scholarly journals An Atypical Case of Head Tremor and Extensive White Matter in an Adult Female Caused by 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1561
Author(s):  
Nassim Boutouchent ◽  
Julie Bourilhon ◽  
Bénédicte Sudrié-Arnaud ◽  
Antoine Bonnevalle ◽  
Lucie Guyant-Maréchal ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Late Onset ◽  
Genetic Disorder ◽  
Severe Hypoglycemia ◽  
Compound Heterozygous ◽  
Lyase Deficiency ◽  
Clinical Onset ◽  
Life Threatening ◽  
Incidental Discovery ◽  
Compound Heterozygous Variants

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease.

scholarly journals Novel Compound Heterozygous Variants of the ABCC8 Gene Warrant Identification of Pancreatic Histology in Infant with Diazoxide-unresponsive Congenital Hyperinsulinism

Children ◽  
2021 ◽  
Vol 8 (10) ◽  
pp. 836
Author(s):  
Rana Al Balwi ◽  
Dalal Bubshait ◽  
Raed Al Nefily ◽  
Omar Al Ghamdi
Keyword(s):  
Autosomal Recessive ◽  
Severe Hypoglycemia ◽  
Katp Channels ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Abcc8 Gene ◽  
Genes Encoding ◽  
One Year ◽  
The One ◽  
Compound Heterozygous Variants

Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion, resulting in severe hypoglycemia. Mutations in the ABCC8 and KCNJ11 genes encoding KATP channels in beta cells of the pancreas are common among patients with CHI. Autosomal recessive CHI with diffuse involvement is the most common type of CHI among Saudi patients. It is relatively common for patients with autosomal recessive CHI to be medically unresponsive and undergo pancreatectomy. In this case report, we describe novel compound heterozygous variants in the ABCC8 gene in a Saudi infant that caused diazoxide-unresponsive CHI. The variants included a monoallelic paternally inherited variant that has been previously reported to cause a focal form of CHI and a maternally inherited variant of unknown significance (VUS). The severity of CHI in this patient was mild over the one-year follow-up period, with a near-optimal glycemic response on a low dose of octreotide. We suspected an atypical subtype of histological involvement in the patient. In this report, we highlight the phenotypic spectrum of novel compound heterozygous variants in a patient with CHI and consider that the report can help establish the pathogenicity of the VUS.

scholarly journals Autosomal Recessive Rod-Cone Dystrophy Associated With Compound Heterozygous Variants in ARL3 Gene

2021 ◽  
Vol 9 ◽  
Author(s):  
Leming Fu ◽  
Ya Li ◽  
Shun Yao ◽  
Qingge Guo ◽  
Ya You ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Protein Structure ◽  
Autosomal Recessive ◽  
Late Onset ◽  
Family Members ◽  
Cone Dystrophy ◽  
Compound Heterozygous ◽  
Protein Structure Analysis ◽  
The Family ◽  
Compound Heterozygous Variants

Purpose:ARL3 (ADP-ribosylation factor-like 3) variants cause autosomal dominant retinitis pigmentosa (RP) or autosomal recessive Joubert syndrome. We found a family with rod-cone dystrophy (RCD) and verified it was associated with compound heterozygous variants in ARL3 gene.Methods: Ophthalmic examinations including optical coherence tomography and electroretinogram (ERG) were performed. Targeted next generation sequencing (NGS) was performed for the proband using a custom designed panel. Sanger sequencing and co-segregation were conducted in the family members. Changes of protein structure mediated by the variants were studied in vitro. ARL3 protein stability and its interaction with RP2 protein were assessed by cycloheximide chase assay and co-immunoprecipitation (Co-IP) assay.Results: Visual acuity of the 18-year-old male proband was 0.25 in the right and 0.20 in the left eye, while his non-consanguineous parents and sister was normal. The proband showed signs of RCD, including nyctalopia, peripheral field loss, bone-spicule deposits in the retina, and reduced ERG responses. The father, aged 50 years old, showed visual acuity of 1.0 in both eyes. Unlike the proband, he presented late onset and mild cone-rod dystrophy (CRD), including macular atrophy, central scotomata, moderate reduction in photopic ERG responses. None of all the family members had hearing abnormality, mental dysplasia or gait instability. We identified two novel compound heterozygous variants (c.91A>G, p.T31A; c.353G>T, p.C118F) in ARL3 in the proband, while his father only had variant c.91A>G. Bioinformatics analysis indicated amino acid positions of the two variants are highly conserved among species. The in silico tools predicted the variants to be harmful. Protein structure analysis showed the two variants had potential to alter the protein structure. Based on the ACMG guidelines, the two variants were likely pathogenic. In addition, the ARL3 mutations destabilized ARL3 protein, and the mutation c.353G>T disrupted the interaction between ARL3 and RP2 in HEK293T cells.Conclusions: We showed novel compound heterozygous variants in ARL3 were associated with early onset of autosomal recessive RCD, while c.91A>G along may be associated with a late onset of dominant CRD. The two variants in ARL3 could be causative by destabilizing ARL3 protein and impairing its interaction with RP2 protein.

scholarly journals A Rare and Fatal Complication of a Self-Limiting Infection: A Case Report on Dengue Associated Hemophagocytic Lymphohistiocytosis

2019 ◽  
Vol 30 (2) ◽  
pp. 93-95
Author(s):  
Alvin Oliver Payus ◽  
Cheong Lei Wah ◽  
Syahrul Sazliyana Shaharir
Keyword(s):  
Case Report ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Autosomal Recessive ◽  
De Novo ◽  
Medical Condition ◽  
Early Recognition ◽  
Genetic Disorder ◽  
Intravenous Methylprednisolone ◽  
Appropriate Treatment ◽  
Life Threatening

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening medical condition characterized by hyperphagocytosis secondary to an inappropriate over-activation of macrophages and lymphocytes that driven by excessive cytokines production which resulted in cellular destructions. It can arise de novo as a result of an autosomal recessive genetic disorder, or in the background of an infection, malignancy or autoimmune disease. Dengue fever is one of the uncommon causes of infection related secondary HLH. Here, we present a case of a Dengue associated HLH which was successfully treated with intravenous methylprednisolone and immunoglobulin G. In conclusion, the purpose of this case report is to illustrate the importance of early recognition and prompt initiation of the appropriate treatment for HLH suspected patient whom otherwise has high mortality rate. Bangladesh J Medicine July 2019; 30(2) : 93-95

scholarly journals Identification of Novel Compound Heterozygous MYO15A Mutations in Two Chinese Families with Autosomal Recessive Nonsyndromic Hearing Loss

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Xiao-Hui Wang ◽  
Le Xie ◽  
Sen Chen ◽  
Kai Xu ◽  
Xue Bai ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Bioinformatics Analysis ◽  
Compound Heterozygous ◽  
Congenital Deafness ◽  
Chinese Families ◽  
Novel Variants ◽  
Common Causes ◽  
Compound Heterozygous Variants ◽  
Generation Sequencing

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the MYO15A gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the MYO15A gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the MYO15A gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the MYO15A gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.

scholarly journals Case Report: Clinical Features of Childhood Leukoencephalopathy With Cerebral Calcifications and Cysts Due to SNORD118 Variants

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong Jin ◽  
Xiaotun Ren ◽  
Husheng Wu ◽  
Yanqi Hou ◽  
Fang Fang
Keyword(s):  
Autosomal Recessive ◽  
Age At Onset ◽  
Compound Heterozygous ◽  
Protein Coding ◽  
Case Presentation ◽  
Cerebral Calcifications ◽  
Clinical Investigations ◽  
Patient Reported ◽  
Cerebral Microangiopathy ◽  
Compound Heterozygous Variants

Background: Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a rare autosomal recessive cerebral microangiopathy. Recently, biallelic variants in a non-protein-coding gene SNORD118 have been discovered to cause LCC.Case Presentation: We here report a genetically confirmed childhood case of LCC. The patient was a 4-year-and-1-month-old boy with focal seizures. The age at onset of his seizure was 10 days after birth. The seizures were well-controlled by antiepileptic treatment but reoccurred twice due to a head impact accident and a fever, respectively. He suffered from a self-limited esotropia and unsteady running gait during the seizure onset. He had the typical neuroimaging triad of multifocal intracranial calcifications, cysts, and leukoencephalopathy. Genetic analysis indicated that he carried compound heterozygous variants of n.*9C>T and n.3C>T in SNORD118, which were inherited from his parents.Conclusion: We report a childhood LCC case with compound heterozygous variants in SNORD118. To the best of our knowledge, the patient reported in our case had the youngest onset age of LCC with a determined genotype. The triad cerebral-imaging findings of calcifications, cysts, and leukoencephalopathy provide a crucial diagnostic basis. Moreover, the gene assessment, together with the clinical investigations, should be considered for the diagnosis of LCC.

scholarly journals Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Evelina Siavrienė ◽  
Gunda Petraitytė ◽  
Birutė Burnytė ◽  
Aušra Morkūnienė ◽  
Violeta Mikštienė ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Autosomal Recessive ◽  
Premature Termination Codon ◽  
Limb Girdle Muscular Dystrophy ◽  
Lower Limbs ◽  
Compound Heterozygous ◽  
Targeted Next Generation Sequencing ◽  
Splicing Variant ◽  
Cdna Analysis ◽  
Compound Heterozygous Variants

Abstract Background Autosomal recessive limb–girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis. Case presentation In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband’s cDNA sample. The results revealed that this splicing variant disrupts the original 3′ splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)). Conclusions Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease.

scholarly journals Compound heterozygous variants in the ABCG8 gene in a Japanese girl with sitosterolemia

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Nobuhiro Hashimoto ◽  
Sumito Dateki ◽  
Eri Suzuki ◽  
Takatoshi Tsuchihashi ◽  
Aiko Isobe ◽  
...  
Keyword(s):  
Plant Sterol ◽  
Autosomal Recessive ◽  
Elevated Serum ◽  
Asian Population ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Heterozygous State ◽  
Single Nucleotide ◽  
Compound Heterozygous Variants ◽  
Compound Heterozygous State

AbstractSitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the ABCG8 gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.

scholarly journals Analysis of common and rare VPS13C variants in late-onset Parkinson disease

2020 ◽  
Vol 6 (1) ◽  
pp. 385 ◽  
Author(s):  
Uladzislau Rudakou ◽  
Jennifer A. Ruskey ◽  
Lynne Krohn ◽  
Sandra B. Laurent ◽  
Dan Spiegelman ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Meta Analysis ◽  
Compound Heterozygous ◽  
Tagging Snp ◽  
Targeted Next Generation Sequencing ◽  
Compound Heterozygous Variants ◽  
Reduced Risk

ObjectiveWe aimed to study the role of coding VPS13C variants in a large cohort of patients with late-onset Parkinson disease (PD) (LOPD).MethodsVPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.ResultsNo biallelic carriers of rare VPS13C variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28–0.82, p = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit.ConclusionsOur results do not support a role for rare heterozygous or biallelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.

scholarly journals Autosomal recessive complete STAT1 deficiency caused by compound heterozygous intronic mutations

2020 ◽  
Vol 32 (10) ◽  
pp. 663-671 ◽  
Author(s):  
Sonoko Sakata ◽  
Miyuki Tsumura ◽  
Tadashi Matsubayashi ◽  
Shuhei Karakawa ◽  
Shunsuke Kimura ◽  
...  
Keyword(s):  
Cellular Response ◽  
Autosomal Recessive ◽  
Viral Infections ◽  
Diagnostic Yield ◽  
Compound Heterozygous ◽  
Rna Seq ◽  
Virus Infections ◽  
Genomic Study ◽  
Severe Impairment ◽  
Life Threatening

Abstract Autosomal recessive (AR) complete signal transducer and activator of transcription 1 (STAT1) deficiency is an extremely rare primary immunodeficiency that causes life-threatening mycobacterial and viral infections. Only seven patients from five unrelated families with this disorder have been so far reported. All causal STAT1 mutations reported are exonic and homozygous. We studied a patient with susceptibility to mycobacteria and virus infections, resulting in identification of AR complete STAT1 deficiency due to compound heterozygous mutations, both located in introns: c.128+2 T&gt;G and c.542-8 A&gt;G. Both mutations were the first intronic STAT1 mutations to cause AR complete STAT1 deficiency. Targeted RNA-seq documented the impairment of STAT1 mRNA expression and contributed to the identification of the intronic mutations. The patient’s cells showed a lack of STAT1 expression and phosphorylation, and severe impairment of the cellular response to IFN-γ and IFN-α. The case reflects the importance of accurate clinical diagnosis and precise evaluation, to include intronic mutations, in the comprehensive genomic study when the patient lacks molecular pathogenesis. In conclusion, AR complete STAT1 deficiency can be caused by compound heterozygous and intronic mutations. Targeted RNA-seq-based systemic gene expression assay may help to increase diagnostic yield in inconclusive cases after comprehensive genomic study.

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