ABSTRACT
BACKGROUND: Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844). METHODS: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing. RESULTS: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping. CONCLUSION: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.
Subject(s)
Spastic Paraplegia, Hereditary , Humans , Female , Adult , Spastic Paraplegia, Hereditary/genetics , Spastic Paraplegia, Hereditary/diagnosis , Spastic Paraplegia, Hereditary/pathology , Exons , Proteins/genetics , Codon, Nonsense , Corpus Callosum/pathology , Corpus Callosum/diagnostic imaging , Sequence Deletion , PhenotypeABSTRACT
The phenotypic repercussion of ZDHHC15 haploinsufficiency is not well-known. This gene was initially suggested as a candidate for X-linked mental retardation, but such an association was later questioned. We studied a multiplex family with three members with autism spectrum disorder (ASD) by array CGH, karyotype, exome sequencing and X-chromosome inactivation patterns. Medical history interviews, cognitive and physical examinations, and sensory profiling were also assessed. The three family members with ASD (with normal cognitive abilities and an abnormal sensory profile) were the only carriers of a 1.7 Mb deletion in the long arm of chromosome X, involving: ZDHHC15, MAGEE2, PBDC1, MAGEE1, MIR384 and MIR325. The normal chromosome X was preferentially inactivated in female carriers, and the whole exome sequencing of an affected family member did not reveal any additional genetic variant that could explain the phenotype. Thus, in the present family, ASD segregates with a deletion on chromosome X that includes ZDHHC15. Considering our results together with gene data (regarding function, expression, conservation and animal/cellular models), ZDHHC15 is a candidate gene for ASD. Emerging evidence also suggests that this gene could be associated with other neurodevelopmental disorders, with incomplete penetrance and variable expressivity.
Subject(s)
Autism Spectrum Disorder , Mental Retardation, X-Linked , Animals , Female , Autism Spectrum Disorder/genetics , Exome Sequencing , PhenotypeABSTRACT
BACKGROUND: The effect of disease-modifying therapies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response is unclear. OBJECTIVES: We aim to determine the immunological responses to SARS-CoV-2 in multiple sclerosis (MS) and anti-CD20-treated patients with other autoimmune diseases (AID). METHODS: Humoral and cellular responses we determined before and 30-90 days after vaccination in patients with MS and anti-CD20-treated patients with other AID in two Catalan centers. RESULTS: 457 patients were enrolled. Findings showed that humoral response decreased under anti-CD20s or sphingosine 1-phosphate receptor modulators (S1PRM) and with longer treatment duration and increased after 4.5 months from the last anti-CD20 infusion. Cellular response decreased in S1PRM-treated. Patients on anti-CD20 can present cellular responses even in the absence of antibodies. CONCLUSION: Anti-CD20s and S1PRM modify the immunological responses to SARS-CoV-2 vaccines.
Subject(s)
COVID-19 , Multiple Sclerosis , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Multiple Sclerosis/drug therapy , SARS-CoV-2 , VaccinationABSTRACT
GLYT1 encephalopathy is a form of glycine encephalopathy caused by disturbance of glycine transport. The phenotypic spectrum of the disease has not yet been completely described, as only four unrelated families with the disorder have been reported to date. Common features of affected patients include neonatal hypotonia, respiratory failure, encephalopathy, myoclonic jerks, dysmorphic features, and musculoeskeletal anomalies. All reported affected patients harbor biallelic genetic variants in SLC6A9. SNP array together with Sanger sequencing were performed in a newborn with arthrogryposis and severe neurological impairment. The novel genetic variant c.997delC in SLC6A9 was detected in homozygous state in the patient. At protein level, the predicted change is p.(Arg333Alafs*3), which most probably results in a loss of protein function. The variant cosegregated with the disease in the family. A subsequent pregnancy with ultrasound anomalies was also affected. The proband presented the core phenotypic features of GLYT1 encephalopathy, but also a burst suppression pattern on the electroencephalogram, a clinical feature not previously associated with the disorder. Our results suggest that the appearance of this pattern correlates with higher cerebrospinal fluid glycine levels and cerebrospinal fluid/plasma glycine ratios. A detailed discussion on the possible pathophysiological mechanisms of the disorder is also provided.
Subject(s)
Arthrogryposis/genetics , Genetic Predisposition to Disease , Glycine Plasma Membrane Transport Proteins/genetics , Hyperglycinemia, Nonketotic/genetics , Abortion, Spontaneous/genetics , Abortion, Spontaneous/pathology , Arthrogryposis/mortality , Arthrogryposis/pathology , Female , Glycine/genetics , Glycine/metabolism , Homozygote , Humans , Hyperglycinemia, Nonketotic/mortality , Hyperglycinemia, Nonketotic/pathology , Infant, Newborn , Male , Mutation/genetics , Pedigree , PhenotypeABSTRACT
Introduction: The cytoplasmic rods-rings (RR) pattern is found in hepatitis C (HCV) patients treated with interferon-ribavirin when studied with ANA-IIF. Ribavirin aggregates/induces antigenic changes in IMPDH-2, an enzyme necessary for ribavirin action. Patients and method: Prospective search for anti-RR autoantibodies (HEp-2, INOVA) in patients treated with direct-acting antivirals (DAAs) from October 2015 to June 2017. HCV-negative patients from up to June 2016 acted as controls. Anti-RR was analyzed at baseline and, mainly, during treatment and follow-up. The Chi-square test, Student's t-test and a logistic regression analysis were performed. Results: Between October 2015 and June 2016, 1258 men and 2389 women who were HCV-negative and 137 men and 112 women who were HCV-positive patients were studied. Approximately 22.9% of HCV-negative and 13.2% of HCV-positive were ANA-IIF-positive (p<0.05). Three HCV-negative (0.08%) and 23 (9.2%) HCV-positive patients had anti-RR (p<0.001). A total of 122 patients received DAAs; 30 received DAA+RBV; 46 pre-treated with IFN-RBV received DAA; 31 pre-treated with IFN-RBV received DAA+RBV; 16 received IFNpeg-RBV; and 24 received IFN-RBV-DAA. None of the 122 DAA-treated patients showed anti-RR; anti-RR were identified in 14.8% of those treated with DAA-RBV; in 25.9% of those pre-treated with IFN-RBV receiving DAA; in 22.2% of IFN-RBV-pre-treated patients who received DAA+RBV; in 7.4% of those treated with IFNpeg-RBV and in 29.6% of those treated with IFNpeg-RBV-DAA. The multivariate analysis showed significant associations between anti-RR and "Exposure to IFN" and "Time of exposure to RBV". Conclusions: Anti-RR autoantibodies were detected only in patients with current or past treatments with RBV, even in cases in which only DAAs were later administered
Introducción: La investigación de ANA-IFI en pacientes con hepatitis C tratados con interferón-ribavirina ha detectado un patrón citoplasmático en bastones y anillos. La ribavirina agregaría e induciría cambios antigénicos en la IMPDH-2, enzima imprescindible para su acción. Pacientes y método: Investigar las tasas de anti-RR (HEp-2, INOVA) en pacientes tratados con antivirales de acción directa (AAD) entre octubre-2015 y junio-2017. Como controles se han utilizado los pacientes VHC-negativo habidos hasta junio-2016. Los anti-RR se analizaron antes del tratamiento y, mayoritariamente, durante y después del mismo. Se han utilizado las pruebas Chi-cuadrado, T de Student y de regresión logística. Resultados: Entre octubre-2015 y junio-2016 hubo 1.258 varones y 2.389 mujeres VHC-negativo y 137 varones y 112 mujeres VHC-positivo. El 22,9% de los VHC-negativo y el 13,2% de los VHC-positivo fueron ANA-IFI-positivo (p<0,05). Tres pacientes (0,08%) VHC-negativo y 23 (9,2%) VHC-positivo fueron anti-RR+ (p<0,001). Ciento veintidós pacientes recibieron AAD; 30, AAD+RBV; 46 pretratados con IFN-RBV recibieron AAD; 31, pretratados con IFN-RBV, recibieron AAD+RBV; 16 IFNpeg-RBV; 24 IFN-RBV-AAD. Ningún paciente con AAD mostró anti-RR; tuvieron anti-RR el 14,8% de los tratados con AAD+RBV; 25,9% de los pretratados con IFN-RBV que recibieron AAD; 22,2% de los pretratados con IFN-RBV que recibieron AAD+RBV; 7,4% de los tratados con IFNpeg-RBV; el 29,6% de los tratados con IFNpeg-RBV-AAD. El análisis multivariante asoció significativamente la presencia de anti-RR con «Exposición al IFN» y «Tiempo de exposición a ribavirina». Conclusiones: Los autoanticuerpos anti-RR solo se han detectado en pacientes tratados con ribavirina, incluso cuando después se utilizaron solamente AAD
Subject(s)
Humans , Male , Female , Middle Aged , Antiviral Agents/therapeutic use , Autoantibodies/immunology , Cytoskeleton/immunology , Interferons/therapeutic use , Ribavirin/therapeutic use , Cohort Studies , Drug Therapy, CombinationABSTRACT
INTRODUCTION: The cytoplasmic rods-rings (RR) pattern is found in hepatitis C (HCV) patients treated with interferon-ribavirin when studied with ANA-IIF. Ribavirin aggregates/induces antigenic changes in IMPDH-2, an enzyme necessary for ribavirin action. PATIENTS AND METHOD: Prospective search for anti-RR autoantibodies (HEp-2, INOVA) in patients treated with direct-acting antivirals (DAAs) from October 2015 to June 2017. HCV-negative patients from up to June 2016 acted as controls. Anti-RR was analyzed at baseline and, mainly, during treatment and follow-up. The Chi-square test, Student's t-test and a logistic regression analysis were performed. RESULTS: Between October 2015 and June 2016, 1258 men and 2389 women who were HCV-negative and 137 men and 112 women who were HCV-positive patients were studied. Approximately 22.9% of HCV-negative and 13.2% of HCV-positive were ANA-IIF-positive (p<0.05). Three HCV-negative (0.08%) and 23 (9.2%) HCV-positive patients had anti-RR (p<0.001). A total of 122 patients received DAAs; 30 received DAA+RBV; 46 pre-treated with IFN-RBV received DAA; 31 pre-treated with IFN-RBV received DAA+RBV; 16 received IFNpeg-RBV; and 24 received IFN-RBV-DAA. None of the 122 DAA-treated patients showed anti-RR; anti-RR were identified in 14.8% of those treated with DAA-RBV; in 25.9% of those pre-treated with IFN-RBV receiving DAA; in 22.2% of IFN-RBV-pre-treated patients who received DAA+RBV; in 7.4% of those treated with IFNpeg-RBV and in 29.6% of those treated with IFNpeg-RBV-DAA. The multivariate analysis showed significant associations between anti-RR and "Exposure to IFN" and "Time of exposure to RBV". CONCLUSIONS: Anti-RR autoantibodies were detected only in patients with current or past treatments with RBV, even in cases in which only DAAs were later administered.