Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. In most cases, it is due to an expansion of the CGG triplet to more than 200 repeats within the promoter region of the FMR1 gene. In the premutation (PM) the trinucleotide is expanded to 55-200 repeats. PM carriers can present with disorders associated with the PM including fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated ovarian insufficiency (FXPOI). Recently fragile X-associated neuropsychiatric disorders (FXAND) was proposed as an umbrella term to include the neuropsychiatric disorders that are more prevalent in PM carriers compared to the general population such as anxiety, depression, chronic fatigue, alcohol abuse, and psychosis, among others. The patient in our study was evaluated by a team of clinicians from the University del Valle in Cali who traveled to Ricaurte, a Colombian town known for being a genetic geographic cluster of FXS. A detailed medical history was collected and complete physical, neurological and psychiatric evaluations were performed in addition to molecular and neuroradiological studies. We report the case of a 78-year-old man, PM carrier, without FXTAS whose main clinical presentation consists of behavioral changes and psychosis. Brain imaging revealed white matter lesions in the periventricular region and mild cerebral atrophy. Although anxiety and depression are the most common neuropsychiatric manifestations in PM carriers, it is important to perform a complete psychiatric evaluation since some patients may present with behavioral changes and psychosis.
Dystroglycan (DG) is a major cell membrane glycoprotein, which is encoded by the DAG1 gene. α-DG is one of DG subunits, belongs to O-mannosylated protein of mammals and was identified in brain, peripheral nerves and muscle. Dystroglycanopathies are a group of heterogeneous congenital muscular dystrophies, which can result from defective α-DG mannosylation. First line of α-DG glycosylation is catalyzed by protein O-mannosyltransferase family (PMT). In this study, the mutation was identified in the POMT2 gene, which encodes O-mannosyltransferase 2 protein and its mutations can be contributed to dystroglycanopathies. A very rare missense mutation in the POMT2 gene (NM_013382: exon9: c. 1106G>A) was identified by next generation sequencing (NGS) and was subsequently confirmed using Sanger sequencing in both affected siblings. There was no report of this mutation in the literature, therefore, the significance was uncertain. Our findings confirmed the pathogenicity of mutation and expanded the mutation spectrum of POMT2, which will be helpful in further molecular evaluations of muscular diseases.
Cystine stones are relatively uncommon compared with other stone compositions, constituting just 1% to 2% of adult urinary tract stone diseases, and accounting for up to 10% of pediatric stone diseases. Two responsible genes of cystinuria have been identified, the SLC3A1 and the SLC7A9. Cystinuria is diagnosed by family history, stone analysis, or by measurement of urine cystine excretion. Current treatments for cystinuria include increased fluid intake to increase cystine solubility by maintaining daily urine volume of greater than 3 Liter (L). Limiting sodium and protein intake can decrease cystine excretion. When conservative therapy fails, then pharmacologic therapy may be effective. Alkaline urine pH in the 7.0-7.5 range will reduce cystine solubility and can be achieved by the addition of alkali therapy. If these measures fail, cystine-binding thiol drugs such as tiopronin and D-penicillamine are considered. These compounds bind cysteine and prevent the formation of less soluble cystine. These drugs, however, have poor patient compliance due to adverse effects. Captopril can be useful in the treatment of cystine stones but the drug has not been tested in rigorous clinical trials. Novel potential therapies such as alpha-lipoic acid and crystal growth inhibitors (L-cystine dimethyl ester (L-CDME) and L-cystine methyl ester (L-CME)) were developed and tested in animals. Those therapies showed promising results. Compliance with treatment was associated with a lower rate of cystine stone formation.
Antinuclear antibodies (ANA) and extractable nuclear antigens (ENA) are instrumental biomarkers crucial in the detection of autoimmune disorders (AID) such as systemic lupus erythematosus (SLE), Sjogren syndrome, etc.. In the present study, an assessment of the most frequent ANA patterns associated with most detectable ENA that could be used as efficient prognostic markers in the diagnosis of autoimmune diseases was conducted. Data was retrospectively analyzed from AID patients, retrieved from the medical records of King Fahad Medical City, Riyadh, KSA, from January 2016 to October 2018 who underwent ANA immunofluorescence of HEp-2 cells and their ENA detection was studied. Of the 453 total patients, 39/55 AID males (71%) and 332/398 AID females (83.4%) exhibited ANA positivity. The most common pattern was speckled S-ANA (32.4%) in females and homogenous H-ANA pattern (25.4%) in males. The histones were found at higher frequency in different ANA patterns. anti-Sjogren syndrome related antigen A (SSA), anti-ribonucleoprotein antibody (RNP-Sm), and histones were observed to be associated with homogenous and speckled nuclear patterns. Frequencies of ENA in all ANA patterns were found significant at p < 0.05 in males and p < 0.001 in females. Spearman's rank correlation of ENA within and among the ANA patterns was non-significant. SSA was significantly correlated with RNP-Sm and Sm at p < 0.05 and p < 0.01, respectively. The extractable nuclear antigens SSA, RNP-Sm, and histones were found associated with the S-ANA and H-ANA patterns. These correlations are of relevance for the accurate diagnosis of autoimmune diseases.
Matching is a common method of adjusting for confounding in observational studies. Studies in rare diseases usually include small numbers of exposed subjects, but the performance of matching methods in such cases has not been evaluated thoroughly. In this study, we compare the performance of several matching methods when number of exposed subjects is small. We used Monte Carlo simulations to compare the following methods: Propensity score matching (PSM) with greedy or optimal algorithm, Mahalanobis distance matching, and mixture of PSM and exact matching. We performed the comparisons in datasets with six continuous and six binary variables, with varying effect size on group assignment and outcome. In each case, there were 1,500 unexposed subjects and a varying number of exposed: N = 25, 50, 100, 150, 200, 250, or 300. The probability of outcome in unexposed subjects was set to 5% (rare), 20% (common), or 50% (frequent). We compared the methods based on the bias of estimate of risk difference, coverage of 95% confidence intervals for risk difference, and balance of covariates. We observed a difference in performance of matching methods in very small samples (N = 25-50) and in moderately small samples (N = 100-300). Our study showed that PSM performs better than other matching methods when number of exposed subjects is small, but the matching algorithm and the matching ratio should be considered carefully. We recommend using PSM with optimal algorithm and one-to-five matching ratio in very small samples, and PSM matching with any algorithm and one-to-one matching in moderately small samples.
Immunodeficiency 10 is an autosomal recessive disorder presenting with iris hypoplasia, muscular hypotonia and nonprogressive myopathy, recurrent bacterial infections, autoimmune hemolytic anemia, hypohidrosis and nail dysplasia caused by the mutation of stromal interaction molecule 1 gene (STIM1). Herein, we present a new case of STIM1 mediated immunodeficiency, carrying a novel frameshift mutation. Our patient presented with nephrotic syndrome, hypotonia, myopathy, recurrent bacterial infections, thrombocytopenia and autoimmune hemolytic anemia. She is now 23 months old and is on steroid, cyclosporine and monthly IVIG. She has had no recent significant infections and is receiving rehabilitation therapy to improve her motor skills. Rare genetic syndromes should be suspected in patients of consanguineous parents, who present with a set of different manifestations. Gathering all the patient's manifestations together and looking them as one disease should be encouraged.
A prenatal sonograph revealed a 26-week-old fetus with short limbs and a narrow chest in a 23-year-old woman with a history of fetal skeletal dysplasia. A single nucleotide polymorphism-based chromosomal microarray (CMA) indicated a normal karyotype, and no chromosomal segments with abnormal copy numbers were noted in the fetus. Whole exome sequencing identified compound heterozygous mutations in the DYNC2H1 gene responsible for a lethal type of bone growth disorder, short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3), and revealed a missense mutation c.515C>A (p. Pro172Gln) of paternal origin and a missense mutation c.5983G>A (p. Ala1995Thr) of maternal origin. These variants were further confirmed by Sanger sequencing. To the extent known, the c.515C>A (p. Pro172Gln) mutation is novel for SRTD3, and the site is conserved across species. This study found a novel mutation of the DYNC2H1 gene for SRTD3 and it has increased the number of reported cases and expanded the spectrum of mutations causing this rare disease.
Paroxysmal sympathetic hyperactivity (PSH) is a clinical condition characterized by abnormal paroxysmal surges in sympathetic nervous system activity. PSH is known to occur after severe head injury and hypoxic encephalopathy. Cases of PSH that develop after stroke have been reported worldwide; however, PSH is not commonly reported in the field of stroke research in Japan. Some studies have suggested that gabapentin may improve the symptoms of PSH. To our knowledge, this is the first case report demonstrating the efficacy of trazodone for the treatment of PSH that developed after temporal subcortical hemorrhage. A 49-year-old woman presented to our clinic with mild confusion and sensory aphasia after experiencing left temporal subcortical hemorrhage; a conservative treatment was initiated at our hospital. Immediately upon hospitalization, she developed prolonged consciousness disorder, high fever, tachycardia, malignant hypertension, tachypnea, constipation, and overactive bladder. The patient's symptoms improved after the administration of trazodone. She was diagnosed with PSH after intracranial hemorrhage and was subsequently transferred to a recovery and rehabilitation hospital unit where the oral administration of trazodone continued. Prolonged PSH contributes significantly to the impairment of daily activities in patients with stroke; therefore, early diagnosis and treatment are critical. Here, we report on the efficacy of trazodone as an effective treatment option for improving clinical outcomes and reducing the stay in the stroke care unit.
Takotsubo syndrome (TTS) is often preceded by emotional or physical stress. Epileptic seizures have been described in more than 100 TTS cases. Due to the lack of typical symptoms, seizure-induced TTS can be overlooked. Here, we describe a rare case where TTS induced by non-convulsive status epilepticus (NCSE) was diagnosed early and successfully treated. An 82-year-old man presented to our hospital with confusion, anorexia, aphagia, and abnormal behavior beginning a few days earlier. Head computed tomography and magnetic resonance imaging did not show any structural abnormalities. Upon hospitalization, blood sampling revealed elevated levels of myocardial escape enzymes; however, cardiac ultrasonography showed apical asystole, and emergency coronary angiography did not show any significant stenosis or occlusion. The patient's symptoms improved after the administration of antiepileptic drugs consisting of diazepam, fosphenytoin, and levetiracetam. On day 2 of hospitalization, an electroencephalogram showed high amplitude slow waves in the left cerebral hemisphere and NCSE-induced TTS was diagnosed. The patient was discharged after 2 weeks with a modified Rankin Scale score of 0 and continuing oral administration of levetiracetam. Delay in the diagnosis of NCSE-induced TTS can lead to a poor prognosis. Early diagnosis and treatment for NCSE and NCSE-induced TTS may result in favorable outcomes for the patient.
Sugars including lactose and fructose, or proteins (gluten), or biogenic amines (histamine), and combinations thereof may cause food intolerance/malabsorption. However, in usually asymptomatic patients with rare diseases, who present with functional, non-specific, non-allergic gastrointestinal (GI) complaints the etiologic factors of food intolerance/malabsorption need to be evaluated. We summarize patients with rare diseases, such as primary epiploic appendagitis, beta-thalassemias minor, Gullo syndrome and anomaly of the inferior vena cava, who presented functional, non-specific, non-allergic GI complaints. As conclusion, these GI symptoms in patients with otherwise asymptomatic, rare diseases were due to fructose malabsorption, histamine-, lactose intolerance and Helicobacter pylori (H.p.) infection. A registered and experienced dietician was employed to design an individually-tailored diet which ensured effective treatments and H.p. infection was accordingly eradicated.
Primary central nervous system lymphoma (PCNSL) is a rare malignant tumor of the central nervous system. It is associated with poor prognosis. Early diagnosis and subsequent planning of adequate treatment strategy are relevant to improve survival and reduce neurological deficit. Specifically, there are no reports of successful endoscopic biopsy for PCNSL of the corpus callosum in the splenium with bilateral visuomotor ataxia. An 74-year-old woman presented to our hospital with anorexia, depression and ataxia beginning six months earlier. Head computed tomography and magnetic resonance imaging showed malignant tumor suspected in the corpus callosum. Endoscopic biopsy was performed via the low parieatal approach, suspecting GBM or PCNSL. She had no new postoperative neurological deficits and was pathologically diagnosed with diffuse large B-cell lymphoma (DLBCL). She is currently undergoing radiation chemotherapy with a modified Rankin Scale score of 2. Regarding preoperative symptoms, ataxia was considered to be bilateral visuomotor ataxia caused by damage to the corpus callosum in the splenium, and anorexia and depression were considered symptoms of the surrounding limbic system. Delay in the diagnosis of PCNSL can lead to a poor prognosis. Visuomotor ataxia should also consider the potential for the corpus callosum in the splenium lesion, including PCNSL, and appropriate imaging and pathological diagnosis with endoscopic biopsy can contribute to a good clinical outcome.
Systemic sclerosis (SSc) is a kind of collagen disease and has an acquired autoimmune activation as represented by the production of autoantibodies. CD27 is a type I glycoprotein and a member of the tumor necrosis factor receptor family. It binds to the CD70 ligand, CD27-CD70 signaling is implicated in the development of various autoimmune diseases, but its role in the regulation of extracellular matrix expression and its contribution to the phenotype of SSc both remain to be elucidated. This study aimed to investigate the associations between CD27 and SSc in the skins and sera. Immunohistochemistry were performed to determine the expression of CD27 in the skin. Enzyme-linked immunosorbent assays were done to the sera of the 54 patients with SSc and 23 normal healthy controls. CD27 expression was significantly increased in the affected regions of the skin and the sera of patients of SSc. Thereafter, we evaluated the correlation between the serum soluble CD27 (sCD27) levels and the clinical symptoms. The study subjects with increased sCD27 levels had a significantly higher ratio of dcSSc and to showed higher modified Rodnan's total skin thickness scores (mRSS) than those with normal sCD27 levels. These results suggest that sCD27 levels might be useful for diagnosis of SSc and its severity.
Extrahepatic portosystemic shunt belongs to a family of rare vascular abnormalities. The clinical importance and manifestations of this vascular abnormality range from asymptomatic cases to liver or metabolic dysfunctions of various degrees. Congenital extrahepatic portosystemic shunt, also termed as Abernethy malformation, is a very rare congenital vascular malformation in which splenomesenteric blood drains into a systemic vein, bypassing the liver through a complete or partial extrahepatic shunt. So far, limited cases of congenital extrahepatic portosystemic shunt have been reported. In this review, incidence, mechanisms, complications, diagnoses and treatments of congenital extrahepatic portosystemic shunt are described.