Hawkinsinuria in two unrelated Greek newborns: identification of a novel variant, biochemical findings and treatment

2016 ◽  
Vol 29 (1) ◽  
Author(s):  
Georgia Thodi ◽  
Kleopatra H. Schulpis ◽  
Yannis Dotsikas ◽  
Christiane Pavlides ◽  
Elina Molou ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Brain Mri ◽  
Liver Function Tests ◽  
Blood Levels ◽  
Chromatographic Techniques ◽  
Expanded Newborn Screening ◽  
Novel Variant ◽  
Tyrosine Metabolism ◽  
Plasma Tyrosine ◽  
Rare Inborn Error

AbstractHawkinsinuria is a rare inborn error of tyrosine metabolism.To study novel hawkinsinuria cases by monitoring their biochemical profile and conducting a mutation analysis.Among 92,519 newborns that underwent expanded newborn screening, two unrelated cases with high tyrosine blood levels were further investigated by chromatographic techniques and via genetic testing for 4-hydroxyphenylpyruvate dioxygenase (HPD) gene.Elevated levels were monitored for blood/plasma tyrosine and for the specific diagnostic markers in urine. The two newborns were put on a special low tyrosine diet. Till completion of the 1st year of their life, liver function tests and brain MRI were normal. The mutation A33T was identified in both cases, while one neonate carried an additional novel mutation ofTwo mutations of

scholarly journals Emergence of a Novel Mutation in the FLLA Region of Hepatitis B Virus during Lamivudine Therapy

2005 ◽  
Vol 49 (7) ◽  
pp. 2618-2624 ◽  
Author(s):  
S. Balakrishna Pai ◽  
A. Mithat Bozdayi ◽  
Rekha B. Pai ◽  
Tolunay Beker ◽  
Mustafa Sarioglu ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Novel Mutation ◽  
Site Directed Mutagenesis ◽  
Human Hepatoma Cells ◽  
Lamivudine Therapy ◽  
Major Mechanism ◽  
B Virus ◽  
Novel Variant ◽  
Ymdd Motif

ABSTRACT The emergence of resistance to lamivudine has been one of the major stumbling blocks to successful treatment and control of hepatitis B virus (HBV) infections. The major mechanism of resistance has been attributed to the alteration in the YMDD motif of the HBV polymerase due to an amino acid change of rtM204 to V/I and an accompanying rtL180M conversion. A novel mutation pattern in a patient having clinical breakthrough under lamivudine therapy was discovered. The mutant had a rtL180C/M204I genotype and was detected after 2 years of therapy with lamivudine. To characterize this novel variant, site-directed mutagenesis was performed using a vector construct containing the HBV genome. Transient transfection studies in human hepatoma cells with HBV carrying the new mutant demonstrated that the rtL180C/M204I mutant was resistant to lamivudine up to 10 μM. The resistance profile was comparable to that of the previously reported rtL180 M/M204I-containing virus. These observations were further confirmed by generation of stable cultures transfected with the mutant virus.

A novel variant in PAX6 as the cause of aniridia in a Chinese family

2020 ◽  
Author(s):  
Xin Jin ◽  
Wei Liu ◽  
HouBin Huang
Keyword(s):  
Nonsense Mutation ◽  
Novel Mutation ◽  
Causative Mutation ◽  
Chinese Family ◽  
The Novel ◽  
Targeted Next Generation Sequencing ◽  
Iris Defect ◽  
The Family ◽  
Novel Variant ◽  
Pax6 Mutation

Abstract Background: Aniridia is a kind of congenital human panocular anomaly, which is related to PAX6 commonly. Methods: A Chinese Aniridia pedigree underwent ophthalmic examinations, including visual acuity, slit lamp and fundoscopy examination. The targeted next-generation sequencing of Aniridia genes was used to identify the causative mutation. Results: A novel heterozygous PAX6 nonsense mutation c.619A>T (p.K207*) was identified in the Chinese autosomal dominant family with aniridia. Phenotypes related to the novel mutation include nystagmus, iris defect, cataract and absence of macular fovea. Conclusion: The novel nonsense mutation in PAX6 was responsible for aniridia phenotype in the family. which expands the spectrum of the PAX6 mutation and its associated phenotype.

scholarly journals Cochlear Implantation in a Patient with a Novel POU3F4 Mutation and Incomplete Partition Type-III Malformation

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xiuhua Chao ◽  
Yun Xiao ◽  
Fengguo Zhang ◽  
Jianfen Luo ◽  
Ruijie Wang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cochlear Implantation ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Bioinformatic Analysis ◽  
Chinese Family ◽  
Whole Exome ◽  
Novel Variant ◽  
Genetic Features ◽  
The Right

Aims. This study is aimed at (1) analyzing the clinical manifestations and genetic features of a novel POU3F4 mutation in a nonsyndromic X-linked recessive hearing loss family and (2) reporting the outcomes of cochlear implantation in a patient with this mutation. Methods. A patient who was diagnosed as the IP-III malformation underwent cochlear implantation in our hospital. The genetic analysis was conducted in his family, including the whole-exome sequencing combined with Sanger sequencing and bioinformatic analysis. Clinical features, preoperative auditory and speech performances, and postoperative outcomes of cochlear implant (CI) were assessed on the proband and his family. Results. A novel variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was detected in the family, which was cosegregated with the hearing loss. This variant was absent in 200 normal-hearing persons. The phylogenetic analysis and structure modeling of Pou3f4 protein further confirmed that the novel mutation was pathogenic. The proband underwent cochlear implantation on the right ear at four years old and gained greatly auditory and speech improvement. However, the benefits of the CI declined about three and a half years postoperation. Though the right ear had been reimplanted, the outcomes were still worse than before. Conclusion. A novel frame shift variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was identified in a Chinese family with X-linked inheritance hearing loss. A patient with this mutation and IP-III malformation could get good benefits from CI. However, the outcomes of the cochlear implantation might decline as the patient grows old.

L-[U-14C] Tyrosine Metabolism of the Perfused Cat Brain with High Plasma Phenylalanine or without Plasma Tyrosine

1970 ◽  
Vol 24 (4) ◽  
pp. 219-226
Author(s):  
Shosuke WATANABE ◽  
Katsusuke MITSUNOBU ◽  
Takanori SANNOMIYA ◽  
Saburo OTSUKI
Keyword(s):  
High Plasma ◽  
Plasma Phenylalanine ◽  
Cat Brain ◽  
Tyrosine Metabolism ◽  
Plasma Tyrosine

scholarly journals Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism

2012 ◽  
Vol 56 (8) ◽  
pp. 540-544 ◽  
Author(s):  
Daiane Beneduzzi ◽  
Ericka B. Trarbach ◽  
Ana Claudia Latronico ◽  
Berenice Bilharinho de Mendonca ◽  
Letícia F. G. Silveira
Keyword(s):  
In Silico ◽  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
In Silico Analysis ◽  
Control Group ◽  
Coding Region ◽  
Novel Variant ◽  
Gonadotropin Releasing Hormone Receptor ◽  
Inactivating Mutation ◽  
Silico Analysis

We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation. Arq Bras Endocrinol Metab. 2012;56(8):540-4

scholarly journals Pelizaeus-Merzbacher Disease with Novel Variant: Case Report

2021 ◽  
Author(s):  
Isadora Souza Rocha ◽  
Paola Nabhan Leonel dos Santos ◽  
João Guilherme Bochnia Küster ◽  
Maria Angélica Vieira Lizama ◽  
Vinícius Riegel Giugno ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Case Report ◽  
Upper Limb ◽  
Brain Mri ◽  
Behavioral Disorder ◽  
Abnormal Development ◽  
Speech Impairment ◽  
Novel Variant ◽  
Plp1 Gene ◽  
Pelizaeus Merzbacher Disease

Context: Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, associated with myelin sheath development and stability. The result is a broad spectrum of clinical phenotypes. Diagnosis is confirmed by genetic testing. Clinical features include hypotonia followed by progressive spasticity, nystagmus, ataxia and cognitive impairment. Males are more affected. Females are asymptomatic or present milder symptoms. Most cases arise from duplications, point and null mutations. Null mutations are associated with milder phenotypes. Brain Magnetic Resonance Imaging (MRI) may reveal hypomyelination. There is no disease modifying treatment for PMD. We aim to present the case of a woman with a novel variant of the PLP1 gene. Case report: A 38-year-old female presented with 23 years of progression of upper limb tremor, speech impairment, lower limb rigidity and urinary incontinence. She reported abnormal development of reading and writing skills. She had a brother with cognitive impairment, delayed motor development, gait disorder and generalized tonic-clonic seizures; and a sister with upper limb tremor, dysarthria and behavioral disorder. Hypomyelination was detected on brain MRI. Complete exome sequencing detected a novel likely pathogenic variant of PLP1 gene: ChrX(GRCh37):NC_000023.10:g.103041651del:NM _000533.3:c449del, p.Asp150AlafsTer10, heterozygous. Conclusions: The patient’s case resembles a milder form of PMD. This is supported by literature linking deletions and female sex to milder phenotypes. In 20 to 40% of cases with suggestive clinical findings, no PLP1 mutation is found. New studies are needed to identify other variants associated with PMD.

scholarly journals Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Layal Abi Farraj ◽  
Wassim Daoud Khatoun ◽  
Naji Abou Chebel ◽  
Victor Wakim ◽  
Katia Dawali ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Developmental Delay ◽  
Novel Mutation ◽  
Blood Levels ◽  
Facial Dysmorphism ◽  
Loss Of Function ◽  
Clinical Genetic ◽  
Severe Intellectual Disability

Abstract Background Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population. Case presentation Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis. Conclusion Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.

TYROSINOSIS: A PATIENT WITHOUT LIVER OR RENAL DISEASE

PEDIATRICS ◽  
1971 ◽  
Vol 48 (3) ◽  
pp. 393-400
Author(s):  
James L. Holston ◽  
Harvey L. Levy ◽  
Gary A. Tomlin ◽  
Ruby J. Atkins ◽  
T. H. Patton ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Mental Retardation ◽  
Renal Disease ◽  
Urinary Excretion ◽  
Hepatic Disease ◽  
Severe Mental Retardation ◽  
Primary Defect ◽  
Biochemical Evidence ◽  
Tyrosine Metabolism ◽  
Plasma Tyrosine

A child institutionalized because of severe mental retardation was found to have biochemical evidence of tyrosinosis. He has had no evidence of hepatic disease. In addition, he has had no hyperaminoaciduria, glycosuria, or rickets. Plasma tyrosine concentrations while he was on a regular diet ranged from 16.0 to 25.6 mg per 100 ml. Urinary excretion of tyrosine and tyrosine metabolites, including p-hydroxyphenylpyruvic acid, p-hydroxyphenyllactic acid, and p-hydroxyphenyl-acetic acid, were markedly increased. This patient appears to have a primary defect in tyrosine metabolism and represents individuals with persisting tyrosinemia and tyrosyluria in whom no hepatorenal disease is found.

Riboflavin-Responsive Multiple Acyl-CoA Dehydrogenase Deficiency Associated with Hepatoencephalomyopathy and White Matter Signal Abnormalities on Brain MRI

2017 ◽  
Vol 48 (03) ◽  
pp. 194-198 ◽  
Author(s):  
Päivi Myllynen ◽  
Marja Perhomaa ◽  
Hannu Tuominen ◽  
Riikka Keski-Filppula ◽  
Seppo Rytky ◽  
...  
Keyword(s):  
White Matter ◽  
Motor Skills ◽  
Dehydrogenase Deficiency ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Acid Oxidation ◽  
Homozygous Mutation ◽  
Liver Size ◽  
Variable Nature ◽  
Rare Inborn Error

AbstractMultiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting both fatty acid and amino acid oxidation. It can manifest at any age, but riboflavin-responsiveness has mainly been described in less severely affected patients. We describe an infant with severe MADD presenting with profound hypotonia and hepatomegaly. Treatment with riboflavin improved his muscle strength, liver size, and biochemical markers. A homozygous mutation of electron transfer flavoprotein dehydrogenase (ETFDH) was found. His motor skills continued to progress until a fatal infection-triggered deterioration at the age of 34 months. We show changes in brain magnetic resonance imaging over the course of the disease, with profound white matter abnormalities during the deterioration phase. Aggregates of mitochondria with abnormal cristae in muscle electron microscopy were noticed already in infancy. An unusual lactate dehydrogenase (LDH) isoenzyme pattern with LDH-1 predominance was additionally observed. This case demonstrates riboflavin-responsiveness in a severely affected infant with both muscular and extramuscular involvement and further underlines the variable nature of this disease.

scholarly journals A novel variant in PAX6  as the cause of aniridia in a Chinese family

2020 ◽  
Author(s):  
Xin Jin ◽  
Wei Liu ◽  
HouBin Huang ◽  
Linghui Qv ◽  
Wenqin Xv
Keyword(s):  
Autosomal Dominant ◽  
Novel Mutation ◽  
Causative Mutation ◽  
Chinese Family ◽  
The Novel ◽  
Slit Lamp ◽  
Targeted Next Generation Sequencing ◽  
Novel Variant ◽  
Foveal Hypoplasia ◽  
Generation Sequencing

Abstract Background: Aniridia is a kind of congenital human pan-ocular anomaly, which is related to PAX6 commonly.Methods: The ophthalmic examinations including visual acuity, slit lamp and fundoscopy examination were performed in a Chinese aniridia pedigree. The targeted next-generation sequencing of aniridia genes was used to identify the causative mutation.Results: A novel heterozygous PAX6 nonsense mutation c.619A>T (p.K207*) was identified in the Chinese autosomal dominant family with aniridia. Phenotype related to the novel mutation included nystagmus, keratopathy, absence of iris, cataract and foveal hypoplasia.Conclusion: The novel nonsense variation in PAX6 was the cause of aniridia in this family, which expanded the spectrum of the PAX6 mutation.

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