NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms.
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ABSTRACT:
SUBMITTER: Zanette V
PROVIDER: S-EPMC8607527 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T?>?C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C?>?T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C?>?T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population-specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations.
| S-EPMC6189076 | biostudies-literature
Project description:Reduced nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) is the largest complex of the mitochondrial respiratory chain and complex I deficiency accounts for approximately 30% cases of respiratory-chain deficiency in humans. Only seven mitochondrial DNA genes, but >35 nuclear genes encode complex I subunits. In an attempt to elucidate the molecular bases of complex I deficiency, we studied the six most-conserved complex I nuclear genes (NDUFV1, NDUFS8, NDUFS7, NDUFS1, NDUFA8, and NDUFB6) in a series of 36 patients with isolated complex I deficiency by denaturing high-performance liquid chromatography and by direct sequencing of the corresponding cDNA from cultured skin fibroblasts. In 3/36 patients, we identified, for the first time, five point mutations (del222, D252G, M707V, R241W, and R557X) and one large-scale deletion in the NDUFS1 gene. In addition, we found six novel NDUFV1 mutations (Y204C, C206G, E214K, IVS 8+41, A432P, and del nt 989-990) in three other patients. The six unrelated patients presented with hypotonia, ataxia, psychomotor retardation, or Leigh syndrome. These results suggest that screening for complex I nuclear gene mutations is of particular interest in patients with complex I deficiency, even when normal respiratory-chain-enzyme activities in cultured fibroblasts are observed.
| S-EPMC1226121 | biostudies-literature
Project description:SCN4A encodes the Nav1.4 channel and mutations in SCN4A lead to different ionic channelopathies. In this study, one sporadic individual of periodic paralysis, one paramyotonia family and 200 normal healthy controls are enrolled. Genomic DNA was extracted from peripheral blood leukocytes, followed by polymerase chain reaction and DNA sequencing of candidate genes, including SCN4A and CACNA1S. As a result, heterozygous mutations c.2024G>A (R675Q) and c.1333G>A (V445M) of gene SCN4A were identified in the hypokalemic periodic paralysis patient and the paramyotonia congenita family respectively. Both mutations were not detected in healthy controls. Compared with reported cases, patients with mutation R675Q usually do not present hypokalemic periodic paralysis but hyperkalemic or normokalemic periodic paralysis. The mutation V445M was first reported in Chinese patients with nondystrophic myotonias. In addition, we carried out literature review by summarizing clinical features of the 2 mutations and establish the genotype-phenotype correlations to provide guidance for diagnosis.
| S-EPMC4594454 | biostudies-literature
Project description:Recently published case reports relating to anesthesia in patients with coronavirus disease (COVID-19) were reviewed. The diagnosis of COVID-19 was confirmed by positive results of reverse transcriptase polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Numerous reports handled emergency cesarean delivery. Primary symptoms and laboratory data of pregnant women with COVID-19 were similar to those of non-pregnant patients. Although the mortality rate is reported to be high after surgery in patients with COVID-19, cesarean delivery was successfully performed under regional anesthesia in most cases and postoperative course was favorable both in the parents and newborns. There is no direct evidence of vertical mother-to-child transmission of SARS-CoV-2; however, a diagnosis of COVID-19 was made in a newborn two hours after delivery from a pregnant woman with COVID-19, based on the increased immunoglobulin levels and deranged liver function, suggesting that its possibility cannot be completely eliminated. Emergency cerebral shunt reconstruction was performed repeatedly in an eight-month-old boy with COVID-19. The tracheal tube was removed in the operating room after surgery and postoperative course was uneventful. All the procedures should be performed in isolated operating rooms with medical staff with level-3 personal protection to ensure the safety of patients and health care providers.
| S-EPMC7354366 | biostudies-literature
Project description:BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is a riboflavin-responsive lipid-storage myopathy caused by mutations in the EFTA, EFTB or ETFDH genes. We report a Chinese family of Southern Min origin with two affected siblings with late-onset riboflavin-responsive MADD due to a homozygous c.250G?>?A EFTDH mutation and review the genetic epidemiology of the c.250G?>?A mutation.Case presentationBoth siblings presented with exercise-induced myalgia, progressive proximal muscle weakness and high levels of serum muscle enzymes and were initially diagnosed as polymyositis after a muscle biopsy. A repeat biopsy in one sibling subsequently showed features of lipid storage myopathy and genetic analysis identified a homozygous mutation (c.250G?>?A) in the ETFDH gene in both siblings and carriage of the same mutation by both parents. Glucocorticoid therapy led to improvement in muscle enzyme levels, but little change in muscle symptoms, and only after treatment with riboflavin was there marked improvement in exercise tolerance and muscle strength. The frequency and geographic distribution of the c.250G?>?A mutation were determined from a literature search for all previously reported cases of MADD with documented mutations. Our study found the c.250G?>?A mutation is the most common EFTDH mutation in riboflavin-responsive MADD (RR-MADD) and is most prevalent in China and South-East Asia where its epidemiology correlates with the distribution and migration patterns of the southern Min population in Southern China and neighbouring countries.ConclusionsMutations in ETFDH should be screened for in individuals with lipid-storage myopathy to identify patients who are responsive to riboflavin. The c.250G?>?A mutation should be suspected particularly in individuals of southern Min Chinese background.
| S-EPMC6921586 | biostudies-literature
Project description:BACKGROUND:Historically, three founder mutations in the BRCA1/2 (OMIM 113705; OMIM 600185) genes have been the focus of cancer risks within the Ashkenazi Jewish (AJ) population. However, there are several additional mutations associated with increased susceptibility to cancer in individuals of AJ ancestry. METHODS:We report three patients who exemplify the need to keep these additional founder mutations in mind when pursuing hereditary cancer genetic testing of individuals in this population. All gene sequences in this paper were aligned to reference sequences based on human genome build GRCh37/UCSC hg19. RESULTS:review of the literature discusses that the combined risk is 12.36%-20.83% forhaving 1 of the 10 hereditary cancer AJ founder mutations in the BRCA1, BRCA2, CHEK2 (OMIM 604373), APC (OMIM 611731), MSH2 (OMIM 609309), MSH6 (OMIM 600678), and GREM1 (OMIM 603054) genes for individuals of AJ ancestry. CONCLUSION:We recommend testing for all 10 of these AJ founder cancer susceptibility mutations for individuals within this population as standard screening in order to ensure appropriate cancer risk management and cascade testing.
| S-EPMC6305650 | biostudies-literature
Project description:IntroductionSince COVID-19 outbreak, various studies mentioned the occurrence of neurological disorders. Of these, encephalitis is known as a critical neurological complication in COVID-19 patients. Numerous case reports and case series have found encephalitis in relation to COVID-19, which have not been systematically reviewed. This study aims to evaluate the clinical symptoms, diagnosis, treatment, and outcome of COVID-19-associated encephalitis.MethodsWe used the Pubmed/Medline, Embase, and Web of Science databases to search for reports on COVID-19-associated encephalitis from January 1, 2019, to March 7, 2021. The irrelevant studies were excluded based on screening and further evaluation. Then, the information relating diagnosis, treatment, clinical manifestations, comorbidities, and outcome was extracted and evaluated.ResultsFrom 4455 initial studies, 45 articles met our criteria and were selected for further evaluation. Included publications reported an overall number of 53 COVID-19-related encephalitis cases. MRI showed hyperintensity of brain regions including white matter (44.68%), temporal lobe (17.02%), and thalamus (12.76%). Also, brain CT scan revealed the hypodensity of the white matter (17.14%) and cerebral hemorrhages/hemorrhagic foci (11.42%) as the most frequent findings. The IV methylprednisolone/oral prednisone (36.11%), IV immunoglobulin (27.77%), and acyclovir (16.66%) were more preferred for COVID-19 patients with encephalitis. From the 46 patients, 13 (28.26%) patients were died in the hospital.ConclusionIn this systematic review, characteristics of COVID-19-associated encephalitis including clinical symptoms, diagnosis, treatment, and outcome were described. COVID-19-associated encephalitis can accompany with other neurological symptoms and involve different brain. Although majority of encephalitis condition are reversible, but it can lead to life-threatening status. Therefore, further investigation of COVID-19-associated encephalitis is required.
| S-EPMC9102669 | biostudies-literature
Project description:BACKGROUND:Proximal femoral focal deficiency is an extremely rare congenital anomaly with an incidence of 1.1-2.0 in 100,000 live births. It is a dysplastic phenomenon with predilections for the proximal two-thirds of the femur leading to limb length discrepancies. We report two cases of proximal femoral focal deficiency, which is a rare entity. CASE PRESENTATIONS:Case 1 A 4.5-month-old baby Annang tribe girl was referred in April 2019 to our Radiology Department, University of Uyo Teaching Hospital, Nigeria for lower limb radiographs. This was on account of her shortened left lower limb from birth despite uneventful antenatal history. An examination revealed bulky left thigh with abduction of her left hip joint. Radiographic evaluations showed absent left femoral capital epiphysis, with deficient proximal left femur. A diagnosis of proximal femoral focal deficiency was made. Sadly, the parents and baby failed to honor future orthopedic consultations on intimation of sequential management protocols. Case 2 A 4-month-old baby Ibibio tribe girl was similarly referred in August 2019 to the same Radiology Department for lower limb conventional radiographs due to short left lower limb that was noticed from birth. An examination showed shortened left lower limb in external rotation. Her right and left lower limbs measured 27?cm and 23?cm, respectively, with landmark taken from anterior superior iliac spine to tip of medial malleolus. A diagnosis of proximal femoral focal deficiency was made. Corroborating radiographs showed shortened and hypoplastic left femoral shaft but preserved femoral capital epiphysis. Coincidentally, the parents have not brought back their baby to our orthopedic clinic. CONCLUSIONS:The discovery of two cases of proximal femoral focal deficiency, a rare entity, from referrals for conventional radiography in our Radiology Department encourages literature documentation. Such recognition will facilitate early institution of management, thus ensuring meaningful childhood growth.
| S-EPMC7001305 | biostudies-literature
Project description:Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D), is a rare autosomal recessive disorder, characterized by life-threatening hyperammonemia. In this study, we presented the detailed clinical features and genetic analysis of two patients with neonatal-onset CPS1D carrying two compound heterozygous variants of c.1631C > T (p.T544M)/c.1981G > T (p.G661C), and c.2896G > T (p.E966X)/c622-3C > G in CPS1 gene, individually. Out of them, three variants are novel, unreported including a missense (c.1981G > T, p.G661C), a nonsense (c.2896G > T, p.E966X), and a splicing change of c.622-3C > G. We reviewed all available publications regarding CPS1 mutations, and in total 264 different variants have been reported, with majority of 157 (59.5%) missense, followed by 35 (13.2%) small deletions. This study expanded the mutational spectrum of CPS1. Moreover, our cases and review further support the idea that most (?90%) of the mutations were "private" and only ?10% recurred in unrelated families.
| S-EPMC6713721 | biostudies-literature
Project description:BackgroundTubulinopathies result from mutations in tubulin genes, including TUBG1, responsible for cell microtubules, are characterized by brain development abnormalities, microcephaly, early-onset epilepsy, and motor impairment. Only eleven patients with TUBG1 mutations have been previously described in literature to our knowledge. Here we present two new patients with novel de novo TUBG1 mutations and review other cases in the literature.Case presentationsBoth patients have microcephaly and intellectual disability. Patient B further fits a more typical presentation, with well-controlled epilepsy and mild hypertonia, whereas Patient A's presentation is much milder without these other features.ConclusionThis report expands the spectrum of TUBG1 mutation manifestations, suggesting the possibility of less severe phenotypes for patients and families, and influencing genetic counselling strategies.
| S-EPMC6545025 | biostudies-literature