Symptomatic Carrier Research Articles

Long-read sequencing and optical mapping generates near T2T assemblies that resolves a centromeric translocation

Long-read genome sequencing (lrGS) is a promising method in genetic diagnostics. Here we investigate the potential of lrGS to detect a disease-associated chromosomal translocation between 17p13 and the 19 centromere. We constructed two sets of phased and non-phased de novo assemblies; (i) based on lrGS only and (ii) hybrid assemblies combining lrGS with optical mapping using lrGS reads with a median coverage of 34X. Variant calling detected both structural variants (SVs) and small variants and the accuracy of the small variant calling was compared with those called with short-read genome sequencing (srGS). The de novo and hybrid assemblies had high quality and contiguity with N50 of 62.85 Mb, enabling a near telomere to telomere assembly with less than a 100 contigs per haplotype. Notably, we successfully identified the centromeric breakpoint of the translocation. A concordance of 92% was observed when comparing small variant calling between srGS and lrGS. In summary, our findings underscore the remarkable potential of lrGS as a comprehensive and accurate solution for the analysis of SVs and small variants. Thus, lrGS could replace a large battery of genetic tests that were used for the diagnosis of a single symptomatic translocation carrier, highlighting the potential of lrGS in the realm of digital karyotyping.

C9ORF72 Gene GGGGCC Hexanucleotide Expansion: A High Clinical Variability from Amyotrophic Lateral Sclerosis to Frontotemporal Dementia.

The expanded GGGGCC hexanucleotide repeat (HRE) in the non-coding region of the C9ORF72 gene (C9ORF72-HRE) is the most common genetic cause of familial forms of amyotrophic lateral sclerosis (ALS), FTD, and concurrent ALS and FTD (ALS-FTD), in addition to contributing to the sporadic forms of these diseases. Both syndromes overlap not only genetically, but also sharing similar clinical and neuropathological findings, being considered as a spectrum. In this paper we describe the clinical-genetic findings in a Basque family with different manifestations within the spectrum, our difficulties in reaching the diagnosis, and a narrative review, carried out as a consequence, of the main features associated with C9ORF72-HRE. Family members underwent a detailed clinical assessment, neurological examination, and genetic analysis by repeat-primed PCR. We studied 10 relatives of a symptomatic carrier of the C9ORF72-HRE expansion. Two of them presented the expansion in the pathological range, one of them was symptomatic whereas the other one remained asymptomatic at 72 years. Given the great intrafamilial clinical variability of C9ORF72-HRE, the characterization of patients and family members with particular clinical and genetic subgroups within ALS and FTD becomes a bottleneck for medication development, in particular for genetically focused medicines for ALS and FTD.

The Proteome Profile of Olfactory Ecto-Mesenchymal Stem Cells-Derived from Patients with Familial Alzheimer's Disease Reveals New Insights for AD Study.

Alzheimer's disease (AD), the most common neurodegenerative disease and the first cause of dementia worldwide, has no effective treatment, and its pathological mechanisms are not yet fully understood. We conducted this study to explore the proteomic differences associated with Familial Alzheimer's Disease (FAD) in olfactory ecto-mesenchymal stem cells (MSCs) derived from PSEN1 (A431E) mutation carriers compared with healthy donors paired by age and gender through two label-free liquid chromatography-mass spectrometry approaches. The first analysis compared carrier 1 (patient with symptoms, P1) and its control (healthy donor, C1), and the second compared carrier 2 (patient with pre-symptoms, P2) with its respective control cells (C2) to evaluate whether the protein alterations presented in the symptomatic carrier were also present in the pre-symptom stages. Finally, we analyzed the differentially expressed proteins (DEPs) for biological and functional enrichment. These proteins showed impaired expression in a stage-dependent manner and are involved in energy metabolism, vesicle transport, actin cytoskeleton, cell proliferation, and proteostasis pathways, in line with previous AD reports. Our study is the first to conduct a proteomic analysis of MSCs from the Jalisco FAD patients in two stages of the disease (symptomatic and presymptomatic), showing these cells as a new and excellent in vitro model for future AD studies.

Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions.

Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from deleterious mutations in the F8 gene encoding FVIII. Over the last 4 decades, the methods aimed at determining the HA carrier status in female relatives of HA patients have evolved from phenotypic studies based on coagulation tests providing merely probabilistic results, via genetic linkage studies based on polymorphic markers providing more accurate results, to next generation sequencing studies enabling highly precise identification of the causative F8 mutation. In parallel, the options for prenatal diagnosis of HA have progressed from examination of FVIII levels in fetal blood samples at weeks 20-22 of pregnancy to genetic analysis of fetal DNA extracted from chorionic villus tissue at weeks 11-14 of pregnancy. In some countries, in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD) has gradually become the procedure of choice for HA carriers who wish to prevent further transmission of HA without the need to undergo termination of pregnancies diagnosed with affected fetuses. In rare cases, genetic analysis of a HA carrier might be complicated by skewed X chromosome inactivation (XCI) of her non-hemophilic X chromosome, thus leading to the phenotypic manifestation of moderate to severe HA. Such skewed XCI may be associated with deleterious mutations in X-linked genes located on the non-hemophilic X chromosome, which should be considered in the process of genetic counseling and PGD planning for the symptomatic HA carrier. Therefore, whole exome sequencing, combined with X-chromosome targeted bioinformatic analysis, is highly recommended for symptomatic HA carriers diagnosed with skewed XCI in order to identify additional deleterious mutations potentially involved in XCI skewing. Identification of such mutations, which may profoundly impact the reproductive choices of HA carriers with skewed XCI, is extremely important.

Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease.

High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous HTRA1 variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous HTRA1 variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous HTRA1 gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous HTRA1 gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic HTRA1 variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, HTRA1 gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous HTRA1 gene variants were mostly missense variants. The two variant sites, 166-182 aa and 274-302 aa, were the most concentrated. Clinicians need to pay attention to de novo data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis.

Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations.

Hereditary transthyretin cardiac amyloidosis (hATTR-CA) is a rare autosomal dominantly inherited disease caused by mutations in the transthyretin (TTR) gene. TTR mutations often cause the instability of transthyretin, production of misfolded proteins, and ultimately excessive deposition of insoluble amyloid fibrils in the myocardium, thereby leading to cardiac dysfunction. Herein, we report a novel transthyretin D39Y mutation in a Chinese family. We characterized the kinetic and thermodynamic stabilities of D39Y mutant TTR, revealing that TTR D39Y mutant was less stable than WT TTR and more stable than amyloidogenic mutation TTR L55P. Meanwhile, the only FDA approved drug Tafamidis showed satisfactory inhibitory effect toward ATTR amyloid formation and strong binding affinity in test tube revealed by isothermal titration calorimetry. Finally, we measured the well-folded tetrameric TTR concentration in patient's and his descents' blood serum using a previously reported UPLC-based assay. Notably, the tetramer concentrations gradually increased from symptomatic D39Y gene carrier father, to asymptomatic D39Y gene carrier daughter, and further to wild type daughter, suggesting the decrease in functional tetrameric TTR concentration may serve as an indicator for disease age of onset in D39Y gene carriers. The study described a Chinese family with hATTR-CA due to the TTR variant D39Y with its destabilizing effect in both kinetic and thermodynamic stabilities.

Novel ABCD1 mutation detected in a symptomatic female carrier of adrenoleukodystrophy

AbstractWe report a case of a symptomatic female carrier of X‐linked adrenoleukodystrophy (ALD) with a novel ABCD1 gene mutation. She has developed slowly progressive gait disturbance since age 40, and her father and sister had similar symptoms. When admitted to our hospital at age 66, blood analysis showed slight increase of very long‐chain fatty acids (VLCFA), and DNA analysis of ABCD1 gene revealed a novel heterozygous missense mutation (c.1700 A>C, p.Gln567Pro). The genetic testing for ABCD1 gene can be considered in female patients over middle age presenting spastic gait, because female ALD carriers tend to be symptomatic beyond age 60.

P.15 Symptomatic DMD carrier as a differential diagnosis in patients presenting asymmetrical limb weakness

Duchenne/Becker muscular dystrophy (DMD) is one of the most common myopathies, characterized by an X-linked recessive disease. Asymmetrical limb weakness is rarely present in patients with muscle diseases such as ANO5-related myopathy, facioscapulohumeral muscular dystrophy, and sporadic inclusion body myositis. We report two cases of symptomatic DMD carriers presenting with asymmetrical limb weakness. A 50-year-old woman visited the department of neurology presenting with slowly progressive weakness of the limbs since childhood. A neurological examination revealed a weakness of the right arm and both legs, which were graded 4 as MRC system. Muscle MRI showed asymmetric fatty infiltration of the limbs, markedly affected by right biceps brachii, latissimus dorsi, and gastrocnemius. Immunohistochemistry (IHC) of the C-terminal region of the dystrophin gene presented several scattered stain-negative fibers. Genetic analysis revealed c.6703delG (p.Ser2235Ilefs*12, NM_004006.2) mimicking single exon 46 deletion in MLPA. A 29-year-old female presented with an elevated level of serum creatine kinase without subjective weakness. Neurologic examination showed the subtle motor weakness of the right arm, graded 4+. Muscle MRI revealed high T1 signal change on the right biceps femoris, which was not affected clinically, in addition to right biceps brachii and latissimus dorsi. IHC showed dystrophic changes and a mosaic pattern of dystrophin expression. The diagnosis was confirmed by MLPA, revealing heterozygous deletion of exon 44 in the DMD gene. Asymmetrical limb weakness can be a remark for the diagnosis of symptomatic DMD carrier. Furthermore, muscle MRI is more sensitive in detecting pathologic changes than routine neurologic examination. And single-base point mutation can mimick the exon deletion in MLPA, which needs sequencing analysis in a case of single exon deletion in DMD. Therefore, a multidisciplinary approach is mandatory for final diagnosis and a better understanding of symptomatic DMD carriers.

VP.25 Muscle MRI in female carriers of Duchenne muscular dystrophy

Muscle magnetic resonance imaging (mMRI) has been proved to be a reliable biomarker of disease severity and progression in patients with Duchenne and Becker muscular dystrophy (DMD/BMD). Although up to 20% of female carriers of DMD/BMD experienced symptoms, there is a paucity of data on mMRI in this patient group. Here, we report a case of a female DMD carrier who had mild clinical symptoms, yet mMRI revealed striking fatty infiltration. A 58-year-old female DMD carrier initially presented in 2020 with a 3-year history of slowly progressive symmetric pelvic girdle weakness since age 53. She was known to be a female DMD carrier at age 26 by linkage analysis, when her brother lost ambulation at age 10 and deceased at age 21 due to cardiopulmonary dysfunction. Subsequently, genetic testing of this patient and her mother both demonstrated deletion of exons 51-55 of the dystrophin gene. X inactivation study was not informative as the patient is homozygous for the polymorphic androgen receptor gene locus analyzed. On exam, the patient has normal muscle strength and a normal walking gait, but slight stepping to ascend steps, jump and hop. Brooke scale and functional Mobility Score were 1. Timed function test remained relatively stable over a time span of 22 months. mMRI of her pelvic and thigh muscles was performed to evaluate the progression of a dystrophic process. There was no significant edema in the musculature of the pelvis and thighs. However, there was striking fatty infiltration in multiple muscle groups, including glutei, adductors, hamstrings, as well as vastus lateralis and intermedius. This case of symptomatic female carrier suggests a possible clinical-radiological mismatch phenomenon in manifesting female carriers of DMD. Further study is indicated to understand the clinical implications of this observation.

Clinical observation of a patient a symptomatic carrier of the hemophilia A

Clinical observation of a patient a symptomatic carrier of the hemophilia A

An inherited sudden cardiac arrest syndrome may be based on primary myocardial and autonomic nervous system abnormalities.

A recently discovered sudden cardiac arrest (SCA) syndrome is linked to a risk haplotype that harbors the dipeptidyl-peptidase 6 (DPP6) gene as a plausible culprit. Because DPP6 impacts both cardiomyocyte and neuronal function, we hypothesized that ventricular fibrillation (VF) in risk haplotype carriers arises from functional changes in both the heart and autonomic nervous system. We studied 6 risk haplotype carriers with previous VF (symptomatic), 8 carriers without VF (asymptomatic), and 7 noncarriers (controls). We analyzed supine and standing heart rate variability, baroreflex sensitivity, pre-VF heart rate changes, and myocardial 123I-meta-iodobenzylguanide (123I-mIBG) scintigraphy. Carriers had longer interbeat intervals than controls (1.03 ± 0.11 seconds vs 0.81 ± 0.07 seconds; P <.001), lower low-frequency (LF) and higher high-frequency (HF) activity, and lower LF/HF ratio (0.68 ± 0.50 vs 2.11 ± 1.10; P = .013) in the supine position. Upon standing up, carriers had significantly larger decrease in interbeat interval and increase in LF than controls (standing-to-supine ratio: 0.78 ± 0.07 vs 0.90 ± 0.07; P = .002; and 1.94 ± 1.03 vs 1.17 ± 0.34; P = .022, respectively), and nonsignificantly larger decrease in HF (0.62 ± 0.36 vs 0.97 ± 0.42; P = .065) and increase in LF/HF ratio (5.55 ± 6.79 vs 1.62± 1.24; P = .054). Sixteen of 17 VF episodes occurred at rest. Heart rate immediately before VF was 110 ± 25 bpm. Symptomatic carriers had less heterogeneous 123I-mIBG distribution in the left ventricle than asymptomatic carriers (single-photon emission computed tomography score ≥3 in 7 asymptomatic and 1 symptomatic carrier; P = .008). It can be speculated that these data are consistent with more labile autonomic tone in carriers, suggesting that the primary abnormalities may reside in both the heart and the autonomic nervous system.

Can symptomatic nmDuchenne carriers benefit from treatment with ataluren? Results of 193-month follow-up.

Duchenne’s muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by deletions (75%), duplications (15-20%) and point mutations (5-10%) in the dystrophin gene. Among the latter, stop-codon point mutations are rare. Female carriers of dystrophin gene mutations are usually asymptomatic as they are “protected” by the second X-chromosome, which produces a normal dystrophin protein. However, about 8-10% of them can present symptoms that set the clinical picture of the manifesting or symptomatic carrier. Although no causative cure there is for DMD, therapies are available to slow the decline of muscle weakness and delay the onset of heart and respiratory involvement. However, there is limited data in the literature documenting the treatment of symptomatic carriers, often entrusted to the sensitivity of individual doctors. In this paper, we report the follow-up outcomes of four European symptomatic nmDMD carriers treated with ataluren, overall followed for 193 months. Annual assessment of muscle strength, pulmonary lung function tests, and echocardiography, indicate a mild attenuation of disease progression under treatment.. There were no adverse clinical effects or relevant abnormalities in routine laboratory tests. We can conclude that ataluren appears to stabilize, if not slightly improve, the clinical course of patients with a good safety profile, especially if we consider that the treatment was late for 3/4 patients, at a mean age of 36.6 ± 10.6 years.

M169 STAT-3 DEFICIENT CHILD FOUND TO BE SYMPTOMATIC CARRIER OF CYSTIC FIBROSIS

Although unlikely, the presence of one immune deficiency does not exclude another. We present a child with STAT-3 deficiency and Hyper IgE Syndrome (HIES) who developed pseudomonas pneumonia and was also found to be a symptomatic carrier for cystic fibrosis (CF).

MiRNome profiling in Duchenne muscular dystrophy; identification of asymptomatic and manifesting female carriers.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder that occurs due to inactivating mutations in DMD gene, leading to muscular dystrophy. Prediction of pathological complications of DMD and the identification of female carriers are important research points that aim to reduce disease burden. Herein, we describe a case of a late DMD patient and his immediate female family members, who all carry same DMD mutation and exhibited varied degrees of symptoms. In our study, we sequenced the whole miRNome in leukocytes and plasma of the family members and results were validated using real-time PCR. Our results highlighted the role of miR-409-3p, miR-424-5p, miR-144-3p as microRNAs that show correlation with the extent of severity of muscular weakness and can be used for detection of asymptomatic carriers. Cellular and circulating levels of miR-494-3p had shown significant increase in symptomatic carriers, which may indicate significant roles played by this miRNA in the onset of muscular weakness. Interestingly, circulating levels of miR-206 and miR-410-3p were significantly increased only in the severely symptomatic carrier. In conclusion, our study highlighted several miRNA species, which could be used in predicting the onset of muscle and/or neurological complications in DMD carriers.

18F]Flortaucipir PET Across Various MAPT Mutations in Presymptomatic and Symptomatic Carriers.

ObjectiveTo assess the [18F]flortaucipir binding distribution across MAPT mutations in presymptomatic and symptomatic carriers.MethodsWe compared regional [18F]flortaucipir binding potential (BPND) derived from a 130-minute dynamic [18F]flortaucipir PET scan in 9 (pre)symptomatic MAPT mutation carriers (4 with P301L [1 symptomatic], 2 with R406W [1 symptomatic], 1 presymptomatic L315R, 1 presymptomatic S320F, and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 patients with Alzheimer disease.Results[18F]Flortaucipir BPND images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal, and frontal lobe. Elevated medial temporal lobe BPND was observed in a presymptomatic R406W carrier. The single symptomatic carrier and 1 of the 3 presymptomatic P301L carriers showed elevated [18F]flortaucipir BPND in the insula, parietal, and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BPND, with at neuropathologic examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BPND compared to controls. The BPND values of the S320F presymptomatic mutation carrier fell within the range of controls.ConclusionPresymptomatic MAPT mutation carriers already showed subtle elevated tau binding, whereas symptomatic MAPT mutation carriers showed a more marked increase in [18F]flortaucipir BPND. Tau deposition was most pronounced in R406W MAPT (pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus, [18F]flortaucipir may serve as an early biomarker for MAPT mutation carriers in mutations that cause 3R/4R tauopathies.

Pathologically and Genetically Diagnosed Subclinical Symptomatic Duchenne Muscular Dystrophy Carrier: Broadened Spectrum of Clinical Phenotype

A 29-year-old female presented with an elevated level of serum creatine kinase without subjective weakness. Neurologic examination showed the subtle motor weakness of the right arm. Muscle biopsy showed dystrophic changes and a mosaic pattern of dystrophin expression. The diagnosis was confirmed by multiplex ligation-dependent probe amplification and whole-exome sequencing, revealing heterozygous deletion of exon 44 in the DMD gene. Here, we introduce a subclinical symptomatic Duchenne muscular dystrophy carrier, which broadens the clinical spectrum of phenotype.

Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study.

IntroductionWe aimed to assess episodic memory in genetic frontotemporal dementia (FTD) with the Free and Cued Selective Reminding Test (FCSRT).MethodsThe FCSRT was administered in 417 presymptomatic and symptomatic mutation carriers (181 chromosome 9 open reading frame 72 [C9orf72], 163 progranulin [GRN], and 73 microtubule‐associated protein tau [MAPT]) and 290 controls. Group differences and correlations with other neuropsychological tests were examined. We performed voxel‐based morphometry to investigate the underlying neural substrates of the FCSRT.ResultsAll symptomatic mutation carrier groups and presymptomatic MAPT mutation carriers performed significantly worse on all FCSRT scores compared to controls. In the presymptomatic C9orf72 group, deficits were found on all scores except for the delayed total recall task, while no deficits were found in presymptomatic GRN mutation carriers. Performance on the FCSRT correlated with executive function, particularly in C9orf72 mutation carriers, but also with memory and naming tasks in the MAPT group. FCSRT performance also correlated with gray matter volumes of frontal, temporal, and subcortical regions in C9orf72 and GRN, but mainly temporal areas in MAPT mutation carriers.DiscussionThe FCSRT detects presymptomatic deficits in C9orf72‐ and MAPT‐associated FTD and provides important insight into the underlying cause of memory impairment in different forms of FTD.

The Free Cued Selective Reminding Test detects episodic memory impairment in the presymptomatic period of familial frontotemporal dementia within the GENFI cohort

AbstractBackgroundEpisodic memory is increasingly reported in frontotemporal dementia (FTD) and it has been suggested to differ between genetic forms of FTD. However, systematic investigations of episodic memory in familial FTD, and specifically the presymptomatic stage, are scarce. This cross‐sectional study investigates performance on the Free Cued and Selective Reminding Test (FCSRT) in the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort.Method685 participants were tested with the FCSRT (52 presymptomatic and 21 symptomatic MAPT, 135 presymptomatic and 42 symptomatic GRN, 109 presymptomatic and 63 symptomatic C9orf72 mutation carriers and 263 non‐carriers). The presymptomatic mutation carriers were split into an early and late presymptomatic period (more than or within ten years of expected symptom onset). Groups were compared using linear regression models, adjusted for age and education, with bootstrapping.ResultPerformance on all FCSRT test scores had a negative correlation with age (0.18 &gt; r &lt; 0.38) and immediate free recall (r = 0.21), immediate total recall (r = 0.14) and delayed free recall (r = 0.24) had a positive correlation with education. All symptomatic mutation carrier groups scored significantly lower than controls on immediate free recall (MAPT: −2.54 ± 1.52; GRN: −3.15 ± 2.13; C9orf72: −2.67 ± 1.32), immediate total recall (MAPT: −4.83 ± 4.42; GRN: −6.65 ± 5.69; C9orf72: −3.63 ± 3.99), delayed free recall (MAPT: −2.66 ± 1.98; GRN: −3.08 ± 2.17; C9orf72: −2.64 ± 1.41) and delayed total recall (MAPT: −4.32 ± 4.49; GRN: −6.48 ± 6.63; C9orf72: −4.32 ± 4.49). In the presymptomatic group, C9orf72 participants performed significantly lower on immediate (late: −0.75 ± 0.93) and delayed free recall (early: −0.11 ± 1.12; late: −0.57 ± 1.14) measures.ConclusionEpisodic memory is impaired in genetic FTD, with decline already starting in the presymptomatic period in C9orf72 mutation carriers. The differences between mutation carriers groups in free versus cued recall formats corroborates the notion that the clinical presentation of episodic memory deficits (i.e. as a result of executive impairment versus “true” consolidation problems) in FTD depend on the underlying mutation, and thus atrophy pattern. Our next step is to replicate results in a larger dataset and correlate performance on the FCSRT to grey matter density in each genetic group using voxel‐based morphometry.

S0211 Emerging Evidence for Frequent Occurrence of Clostridioides difficile-Associated Diarrhea in Untreated Symptomatic Clostridioides difficile Carriers

INTRODUCTION: Currently, the diagnosis of Clostridioides difficile infection (CDI) is based on stool testing for the detection of C.diff glutamate dehydrogenase antigen (Ag), C.diff toxin (A or B), and toxin gene sequences (PCR, Amplified test). The sensitivity and specificity of these tests ranges between 90% and 99%. The results are interpreted as Ag (+/-) Toxin (+/-) and Amplified (+/-). Based on these results, the patients are classified as having C.diff infection, C.diff carriers or C.diff negative. The subset of patients who are Ag(+)Toxin(-) and Amplified (-) are classified as C.diff carriers. To date, there are no guidelines for management of symptomatic C.diff carriers, nor is there a longitudinal follow up of these patients in the literature. METHODS: A retrospective study was conducted for all the patients who were admitted for or developed diarrhea and who tested positive for C.diff Antigen (n = 86) between July, 2017 and June, 2018. RESULTS: Of the 86 patients, 29 were Ag(+) Toxin(+) and 35 were Ag(+) Toxin(-) Amplified(+), these group of patients were identified as having CDI and were treated. However, a subset of patients (n = 22) who were Ag(+) Toxin(-) Amplified(-) who were symptomatic, were classified as Symptomatic C.diff carriers (Table 1). The mean age of this subgroup was 59.3 years(+/- 24.2 years, SD) and it consisted of 10 males and 12 females. It is noteworthy, that 19 out of these 22 symptomatic carriers were not given any antibiotic treatment. A longitudinal follow up of this group of patients, for a period of 6-12 months revealed that 6 out of these 22 C.diff carriers went on to develop CDI and requiring multiple admissions (1–3) to the hospital.Table 1CONCLUSION: As many as 22 out of 86 patients were identified as symptomatic C.diff carriers, and the majority of these patients (86.3%) went untreated. The prevalence of the symptomatic carrier is quite significant (25.6%) in our study population. Of the untreated symptomatic C.diff carriers, six patients (27.3%) developed subsequent CDI and required readmissions to the hospital (1–3) within 6–12 months. The cost of a single hospitalization due to a single incidence of CDI is roughly $43,000. These data suggest that symptomatic C.diff carriers should be treated with antibiotics to prevent CDI and readmission to the hospital. Additional prospective clinical studies on larger group of patients with longitudinal follow up are needed for optimum guidelines for the management of this group of patients.

DMD – BIOMARKERS & OUTCOME MEASURES: P.132 Symptomatic female carrier of Duchenne muscular dystrophy with a novel single-base deletion mutation mimicking exon deletion in MLPA

Duchenne/Becker muscular dystrophy (DMD/BMD) is one of the most common muscle disorders characterized by an X-linked recessive inheritance pattern affecting male patients traditionally. Most DMD/BMD carriers remain asymptomatic, while only 2.5–10% of carriers are symptomatic and classified as symptomatic carriers. A 50-year-old female patient visited the neurological outpatient clinic complaining of progressive weakness of the lower legs since childhood. She also complained of frequent falls while walking and presented with an enlarged calf and Gowers' sign.