Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies

Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%). Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy available for treating these patients. Four patients underwent HSCT in our cohort but had a poor survival outcome. Lymphopenia (absolute lymphocyte counts/μL <2,500) was noted in 63% of the patients. Based on immunophenotypic pattern, majority of the cases were T−B− SCID (39%) followed by T−B+ SCID (28%). MHC class II deficiency accounted for 10.5% of our patient group. A total of 49 patients were molecularly characterized in this study and 32 novel variants were identified in our cohort. The spectrum of genetic defects in our cohort revealed a wide genetic heterogeneity with the major genetic cause being RAG1/2 gene defect (n = 12) followed by IL2RG (n = 9) and JAK3 defects (n = 9). Rare forms of SCID like Purine nucleoside phosphorylase (PNP) deficiency, reticular dysgenesis, DNA-Protein Kinase (DNA-PKcs) deficiency, six cases of MHC class II deficiency and two ZAP70 deficiency were also identified in our cohort. Fourteen percent of the defects still remained uncharacterized despite the application of next generation sequencing. With the exception of MHC class II deficiency and ZAP70 deficiency, all SCID patients had extremely low T cell receptor excision (TRECs) (<18 copies/μL)

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies

An overview of CD19 in COVID-19: Insights from Primary Immunodeficiencies and B cell depleting therapies

The evolution of COVID-19 as a global pandemic and emerging evidence from cohorts of patients have provided an immense opportunity to understand biological processes pertinent to development of the disease. The immune system is central to the development of characteristic hyperinflammation. In an attempt to understand the role of humoral immunity in COVID-19, reports encompassing patients with primary immunodeficiency (PID)(13 patients) and on B cell depletion therapies(39 patients) who had concurrent COVID-19 were reviewed. In PIDs, patients with common variable immunodeficiency had worse outcomes than patients with agammaglobulinemia. Among the patients on B cell depletion therapy, heterogenous outcome was seen. As a group, patients with multiple sclerosis had better outcomes as compared to patients with systemic autoimmunity. Further, increasing reports of autoimmunity and autoinflammatory diseases occurring in temporal relation to COVID-19 is also evidence for the pathogenic role played by B cells. B cell depletion in the setting of COVID-19 may not be harmful in all patients and in fact may be protective in some scenarios. Identification of risk factors associated with a worse outcome in patients on B cell therapy could provide a rationale for individualised management

Chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis is a rare entity characterized by isolated defective immunity against candida infection. It manifests with resistant and relapsing superficial candida infection affecting skin, hair, nails, and mucosae. Although serious invasive disease is uncommon, this condition produces considerable morbidity in the affected. Long-term antifungal treatment is the preferred option. We report a 3½-year-old female child who presented with chronic mucocutaneous candidiasis and who showed a gradual response to long-term treatment with itraconazole

X-linked agammaglobulinemia and COVID-19: Two case reports and review of literature

COVID-19 has caused a global crisis, infecting millions, and mainly manifesting with mild to moderate symptoms. The severity of disease occurred in a minority of those with comorbidities, who had an enhanced rate of disease progression and death. We present two case reports of adolescents with XLA from the state of Kerala in South India who were infected by SARS-CoV-2 and recovered without the need for artificial ventilation or convalescent plasma. In both the patients, the diagnosis of XLA had been confirmed with whole-exome sequencing. Rapid antigen tests for SARS-C0V-2 remained positive for more than two weeks in both cases. However, no post-COVID illness or re-infection has been reported in either patient. We have also reviewed all the cases with XLA infected by SARS-CoV-2 to date

Case Report: Whole exome sequencing identifies variation c.2308G>A p.E770K in RAG1 associated with B- T- NK+ severe combined immunodeficiency [version 2; referees: 2 approved, 1 not approved]

Severe combined immunodeficiency is a large clinically heterogeneous group of disorders caused by a defect in the development of humoral or cellular immune responses. At least 13 genes are known to be involved in the pathophysiology of the disease and the mutation spectrum in SCID has been well documented. Mutations of the recombination-activating genes RAG 1 and RAG 2 are associated with a range of clinical presentations including, severe combined immunodeficiency and autoimmunity. Recently, our understanding of the molecular basis of immune dysfunction in RAG deficiency has improved tremendously with newer insights into the ultrastructure of the RAG complex. In this report, we describe the application of whole exome sequencing for arriving at a molecular diagnosis in a child suffering from B- T- NK+ severe combined immunodeficiency. Apart from making the accurate molecular diagnosis, we also add a genetic variation c.2308G>A p.E770K to the compendium of variations associated with the disease

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Lischka A, Eggermann K, Record CJ, et al. Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies. Brain. 2023;146(12):4880-4890.Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited.Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign.The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies