Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 229
Filter
1.
Clin Genet ; 92(3): 306-317, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28255985

ABSTRACT

BACKGROUND: Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability. AIMS: To update disease-causing mutations and current clinical knowledge of the disease. MATERIALS AND METHODS: Genetic and clinical information were obtained from a collection of both unreported and previously reported cases. RESULTS: We report 106 families, represented by 143 individuals, carrying a total of 36 genetic variants, 11 of them not previously known to be associated with the disease. Variants include 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants. We also report 5 patients from Gran Canaria, representing the largest known group of unrelated families sharing the same P406L mutation. CONCLUSIONS: Data analysis did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis: All patients improved the oculocutaneous lesions after dietary treatment but neurological symptoms prevailed. The discovery of founder mutations in isolated populations, and the benefits of early intervention, should increase diagnostic awareness in newborns.


Subject(s)
Founder Effect , Genetic Association Studies , Mutation , Phenotype , Tyrosinemias/diagnosis , Tyrosinemias/genetics , Adolescent , Age of Onset , Alleles , Child , Child, Preschool , Female , Genetic Loci , Genotype , Humans , Infant , Infant, Newborn , Male , Pedigree , Polymorphism, Single Nucleotide , Tyrosine Transaminase/genetics , Tyrosinemias/diet therapy , Young Adult
2.
Cancer Chemother Pharmacol ; 71(5): 1173-82, 2013 May.
Article in English | MEDLINE | ID: mdl-23435876

ABSTRACT

BACKGROUND: Preclinical studies demonstrated antiproliferative synergy of 1,25-D3 (calcitriol) with cisplatin. The goals of this phase I/II study were to determine the recommended phase II dose (RP2D) of 1,25-D3 with cisplatin and docetaxel and its efficacy in metastatic non-small-cell lung cancer. METHODS: Patients were ≥18 years, PS 0-1 with normal organ function. In the phase I portion, patients received escalating doses of 1,25-D3 intravenously every 21 days prior to docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) using standard 3 + 3 design, targeting dose-limiting toxicity (DLT) rate <33 %. Dose levels of 1,25-D3 were 30, 45, 60, and 80 mcg/m(2). A two-stage design was employed for phase II portion. We correlated CYP24A1 tagSNPs with clinical outcome and 1,25-D3 pharmacokinetics (PK). RESULTS: 34 patients were enrolled. At 80 mcg/m(2), 2/4 patients had DLTs of grade 4 neutropenia. Hypercalcemia was not observed. The RP2D of 1,25-D3 was 60 mcg/m(2). Among 20 evaluable phase II patients, there were 2 confirmed, 4 unconfirmed partial responses (PR), and 9 stable disease (SD). Median time to progression was 5.8 months (95 % CI 3.4, 6.5), and median overall survival 8.7 months (95 % CI 7.6, 39.4). CYP24A1 SNP rs3787554 (C > T) correlated with disease progression (P = 0.03) and CYP24A1 SNP rs2762939 (C > G) trended toward PR/SD (P = 0.08). There was no association between 1,25-D3 PK and CYP24A1 SNPs. CONCLUSIONS: The RP2D of 1,25-D3 with docetaxel and cisplatin was 60 mcg/m(2) every 21 days. Pre-specified endpoint of 50 % confirmed RR was not met in the phase II study. Functional SNPs in CYP24A1 may inform future studies individualizing 1,25-D3.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Steroid Hydroxylases/genetics , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Calcitriol/administration & dosage , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/administration & dosage , Disease Progression , Docetaxel , Dose-Response Relationship, Drug , Drug Synergism , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Pharmacogenetics , Polymorphism, Single Nucleotide , Survival Rate , Taxoids/administration & dosage , Treatment Outcome , Vitamin D3 24-Hydroxylase
3.
Eye (Lond) ; 25(7): 922-8, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21527955

ABSTRACT

PURPOSE: To correlate the response of topical dorzolamide (Trusopt; Merck) in patients with X-linked retinoschisis (XLRS) with genotype. METHODS: We carried out a retrospective evaluation of four patients (seven eyes) with XLRS, treated with topical dorzolamide. The change in best-corrected visual acuity (VA) and central macular thickness (CMT; central 1 mm subfield thickness) from optical coherence tomography (OCT) was analysed over the follow-up period, using Student's t-test. Each patient also had genetic analysis for mutations in the retinoschisisgene (RS1). RESULTS: The mean age at the start of treatment was 14.7±11 years, and mean follow-up duration was 21.7±7.7 months. Mean CMT at the final follow-up was significantly better than at baseline (291±123 vs 352±119 µm, P=0.007); however, mean VA was worse (0.38±0.25 vs 0.31±0.24 logMAR score, P=0.041). All four patients had a mutation in the RS1gene; there was no apparent association between the type of mutation and the response to topical dorzolamide. CONCLUSION: Topical dorzolamide may have some effect in reducing central macular thickness in patients with XLRS, but this does not necessarily correlate with improvement in VA. In our case series, genotypic information did not predict the response to this treatment.


Subject(s)
Eye Proteins/genetics , Genetic Diseases, X-Linked/drug therapy , Genetic Diseases, X-Linked/genetics , Retinoschisis/drug therapy , Retinoschisis/genetics , Sulfonamides/administration & dosage , Thiophenes/administration & dosage , Administration, Topical , Adolescent , Adult , Child , Female , Genotype , Humans , Macula Lutea/pathology , Male , Retinoschisis/physiopathology , Retrospective Studies , Tomography, Optical Coherence , Visual Acuity , Young Adult
4.
Vet Comp Oncol ; 8(3): 209-20, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20691028

ABSTRACT

Calcitriol potentiates the effect of multiple chemotherapy agents in a variety of tumour models. In this study, we examine whether calcitriol increases chemotherapy or tyrosine kinase inhibitor in vitro cytotoxicity in canine mastocytoma C2 cells. We also evaluate the in vivo effect of DN101, a highly concentrated oral formulation of calcitriol designed specifically for cancer therapy, as a single-agent therapy in dogs with mast cell tumours (MCTs). Calcitriol exhibits synergistic, antiproliferative activity when used in combination with CCNU, vinblastine, imatinib or toceranib in vitro. The concentrations required for 50% growth inhibition were generally two- to six-fold lower when the drugs were used in combination than when used individually. High-dose oral calcitriol induced remission in 4 of 10 dogs (one complete remission, three partial remissions), although the majority experienced toxicity, necessitating discontinuation of the trial. Further evaluation of calcitriol in combination therapy for dogs with MCTs is warranted.


Subject(s)
Calcitriol/therapeutic use , Calcium Channel Agonists/therapeutic use , Dog Diseases/drug therapy , Mastocytoma/veterinary , Skin Neoplasms/veterinary , Animals , Antineoplastic Agents/pharmacology , Benzamides , Blotting, Western/veterinary , Calcitriol/adverse effects , Calcitriol/pharmacology , Calcium Channel Agonists/adverse effects , Calcium Channel Agonists/pharmacology , Cell Line, Tumor , Dogs , Dose-Response Relationship, Drug , Drug Synergism , Female , Imatinib Mesylate , Indoles/pharmacology , Lomustine/pharmacology , Male , Mastocytoma/drug therapy , Mastocytoma/pathology , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Receptors, Calcitriol/analysis , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Treatment Outcome , Vinblastine/pharmacology
5.
Oncogene ; 29(47): 6216-21, 2010 Nov 25.
Article in English | MEDLINE | ID: mdl-20729918

ABSTRACT

Biallelic inactivation of the NF2 gene occurs in the majority of schwannomas. This usually involves a combination of a point mutation or multiexon deletion, in conjunction with either a second point mutation or loss of heterozygosity (LOH). We have performed DNA sequence and dosage analysis of the NF2 gene in a panel of 239 schwannoma tumours: 97 neurofibromatosis type 2 (NF2)-related schwannomas, 104 sporadic vestibular schwannomas (VS) and 38 schwannomatosis-related schwannomas. In total, we identified germline NF2 mutations in 86 out of 97 (89%) NF2 patients and a second mutational event in 77 out of 97 (79%). LOH was by far the most common form of second hit. A combination of microsatellite analysis with either conventional comparative genomic hybridization (CGH) or multiplex ligation-dependent probe amplification (MLPA) identified mitotic recombination (MR) as the cause of LOH in 14 out of 72 (19%) total evaluable tumours. Among sporadic VS, at least one NF2 mutation was identified by sequence analysis or MLPA in 65 out of 98 (66%) tumours. LOH occurred in 54 out of 96 (56%) evaluable tumours, but MR only accounted for 5 out of 77 (6%) tested. LOH was present in 28 out of 34 (82%) schwannomatosis-related schwannomas. In all eight patients who had previously tested positive for a germline SMARCB1 mutation, this involved loss of the whole, or part of the long arm, of chromosome 22. In contrast, 5 out of 22 (23%) tumours from patients with no germline SMARCB1 mutation exhibited MR. High-resolution Affymetrix SNP6 genotyping and copy number (CN) analysis (Affymetrix, Santa Clara, CA, USA) were used to determine the chromosomal breakpoint locations in tumours with MR. A range of unique recombination sites, spanning approximately 11.4 Mb, were identified. This study shows that MR is a mechanism of LOH in NF2 and SMARCB1-negative schwannomatosis-related schwannomas, occurring less frequently in sporadic VS. We found no evidence of MR in SMARCB1-positive schwannomatosis, suggesting that susceptibility to MR varies according to the disease context.


Subject(s)
Loss of Heterozygosity/genetics , Mitosis/genetics , Neurofibromatosis 2/genetics , Recombination, Genetic/genetics , Adolescent , Adult , Child , Chromosome Breakpoints , Gene Dosage/genetics , Genes, Neurofibromatosis 2 , Homozygote , Humans , Neurilemmoma/genetics , Neurofibromatoses/genetics , Polymorphism, Single Nucleotide/genetics , Skin Neoplasms/genetics , Young Adult
6.
J Med Genet ; 47(8): 567-8, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20472658

ABSTRACT

BACKGROUND: Schwannomas and meningiomas are both part of the tumour spectrum of neurofibromatosis type 2 (NF2) and are associated with somatic loss of chromosome 22. They are also found commonly within the general population, unrelated to NF2. Germline SMARCB1 mutations have recently been identified as a pathogenic cause of a subset of familial schwannomatosis cases, and SMARCB1 is a candidate gene for causation of both schwannomas and meningiomas. Recently, Bacci et al reported a germline SMARCB1 mutation associated with familial schwannomatosis and multiple meningiomas. They concluded that SMARCB1 mutations can predispose to multiple meningiomas. METHODS: We screened the SMARCB1 gene in a panel of 47 patients with multiple meningioma unrelated to NF2. RESULTS: We found no germline mutations. CONCLUSION: We conclude that while meningiomas may be associated with the schwannomatosis phenotype, SMARCB1 is not a major contributor to multiple meningioma disease.


Subject(s)
Chromosomal Proteins, Non-Histone/genetics , DNA-Binding Proteins/genetics , Meningeal Neoplasms/genetics , Meningioma/genetics , Mutation/genetics , Transcription Factors/genetics , Humans , SMARCB1 Protein
7.
Acta Physiol (Oxf) ; 194(4): 311-23, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18616619

ABSTRACT

AIM: We compared the clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in domain II (S5-S6) of human, hNa(v)1.5, cardiac Na(+) channels. METHODS: Full clinical evaluation of pedigree members through three generations of a Chinese family combined with SCN5A sequencing from genomic DNA was compared with patch and voltage-clamp results from two independent expression systems. RESULTS: The four mutation carriers showed bradycardia, and slowed sino-atrial, atrioventricular and intraventricular conduction. Two also showed sick sinus syndrome; two had ST elevation in leads V1 and V2. Unlike WT-hNa(v)1.5, whole-cell patch-clamped HEK293 cells expressing R878C-hNa(v)1.5 showed no detectable Na(+) currents (i(Na)), even with substitution of a similarly charged lysine residue. Voltage-clamped Xenopus oocytes injected with either 0.04 or 1.5 microg microL(-1) R878C-hNa(v)1.5 cRNA similarly showed no i(Na), yet WT-hNa(v)1.5 cRNA diluted to 0.0004-0.0008 ng microL(-1)resulted in expression of detectable i(Na). i(Na) was simply determined by the amount of injected WT-hNa(v)1.5: doubling the dose of WT-hNa(v)1.5 cRNA doubled i(Na). i(Na) amplitudes and activation and inactivation characteristics were similar irrespective of whether WT-hNa(v)1.5 cRNA was given alone or combined with equal doses of R878C-hNa(v)1.5 cRNA therefore excluding dominant negative phenotypic effects. Na(+) channel function in HEK293 cells transfected with R878C-hNa(v)1.5 was not restored by exposure to mexiletine (200 microM) and lidocaine (100 microM). Fluorescence confocal microscopy using E3-Nav1.5 antibody demonstrated persistent membrane expression of both WT and R878C-hNa(v)1.5. Modelling studies confirmed that such i(Na) reductions reproduced the SSS phenotype. CONCLUSION: Clinical consequences of the novel R878C mutation correlate with results of physiological studies.


Subject(s)
Arrhythmias, Cardiac/genetics , Mutation/genetics , Myocardium/metabolism , Sodium Channels/genetics , Adult , Animals , Arrhythmias, Cardiac/metabolism , Electrocardiography , Female , Heterozygote , Humans , Immunohistochemistry , Male , Microscopy, Confocal , Pedigree , Sick Sinus Syndrome/genetics , Sick Sinus Syndrome/metabolism , Xenopus
8.
J Med Genet ; 45(6): 332-9, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18285426

ABSTRACT

BACKGROUND: Schwannomatosis is a rare condition characterised by multiple schwannomas and lack of involvement of the vestibular nerve. A recent report identified bi-allelic mutations in the SMARCB1/INI1 gene in a single family with schwannomatosis. We aimed to establish the contribution of the SMARCB1 and the NF2 genes to sporadic and familial schwannomatosis in our cohort. METHODS: We performed DNA sequence and dosage analysis of SMARCB1 and NF2 in 28 sporadic cases and 15 families with schwannomatosis. RESULTS: We identified germline mutations in SMARCB1 in 5 of 15 (33.3%) families with schwannomatosis and 2 of 28 (7.1%) individuals with sporadic schwannomatosis. In all individuals with a germline mutation in SMARCB1 in whom tumour tissue was available, we detected a second hit with loss of SMARCB1. In addition, in all affected individuals with SMARCB1 mutations and available tumour tissue, we detected bi-allelic somatic inactivation of the NF2 gene. SMARCB1 mutations were associated with a higher number of spinal tumours in patients with a positive family history (p = 0.004). CONCLUSION: In contrast to the recent report where no NF2 mutations were identified in a schwannomatosis family with SMARCB1 mutations, in our cohort, a four hit model with mutations in both SMARCB1 and NF2 define a subset of patients with schwannomatosis.


Subject(s)
Chromosomal Proteins, Non-Histone/genetics , DNA-Binding Proteins/genetics , Neurilemmoma/genetics , Neurofibromin 2/genetics , Transcription Factors/genetics , Adolescent , Adult , Amino Acid Sequence , Base Sequence , Child , Chromosomal Proteins, Non-Histone/chemistry , DNA Mutational Analysis , DNA-Binding Proteins/chemistry , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Mutation/genetics , Pedigree , Phenotype , SMARCB1 Protein , Sequence Alignment , Transcription Factors/chemistry
9.
Prostate Cancer Prostatic Dis ; 10(4): 396-7, 2007.
Article in English | MEDLINE | ID: mdl-17404582

ABSTRACT

We report a 71-year male with castration-resistant metastatic prostate cancer who was treated with weekly docetaxel for 12 weeks and developed significant eye irritation and dryness during treatment. Subsequently, the patient presented with a lower eyelid mass, which on excision was demonstrated to be a chalazion. Docetaxel induced Meibomian duct inflammation and blockage is the likely cause of this presentation in a patient with no history of eyelid masses in the past.


Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Chalazion/chemically induced , Eyelid Diseases/chemically induced , Meibomian Glands/drug effects , Prostatic Neoplasms/drug therapy , Taxoids/adverse effects , Aged , Antineoplastic Agents, Phytogenic/therapeutic use , Castration , Chalazion/diagnosis , Chalazion/surgery , Docetaxel , Eyelid Diseases/diagnosis , Eyelid Diseases/surgery , Humans , Male , Meibomian Glands/pathology , Taxoids/therapeutic use
10.
Clin Genet ; 70(5): 388-95, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17026620

ABSTRACT

We assessed the association between breast cancer (BC) and colorectal cancer (CRC) from referral pattern to the Regional Genetics Service including molecular analysis. Hospital computer records and/or department referral books were used to identify cases referred to the Regional Genetic Service during a 16-year period (1990-2005 inclusive). All files were reviewed along with associated demographic data, risk assessments, referral details and results from mutation testing. Families were assessed for hereditary breast and colorectal cancer (HBCC) criteria, and all families with eligible individuals were tested for the 1100delC mutation in CHEK2. A total of 8,612 families were identified. One hundred and sixteen of 1,631 (7.5%) families with a primary referral for CRC fulfilled the criteria for HBCC, whereas only 68/6981 (1%) BC referrals fulfilled these criteria. Blood samples were obtained from 113 individuals from 83/184 families. Only 1/113 (1%) has screened positive for the CHEK2 mutation, whereas 14 (17%) families segregate BRCA1/2 mutations and at least 7 (8.5%) carry MLH1/MSH2 mutations. HBCC syndrome, if it exists as a separate entity, is not likely to be due to CHEK2 mutations. Many families are explicable by existing high-penetrance genes, and further work is necessary to elucidate whether the remainder is due to chance or as yet undiscovered genes.


Subject(s)
Breast Neoplasms/genetics , Colorectal Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , Base Sequence , Breast Neoplasms/enzymology , Checkpoint Kinase 2 , Colorectal Neoplasms/enzymology , DNA Primers/genetics , Female , Genes, BRCA1 , Genes, BRCA2 , Humans , Male , Mutation , Retrospective Studies , Syndrome , United Kingdom
12.
Br J Ophthalmol ; 90(1): 81-6, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16361673

ABSTRACT

BACKGROUND/AIM: X linked retinoschisis (XLRS) is caused by mutations in RS1 which encodes the discoidin domain protein retinoschisin, secreted by photoreceptors and bipolar cells. Missense mutations occur throughout the gene and some of these are known to interfere with protein secretion. This study was designed to investigate the functional consequences of missense mutations at different locations in retinoschisin. METHODS AND RESULTS: The authors developed a structural model of the retinoschisin discoidin domain and used this to predict the effects of missense mutations. They expressed disease associated mutations and found that those affecting conserved residues prevented retinoschisin secretion. Most of the remaining mutations cluster within a series of loops on the surface of the beta barrel structure and do not interfere with secretion, suggesting this region may be a ligand binding site. They also demonstrated that wild type retinoschisin octamerises and associates with the cell surface. A subgroup of secreted mutations reduce oligomerisation (C59S, C219G, C223R). CONCLUSIONS: It is suggested that there are three different molecular mechanisms which lead to XLRS: mutations interfering with secretion, mutations interfering with oligomerisation, and mutations that allow secretion and oligomerisation but interfere with retinoschisin function. The authors conclude that binding of oligomerised retinoschisin at the cell surface is important in its presumed role in cell adhesion.


Subject(s)
Eye Proteins/genetics , Mutation, Missense , Retinoschisis/genetics , Amino Acid Sequence , Animals , Blotting, Western , COS Cells , Chlorocebus aethiops , Dimerization , Eye Proteins/metabolism , Factor Va/genetics , Humans , Male , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Photoreceptor Cells, Vertebrate/metabolism , Retinoschisis/metabolism , Sequence Alignment
14.
Eur J Ophthalmol ; 15(5): 638-40, 2005.
Article in English | MEDLINE | ID: mdl-16167295

ABSTRACT

PURPOSE: To characterize electroretinogram (ERG) and molecular genetic findings in a family with XLRS1 mutation. The authors present two cases of a Portuguese family with juvenile retinoschisis with a mutation in exon 6. METHODS: Two brothers and their parents, grandmother, and uncle underwent a full ophthalmic examination. The two brothers with ophthalmic disease were evaluated with color fundus photography, fluorescein angiography, optical coherence tomography (OCT), molecular genetic study (Group VI of Retinoschisis Consortium), pattern visual evoked potential (PVEP), and full field ERG. RESULTS: Both patients presented funduscopic manifestations of vitre o retinal degeneration. They presented peripheral schisis and retinal detachment. However, foveal schisis had never been observed at funduscopy. A negative ERG was recorded in both. Six months after that, the younger brother showed a typical foveal schisis at fundus examination. A retinoschisis gene (XLRS1) mutation with transition of cytosine by thymine at position 608 (608C > T) had been identified in both. CONCLUSIONS: Negative ERG is the most secure clinical marker to establish the diagnosis of juvenile retinoschisis. XLRS1 gene 608C > T mutation was described for the first time in a Portuguese family.


Subject(s)
Eye Proteins/genetics , Point Mutation , Retinoschisis/genetics , Child , Child, Preschool , Electroretinography , Evoked Potentials, Visual , Exons/genetics , Fluorescein Angiography , Humans , Male , Pedigree , Portugal , Retina/physiopathology , Retinoschisis/diagnosis , Retinoschisis/physiopathology , Tomography, Optical Coherence
15.
J Med Genet ; 42(6): e35, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15937075

ABSTRACT

BACKGROUND: Inactivating mutations of the gene RS1 lead to X-linked retinoschisis, a progressive retinal dystrophy characterised by schisis within the inner layers of the neuroretina. The mutation spectrum is large and the phenotype variable. AIM: To determine whether there is a correlation between mutation type and disease severity. METHODS: We identified the causative mutation in 86 affected patients and examined each of these patients in detail. Different categories of mutation were compared for each phenotypic characteristic. RESULTS: We found a reduction in visual acuity with increasing age and worsening macular pathology in patients over 30 years old (p < or = 0.001), but there was no correlation between mutation type and severity of disease. Furthermore, we found a wide variation in phenotype even within families. CONCLUSIONS: Identifying the causative mutation in patients with X-linked retinoschisis is helpful in confirming diagnosis and in counselling of family members but cannot be used to predict prognosis for an individual patient.


Subject(s)
Eye Proteins/genetics , Retinoschisis/diagnosis , Adolescent , Adult , Aged , Child , Child, Preschool , DNA Mutational Analysis , Female , Genotype , Humans , Male , Middle Aged , Phenotype , Retinoschisis/genetics , United Kingdom
16.
Eur J Ophthalmol ; 15(5): 638-640, 2005.
Article in English | MEDLINE | ID: mdl-28221463

ABSTRACT

PURPOSE: To characterize electroretinogram (ERG) and molecular genetic findings in a family with XLRS1 mutation. The authors present two cases of a Portuguese family with juvenile retinoschisis with a mutation in exon 6. METHODS: Two brothers and their parents, grandmother, and uncle underwent a full ophthalmic examination. The two brothers with ophthalmic disease were evaluated with color fundus photography, fluorescein angiography, optical coherence tomography (OCT), molecular genetic study (Group VI of Retinoschisis Consortium), pattern visual evoked potential (PVEP), and full field ERG. RESULTS: Both patients presented funduscopic manifestations of vitre o retinal degeneration. They presented peripheral schisis and retinal detachment. However, foveal schisis had never been observed at funduscopy. A negative ERG was recorded in both. Six months after that, the younger brother showed a typical foveal schisis at fundus examination. A retinoschisis gene (XLRS1) mutation with transition of cytosine by thymine at position 608 (608C>T) had been identified in both. CONCLUSIONS: Negative ERG is the most secure clinical marker to establish the diagnosis of juvenile retinoschisis. XLRS1 gene 608C>T mutation was described for the first time in a Portuguese family. (Eur J Ophthalmol 2005; 15: 638-40 ).

17.
Doc Ophthalmol ; 111(3): 169-78, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16523234

ABSTRACT

PURPOSE: To determine whether patients with congenital stationary night blindness (CSNB) have electrophysiological evidence of optic nerve fibre mis-routing similar to that found in patients with ocular albinism (OA). METHOD: We recorded the Pattern Onset VEP using a protocol optimised to detect mis-routing of optic nerve fibres in older children and adults. We tested 20 patients (age 15-69 yrs) with X-linked or autosomal recessive CSNB, 14 patients (age 9-56 yrs) with OA and 13 normally pigmented volunteers (age 21-66 yrs). We measured the amplitude and latency of the CI component at the occipital midline and over left and right occipital hemispheres. We also assessed the computed inter-hemispheric "difference" signal. Subjects with CSNB were classified as having the "complete" or "incomplete" phenotype on the basis of their ERG characteristics. Members of X-linked CSNB pedigrees underwent mutation screening of the NYX and CACNA1F genes. RESULTS: CI was significantly smaller over the ipsilateral hemisphere and more prominent over the contralateral hemisphere in OA patients compared with both controls and CSNB patients. In CSNB patients CI response amplitudes were not significantly different from controls but peak latency was prolonged at all three electrodes compared with controls. The inter-hemispheric "difference" signal was abnormal for the OA group but not for the CSNB group. Contralateral dominance of CI could be identified in the majority of OA patients and the "difference" signal was opposite in polarity for left compared with right eye stimulation in every patient in this group. Only 3 of 20 patients with CSNB showed significant inter-hemispheric asymmetry similar to that seen in the OA patients. All 3 CSNB patients with evidence for optic nerve fibre mis-routing had X-linked pedigrees: 2 had an identified mutation in the NYX gene but no mutation in either the NYX or CACNA1F genes was identified in the third. VEP evidence of optic nerve fibre mis-routing was present in 3 of the 11 subjects with "complete" phenotype and none of the 9 patients with "incomplete" phenotype CSNB. CONCLUSION: Mis-routing of optic nerve fibres does occur in CSNB but we found evidence of it in only 15% of our patients.


Subject(s)
Evoked Potentials, Visual , Nerve Fibers/physiology , Night Blindness/congenital , Night Blindness/diagnosis , Optic Nerve/physiopathology , Adolescent , Adult , Aged , Child , Genotype , Humans , Middle Aged , Severity of Illness Index
18.
Child Care Health Dev ; 30(5): 551-5, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15320931

ABSTRACT

Universal screening introduced in the 1960s has reduced the incidence of learning disability resulting from phenylketonuria (PKU), which is a treatable condition. Nonetheless, PKU may still be having an impact on the paediatric-age population. We report a woman with previously undiagnosed PKU who was born before the onset of universal screening. She is of normal intelligence, and so the diagnosis was not suspected until after the birth of her three children. Her serum phenylalanine concentration was found to be in excess of 1 mmol/L, well into the toxic range. She has had three sons, all of whom have a significant degree of learning disability resulting from intrauterine exposure to toxic levels of phenylalanine. None of the sons had microcephaly, a physical sign that, if present, might have helped to point towards the correct diagnosis. We suggest that maternal PKU should be suspected where there is sibling recurrence of cognitive impairment, particularly where the mother was born before the initiation of the neonatal screening programme for PKU.


Subject(s)
Child Behavior Disorders/genetics , Learning Disabilities/genetics , Phenylketonuria, Maternal/genetics , Adult , Child , Female , Humans , Male , Pedigree , Phenotype , Phenylalanine/blood , Phenylketonuria, Maternal/blood , Pregnancy
19.
Br J Ophthalmol ; 87(11): 1413-20, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14609846

ABSTRACT

AIM: To correlate the phenotype of X linked congenital stationary night blindness (CSNBX) with genotype. METHODS: 11 CSNB families were diagnosed with the X linked form of the disease by clinical evaluation and mutation detection in either the NYX or CACNA1F gene. Phenotype of the CSNBX patients was defined by clinical examination, psychophysical, and standardised electrophysiological testing. RESULTS: Comprehensive mutation screening identified NYX gene mutations in eight families and CACNA1F gene mutations in three families. Electrophysiological and psychophysical evidence of a functioning but impaired rod system was present in subjects from each genotype group, although the responses tended to be more severely affected in subjects with NYX gene mutations. Scotopic oscillatory potentials were absent in all subjects with NYX gene mutations while subnormal OFF responses were specific to subjects with CACNA1F gene mutations. CONCLUSIONS: NYX gene mutations were a more frequent cause of CSNBX than CACNA1F gene mutations in the 11 British families studied. As evidence of a functioning rod system was identified in the majority of subjects tested, the clinical phenotypes "complete" and "incomplete" do not correlate with genotype. Instead, electrophysiological indicators of inner retinal function, specifically the characteristics of scotopic oscillatory potentials, 30 Hz flicker and the OFF response, may prove more discriminatory.


Subject(s)
Calcium Channels, L-Type , Calcium Channels/genetics , Genetic Diseases, X-Linked/genetics , Night Blindness/genetics , Proteoglycans/genetics , Base Sequence , Color Perception Tests , Dark Adaptation , Electroretinography , Female , Genetic Diseases, X-Linked/physiopathology , Genotype , Humans , Male , Molecular Sequence Data , Mutation , Night Blindness/physiopathology , Phenotype , Prospective Studies , Retina/physiopathology , Vision Disorders/physiopathology , Visual Acuity , Visual Field Tests
SELECTION OF CITATIONS
SEARCH DETAIL
...