Simplified Technique of Conventional Cholecystectomy in a Patient with Situs Inversus Totalis: A Case Report from Nepal

Introduction: Situs inversus is a rare autosomal recessive disorder occurring in 1:5,000 to 1:20,000 indiviuals. Cholecystectomy is a standard treatment for symptomatic gallbladder stone. We report a case of cholelithiasis in patient with inversus totalis who underwent cholecystectomy. Case presentation: A 48 years old obese female patient with dextrocardia and hypertention presented with a recurrent left upper abdominal pain for two years. Ultrasound abdomen showed gallbladder stone. Conventional cholecystectomy was done with a small left subcostal incision. The postoperative period was uneventful and the patient was discharged on 3rd post operative day. Conclusion: Cholecystectomy is the treatment of choice in patients with a left sided gallbladder stone, like in normal gallbladder and it is safe.

Allelic dropout in PAH affecting the results of genetic diagnosis in phenylketonuria

Objectives Phenylketonuria (PKU) is an inherited autosomal recessive disorder of phenylalanine metabolism. It is mainly caused by a deficiency in phenylalanine hydroxylase (PAH) and frequently diagnosed with Sanger sequencing. To some extent, allelic dropout can explain the inconsistency in genotype and phenotype. Methods Three families were evaluated through DNA sequence analysis, multiplex ligation-dependent probe amplification (MLPA) and prenatal diagnosis technologies. The possibility of inconsistency in phenotype and genotype with c.331C>T variant was analysed. Results Through pedigree analysis, three mothers carried a homozygous c.331C>T variant, which was a false-positive result. New primers were used, and this error was caused by allelic dropout. In this case, c.158G>A was likely a benign variant. Conclusions Sequence variants in primer-binding regions could cause allelic dropout, creating unpredictable errors in genotyping. Our results emphasised the need for careful measures to treat genotype–phenotype inconsistencies.

Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum

Background: Wolfram syndrome (WS) is a rare autosomal recessive disorder that is characterized by the presence of diabetes mellitus, optic atrophy and hearing loss, all of which are crucial elements for the diagnosis. WS is variably associated with diabetes insipidus, neurological disorders, urinary tract anomalies, endocrine dysfunctions and many other systemic manifestations. Since Wolfram and Wagener first described WS in 1938, new phenotypic/genotypic variants of the syndrome have been observed and the clinical picture has been significantly enriched. To date, two main subtypes of WS that associated with two different mutations are known: WS type 1 (WS1), caused by the mutation of the wolframine gene (WS1; 606201), and WS type 2 (WS2), caused by the mutation of the CISD2 gene (WS2; 604928). Methods: A systematic review of the literature was describe the phenotypic characteristics of WS2 in order to highlight the key elements that differentiate it from the classic form. Conclusion: WS2 is the rarest and most recently identified subtype of WS; its clinical picture is partially overlapping with that of WS1, from which it traditionally differs by the absence of diabetes insipidus and the presence of greater bleeding tendency and peptic ulcers.

Severe COVID-19 illness in an Indian adolescent with autoimmune polyendocrinopathy syndrome-1

Autoimmune polyglandular syndrome-1 (APS-1)also known as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare autosomal recessive disorder caused by mutation of AIRE gene on chromosome 21q22.3 with an overall prevalence of <1:100,000. Here, we present a 16-year-old male having clinical history of evolution of symptoms for oral candidiasis, hypoparathyroidism, and adrenal insufficiency (AI). He developed rare endocrine and non-endocrine manifestations such as type-1 diabetes (T1D) and autoimmune hepatitis, respectively. The patient while on hormone replacement therapy along with immunosuppressants developed liver cirrhosis and portal hypertension with esophageal varices and candidiasis. Subsequently, he was admitted for complaints of cough, cold and fever and was confirmed to be affected by SARS-CoV-2 by reverse transcription-polymerase chain reaction method. In his prolonged ICU stay of 26 days, he required oxygen therapy, intravenous glucocorticoids, remdesivir, low molecular weight heparin, and hemodynamic support with inotropes. His medical management with subcutaneous insulin therapy and azathioprine was continued. He was discharged after complete resolution of symptoms and negative tests for SARS-CoV-2 and was advised radiological and clinical follow-up. Reports suggest that risk of severe COVID does not increase in patients with AI or autoimmunity. However, our patient possibly developed severe COVID not only due to AI and autoimmunity but also associated rare manifestations like hyperglycemia due to T1D and cirrhosis. Thus, good glycemic control and well-tolerated modern immunosuppressant therapy may be useful in improving prognosis of severe COVID-19 illness in patients with APS-1.

A Novel Coq8a Mutation in a Case with Juvenile Onset Coq10d4: Case Report and Literature Review

Primary coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Molecular pathology responsible for clinical findings is mitochondrial respiratory chain dysfunction. The main clinical manifestation involves early onset exercise intolerance, progressive cerebellar ataxia and movement disorders. Some affected individuals develop seizures and have mild mental impairment, indicating variable severity. COQ8A gene mutations are responsible for this disease. Here we present a patient with tremor and cerebellar atrophy in which we detected a new mutation in the COQ8A gene. The patient's clinical findings were compatible with juvenile onset COQ10D4. Therefore, we reviewed the clinical, laboratory and genetic findings of 11 juvenile-onset COQ10D4 patients reported to date, as well as the patient's presentation.

Autosomal Recessive Autism: Cure of the Major Autistic Features

Background: We have previously reported our extensive experiences with autism disorders and their treatments, and we showed the possibility of curing the major autistic features with a new therapeutic approach which included individualized courses of intramuscular cerebrolysin as the main therapy for the main autistic features. Our previously published experiences included observing the occurrence of atypical autism associated with evidence of mental retardation in four brothers from outside Baghdad, each two of them from two unrelated families. The four patients were treated based on our extensive published experiences with the pharmacological treatments of autism disorders; however, the follow-up and the outcome of treatments of these four children were not described in the previous publications. The aim of this paper is to report the cure of the major autistic features in 2 brothers with autosomal recessive autism. Patients and methods: It was possible to follow the first two brothers for only few weeks and to see them after the first course of treatment, however, the second brothers were followed for more than one year, and it was possible to achieve cure of the main autistic features. Results: After one short course, the first two brothers showed slight but noticeable improvement. The younger brother showed some reduction in autistic features as he developed rather an acceptable eye contact. However, the two brothers were still not responding to name and didn’t say any word. After, treatment, the second two brothers showed no autistic features, and experienced significant improvements in speech and cognitive functions. The older brother was not having autistic features after eighth months, and was obeying commands, but was still saying only few words. The younger brother joined primary school and was doing well apart from some behavioral problems especially running away from school and sometimes breaks things. Conclusion: In this paper, cure of autism has been achieved in two boys with autosomal recessive disorder. However, cure of autism in older children has never been expected to totally normalizes them, as the patients have already lost several years of learning, social adaptation, and maturation of personality and behavior.

Diagnostic and management considerations in pseudohypoaldosteronism type 1b

Pseudohypoaldosteronism type 1B is a rare autosomal recessive disorder caused by dysfunction of amiloride-sensitive epithelial sodium channels (ENaCs). We present the case of a neonate with cardiogenic shock after cardiac arrest due to profound hyperkalaemia. Genetic testing revealed a novel homozygous variant in SCNNIA. We review diagnostic considerations including the molecular mechanisms of disease, discuss treatment approaches and highlight the possible significance of the diversity of pulmonary ENaCs.

Canavan Disease - A Rare Case Report

Canavan disease is a rare autosomal recessive disorder characterized by progressive leukodystrophy involving white matter of the brain. Disease leads to severe psychomotor retardation, seizures and premature death. More prevalent among Jewish population. Among non-Jewish population incidence is approximately 1:100000. Prognosis is guarded with current management only symptomatic and supportive. There is no effective treatment, however early gene therapy has improved the quality of life of patients. Furthermore, Lithium citrate has also shown certain positive results in experimental models using rats. Even few human studies have also been done, however promising results require larger controlled trials. Keywords: MRI: Magnetic Resonance and Imaging, EEG: Electro Encephalogram, CD: Canavan Disease, ASPA: acetyl aspartate, LUCS: Lower Uterine Cesarean Section, OFC: Occipito Frontal Circumference, NAA: N-acetyl aspartate

Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies

McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute “crises” of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient’s phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients.

A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene

PurposeWe sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause.MethodsExome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed.ResultsWe identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes.ConclusionWe describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.