Search results for: autosomal recessive genetic disorder (ARGD)

Authors: Bajraktarevic Adnan, Djukic Branka, Sporisevic Lutvo, Krdzalic Zecevic Belma, Uzicanin Sajra, Hadzimuratovic Admir, Hadzimuratovic Hadzipasic Emina, Abduzaimovic Alisa, Kustric Amer, Suljevic Ismet, Serafi Ismail, Tahmiscija Indira, Khatib Hakam, Semic Jusufagic Aida, Haas Helmut, Vladicic Aleksandra, Aplenc Richard, Kadic Deovic Aida

Abstract:

Introduction: Joubert syndrome has an autosomal recessive pattern of inheritance. It is referred as the brain malfunctioning and caused due to the underdevelopment of the cerebellar vermis. Associated conditions involving the eye, the kidney, and ocular disease are well described. Aims: Research helps us better understand this diseases, Joubert syndrome and can lead to advances in diagnosis and treatment. Methods: Different several conditions have been described in which the molar tooth sign and characteristics of Joubert syndrome in ten different places in the world. Carrier testing and diagnosis are available if one of these gene mutations has been identified in an affected family member. Results: Authors have described eleven cases during twenty years of Joubert syndrome. It is a clinically and genetically heterogeneous group of disorders characterized by hypoplasia of the cerebellar vermis with the characteristic neuroradiologic molar tooth sign, and accompanying neurologic symptoms, including dysregulation of breathing pattern and developmental delay. We made confirmation of diagnosis in twin sisters with Joubert syndrome with renal anomalies. Ocular symptoms have existed in seven cases (63.64%) from total eleven. Eleven cases were different sex, five boys (45.45%) and six girls (54.44%). Conclusions: Joubert syndrome is inherited as an autosomal recessive genetic disorder with several features of the disease.

Keywords: Joubert syndrome, cerebellooculorenal syndrome, autosomal recessive genetic disorder (ARGD), children

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Authors: Yessengali Ussenbekov, Valery Terletskiy, Orik Zhanserkenova, Shynar Kasymbekova, Indira Beyshova, Aitkali Imanbayev, Almas Serikov

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Currently, there are 46 hereditary diseases afflicting cattle with known molecular genetic diagnostic methods developed for them. Genetic anomalies frequently occur in the Holstein cattle breeds from American and Canadian bloodlines. The data on the incidence of BLAD, CVM, DUMPS and BC autosomal recessive lethal mutations in pedigree animals are discordant, the detrimental allele incidence rates are high for the Holstein cattle breed, whereas the incidence rates of these mutations are low in some breeds or they are completely absent. Data were obtained on the basis of frozen semen of stud bulls. DNA was extracted from the semen with the DNA-Sorb-B extraction kit. The lethal mutation in the genes CD18, SLC35A3, UMP and ASS of Alatau stud bulls (N=124) was detected by polymerase chain reaction and RFLP analysis. It was established that stud bulls of the local Alatau breed were not carriers of the BLAD, CVM, DUMPS, and BC detrimental mutations. However, with a view to preventing the dissemination of hereditary diseases it is recommended to monitor the pedigree stock using molecular genetic methods.

Keywords: PCR, autosomal recessive point mutation, BLAD, CVM, DUMPS, BC, stud bulls

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Authors: Dana Gabriková, Martin Mistrík, Jarmila Bernasovská, Iveta Tóthová, Jana Kisková

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The Roma (Gypsies) is a transnational minority with a high degree of consanguineous marriages. Similar to other genetically isolated founder populations, the Roma harbor a number of unique or rare genetic disorders. This paper discusses about a rare form of Charcot-Marie-Tooth disease – type 4G (CMT4G), also called Hereditary Motor and Sensory Neuropathy type Russe, an autosomal recessive disease caused by mutation private to Roma characterized by abnormally increased density of non-myelinated axons. CMT4G was originally found in Bulgarian Roma and in 2009 two putative causative mutations in the HK1 gene were identified. Since then, several cases were reported in Roma families mainly from Bulgaria and Spain. Here we present a Slovak Roma family in which CMT4G was diagnosed on the basis of clinical examination and genetic testing. This case is a further proof of the role of the HK1 gene in pathogenesis of the disease. It confirms that mutation in the HK1 gene is a common cause of autosomal recessive CMT disease in Roma and should be considered as a common part of a diagnostic procedure.

Keywords: gypsies, HK1, HSMN-Russe, rare disease

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Authors: Mary Rose Eunice S. Gundayao, Manolo M. Fernandez

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Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder with an autosomal recessive inheritance pattern. Lysosomal storage disorders are often severe, follow a progressively neurodegenerative path, and may result in multi-organ failure, potentially leading to death within 5 to 6 years in cases of early-onset forms. There are limited data regarding cases of MLD in Filipino children. This is the case of a 2-year-old Filipino girl who presented with progressive neurological deterioration and was diagnosed with metachromatic leukodystrophy by molecular genetic testing. This case report aims to present this patient’s clinical history, neurological findings, diagnosis and novel genetic mutations causing MLD. A concise review of updated literature on MLD will be discussed.

Keywords: metachromatic leukodystrophy, ARSA gene, peripheral neuropathy, case report, demyelinating disease

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Authors: Aran Abd Al Rahman

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Joubert syndrome regards as a congenital cerebellar ataxia caused by autosomal recessive carried on X chromosome. The disease diagnosed by brain imaging—the so-called molar tooth sign. Neurological signs were present from the neonatal period and include hypotonia progressing to ataxia, global developmental delay, ocular motor apraxia, and breathing dysregulation. These signs are variably associated with multiorgan involvement, mainly of the retina, kidneys, skeleton, and liver. 30 causative genes have been identified so far, all of which encode for proteins of the primary cilium or its apparatus, The purpose of our project was to detect the mutant gene (INPP5E gene) which cause Joubert syndrome. There were many methods used for diagnosis such as MRI and CT- scan and molecular diagnosis by doing ARMS PCR for detection of mutant gene that we were used in this research project. In this research for individual family which reported, the two children with parents, the two children were affected and were carrier.

Keywords: Joubert syndrome, genetic disease, Kurdistan region, Sulaimani

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Authors: Huong M. T. Nguyen, Hoa A. P. Nguyen, Chi V. Phan, Mai P. T. Nguyen, Ngoc D. Ngo, Van T. Ta, Hai T. Le

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Wilson’s disease is an autosomal recessive disorder of copper metabolism, which is caused by mutation in copper- transporting P-type ATPase (ATP7B). The mechanism of this disease is a failure of hepatic excretion of copper to the bile, and it leads to copper deposits in the liver and other organs. Most clinical symptoms of Wilson’s disease can present as liver disease and/or neurologic disease. Objective: The goal of the study is prenatal diagnosis for pregnant women at high risk of Wilson’s disease in Northern Vietnam. Material and method: Three probands with clinically diagnosed liver disease were detected in the mutations of 21 exons and exon-intron boundaries of the ATP7B gene by direct Sanger-sequencing. Prenatal diagnoses were performed by amniotic fluid sampling from pregnant women in the 16th-18th weeks of pregnancy after the genotypes of parents with the probands were identified. Result: A total of three different mutations of the probands, including of S105*, P1052L, P1273G, were detected. Among three fetuses which underwent prenatal genetic testing, one fetus was homozygote; two fetuses were carriers. Conclusion: Genetic testing provided a useful method for prenatal diagnosis, and is a basis for genetic counseling.

Keywords: ATP7B gene, genetic testing, prenatal diagnosis, pedigree, Wilson disease

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Authors: H. Imad, Q. Cheah, J. Mohammad, O. Aamera

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The aim of this study is twofold. One is to determine the genetic structure of Iraq population and the second objective of the study was to evaluate the importance of these loci for forensic genetic purposes. FTA® Technology (FTA™ paper DNA extraction) utilized to extract DNA. Twenty STR loci and Amelogenin including D3S1358, D13S317, PentaE, D16S539, D18S51, D2S1338, CSF1PO, Penta D, THO1, vWA, D21S11, D7S820, TPOX, D8S1179, FGA, D2S1338, D5S818, D6S1043, D12S391, D19S433, and Amelogenin amplified by using power plex21® kit. PCR products detected by genetic analyzer 3730xL then data analyzed by PowerStatsV1.2. Based on the allelic frequencies, several statistical parameters of genetic and forensic efficiency have been estimated. This includes the homozygosity and heterozygosity, effective number of alleles (n), the polymorphism information content (PIC), the power of discrimination (DP), and the power of exclusion (PE). The power of discrimination values for all tested loci was from 75% to 96% therefore, those loci can be safely used to establish a DNA-based database for Iraq population.

Keywords: autosomal STR, genetic variation, Middle and South of Iraq, statistical parameters

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Authors: Emna Abid, Linda Chebbi, Yosra Mabrouk, Amel Labidi, Lamia Mansour

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Werner syndrome (WS) is a rare genetic disorder inherited in an autosomal recessive pattern characterized by accelerated aging. While extensive research has been conducted on its systemic manifestations, the specific dental implications of WS remain poorly understood. The medical history and the oral health status of two patients diagnosed with WS were detailed. Our findings revealed a high prevalence of dental problems in both patients, including periodontitis, xerostomia, and temporomandibular joint disorders. This article aims to investigate the dental challenges faced by individuals with WS as well as the prosthetic options envisaged through two clinical cases contributing to a deeper understanding of the dental implications of WS and to choose the appropriate prosthetic solution in this population. Future research should focus on larger scale studies and clinical trials to validate these proposed strategies.

Keywords: adult progeria, clinical symptoms, oral manifestations, dental care, prosthetic management

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Authors: Lakshmi Rao Kandukuri, Mamata Deenadayal, Suma Prasad, Bipin Sethi, Srinadh Buragadda, Lalji Singh

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Worldwide; at least 7.6 million children are born annually with severe genetic or congenital malformations and among them 90% of these are born in mid and low-income countries. Precise prevalence data are difficult to collect, especially in developing countries, owing to the great diversity of conditions and also because many cases remain undiagnosed. The genetic and congenital disorder is the second most common cause of infant and childhood mortality and occurs with a prevalence of 25-60 per 1000 births. The higher prevalence of genetic diseases in a particular community may, however, be due to some social or cultural factors. Such factors include the tradition of consanguineous marriage, which results in a higher rate of autosomal recessive conditions including congenital malformations, stillbirths, or mental retardation. Genetic diseases can vary in severity, from being fatal before birth to requiring continuous management; their onset covers all life stages from infancy to old age. Those presenting at birth are particularly burdensome and may cause early death or life-long chronic morbidity. Genetic testing for several genetic diseases identifies changes in chromosomes, genes, or proteins. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person's chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use and more are being developed. Chromosomal abnormalities are the major cause of human suffering, which are implicated in mental retardation, congenital malformations, dysmorphic features, primary and secondary amenorrhea, reproductive wastage, infertility neoplastic diseases. Cytogenetic evaluation of patients is helpful in the counselling and management of affected individuals and families. We present here especially chromosomal abnormalities which form a major part of genetic disease burden in India. Different programmes on chromosome research and human reproductive genetics primarily relate to infertility since this is a major public health problem in our country, affecting 10-15 percent of couples. Prenatal diagnosis of chromosomal abnormalities in high-risk pregnancies helps in detecting chromosomally abnormal foetuses. Such couples are counselled regarding the continuation of pregnancy. In addition to the basic research, the team is providing chromosome diagnostic services that include conventional and advanced techniques for identifying various genetic defects. Other than routine chromosome diagnosis for infertility, also include patients with short stature, hypogonadism, undescended testis, microcephaly, delayed developmental milestones, familial, and isolated mental retardation, and cerebral palsy. Thus, chromosome diagnostics has found its applicability not only in disease prevention and management but also in guiding the clinicians in certain aspects of treatment. It would be appropriate to affirm that chromosomes are the images of life and they unequivocally mirror the states of human health. The importance of genetic counseling is increasing with the advancement in the field of genetics. The genetic counseling can help families to cope with emotional, psychological, and medical consequences of genetic diseases.

Keywords: India, chromosome abnormalities, genetic disorders, cytogenetic study

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Authors: Swarkar Sharma, Ekta Rai, Ankit Mahajan, Parvinder Kumar, Manoj K Dhar, Sushil Razdan, Kumarasamy Thangaraj, Carol Wise, Shiro Ikegawa M.D., K.K. Pandita M.D.

Abstract:

Rare disorders are poorly understood hence, remain uncharacterized or patients are misdiagnosed and get poor medical attention. A rare mysterious skeletal disorder that remained unidentified for decades and rendered many people physically challenged and disabled for life has been reported in an isolated remote village ‘Arai’ of Poonch district of Jammu and Kashmir. This village is located deep in mountains and the population residing in the region is highly consanguineous. In our survey of the region, 70 affected people were reported, showing similar phenotype, in the village with a population of approximately 5000 individuals. We were able to collect samples from two multi generational extended families from the village. Through Whole Exome sequencing (WES), we identified a rare variation NM_003880.3:c.156C>A NP_003871.1:p.Cys52Ter, which results in introduction of premature stop codon in WISP3 gene. We found this variation perfectly segregating with the disease in one of the family. However, this variation was absent in other family. Interestingly, a novel splice site mutation at position c.643+1G>A of WISP3 gene, perfectly segregating with the disease was observed in the second family. Thus, exploiting WES and putting different evidences together (familial histories and genetic data, clinical features, radiological and biochemical tests and findings), the disease has finally been diagnosed as a very rare recessive hereditary skeletal disease “Progressive Pseudorheumatoid Arthropathy of Childhood” (PPAC) also known as “Spondyloepiphyseal Dysplasia Tarda with Progressive Arthropathy” (SEDT-PA). This genetic characterization and identification of the disease causing mutations will aid in genetic counseling, critically required to curb this rare disorder and to prevent its appearance in future generations in the population. Further, understanding of the role of WISP3 gene the biological pathways should help in developing treatment for the disorder.

Keywords: whole exome sequencing, Next Generation Sequencing, rare disorders

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Authors: Huong M. T. Nguyen, Hoa A. P. Nguyen, Mai P. T. Nguyen, Ngoc D. Ngo, Van T. Ta, Hai T. Le, Chi V. Phan

Abstract:

Wilson’s disease (WD) is an autosomal recessive disorder of the copper metabolism, which is caused by a mutation in the copper-transporting P-type ATPase (ATP7B). The mechanism of this disease is the failure of hepatic excretion of copper to bile, and leads to copper deposits in the liver and other organs. The ATP7B gene is located on the long arm of chromosome 13 (13q14.3). This study aimed to investigate the gene mutation in the Vietnamese patients with WD, and make a presymptomatic diagnosis for their familial members. Forty-three WD patients and their 65 siblings were identified as having ATP7B gene mutations. Genomic DNA was extracted from peripheral blood samples; 21 exons and exon-intron boundaries of the ATP7B gene were analyzed by direct sequencing. We recognized four mutations ([R723=; H724Tfs*34], V1042Cfs*79, D1027H, and IVS6+3A>G) in the sum of 20 detectable mutations, accounting for 87.2% of the total. Mutation S105* was determined to have a high rate (32.6%) in this study. The hotspot regions of ATP7B were found at exons 2, 16, and 8, and intron 14, in 39.6 %, 11.6 %, 9.3%, and 7 % of patients, respectively. Among nine homozygote/compound heterozygote siblings of the patients with WD, three individuals were determined as asymptomatic by screening mutations of the probands. They would begin treatment after diagnosis. In conclusion, 20 different mutations were detected in 43 WD patients. Of this number, four novel mutations were explored, including [R723=; H724Tfs*34], V1042Cfs*79, D1027H, and IVS6+3A>G. The mutation S105* is the most prevalent and has been considered as a biomarker that can be used in a rapid detection assay for diagnosis of WD patients. Exons 2, 8, and 16, and intron 14 should be screened initially for WD patients in Vietnam. Based on risk profile for WD, genetic testing for presymptomatic patients is also useful in diagnosis and treatment.

Keywords: ATP7B gene, mutation detection, presymptomatic diagnosis, Vietnamese Wilson’s disease

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Authors: Amirreza Razzaghipour Sorkhab

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One of the most common disorders among humans is hearing impairment. This paper provides an evidence base that recovers understanding of Meniere’s disease and highlights the physical and mental health correlates of the disorder. Meniere's disease is more common in the elderly. The term idiopathic endolymphatic hydrops has been attributed to this disease by some in the previous. Meniere’s disease demonstrations a genetic tendency, and a family history is found in 10% of cases, with an autosomal dominant inheritance pattern. The COCH gene may be one of the hereditary factors contributing to Meniere’s disease, and the possibility of a COCH mutation should be considered in patients with Meniere’s disease symptoms. Should be considered Missense mutations in the COCH gene cause the autosomal dominant sensorineural hearing loss and vestibular disorder. Meniere’s disease is a complex, heterogeneous disorder of the inner ear and that is characterized by episodes of vertigo lasting from minutes to hours, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. The existing evidence supports the suggestion that age and sleep disorder are risk factors for Meniere's disease. Many factors have been reported to precipitate the progress of Menier, including endolymphatic hydrops, immunology, viral infection, inheritance, vestibular migraine, and altered intra-labyrinthine fluid dynamics. Although there is currently no treatment that has a proven helpful effect on hearing levels or on the long-term evolution of the disease, however, in the primary stages, the hearing may improve among attacks, but a permanent hearing loss occurs in the majority of cases. Current publications have proposed a role for the intratympanic use of medicine, mostly aminoglycosides, for the control of vertigo. more than 85% of patients with Meniere's disease are helped by either changes in lifestyle and medical treatment or minimally aggressive surgical procedures such as intratympanic steroid therapy, intratympanic gentamicin therapy, and endolymphatic sac surgery. However, unilateral vestibular extirpation methods (intratympanic gentamicin, vestibular nerve section, or labyrinthectomy) are more predictable but invasive approaches to control the vertigo attacks. Medical therapy aimed at reducing endolymph volume, such as low-sodium diet, diuretic use, is the typical initial treatment.

Keywords: meniere's disease, endolymphatic hydrops, hearing loss, vertigo, tinnitus, COCH gene

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Authors: Vidhi Chandra, Arshpreet Singh Grewal

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A five-year-old male child born from non-consanguineous marriage, who presented with complaints of growth retardation and no appreciable increase in the penile size since birth and he was posted for de-gloving of penis with dissection of corpora under anaesthesia. After thorough preoperative evaluation it was revealed that patient had peculiar facial dysmorphism that of Robinow Syndrome, high arched palate, Mallampati grade III, mesomelic limbs, scoliotic spine and short stature. All routine investigation were within normal limit, electrocardiography (ECG) and 2D-Echocardiography (ECHO) were normal. In antero-posterior roentgenogram chest showed butterfly and hemivertebrae at multiple levels. The patient was considered to be ASA II. On the day of surgery after ensuring fasting of 6 hours, patient was taken in operation theatre, all standard ASA monitoring was done with ECG, non-invasive blood pressure, peripheral oxygen saturation (SpO2) and body temperature. The patient was pre-oxygenated with 100% oxygen with anatomical face mask. General anaesthesia was induced with Sevoflurane 1-8%, and airway was secured with an appropriate size supraglottic airway and anaesthesia was maintained with nitrous oxide and oxygen in 1:1 ratio along with sevoflurane 2%. An ultrasound guided caudal block was given owing to the skeletal deformities making it difficult even under USG guidance. Post operatively patient was given supportive care with proper hydration, antibiotics, anti-inflammatory and analgesics. He was discharged the next day and followed up weekly for a month. DISCUSSION Robinow syndrome is genetically inherited as autosomal dominant, autosomal recessive or heterogenous disorder involving tyrosine kinase ROR2 gene located on chromosome 9. It has low incidence with no preponderance for any gender. Though intelligence is normal but developmental delay and mental retardation occurs in 20%cases

Keywords: Robinow Syndrome, dwarfism, paediatric, anaesthesia

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Authors: Koteswara Rao Pagolu, Raghava Rao Tamanam

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In India, genetic disease is a disregarded service element in the community health- protection system. This study aims to gauge the accessibility of services for treating genetic disorders and also to evaluate the practices on deterrence and management services in the district health system. A cross-sectional survey of selected health amenities in the government health sector was conducted from 15 primary health centers (PHC’s), 4 community health centers (CHC’s), 1 district government hospital (DGH) and 3 referral hospitals (RH’s). From these, the existing manpower like 130 medical officers (MO’s), 254 supporting staff, 409 nursing staff (NS) and 45 lab technicians (LT’s) was examined. From the side of private health institutions, 25 corporate hospitals (CH’s), 3 medical colleges (MC’s) and 25 diagnostic laboratories (DL’s) were selected for the survey and from these, 316 MO’s, 995 NS and 254 LT’s were also reviewed. The findings show that adequate staff was in place at more than 70% of health centers, but none of the staff have obtained any operative training on genetic disease management. The largest part of the DH’s had rudimentary infrastructural and diagnostic facilities. However, the greater part of the CHC’s and PHC’s had inadequate diagnostic facilities related to genetic disease management. Biochemical, molecular, and cytogenetic services were not available at PHC’s and CHC’s. DH’s, RH’s, and all selected medical colleges were found to have offered the basic Biochemical genetics units during the survey. The district health care infrastructure in India has a shortage of basic services to be provided for the genetic disorder. With some policy resolutions and facility strengthening, it is possible to provide advanced services for a genetic disorder in the district health system.

Keywords: district health system, genetic disorder, infrastructural amenities, management practices

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Authors: Y. Ruchi, A. Prerna, S. Deepshikha

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Amyotrophic lateral sclerosis (ALS), also known as “Lou Gehrig’s disease”. It is a neurodegenerative disease associated with degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cord characterized by distal muscle weakness, atrophy, normal sensation, pyramidal signs and progressive muscular paralysis reflecting. ALS2 is a juvenile autosomal recessive disorder, slowly progressive, that maps to chromosome 2q33 and is associated with mutations in the alsin gene, a putative GTPase regulator. In this paper we have done homology modeling of alsin2 protein using multiple templates (3KCI_A, 4LIM_A, 402W_A, 4D9S_A, and 4DNV_A) designed using the Prime program in Schrödinger software. Further modeled structure is used to identify effective binding sites on the basis of structural and physical properties using sitemap program in Schrödinger software, structural and function analysis is done by using Prosite and ExPASy server that gives insight into conserved domains and motifs that can be used for protein classification. This paper summarizes the structural, functional and binding site property of alsin2 protein. These binding sites can be potential drug target sites and can be used for docking studies.

Keywords: ALS, binding site, homology modeling, neuronal degeneration

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Authors: Clara Franch de la Cal, Christopher J Morris, Michael McArthur

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Cystic fibrosis (CF) is an autosomal recessive genetic disorder characterized by abnormal transport of chloride and sodium across the lung epithelium, leading to thick and viscous secretions. Within which CF patients suffer from repeated bacterial pulmonary infections, with Pseudomonas aeru-ginosa (PA) eliciting the greatest inflammatory response, causing an irreversible loss of lung func-tion that determines morbidity and mortality. The cell wall of PA is a permeability barrier to many antibacterials and the rise of Mutli-Drug Resistant strains (MDR) is eroding the efficacy of the few remaining clinical options. In addition when PA infection becomes established it forms an antibi-otic-resistant biofilm, embedded in which are slow growing cells that are refractive to drug treat-ment. Making the development of new antibacterials a major challenge. This work describes the development of new type of nanoparticulate oligonucleotide antibacterial capable of tackling PA infections, including MDR strains. It is being developed to both block growth and prevent biofilm formation. These oligonucleotide therapeutics, Transcription Factor Decoys (TFD), act on novel genomic targets by capturing key regulatory proteins to block essential bacterial genes and defeat infection. They have been successfully transfected into a wide range of pathogenic bacteria, both in vitro and in vivo, using a proprietary delivery technology. The surfactant used self-assembles with TFD to form a nanoparticle stable in biological fluids, which protects the TFD from degradation and preferentially transfects prokaryotic membranes. Key challenges are to adapt the nanoparticle so it is active against PA in the context of biofilms and to formulate it for administration by inhalation. This would allow the drug to be delivered to the respiratory tract, thereby achieving drug concentrations sufficient to eradicate the pathogenic organisms at the site of infection.

Keywords: antibacterials, transcriptional factor decoys (TFDs), pseudomonas aeruginosa

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Authors: Yun-Hsuan Chang, Chih-Chun Huang, Ru-Band Lu

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Dopamine, metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase 2 (ALDH2), ALDH2*1/*1, and ALDH2*1/*2+ALDH*2/*2 equally carried in Han Chinese. The relationship between dopamine metabolic enzyme and cognitive performance in bipolar II disorder comorbid with anxiety disorder (AD) remains unclear. This study proposed to explore the association between ALDH2 polymorphisms, anxiety comorbidity in bipolar II disorder. One hundred and ninety-seven BPII with or without AD comorbidity were recruited and compared with 130 Health controls (HC). A polymerase chain reaction and restriction fragment length polymorphism analysis was used to determine genotypes for ALDH2, and neuropsychological battery was performed. Two factor analyses with AD comorbidity and ALDH2 showed a significant main effect of ALDH2 on attention and marginally significant interaction between AD and ALDH2 memory performance. The ALDH2 polymorphisms may play a different role in the neuropsychological performance on varied neuropsychological performance in BPII comorbid with and without AD.

Keywords: anxiety disorder, bipolar II disorder, comorbidity, genetic

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Authors: Reham Khalaf-Nazzal, Imad Dweikat, Paula Gimenez, Iker Oyenarte, Alfonso Martinez-Cruz, Domonik Muller

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Metal cation transport mediator (CNNM) gene family comprises 4 isoforms that are expressed in various human tissues. Structurally, CNNMs are complex proteins that contain an extracellular N-terminal domain preceding a DUF21 transmembrane domain, a ‘Bateman module’ and a C-terminal cNMP-binding domain. Mutations in CNNM2 cause familial dominant hypomagnesaemia. Growing evidence highlights the role of CNNM2 in neurodevelopment. Mutations in CNNM2 have been implicated in epilepsy, intellectual disability, schizophrenia, and others. In the present study, we aim to elucidate the function of CNNM2 in the developing brain. Thus, we present the genetic origin of symptoms in two family cohorts. In the first family, three siblings of a consanguineous Palestinian family in which parents are first cousins, and consanguinity ran over several generations, presented a varying degree of intellectual disability, cone-rod dystrophy, and autism spectrum disorder. Exome sequencing and segregation analysis revealed the presence of homozygous pathogenic mutation in the CNNM2 gene, the parents were heterozygous for that gene mutation. Magnesium blood levels were normal in the three children and their parents in several measurements. They had no symptoms of hypomagnesemia. The CNNM2 mutation in this family was found to locate in the CBS1 domain of the CNNM2 protein. The crystal structure of the mutated CNNM2 protein was not significantly different from the wild-type protein, and the binding of AMP or MgATP was not dramatically affected. This suggests that the CBS1 domain could be involved in pure neurodevelopmental functions independent of its magnesium-handling role, and this mutation could have affected a protein partner binding or other functions in this protein. In the second family, another autosomal dominant CNNM2 mutation was found to run in a large family with multiple individuals over three generations. All affected family members had hypomagnesemia and hypermagnesuria. Oral supplementation of magnesium did not increase the levels of magnesium in serum significantly. Some affected members of this family have defects in fine motor skills such as dyslexia and dyslalia. The detected mutation is located in the N-terminal part, which contains a signal peptide thought to be involved in the sorting and routing of the protein. In this project, we describe heterogenous clinical phenotypes related to CNNM2 mutations and protein functions. In the first family, and up to the authors’ knowledge, we report for the first time the involvement of CNNM2 in retinal photoreceptor development and function. In addition, we report the presence of a neurophenotype independent of magnesium status related to the CNNM2 protein mutation. Taking into account the different modes of inheritance and the different positions of the mutations within CNNM2 and its different structural and functional domains, it is likely that CNNM2 might be involved in a wide spectrum of neuropsychiatric comorbidities with considerable varying phenotypes.

Keywords: magnesium transport, autosomal recessive, autism, neurodevelopment, CBS domain

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Authors: Paula I. Buonfiglio, Carlos David Bruque, Lucia Salatino, Vanesa Lotersztein, Sebastián Menazzi, Paola Plazas, Ana Belén Elgoyhen, Viviana Dalamón

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Hearing loss (HL) is the most prevalent sensorineural disorder affecting about 10% of the global population, with more than half due to genetic causes. About 1 in 500-1000 newborns present congenital HL. Most of the patients are non-syndromic with an autosomal recessive mode of inheritance. To date, more than 100 genes are related to HL. Therefore, the Whole-exome sequencing (WES) technique has become a cost-effective alternative approach for molecular diagnosis. Nevertheless, new challenges arise from the detection of novel variants, in particular missense changes, which can lead to a spectrum of genotype-to-phenotype correlations, which is not always straightforward. In this work, we aimed to identify the genetic causes of HL in isolated and familial cases by designing a multistep approach to analyze target genes related to hearing impairment. Moreover, we performed in silico and in vivo analyses in order to further study the effect of some of the novel variants identified in the hair cell function using the zebrafish model. A total of 650 patients were studied by Sanger Sequencing and Gap-PCR in GJB2 and GJB6 genes, respectively, diagnosing 15.5% of sporadic cases and 36% of familial ones. Overall, 50 different sequence variants were detected. Fifty of the undiagnosed patients with moderate HL were tested for deletions in STRC gene by Multiplex ligation-dependent probe amplification technique (MLPA), leading to 6% of diagnosis. After this initial screening, 50 families were selected to be analyzed by WES, achieving diagnosis in 44% of them. Half of the identified variants were novel. A missense variant in MYO6 gene detected in a family with postlingual HL was selected to be further analyzed. A protein modeling with AlphaFold2 software was performed, proving its pathogenic effect. In order to functionally validate this novel variant, a knockdown phenotype rescue assay in zebrafish was carried out. Injection of wild-type MYO6 mRNA in embryos rescued the phenotype, whereas using the mutant MYO6 mRNA (carrying c.2782C>A variant) had no effect. These results strongly suggest the deleterious effect of this variant on the mobility of stereocilia in zebrafish neuromasts, and hence on the auditory system. In the present work, we demonstrated that our algorithm is suitable for the sequential multigenic approach to HL in our cohort. These results highlight the importance of a combined strategy in order to identify candidate variants as well as the in silico and in vivo studies to analyze and prove their pathogenicity and accomplish a better understanding of the mechanisms underlying the physiopathology of the hearing impairment.

Keywords: diagnosis, genetics, hearing loss, in silico analysis, in vivo analysis, WES, zebrafish

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Authors: Fouad Chebib, Marie Hogan, Ziad El-Zoghby, Maria Irazabal, Sarah Senum, Christina Heyer, Charles Madsen, Emilie Cornec-Le Gall, Atta Behfar, Barbara Ehrlich, Peter Harris, Vicente Torres

Abstract:

Background: Mutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2) cause autosomal dominant polycystic kidney disease (ADPKD). ADPKD is a systemic disease associated with several extrarenal manifestations. Animal models have suggested an important role for the polycystins in cardiovascular function. The aim of the current study is to evaluate the association of various cardiomyopathies in a large cohort of patients with ADPKD. Methods: Clinical data was retrieved from medical records for all patients with ADPKD and cardiomyopathies (n=159). Genetic analysis was performed on available DNA by direct sequencing. Results: Among the 58 patients included in this case series, 39 patients had idiopathic dilated cardiomyopathy (IDCM), 17 had hypertrophic obstructive cardiomyopathy (HOCM), and 2 had left ventricular noncompaction (LVNC). The mean age at cardiomyopathy diagnosis was 53.3, 59.9 and 53.5 years in IDCM, HOCM and LVNC patients respectively. The median left ventricular ejection fraction at initial diagnosis of IDCM was 25%. Average basal septal thickness was 19.9 mm in patients with HOCM. Genetic data was available in 19, 8 and 2 cases of IDCM, HOCM, and LVNC respectively. PKD1 mutations were detected in 47.4%, 62.5% and 100% of IDCM, HOCM and LVNC cases. PKD2 mutations were detected only in IDCM cases and were overrepresented (36.8%) relative to the expected frequency in ADPKD (~15%). The prevalence of IDCM, HOCM, and LVNC in our ADPKD clinical cohort was 1:17, 1:39 and 1:333 respectively. When compared to the general population, IDCM and HOCM was approximately 10-fold more prevalent in patients with ADPKD. Conclusions: In summary, we suggest that PKD1 or PKD2 mutations may predispose to idiopathic dilated or hypertrophic cardiomyopathy. There is a trend for patients with PKD2 mutations to develop the former and for patients with PKD1 mutations to develop the latter. Predisposition to various cardiomyopathies may be another extrarenal manifestation of ADPKD.

Keywords: autosomal dominant polycystic kidney (ADPKD), polycystic kidney disease, cardiovascular, cardiomyopathy, idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, left ventricular noncompaction

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Authors: Dost Muhammad Halepoto, Laila AL-Ayadhi

Abstract:

Neurodevelopmental disorders such as autism can cause lifelong disability. Genetic and environmental factors are believed to contribute to the development of autism spectrum disorder (ASD), but relatively few studies have considered potential environmental risks. Several industrial chemicals and other environmental exposures are recognized causes of neurodevelopmental disorders and subclinical brain dysfunction. The toxic effects of such chemicals in the developing human brain are not known. This review highlights the role of environmental risk factors including drugs, toxic chemicals, heavy metals, pesticides, vaccines, and other suspected neurotoxicants including persistent organic pollutants for ASD. It also provides information about the environmental toxins to yield new insights into factors that affect autism risk as well as an opportunity to investigate the relation between autism and environmental exposure.

Keywords: Autism Spectrum Disorder, ASD, environmental factors, neurodevelopmental disorder

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Authors: Matthew T. Wilson

Abstract:

This paper covers a selection of research utilizing grammar-based genetic programming, and illustrates how context-free grammar can be used to constrain genetic programming. It focuses heavily on grammatical evolution, one of the most popular variants of grammar-based genetic programming, and the way its operators and terminals are specialized and modified from those in genetic programming. A variety of implementations of grammatical evolution for general use are covered, as well as research each focused on using grammatical evolution or grammar-based genetic programming on a single application, or to solve a specific problem, including some of the classically considered genetic programming problems, such as the Santa Fe Trail.

Keywords: context-free grammar, genetic algorithms, genetic programming, grammatical evolution

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Authors: Murat Emre, Zeynep Tufekcioglu

Abstract:

Objective: We describe a patient with late onset phenylketonuria which presented with rapidly progressive dementia and parkinsonism that were reversible after management. Background: Phenylketonuria is an autosomal recessive disorder due to mutations in the phenylalanine hydroxlase gene. It normally presents in childhood, in rare cases, however, it may have its onset in adulthood and may mimic other neurological disorders. Case description: A previously normal functioning, 59 year old man was admitted for blurred vision, cognitive impairment and gait difficulty which emerged over the past eight months. In neurological examination he had brisk reflexes, slow gait and left-dominant parkinsonism. Mini-mental state examination score was 25/30, neuropsychological testing revealed a dysexecutive syndrome with constructional apraxia and simultanagnosia. In cranial MRI there were bilateral diffuse hyper-intense lesions in parietal and occipital white matter with no significant atrophy. Electroencephalography showed diffuse slowing with predominance of teta waves. In cerebrospinal fluid examination protein level was slightly elevated (61mg/dL), oligoclonal bands were negative. Electromyography was normal. Routine laboratory examinations for rapidly progressive dementia and parkinsonism were also normal. Serum amino acid levels were determined to explore metabolic leukodystrophies and phenylalanine level was found to be highly elevated (1075 µmol/L) with normal tyrosine (61,20 µmol/L). His cognitive impairment and parkinsonian symptoms improved following three months of phenylalanine restricted diet. Conclusions: Late onset phenylketonuria is a rare, potentially reversible cause of rapidly progressive parkinsonism with dementia. It should be considered in the differential diagnosis of patients with suspicious features.

Keywords: dementia, neurology, Phenylketonuria, rapidly progressive parkinsonism

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Authors: Agi Sunday

Abstract:

A descriptive analysis of reported cases of sickle cell disease and the level of awareness about genetic counselling in 30 hospitals were carried out. Additionally, 150 individuals between ages 16-45 were randomly selected for evaluation of genetic counselling awareness. The main tools for this study were questionnaires which were taken to hospitals, and individuals completed the others. The numbers of reported cases of sickle cell disease recorded in private, public and teaching hospitals were 14 and 57; 143 and 89; 272 and 57 for the periods of 1995-2000 and 2001-2005, respectively. A general informal genetic counselling took place mostly in the hospitals visited. 122 (86%) individuals had the knowledge of genetic disease and only 43 (30.3%) individuals have been exposed to genetic counselling. 64% of individuals agreed that genetic counselling would help in the prevention of genetic disease.

Keywords: sickle disease, genetic counseling, genetic testing, advocacy

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Authors: Dalia Elleuch

Abstract:

Narcissistic Personality Disorder (NPD) manifests as a personality disorder marked by inflated self-importance, heightened sensitivity to criticism, a lack of empathy, a preoccupation with appearance over substance, and features such as arrogance, grandiosity, a constant need for admiration, a tendency to exploit others, and an inclination towards demanding special treatment due to a sense of excessive entitlement (APA, 2013). This interdisciplinary study delves into NPD through the systematic synthesis of psycholinguistic analysis and neuroscientific correlates. The cognitive and emotional dimensions of NPD reveal linguistic patterns, including grandiosity, entitlement, and manipulative communication. Neuroscientific investigations reveal structural brain differences and alterations in functional connectivity, further explaining the neural underpinnings of social cognition deficits observed in individuals with NPD. Genetic predispositions and neurotransmitter imbalances add a layer of complexity to the understanding of NPD. The necessity for linguistic intervention in diagnosing and treating Narcissistic Personality Disorder is underscored by an interdisciplinary study that intricately synthesizes psycholinguistic analysis and neuroscientific correlates, offering a comprehensive understanding of NPD’s cognitive, emotional, and neural dimensions and paving the way for future practical, theoretical, and pedagogical approaches to address the complexities of this personality disorder.

Keywords: Narcissistic Personality Disorder (NPD), psycholinguistic analysis, neuroscientific correlates, interpersonal dysfunction, cognitive empathy

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Authors: Eda Jazexhiu-Postoli, Gladiola Hoxha, Ada Simeoni, Sonila Biba

Abstract:

Background Neonatal hypotonia represents a commonly encountered issue in the Neonatal Intensive Care Unit and newborn nursery. The differential diagnosis is broad, encompassing chromosome abnormalities, primary muscular dystrophies, neuropathies and inborn errors of metabolism. Aim of study Our study describes some of the main clinical features of hypotonia in newborns and presents clinical cases of neonatal hypotonia we treated in our Neonatal unit in the last 3 years. Case reports Four neonates born in our hospital presented with hypotonia after birth, one preterm newborn 35-36 weeks of gestational age and three other term newborns (38-39 weeks of gestational age). Prenatal data revealed a decrease in fetal movements in both cases. Intrapartum meconium-stained amniotic fluid was found in 75% of our hypotonic newborns. Clinical features included inability to establish effective respiratory movements and need for resuscitation in the delivery room, respiratory distress syndrome, feeding difficulties and need for oro-gastric tube feeding, dysmorphic features, hoarse voice and moderate to severe muscular hypotonia. The genetic workup revealed the diagnosis of Autosomal Recessive Congenital Myasthenic Syndrome 1-B, Sotos Syndrome, Spinal Muscular Atrophy Type 1 and Transient Hypotonia of the Newborn. Two out of four hypotonic neonates were transferred to the Pediatric Intensive Care Unit and died at the age of three to five months old. Conclusion Hypotonia is a concerning finding in neonatal care and it is suggested by decreased intrauterine fetal movements, failure to establish first breaths, respiratory distress and feeding difficulties in the neonate. Prognosis is determined by its etiology and time of diagnosis and intervention.

Keywords: hypotonic neonate, respiratory distress, feeding difficulties, fetal movements

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Authors: Ramona Moldovan, Doina Cosman, Sebastian Moldovan, Radu Popp, Victor Pop

Abstract:

MENTALICA is a project aimed at developing and evaluating a platform that can assist individuals diagnosed with severe mental disorders and their families in managing the consequences associated with severe mental disorders, recurrence risks, prevention strategies and treatment options. MENTALICA is a platform based on guidance issued by some of the most prominent scientific organizations in the world. In order to personalize the information provided, the program explores details about the personal and family history of mental disorders. MENTALICA summarizes the answers and gives respondents a personal assessment. This includes personalized information and support about schizophrenia, bipolar disorder and schizoaffective disorder. MENTALICA includes several modules: Family history tools, Risk assessment tools and Risk factor sheets, Practical guides for patients, Practical guides for families, Guidelines for clinicians. Currently, there are no available guidelines for genetic counselling for mental disorders. Respondents can print out their reports and discuss them with family members or their doctors. We will briefly present the current status of MENTALICA and its implications for patients, professionals and the community.

Keywords: genetic counseling, mental disorders, platform

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Authors: Imaneh Abbasi, Ladan Fata, Majid Sadeghi, Sara Banihashemi, Abolfazl Mohammadee

Abstract:

Background: Dimensional and transdiagnostic approaches as a result of high comorbidity among mental disorders have captured researchers and clinicians interests for exploring the latent factors of development and maintenance of some psychological disorders. The goal of present study is to compare some of these common factors between generalized anxiety disorder and unipolar mood disorder. Methods: 27 patients with generalized anxiety disorder, 29 patients with depression disorder were recruited using SCID-I and 69 non-clinical population were selected using GHQ cut off point. MANCOVA was used for analyzing data. Results: The results show that worry, rumination, intolerance of uncertainty, maladaptive metacognitive beliefs, and experiential avoidance were all significantly different between GAD and unipolar mood disorder groups. However, there were not any significant differences in difficulties in emotion regulation and neuroticism between GAD and unipolar mood disorder groups. Discussion: Results indicate that although there are some transdiagnostic and common factors in GAD and unipolar mood disorder, there may be some specific vulnerability factors for each disorder. Further study is needed for answering these questions.

Keywords: transdiagnostic, depression, generalized anxiety disorder, emotion regulation

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Authors: Merve Cebi, Turker Tekin Erguzel, Gokben Hizli Sayar

Abstract:

Understanding the biological mechanisms of dissociation in patients with bipolar disorder is important for developing new treatment approaches for the disorder as well as using the appropriate treatment strategies. In this study, we compared EEG power and coherence values for alpha, theta and beta frequency bands between patients having bipolar disorder with dissociation as compared to the bipolar patients without dissociation. Accordingly, we did not find any statistically significant difference in either the absolute or the relative power between the groups. Coherence values were not found to be statistically different, as well. Therefore, our results demonstrated that the existence of dissociation did not influence electrophysiological correlates in bipolar disorder.

Keywords: bipolar disorder, dissociation, absolute power, coherence

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Authors: Ali Al Orf, Khawaja Bilal Waheed

Abstract:

Background and objective: Joubert syndrome (JS) is a rare, autosomal-recessive condition. Early recognition is important for management and counseling. Magnetic resonance imaging (MRI) can help in diagnosis. Therefore, we sought to evaluate clinical presentation and MRI findings in Joubert syndrome and related disorders. Method: A retrospective review of genetically proven cases of Joubert syndromes and related disorders was reviewed for their clinical presentation, demographic information, and magnetic resonance imaging findings in a period of the last 10 years. Two radiologists documented magnetic resonance imaging (MRI) findings. The presence of hypoplasia of the cerebellar vermis with hypoplasia of the superior cerebellar peduncle resembling the “Molar Tooth Sign” in the mid-brain was documented. Genetic testing results were collected to label genes linked to the diagnoses. Results: Out of 12 genetically proven JS cases, most were females (9/12), and nearly all presented with hypotonia, ataxia, developmental delay, intellectual impairment, and speech disorders. 5/12 children presented at age of 1 or below. The molar tooth sign was seen in 10/12 cases. Two cases were associated with other brain findings. Most of the cases were found associated with consanguineous marriage Conclusion and discussion: The molar tooth sign is a frequent and reliable sign of JS and related disorders. Genes related to defective cilia result in malfunctioning in the retina, renal tubule, and neural cell migration, thus producing heterogeneous syndrome complexes known as “ciliopathies.” Other ciliopathies like Senior-Loken syndrome, Bardet Biedl syndrome, and isolated nephronophthisis must be considered as the differential diagnosis of JS. The main imaging findings are the partial or complete absence of the cerebellar vermis, hypoplastic cerebellar peduncles (giving MTS), and (bat-wing appearance) fourth ventricular deformity. LimitationsSingle-center, small sample size, and retrospective nature of the study were a few of the study limitations.

Keywords: Joubart syndrome, magnetic resonance imaging, molar tooth sign, hypotonia

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