Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

Download Full-text

Complications and Sequelae in Patients With Congenital Microcephaly Associated With Zika Virus Infection: Two-Year Follow-Up

Journal of Child Neurology ◽

10.1177/0883073820983163 ◽

2021 ◽

pp. 088307382098316

Author(s):

Luane A. Gouvea ◽

Marlos Martins ◽

Daniela Vivacqua ◽

Julia Rosseto ◽

Giulia Lima ◽

...

Keyword(s):

Developmental Delay ◽

Zika Virus ◽

Median Number ◽

Global Developmental Delay ◽

Spastic Diplegia ◽

Long Term Follow Up ◽

Congenital Microcephaly ◽

Auditory Impairment ◽

Worse Prognosis

Background: We aim to describe the long term follow-up of a cohort of children exposed in utero to the Zika virus. Methods: Descriptive study of a cohort of microcephalic children due to Zika virus. Logistic regression was used to evaluate variables associated with worse prognosis epilepsy. Results: We followed 28 children (15 females), with a median follow-up of 24 months (IQR = 12-28). During the follow-up, 1 infant died. The median head circumference at birth was 29 cm (IQR = 27-31). All presented a global developmental delay. The most frequent central nervous system abnormalities were on cortical development in 22 participants; dysgenesis of corpus callosum in 13; ventriculomegaly in 25; and calcifications in 24. A total of 9 presented ocular abnormalities, 4 auditory impairment. During follow-up, 12 presented with sleep disorders, 10 with irritability, and 23 with epilepsy (2 with generalized tonic-clonic, 3 with generalized tonic-clonic and spasms, 12 with spasms, 3 tonic and spasms, and 3 motor focal and spasms). The median age at the begin of the epilepsy was 4 months (IQR = 2-10), the median number of drugs used to control the epilepsy was 2 (IQR = 2-3). Maternal illicit drug use during pregnancy was associated with worse prognosis epilepsy (Lennox-Gastaut syndrome, West syndrome, or status epilepticus). A total of 19 presented with dysphagia, 10 children required gastrostomy. Conclusion: Children with microcephaly due to Zika virus presented with several complications during follow-up, as epilepsy, spastic diplegia, and global developmental delay.

Download Full-text

DNM1 encephalopathy

Neurology ◽

10.1212/wnl.0000000000004152 ◽

2017 ◽

Vol 89 (4) ◽

pp. 385-394 ◽

Cited By ~ 31

Author(s):

Sarah von Spiczak ◽

Katherine L. Helbig ◽

Deepali N. Shinde ◽

Robert Huether ◽

Manuela Pendziwiat ◽

...

Keyword(s):

Functional Data ◽

De Novo ◽

Structural Modeling ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Global Developmental Delay ◽

Epilepsy Syndrome ◽

De Novo Mutations ◽

Phenotypic Data ◽

Phenotypic Spectrum

Objective:To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.Methods:We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.Results:We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.Conclusions:The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.

Download Full-text

Phenotypes in Children With SYNGAP1 Encephalopathy in China

Frontiers in Neuroscience ◽

10.3389/fnins.2021.761473 ◽

2021 ◽

Vol 15 ◽

Author(s):

Huiting Zhang ◽

Liu Yang ◽

Jing Duan ◽

Qi Zeng ◽

Li Chen ◽

...

Keyword(s):

Developmental Delay ◽

Behavioral Problems ◽

Disease Onset ◽

Gene Mutations ◽

Global Developmental Delay ◽

Clinical Trial Registry ◽

Neurodevelopmental Delay ◽

Epileptic Spasms ◽

Registration Number ◽

Drug Resistant Epilepsy

Objective: We aimed to explore the associated clinical phenotype and the natural history of patients with SYNGAP1 gene variations during early childhood and to identify their genotype–phenotype correlations.Methods: This study used a cohort of 13 patients with epilepsy and developmental disorder due to SYNGAP1 mutations, namely, 7 patients from Shenzhen Children’s Hospital between September 2014 and January 2020 and 6 patients from previously published studies. Their clinical data were studied.Results: A total of 13 children with SYNGAP1 gene variants (eight boys and five girls) were identified. The age of disease onset was in infancy. Mutations were located between exons 8 and 15; most were frameshift or truncated mutations. Four mutation sites (c.924G > A, c.1532-2_1532del, c.1747_1755dup, and c.1735_1738del) had not been reported before. All patients had global developmental delay within the first year of life, and intellectual impairment became gradually apparent. Some of them developed behavioral problems. The developmental delay occurred before the onset of seizures. All seven patients in our cohort presented with epilepsy; myoclonic seizures, absence seizures, and epileptic spasms were the most common seizure types. Abnormal electroencephalograms were identified from five patients before the onset of their seizures. All patients suffered from drug-resistance seizures. However, comorbidities such as behavioral problems were less frequently observed.Conclusion: The most common age of disease onset in SYNGAP1 gene mutations is in infancy, while neurodevelopmental delay and epilepsy are the major phenotypes. They have a higher percentage of drug-resistant epilepsy and epileptic spasms than those in previous reports. We should give attention to the patients with abnormal EEGs without seizures and think about the suitable time of the anti-seizure medications for them. We have not found the genotype–phenotype correlation.Trial registration: Chinese Clinical Trial Registry, Registration number: ChiCTR2100049289 (https://www.chictr.org.cn/listbycreater.aspx).

Download Full-text

Orthostatic intolerance: orthostatic hypotension and postural orthostatic tachycardia syndrome

ESC CardioMed ◽

10.1093/med/9780198784906.003.0472_update_001 ◽

2018 ◽

pp. 2032-2037

Author(s):

Artur Fedorowski

Keyword(s):

Orthostatic Hypotension ◽

Orthostatic Intolerance ◽

Wide Spectrum ◽

Standing Position ◽

Diagnostic Methods ◽

Postural Orthostatic Tachycardia Syndrome ◽

Unexplained Syncope ◽

Clinical Variants ◽

Age Range ◽

Specific Symptoms

The impairment of adaptive mechanisms during orthostatic challenge may evoke orthostatic intolerance, a heterogeneous condition, in which the standing position elicits a fall in blood pressure and/or excessive tachycardia, accompanied by a wide spectrum of subjective symptoms such as dizziness, discomfort, nausea, and palpitations. Apart from chronic and potentially debilitating symptoms, orthostatic intolerance may occasionally lead to sudden loss of consciousness and fall injuries. Consequently, orthostatic intolerance should be considered as a possible cause of unexplained syncope. Two main forms of orthostatic intolerance are orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS). Clinical variants of OH include initial, classical, and delayed forms. The prevalence of OH increases with age, ranging from less than 5% under 40 years to about 20% above 70 years of age, and is higher in chronic diseases, such as hypertension and diabetes, reaching above 35% in Parkinson’s disease and advanced kidney failure. The presence of OH is associated with a higher mortality and an increased incidence of cardiovascular disease, with the majority of patients being asymptomatic in normal conditions. In contrast, POTS affects predominantly young women (70–80%) within an age range of 15–40 years and is usually accompanied by non-specific symptoms: deconditioning, headache, cognitive impairment, and gastrointestinal dysfunction. Management of orthostatic intolerance includes both non-pharmacological and pharmacological methods with limited efficacy in the severe cases. Empirical treatment with vasoactive and volume expanding drugs for OH and POTS, and rhythm controlling therapy for POTS are recommended. Future studies on syndromes of orthostatic intolerance should focus on mechanisms leading to OH and POTS, novel diagnostic methods, and more effective therapeutic options.

Download Full-text

Orthostatic intolerance: orthostatic hypotension and postural orthostatic tachycardia syndrome

ESC CardioMed ◽

10.1093/med/9780198784906.003.0472 ◽

2018 ◽

pp. 2032-2037

Author(s):

Artur Fedorowski

Keyword(s):

Orthostatic Hypotension ◽

Orthostatic Intolerance ◽

Wide Spectrum ◽

Standing Position ◽

Diagnostic Methods ◽

Postural Orthostatic Tachycardia Syndrome ◽

Unexplained Syncope ◽

Clinical Variants ◽

Age Range ◽

Specific Symptoms

The impairment of adaptive mechanisms during orthostatic challenge may evoke orthostatic intolerance, a heterogeneous condition, in which the standing position elicits a fall in blood pressure and/or excessive tachycardia, accompanied by a wide spectrum of subjective symptoms such as dizziness, discomfort, nausea, and palpitations. Apart from chronic and potentially debilitating symptoms, orthostatic intolerance may occasionally lead to sudden loss of consciousness and fall injuries. Consequently, orthostatic intolerance should be considered as a possible cause of unexplained syncope. Two main forms of orthostatic intolerance are orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS). Clinical variants of OH include initial, classical, and delayed forms. The prevalence of OH increases with age, ranging from less than 5% under 40 years to about 20% above 70 years of age, and is higher in chronic diseases, such as hypertension and diabetes, reaching above 35% in Parkinson’s disease and advanced kidney failure. The presence of OH is associated with a higher mortality and an increased incidence of cardiovascular disease, with the majority of patients being asymptomatic in normal conditions. In contrast, POTS affects predominantly young women (70–80%) within an age range of 15–40 years and is usually accompanied by non-specific symptoms: deconditioning, headache, cognitive impairment, and gastrointestinal dysfunction. Management of orthostatic intolerance includes both non-pharmacological and pharmacological methods with limited efficacy in the severe cases. Empirical treatment with vasoactive and volume expanding drugs for OH and POTS, and rhythm controlling therapy for POTS are recommended. Future studies on syndromes of orthostatic intolerance should focus on mechanisms leading to OH and POTS, novel diagnostic methods, and more effective therapeutic options.

Download Full-text

Canine Brucellosis: An Update

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.594291 ◽

2021 ◽

Vol 8 ◽

Author(s):

Renato L. Santos ◽

Tayse D. Souza ◽

Juliana P. S. Mol ◽

Camila Eckstein ◽

Tatiane A. Paíxão

Keyword(s):

Close Contact ◽

Diagnostic Methods ◽

Health Concern ◽

Effective Control ◽

Molecular Diagnostic ◽

Source Of Infection ◽

Zoonotic Risk ◽

Laboratory Workers ◽

Canine Brucellosis ◽

Specific Symptoms

Canine brucellosis is an infectious and zoonotic disease caused by Brucella canis, which has been reported worldwide, and is a major public health concern due to close contact between dogs and humans. In dogs, canine brucellosis manifests with abortion outbreaks, reproductive failure, enlargement of lymph nodes, and occasionally affects the osteoarticular system, although the occurrence of asymptomatic infections in dogs are not uncommon. In humans, the disease is associated with a febrile syndrome, commonly with non-specific symptoms including splenomegaly, fatigue, and weakness. Infection of dogs occurs mostly by the oronasal route when in contact with contaminated tissues such as aborted fetuses, semen, urine, and vaginal secretions. In humans, contact with contaminated fluids from infected dogs is an important source of infection, and it is an occupational risk for veterinarians, breeders, laboratory workers, among other professionals who deal with infected animals or biological samples. The diagnosis in dogs is largely based on serologic methods. However, serologic diagnosis of canine brucellosis remains very challenging due to the low accuracy of available tests. Molecular diagnostic methods have been increasingly used in the past few years. Treatment of infected dogs is associated with a high frequency of relapse, and should be employed only in selected cases. Currently there are no commercially available vaccines for prevention of canine brucellosis. Therefore, development of novel and improved diagnostic methods as well as the development of efficacious and safe vaccination protocols are needed for an effective control of canine brucellosis and its associated zoonotic risk.

Download Full-text

COVID-19 Microbiological and Radiological Diagnostics

Infektološki glasnik ◽

10.37797/ig.40.3.3 ◽

2021 ◽

Vol 40 (3) ◽

pp. 97-106

Author(s):

Karlo Jeličić ◽

Oktavija Đaković Rode ◽

Klaudija Višković ◽

Armin Mehmedović ◽

Ivan Christian Kurolt

Keyword(s):

Tissue Sample ◽

Sampling Site ◽

Disease Onset ◽

Diagnostic Methods ◽

Diagnostic Tools ◽

Reticular Pattern ◽

Polymerase Chain ◽

Main Routine ◽

Test Result ◽

Optimal Implementation

The purpose of this paper is to present SARS-CoV-2 diagnostic methods and their optimal implementation. The main routine microbiological diagnostic tools are molecular and serological methods. Sensitivity and utilisation of molecular methods is the best at the disease onset, while serological methods are the best if used at least 5-7 days after disease onset. Positive molecular test result (real-time polymerase chain reaction; RT-PCR) must be interpreted in the clinical presentation context. A sampling site for molecular analysis is based on disease severity; upper and lower respiratory tract samples are used for mild and severe presentations, respectively. Virus cultivation is the only method of proving the existence of a viable virus in a tissue sample, but due to the method complexity, it is not a part of a routine process. Ground glass opacities with or without reticular pattern and/or consolidation are typical findings for COVID-19 pneumonia. Multi-slice computerized tomography (MSCT) is a superior radiological method for performing X-ray of the chests.

Download Full-text

Diagnostic Delay of Pulmonary Embolism in COVID-19 Patients

Frontiers in Medicine ◽

10.3389/fmed.2021.637375 ◽

2021 ◽

Vol 8 ◽

Author(s):

Federica Melazzini ◽

Margherita Reduzzi ◽

Silvana Quaglini ◽

Federica Fumoso ◽

Marco Vincenzo Lenti ◽

...

Keyword(s):

Pulmonary Embolism ◽

Diagnostic Delay ◽

Time Lapse ◽

Medical Examination ◽

Life Threatening ◽

Patient’S Outcome ◽

The Right ◽

Specific Symptoms ◽

The Impact ◽

Rule Out

Pulmonary embolism (PE) is a frequent, life-threatening COVID-19 complication, whose diagnosis can be challenging because of its non-specific symptoms. There are no studies assessing the impact of diagnostic delay on COVID-19 related PE. The aim of our exploratory study was to assess the diagnostic delay of PE in COVID-19 patients, and to identify potential associations between patient- or physician-related variables and the delay. This is a single-center observational retrospective study that included 29 consecutive COVID-19 patients admitted to the San Matteo Hospital Foundation between February and May 2020, with a diagnosis of PE, and a control population of 23 non-COVID-19 patients admitted at our hospital during the same time lapse in 2019. We calculated the patient-related delay (i.e., the time between the onset of the symptoms and the first medical examination), and the physician-related delay (i.e., the time between the first medical examination and the diagnosis of PE). The overall diagnostic delay significantly correlated with the physician-related delay (p < 0.0001), with the tendency to a worse outcome in long physician-related diagnostic delay (p = 0.04). The delay was related to the presence of fever, respiratory symptoms and high levels of lactate dehydrogenase. It is important to rule out PE as soon as possible, in order to start the right therapy, to improve patient's outcome and to shorten the hospitalization.

Download Full-text

High Grade Serous Carcinoma Presenting as a Huge Pelvic Mass with Normal Looking Ovaries: A Diagnostic Challenge for Pathologist

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2020/44502.13908 ◽

2020 ◽

Author(s):

Vaishali Walke ◽

Amrapali Gaikwad ◽

Madiha Shaikh ◽

Balwant Kowe

Keyword(s):

Correct Diagnosis ◽

Diagnostic Delay ◽

Delayed Diagnosis ◽

Pelvic Mass ◽

Clinical Findings ◽

Serous Carcinoma ◽

High Grade ◽

Diagnostic Challenge ◽

Immunohistochemical Markers ◽

Specific Symptoms

High-grade serous carcinoma represents 50-60% of all ovarian cancers and is the most common type of malignant surface epithelial tumour. Serous carcinoma is often diagnosed in the sixth and seventh decade, while the mean age for high-grade tumours is 63 year. It’s not only the non-specific symptoms like vague abdominal pain, nausea, gastrointestinal disturbances, but also the unusual presentation which is responsible for delayed diagnosis. This diagnostic delay can become the reason for increased mortality, despite advances in surgical management and chemotherapy. Here, authors discuss a case of 60-year-old postmenopausal women who presented with a huge pelvi-peritoneal mass and with grossly normal ovaries. Considering clinical findings and histomorphology, the possibility of malignant mesothelioma was considered as the first differential diagnosis; however extensive sampling of ovaries and supportive immunohistochemical markers helped us to arrive at a definitive diagnosis. The present case emphasises the importance of extensive tissue sampling and ancillary techniques in arriving at a correct diagnosis.

Download Full-text