SCA1-3, 6-8,12,17, DRPLA), other forms [Fragile X-associated tremor/ataxia syndrome (FXTAS), Friedreich ataxia (FRDA) and mitochondrial DNA-related ataxia, RFC1-related ataxia/CANVAS] or inconclusive phenotype-guided specific single gene sequencing. A definitive diagnosis was reached in 36.7% of the cases. TREs testing was diagnostic in 30.4% of patients. The three most common TREs ataxias were FRDA (36.1%), SCA2 (27.8%), and RFC1-related ataxia/CANVAS (11.1%). In five patients, the molecular diagnosis was achieved by single gene sequencing and causative mutations were identified in POLG (2), SACS (1), DARS2 (1), MT-ATP6 (1). Of 94 patients with a suspicion of HAs of indeterminate genetic origin, 68 underwent new molecular evaluation using the NGS approach. In 28 of these cases, CES was performed after the TP sequencing resulted negative. In 13 patients, the diagnosis was achieved by NGS approach. In 7 of these 13 patients, the diagnosis was made by CES. Genes mutations identified as causative of HAs were found in SPG7 (4), SACS (1), CACNA1A (1), CACNA1G (1), EEF2 (1), PRKCG (1), KCNC3 (1), ADCK3 (1), SYNE1 (1), ITPR1 (1). A positive family history of ataxia and early onset of symptoms were associated with a higher likelihood of obtaining a definite diagnosis. The molecular diagnosis of HAs remains a significant challenge for neurologists. Our data indicate that, in most cases, a diagnosis of HA can be established through first line genetic testing, particularly TREs testing. However, for patients with a clinical diagnosis of HA who do not achieve a molecular diagnosis through initial genetic tests, the use of NGS proves to be a valuable tool, providing a definitive diagnosis in approximately 20% of cases. Therefore, when feasible in clinical practice, integrating NGS testing, especially exome sequencing, into the diagnostic decision-making process for unsolved cases is crucial.

Analytical review of facial nerve palsy following SARS-CoV-2 vaccination: comprehensive assessment.

The SARS-CoV-2 vaccination has reduced COVID-19 infection, though facial nerve palsy (FNP) has emerged as a notable side effect of the vaccine. We evaluated the current literature on the clinical presentation and outcomes of FNP related to COVID-19 vaccination. A comprehensive search of seven databases was conducted for studies up to January 2023. We included individually reported patients on FNP following COVID-19 vaccination, while cases with co-existing neurological disorders or secondary causes of FNP were excluded. Pooled descriptive and inferential analyses were conducted, with prognostic factors evaluated through regression and Kaplan-Meier survival analysis. A total of 33 studies were included, with data from 52 patients who developed post-COVID-19 vaccination FNP (PV-FNP). Most cases (71%) followed mRNA vaccines, primarily occurring after the first dose and within the first week post-vaccination. Nearly all cases (98%) were unilateral, with Grade III palsy being most common. Complete recovery was achieved in 55% of patients, significantly lower than pre-pandemic rate (83%). A longer latency period was associated with a reduced likelihood of full recovery, and females experienced faster recovery compared to males. FNP following SARS-CoV-2 vaccination tends to present as mild and unilateral, with a lower full recovery rate compared to pre-pandemic cases. Symptoms often develop within the first week after vaccination, and earlier symptom onset is associated with a higher likelihood of full recovery. Recognizing these patterns provides valuable guidance for clinicians in counseling patients about prognosis and managing follow-up care effectively.

Framework and overview of the Pediatric Spinal Muscular Atrophy Registry Program of Iran

BackgroundThe Pediatric Spinal Muscular Atrophy Registry Program of Iran (PSMAIR) was established as part of the global TREAT-NMD network, which collects data from spinal muscular atrophy (SMA) patients under 18 years of age in Iran. The registry employs a web-based data entry system to collect detailed longitudinal demographic, geographic, clinical, genetic, and treatment outcome data of Iranian children who suffer from SMA.ResultsFrom October 2021 to September 2022, 59 SMA patients were enrolled; 52.5% were female, 47.5% were male, and the average age was 4.98 ± 4.08 years. The majority of registered patients were diagnosed with SMA Type I (47%), followed by Type II (29%) and Type III (24%). Overall, about 19% of the registered patients died; all of them were Type I patients. In the registry, 44% of patients had been hospitalized previously. Usage rates for wheelchairs or other mobility assistive devices, occurrence of scoliosis, tube feeding, and mechanical ventilation among these patients were 15%, 15%, 19%, and 20%, respectively. The data reveal a gradient of severity across SMA types, with earlier symptom onset, lower CMAP amplitude, and lower ACTIVLIM scores associated with more severe SMA (type I), and increments observed moving towards milder forms (type III). The data reveal that symptom onset age, CMAP amplitude, and ACTIVLIM scores progressively increase from SMA type I to SMA type III. The CHOP-INTEND questionnaire's average score was notably higher in children with SMA type II compared to those with type I, while the HFMSE questionnaire scores were notably increased in type III compared to type II patients. A significant correlation between the SMN2 copy number and the SMA phenotype was observed in the population. The geographic distribution of the enrolled patients covers 15 and 18 (out of the 31) provinces of Iran for place of birth and current place of residence, respectively. For patients residing outside Tehran city (where the registry’s referral center is located), the average distance to the registry’s referral center was roughly 463 km.ConclusionsThe PSMAIR offers an important step toward understanding the characteristics of Iranian pediatric SMA patients. The outcome of PSMAIR facilitates data-driven planning and decision-making for Iranian pediatric SMA patients and can help in the advancement of SMA care standards, management, and therapies.

Role of TLR7 in the immunopathogenesis of psoriasis and psoriatic arthritis

BACKGROUND: Toll-like receptor 7 (TLR7) plays a significant role in the development of inflammation in psoriasis. However, there are very few data on the role of different polymorphic markers of the TLR7 gene in psoriasis and psoriatic arthritis. AIM: Study of the role of polymorphic marker rs179009 of TLR7 gene in patients with severe psoriasis. MATERIALS AND METHODS: The study was conducted during the period of 2016–2024. The analysis of innate immunity indicators in the study group was performed by obtaining RNA in peripheral venous blood and polymorphisms of the gene recognizing marker rs179009 of the TLR7 receptor were investigated by polymerase chain reaction with TaqMan probes. To assess the area and severity of psoriatic lesions of the skin process, we used a standardised method of assessment — determination of the PASI index. RESULTS: The main group consisted of 168 patients (100%) with psoriasis. Of these, 45 (26.8%) were women and 123 men (73.2%). The average age of the patients was 54.0±14.0 years. The mean duration of psoriasis course was 11.8±0.6 years. The mean psoriasis area and severity index (PASI) value was 17.7±7.2. When analyzing the genotypes of polymorphic marker rs179009 in the TLR7 gene in patients with psoriasis of different severity, it was revealed that heterozygote CT was significantly more frequent in patients with mild psoriasis, and homozygote CC and homozygote TT were registered at PASI 10 (p 0.05). The C allele of the studied marker was significantly more frequent in patients with late psoriasis debut and late development of psoriatic arthritis (p 0.01). In contrast, the T allele was significantly more frequent in patients with early debut of psoriasis and psoriatic arthritis (p 0.01). When analyzing the genotypes of polymorphic marker rs179009 in the TLR7 gene, the occurrence of homozygous CC and TT genotypes was also found to have statistically significant differences. The CC genotype was more frequently registered in patients with late onset of psoriasis and late onset of arthritis (p 0.05). In contrast, the TT genotype was significantly more frequently registered in patients with the debut of skin and joint process before 40 years of age (p 0.05). CONCLUSION: In our study it was found that homozygous carriage of CC and TT genotypes of polymorphic marker rs179009 in the TLR7 gene predisposes to a more severe course of the skin process in psoriasis. Also, the presence in the patient of allele C or homozygote CC of marker rs179009 in the TLR7 gene is a predictor of late onset of the skin process and the development of arthritis. While the presence of the T allele or TT homozygote statistically significantly predisposes to early onset of psoriasis and early onset of joint symptoms with the development of psoriatic arthritis.

Identification of a novel pathogenic gene, NDUFA3, in Leigh Syndrome through whole exome sequencing

BackgroundLeigh syndrome is a common mitochondrial disorder caused by gene mutations in the nucleus and mitochondria. When building mitochondrial complex I, the main subunit ND1 combines with the Q module to form a 273 kDa complex, which then adds Ndufa3, Ndufa8, and Ndufa13 to create an intermediate product of about 283 kDa called Q/Pp-a. Although Ndufa8 and Ndufa13 have been linked to mitochondrial diseases, the role of Ndufa3 in disease development is still not fully understood.MethodsA family suspected of having Leigh syndrome was examined. Subjects (two brothers and a sister) underwent brain imaging, and their clinical symptoms were evaluated. Also, whole exome sequencing and minigene testing were performed by examining peripheral blood samples (2 ml) collected from the proband, his parents, and brothers.ResultsThree affected children showed early-onset symptoms, including abnormalities in muscle tone and delayed motor and language development. Symptoms were relatively mild. The second child of the second pregnancy experienced worsened muscle tone abnormalities after injury, slow wound healing, and sustained increased muscle tone up to a year after wound closure. His brain scans revealed lesions in the basal ganglia and brainstem, consistent with Leigh syndrome diagnosis. Genetic analysis identified compound heterozygous mutations in the Ndufa3 gene in all affected family members.ConclusionThis is the first report of a family affected by Leigh syndrome associated with mutations in the Ndufa3 gene. Our analyses of clinical symptoms, radiological scans, and genetic investigations broaden our understanding of Ndufa3 gene mutations and their role in the development of Leigh syndrome.

A novel SBF1 missense mutation causes autosomal dominant Charcot-Marie-Tooth disease type 4B3.

We present a case of autosomal dominant Charcot-Marie-Tooth disease type 4B3 (CMT4B3) in a family caused by a novel SBF1 missense mutation. Two patients, a mother and daughter, were recruited from our hospital. Both exhibited early-onset symptoms, including distal muscle atrophy of the limbs, without cranial nerve involvement. Electromyography was performed to assess nerve amplitudes and conduction velocities. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify genetic mutations. Electromyography revealed a significant decline in nerve amplitudes, while the nerve conduction velocities (NCVs) remained normal in the extremities. Sequencing identified a novel missense mutation (c.1398C > A, p.H466Q) in exon 13 of the SET binding factor 1 (SBF1) gene in both patients, indicating an autosomal dominant inheritance pattern. Pathogenicity and protein predictions suggest that the myotubularin-related protein 5 (MTMR5), encoded by the mutated SBF1, may possess an altered structure, resulting in disease. These findings will help expand the phenotypic and genetic spectrum of CMT4B3.

A phenotypic comparison of the Romanian and French ATTRv cohorts: Glu54Gln founder pathogenic variant vs the most common variants in Western Europe

Aim and methodsWe conducted a retrospective observational study of the ATTRv heterozygous mutation frequency, phenotype, and all-cause mortality at two cardiac amyloidosis centers in Romania and France. Results291 patients were included: 26 Glu54Gln (all Romanian), 200 Val122Ile, 47 Val30Met and 18 Ser77Tyr. On diagnosis, Gu54Gln patients were younger than Val122Ile or late-onset Val30Met (median age: 46 [42–50], 76 [71–80] and 70 [61–76], respectively; p < 0.001) and had more autonomic dysfunction (50 %, 6.3 %, and 7.7 %, respectively; p < 0.001) and similar cardiac symptom profiles. They had fewer conduction disorders (11.5 %) than early-onset Val30Met (76.9 %, p < 0.001) and Ser77Tyr group, notably less cardiac pacemaker present on diagnosis: 3.8 % for Glu54Gln vs. 23.5 % for Ser77Tyr; p = 0.014. Glu54Gln, Val122Ile, late-onset Val30Met and Ser77Tyr patients had similar left ventricular mass and systolic function values. Median survival for Glu54Gln patients was 58.7 years (95 %CI 55.9 – upper bound indeterminable), significantly lower than that of Val122Ile (83.6 years 95 %CI 81.6–85.5, log-rank test p < 0.001), late-onset Val30Met (83.4 years 95 %CI 81.9–84.9, log-rank test p < 0.001) and Ser77Tyr (74.8 years 95 %CI 68.7–80.9, log-rank test p = 0.022). Median survival after diagnosis was 5.7 years for Glu54Gln patients (95 %CI 4.7–6.4). ConclusionWe established that the Glu54Gln variant has an aggressive, mixed phenotype, with an early onset of autonomic dysfunction and heart failure symptoms. We emphasize the need for systematic genetic testing in patients with ATTR as understanding genotype-phenotype correlations is key for the management and the counseling of patients and their family members.

Mapping the diagnostic odyssey of congenital disorders of glycosylation (CDG): insights from the community

BackgroundCongenital disorders of glycosylation (CDG) are a group of rare metabolic diseases with heterogeneous presentations, leading to substantial diagnostic challenges, which are poorly understood. Therefore, this study aims to elucidate this diagnostic journey by examining families’ and professionals’ experiences.Results and discussionA questionnaire was designed for CDG families and professionals, garnering 160 and 35 responses, respectively. Analysis revealed the lack of seizures as a distinctive feature between PMM2-CDG (11.2%) with Other CDG (57.7%) at symptom onset. Hypotonia and developmental disability were prevalent symptoms across all studied CDG. Feeding problems were identified as an early onset symptom in PMM2-CDG (Cramer’s V (V) = 0.30, False Discovery Rate (FDR) = 3.8 × 10− 9), and hypotonia in all studied CDG (V = 0.34, FDR = 7.0 × 10− 3). The average time to diagnosis has decreased in recent years (now ~ 3.9 years), due to advancements namely the increased use of whole genome and exome sequencing. However, misdiagnoses remain prevalent (PMM2-CDG – 44.9%, non-PMM2-CDG – 64.8%). To address these challenges, we propose adapting medical training to increase awareness of CDG and other rare diseases, ongoing education for physicians, the development of educational resources for relevant medical units, and empowerment of families through patient organizations and support networks.ConclusionThis study emphasizes the crucial role of community-centered research, and the insights families can offer to enhance CDG management. By pinpointing existing gaps and needs, our findings can inform targeted interventions and support systems to improve the lives of those impacted by CDG.

A New Case of Mitochondrial RNA Helicase SUPV3L1-Associated Neurodegenerative Disease: Ataxia, Spasticity, Optic Atrophy, and Skin Hypopigmentation (ASOASH).

The SUPV3L1 gene encodes ATP-dependent RNA helicase SUPV3L1, which is a part of the mitochondrial degradosome complex or SUV3. SUPV3L1 unwinds secondary structures of mitochondrial RNA (mtRNA) and facilitates the degradation of mtRNA molecules. A nonsense homozygous variant in the SUPV3L1 gene was recently associated with mitochondrial disease. Our study presents the second documented case of SUPV3L1 pathology in humans. Whole-genome sequencing was performed on the NovaSeq 6000 platform using pair-end reading. Data analysis was performed with an in-house developed pipeline. The 17-year-old female patient exhibited a diverse array of symptoms, including ataxia, spastic paraparesis, cognitive deficit, optic atrophy, and horizontal gaze-evoked nystagmus. Early onset of symptoms, such as ataxic gait and nystagmus, was noted, with subsequent progression of neurological manifestations. At the time of the observation, the proband had extensive regions of hypopigmented skin patches on the body and extremities, which have progressed over time. Whole-genome sequencing revealed compound heterozygous variants in the SUPV3L1 gene: c.272-2A>G and c.1924A>C; p.(Ser642Arg). RNA analysis demonstrated splicing changes attributable to the c.272-2A>G variant. ELISA assay showed increased Complex I content in the patient's fibroblasts. This case underscores the phenotypic diversity associated with SUPV3L1 mutations, emphasizing the importance of considering mitochondrial RNA helicase dysfunction in the differential diagnosis of neurodegenerative disorders. Further elucidation of the molecular mechanisms underlying SUPV3L1-associated pathology may provide valuable insights into targeted therapeutic interventions.

Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study.

Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease. A total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-. SAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. These results highlight the interplay between amyloid and α-syn and their association with disease progression. Seed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression.

TCT-648 HFpEF Phenotype Is Associated With Early Symptom Onset in Aortic Stenosis and Residual Symptomatic Burden After Transcatheter Aortic Valve Replacement

TCT-648 HFpEF Phenotype Is Associated With Early Symptom Onset in Aortic Stenosis and Residual Symptomatic Burden After Transcatheter Aortic Valve Replacement

Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern China

BackgroundThis study aimed to investigate the clinical and molecular genetic characteristics of ten children with ornithine carbamoyltransferase deficiency (OTCD) in southeastern China, as well as the correlation between the genotype and phenotype of OTCD.MethodsA retrospective analysis was performed on the clinical manifestations, laboratory testing, and genetic test findings of ten children with OTCD admitted between August 2015 and October 2021 at Quanzhou Maternity and Children’s Hospital of Fujian Province in China.ResultsFive boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. In contrast, five patients (one boy and four girls) had late-onset gastrointestinal symptoms as the primary clinical manifestation, all presenting with hepatic impairment, and four with hepatic failure.Nine distinct variants of the OTC gene were identified, including two novel mutations: c.1033del(p.Y345Tfs*50) and c.167T > A(p.M56K). Of seven patients who died, five had early-onset disease despite active treatment. Three patients survived, and two of them underwent liver transplantation.ConclusionsThe clinical manifestations of OTCD lack specificity. However, elevated blood ammonia levels serve as a crucial diagnostic clue for OTCD. Genetic testing aids in more accurate diagnosis and prognosis assessment by clinicians. In addition, we identified two novel pathogenic variants and expand the mutational spectrum of the gene OTC, which may contribute to a better understanding of the clinical and genetic characteristics of OTCD patients.

Investigating the associations between early labour onset symptoms and self-diagnosed labour onset in a cohort study of primiparas

ObjectiveThe early recognition of possible labour onset symptoms may be pivotal to identifying the beginning of early labour and are usually recognised by the birthing women themselves. The present study illustrates the interrelationship among five labour-onset symptoms and explores the association of these labour-onset symptoms with the self-diagnosed labour onset of primiparas. MethodsA prospective cohort study on a sample of 69 primigravida in Giessen, Germany, expecting spontaneous onset of labour at term. The participants filled in a diary from ≥37 + 0 weeks gestation until self-diagnosed labour onset. Descriptive, bivariate and inferential analysis explored association of labour onset symptoms with self-diagnosed labour onset while accounting for maternal and newborn characteristics. ResultsSelf-diagnosed labour onset was positively associated with all symptoms and clinical characteristics, apart from irregular pain and maternal weight and age. Moreover, regular pain was negatively correlated with irregular pain; having regular pain increased the odds of self-diagnosed labour onset substantially (OR: 10.18, 95 % CI: 2.39–66.27), followed by gastrointestinal symptoms (OR: 2.07, 95 % CI: 0.40–13.10) and emotional symptoms (OR: 2.05, 95% CI: 0.30–13.98). ConclusionBeing the initiator of intrapartum care without any birth experience, primiparas are prone to experiencing dissatisfaction in care and may enter professional care too late or too early. The present study showed that regular pain may signify primiparas to self-diagnose labour onset within 24 h and indicate early labour symptoms that may be relevant for a self-diagnosed labour onset.

High-risk screening for late-onset Pompe disease in China: An expanded multicenter study.

Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.

THE IMPACT OF EARLY SURGICAL INTERVENTION ON ANISEIKONIA IN PATIENTS WITH EPIRETINAL MEMBRANE: A Prospective Cohort Study.

To investigate the efficacy of early surgical intervention in ameliorating aniseikonia among patients with epiretinal membrane. This prospective cohort study enrolled patients who underwent surgery for epiretinal membrane. Patients were divided into early (symptom onset within 1 year) and late (symptom onset ≥1 year) treatment groups. Changes in aniseikonia, best-corrected visual acuity, and tangential retinal displacement were assessed and compared at 6 and 12 months postoperatively. Of the 56 patients, 30 (53.6%) belonged to the early treatment group and 26 (46.4%) to the late treatment group. The early treatment group demonstrated a significant reduction in aniseikonia score at 6- and 12-month follow-up visits (-1.10 ± 1.50 [P = 0.002] and -1.18 ± 1.79 [P = 0.003], respectively); however, no improvement was observed in the late treatment group (0.98 ± 4.62 [P = 0.310] and 1.52 ± 4.35 [P = 0.124], respectively). The early treatment group showed larger tangential retinal displacement at the 12-month postoperative follow-up visit. In addition, the amount of tangential retinal displacement was associated with postoperative changes in aniseikonia. Early surgical intervention is helpful in improving aniseikonia in patients with epiretinal membrane. The degree of recovery in inner retinal displacement was associated with the improvement of aniseikonia.

Identification of biallelic mutations in MCM3AP and comprehensive literature analysis.

Minichromosome maintenance complex component 3 associated protein (MCM3AP) is a gene in which mutations can result in autosomal recessive peripheral neuropathy with or without impaired intellectual development. The MCM3AP genotype-phenotype correlation and prognosis remain unclear. The aim of this study was to explore the genotype-phenotype correlations pertaining to MCM3AP. Whole-exome sequencing (WES) combined with copy number variation sequencing (CNV-seq) were performed on the genomic DNA isolated from a Chinese family, and Sanger sequencing, quantitative PCR and cDNA analyses were performed to examine the mutations. The retrospective study was conducted on 28 individuals with biallelic MCM3AP mutation-related diseases, including features such as mutations, motor development impairment, intellectual disability, weakness/atrophy, and cerebral magnetic resonance imaging abnormalities. Sequencing identified novel compound heterozygous mutations in MCM3AP, namely, a paternal variant c.1_5426del (loss of exons 1-25) and a maternal splicing variant c.1858 + 3A>G. Functional studies revealed that the variant c.1858 + 3A>G resulted in the heterozygous deletion of exon 5, thereby affecting splicing functionality. Furthermore, the compound heterozygous mutation may affect the functionality of the protein domain. Retrospective analysis revealed different genotype-phenotype correlations for the pathogenic variants in biallelic MCM3AP: all individuals (100%) with mutations outside the Sac3 domain exhibited early-onset symptoms, motor developmental delays, and cognitive abnormalities, conversely, the proportions of individuals carrying mutations within the domain were 26.7% (motor delays) and 46.7% (cognitive abnormalities). Our findings further expand the genetic mutation spectrum of biallelic MCM3AP and highlight the genotype-phenotype associations. Additionally, we elaborate on the importance of rehabilitation intervention.

CDH23-Associated Usher Syndrome: Clinical Features, Retinal Imaging, and Natural History.

The purpose of this study was to analyze the clinical spectrum and natural history of CDH23-associated Usher syndrome type ID (USH1D). Molecularly-confirmed individuals had data extracted from medical records. Retinal imaging was extracted from an in-house database. The main outcome measurements were retinal imaging and electroretinography (ERG) and clinical findings, including age of onset, symptoms, best-corrected visual acuity (BCVA), outer nuclear layer (ONL) thickness, ellipsoid zone width (EZW), and hyperautofluorescent ring area. Thirty-one patients were identified, harboring 40 variants in CDH23 (10 being novel). The mean (range, ±SD) age of symptom onset was 10.1years (range = 1-18, SD = ±4.1). The most common visual symptoms at presentation were nyctalopia (93.5%) and peripheral vision difficulties (61.3%). The mean BCVA at baseline was 0.25 ± 0.22 in the right eyes and 0.35 ± 0.58 LogMAR in the left eyes. The mean annual loss rate in BCVA was 0.018 LogMAR/year over a mean follow-up of 9.5years. Individuals harboring the c.5237G>A p.(Arg1746Gln) allele had retinitis pigmentosa (RP) sparing the superior retina. Seventy-seven percent of patients had hyperautofluorescent rings in fundus autofluorescence. Full-field and pattern ERGs indicated moderate-severe rod-cone or photoreceptor dysfunction with relative sparing of macular function in most patients tested. Optical coherence tomography (OCT) revealed intraretinal cysts in the transfoveal B-scan of 13 individuals (43.3%). The rate of EZW and ONL thickness loss was mild and suggestive of a wide window of macular preservation. Despite the early onset of symptoms, USH1D has a slowly progressive phenotype. There is high interocular symmetry across all parameters, making it an attractive target for novel therapies.

Association of CSF α-Synuclein Seed Amplification Assay Positivity with Disease Progression and Cognitive Decline: A Longitudinal Alzheimer's Disease Neuroimaging Initiative Study.

CSF α-synuclein seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body (LB) co-pathology in AD. 1637 cross-sectional and 407 longitudinal CSF samples from ADNI were tested with SAA. We examined longitudinal dynamics of Aβ, α-synuclein seeds, and p-tau181, along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-. SAA+ individuals had faster cognitive decline than SAA-, notably in MCI, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42-positivity but did not impact progression of either Aβ42 or p-tau181 status. Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly Aβ42. In vitro α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. These results highlight the interplay between Aβ and α-synuclein and their association with disease progression.

Multimodal prediction of the need of clozapine in treatment resistant schizophrenia; a pilot study in first-episode psychosis

As many as one third of the patients diagnosed with schizophrenia do not respond to first-line antipsychotic medication. This group may benefit from the atypical antipsychotic medication clozapine, but initiation of treatment is often delayed, which may worsen prognosis. Predicting which patients do not respond to traditional antipsychotic medication at the onset of symptoms would provide fast-tracked treatment for this group of patients. We collected data from patient records of 38 first-episode psychosis patients, of whom seven did not respond to traditional antipsychotic medications. We used clinical data including medical records, voxel-based morphometry MRI data and inter-subject correlation fMRI data, obtained during movie viewing, to predict future treatment resistance. Using a neural network model, we correctly predicted future treatment resistance in six of the seven treatment resistance patients and 25 of 31 patients who did not require clozapine treatment. Prediction improved significantly when using imaging data in tandem with clinical data. The accuracy of the neural network model was significantly higher than the accuracy of a support vector machine algorithm. These results support the notion that treatment resistant schizophrenia could represent a separate entity of psychotic disorders, characterized by morphological and functional changes in the brain which could represent biomarkers detectable at early onset of symptoms.

Hyperornithinemia-hyperammonemia-homocitrullinuria: a rare neurometabolic disorder in two siblings.

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is an extremely rare disorder of urea cycle, with few patients reported worldwide. Despite hyperammonemia control, the long-term outcome remains poor with progressive neurological deterioration. We report the clinical, biochemical, and molecular features of two Lebanese siblings diagnosed with this disorder and followed for 8 and 15years, respectively. Variable clinical manifestations and neurological outcome were observed. The patient with earlier onset of symptoms had a severe neurological deterioration while the other developed a milder form of the disease at an older age. Diagnosis was challenging in the absence of the complete biochemical triad and the non-specific clinical presentations. Whole exome sequencing revealed a homozygous variant, p.Phe188del, in the SLC25A15 gene, a French- Canadian founder mutation previously unreported in Arab patients. Hyperammonemia was controlled in both patients but hyperonithinemia persisted. Frequent hyperalaninemia spikes and lactic acidosis occured concomitantly with the onset of seizures in one of the siblings. Variable neurological deterioration and outcome were observed within the same family. This is the first report from the Arab population of the long-term outcome of this devastating neurometabolic disorder.