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Autosomal Dominant (autosomal + dominant)
Terms modified by Autosomal Dominant Selected AbstractsGenotype,phenotype correlation in some autosomal recessive hereditary spastic paraplegiasJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2004F Manganelli Hereditary spastic paraplegias (HSPs) are a group of clinically and genetically inherited disorders. Spastic paraparesis (SP), the main clinical feature of all HSPs can occur in relative isolation in the "pure" form or in combination with other neurological deficits in "complicated" forms. Autosomal dominant, autosomal recessive (AR) and X-linked recessive inheritance pattern of HSPs have been reported. At present, among AR-HSPs, three genes, paraplegin (SPG7), spartin (SPG20 , Troyer syndrome) and maspardin (SPG21) have been identified and six genetic loci have been mapped (SPG5, SPG11, SPG14, SPG15, SPG24, SPG25). We have evaluated 11 patients belonging to six AR-HSP families genetically identified as SPG5, SPG7, SPG11 and SPG15. In all patients electromyography, nerve conduction velocity studies, visual (VEPs), somatosensory (SSEPs), brainstem auditory (BAEPs) and magnetic motor (MMEPs) evoked potentials were performed. All 4 SPG5 patients, affected by a pure form of SP, showed abnormalities of both MMEPs and SSEPs, and two of them also VEP alterations. In the two SPG7 patients with complicated SP, MMEP abnormalities only were discovered. Among the three SPG11 patients affected by SP, complicated by mental retardation and thin corpus callosum, electrophysiological studies revealed MMEP abnormalities and signs of motor neuropathy in one of them. Finally, in the SPG15 family, presenting with SP associated with mental retardation and neurosensorial deafness, MMEP and BAEP alterations were found. [source] An autosomal dominant genetically heterogeneous variant of rolandic epilepsy and speech disorderEPILEPSIA, Issue 6 2008Steven L. Kugler Summary We report a three generation pedigree with 11 of 22 affected with a variant form of rolandic epilepsy, speech impairment, oromotor apraxia, and cognitive deficit. The core features comprised nocturnal rolandic seizures, interictal centrotemporal spike waves with early age of onset and late age of offset. The transmission of the phenotype was consistent with autosomal dominant inheritance, with variable expressivity but no evidence of anticipation. We found evidence that the seizure and speech traits may be dissociated. No abnormalities were found by cytogenetic analysis. Linkage analysis excluded loci at 11p, 15q, 16p12, and Xq22 for related phenotypes, suggesting genetic heterogeneity. [source] Autosomal Dominant Inheritance of Centrotemporal Sharp Waves in Rolandic Epilepsy FamiliesEPILEPSIA, Issue 12 2007Bhavna Bali Summary Purpose: Centrotemporal sharp (CTS) waves, the electroencephalogram (EEG) hallmark of rolandic epilepsy, are found in approximately 4% of the childhood population. The inheritance of CTS is presumed autosomal dominant but this is controversial. Previous studies have varied considerably in methodology, especially in the control of bias and confounding. We aimed to test the hypothesis of autosomal dominant inheritance of CTS in a well-designed family segregation analysis study. Methods: Probands with rolandic epilepsy were collected through unambiguous single ascertainment. Siblings in the age range 4,16 years underwent sleep-deprived EEG; observations from those who remained awake were omitted. CTS were rated as present or absent by two independent observers blinded to the study hypothesis and subject identities. We computed the segregation ratio of CTS, corrected for ascertainment. We tested the segregation ratio estimate for consistency with dominant and recessive modes of inheritance, and compared the observed sex ratio of those affected with CTS for consistency with sex linkage. Results: Thirty siblings from 23 families underwent EEG examination. Twenty-three showed evidence of sleep in their EEG recordings. Eleven of 23 recordings demonstrated CTS, yielding a corrected segregation ratio of 0.48 (95% CI: 0.27,0.69). The male to female ratio of CTS affectedness was approximately equal. Conclusions: The segregation ratio of CTS in rolandic epilepsy families is consistent with a highly penetrant autosomal dominant inheritance, with equal sex ratio. Autosomal recessive and X-linked inheritance are rejected. The CTS locus might act in combination with one or more loci to produce the phenotype of rolandic epilepsy. [source] A locus for an auditory processing deficit and language impairment in an extended pedigree maps to 12p13.31-q14.3GENES, BRAIN AND BEHAVIOR, Issue 6 2010L. Addis Despite the apparent robustness of language learning in humans, a large number of children still fail to develop appropriate language skills despite adequate means and opportunity. Most cases of language impairment have a complex etiology, with genetic and environmental influences. In contrast, we describe a three-generation German family who present with an apparently simple segregation of language impairment. Investigations of the family indicate auditory processing difficulties as a core deficit. Affected members performed poorly on a nonword repetition task and present with communication impairments. The brain activation pattern for syllable duration as measured by event-related brain potentials showed clear differences between affected family members and controls, with only affected members displaying a late discrimination negativity. In conjunction with psychoacoustic data showing deficiencies in auditory duration discrimination, the present results indicate increased processing demands in discriminating syllables of different duration. This, we argue, forms the cognitive basis of the observed language impairment in this family. Genome-wide linkage analysis showed a haplotype in the central region of chromosome 12 which reaches the maximum possible logarithm of odds ratio (LOD) score and fully co-segregates with the language impairment, consistent with an autosomal dominant, fully penetrant mode of inheritance. Whole genome analysis yielded no novel inherited copy number variants strengthening the case for a simple inheritance pattern. Several genes in this region of chromosome 12 which are potentially implicated in language impairment did not contain polymorphisms likely to be the causative mutation, which is as yet unknown. [source] p.Gln200Glu, a putative constitutively active mutant of rod ,-transducin (GNAT1) in autosomal dominant congenital stationary night blindness,,HUMAN MUTATION, Issue 7 2007Viktoria Szabo Abstract Congenital stationary night blindness (CSNB) is a non-progressive Mendelian condition resulting from a functional defect in rod photoreceptors. A small number of unique missense mutations in the genes encoding various members of the rod phototransduction cascade, e.g. rhodopsin (RHO), cGMP phosphodiesterase ,-subunit (PDE6B), and transducin ,-subunit (GNAT1) have been reported to cause autosomal dominant (ad) CSNB. While the RHO and PDE6B mutations result in constitutively active proteins, the only known adCSNB-associa-ted GNAT1 change (p.Gly38Asp) produces an ,-transducin that is unable to activate its downstream effector molecule in vitro. In a multigeneration Danish family with adCSNB, we identified a novel heterozygous C to G transversion (c.598C>G) in exon 6 of GNAT1 that should result in a p.Gln200Glu substitution in the evolutionarily highly conserved Switch 2 region of ,-transducin, a domain that has an important role in binding and hydrolyzing GTP. Computer modeling based on the known crystal structure of transducin suggests that the p.Gln200Glu mutant exhibits impaired GTPase activity, and thereby leads to constitutive activation of phototransduction. This assumption is in line with our results of trypsin protection assays as well as previously published biochemical data on mutants of this glutamine in the GTPase active site of ,-transducin following in vitro expression, and observations that inappropriately activating mutants of various members of the rod phototransduction cascade represent one of the major molecular causes of adCSNB. © 2007 Wiley-Liss, Inc. [source] Electrophysiological Basis and Genetics of Brugada SyndromeJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 2005AUGUSTUS O. GRANT M.B.Ch.B., Ph.D. Brugada syndrome is a primary arrhythmic syndrome arising in the structurally normal heart. Any proposed mechanism should account for the major features of the syndrome: localization of the ST segment and T-wave changes to the right precordial leads, association of conduction slowing at several levels, precipitation or aggravation of the major ECG changes by sodium channel-blocking drugs and the occurrence of ventricular fibrillation. Heterogeneity of repolarization across the ventricle wall plays a major role. Any agency that shifts the net current gradient during phase I outward would exaggerate the normal heterogeneity of repolarization and result in the ST segment and T-wave changes characteristic of the syndrome. When the outward current shift is marked, premature repolarization may occur in epicardial zone and the resulting gradient may precipitate reentry. The syndrome is inherited as an autosomal dominant. However, 75% of clinically affected individuals are males. In 20% of cases, the syndrome is associated with mutations of the cardiac sodium channel gene SCN5A. The mutations result in a loss-of-function as a result of the synthesis of a non-functional protein, altered protein trafficking, or change in gating. Agencies that reduce the sodium current may precipitate the characteristic ECG changes, for example, sodium channel blockers and membrane depolarization by hyperkalemia. Sympathetic stimulation may reverse the ECG changes and reduce arrhythmia recurrence. By its nonspecific potassium channel blocking action, quinidine may also reduce arrhythmia recurrence. We still do not know the basis for defect in the majority of patients with Brugada syndrome. [source] Acellular dermal matrix allograft used to gain attached gingiva in a case of epidermolysis bullosaJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 11 2003Eralp Buduneli Abstract Background: Epidermolysis bullosa (EB) is an acquired disease or inherited as either autosomal dominant or recessive with an incidence of 1/50,000. The prominent clinical characteristic of the disease is the development of bullae or vesicles in mucosa or skin in response to minor trauma. Aim: A female patient with a dystrophic type of EB had been put in a maintenance regimen after completion of the initial phase of periodontal therapy and followed for 7 years. The purpose of this report is to document acellular dermal matrix allograft application to increase the width of the attached gingiva in this patient experiencing difficulty in chewing and performing plaque control due to the dramatic loss of attached gingiva after 7 years of supportive periodontal therapy. Methods: Under local anaesthesia and antibiotic coverage, the acellular dermal matrix allograft was applied in the anterior region of the upper jaw in order to increase the width of attached gingiva, thereby improving patient comfort. Results: The healing was uneventful and a significant gain in attached gingiva dimensions was observed 9 months after the periodontal surgery. The procedure avoided a second surgical site, provided satisfactory results from an aesthetic point of view, and improved patient comfort. Conclusion: Acellular dermal matrix allograft may be regarded as an alternative in the treatment of EB cases to increase the width of attached gingiva and facilitate maintenance of the dentition. Zusammenfassung Hintergrund: Die Epidermolysis bullosa (EB) ist eine erworbene oder eine autosomal dominant oder rezessiv vererbte Krankheit mit einer Incidenz von 1:50,000. Die hervorstechenden klinischen Symptome dieser Erkrankung sind die Entwicklung von Blasen oder Vesikeln in der Mukosa oder in der Haut auf geringste Traumen. Ziel: Eine Frau mit dem dystrophischen Typ von EB wurde in der Erhaltungsphase seit 7 Jahren geführt, nachdem die initiale Phase der parodontalen Therapie beendet worden war. Der Zweck dieser Studie ist die Dokumentation der Applikation eines azellulären Hautmatrixtransplantats für die Verbreiterung der fest angewachsenen Gingiva bei dieser Patientin, die nach 7 Jahren der erhaltenden parodontalen Therapie Probleme beim Kauen und bei der Durchführung der Plaquekontrolle durch einen starken Verlust an fest angewachsener Gingiva hatte. Methoden: Unter lokaler Anästhesie und antibiotischer Abschirmung wurde das azelluläre Hautmatrixtransplantat in die anteriore Region des Oberkiefers appliziert, um die Breite der fest angewachsenen Gingiva zu vergrößern und so das Befinden der Patientin zu verbessern. Ergebnisse: Die Heilung war komplikationslos, und ein signifikanter Gewinn an fest angewachsener Gingiva 9 Monate nach der parodontalen Operation wurde beobachtet. Die Methode vermied eine zweite chirurgische Region, erbrachte zufriedenstellende Ergebnisse aus ästhetischer Sicht und verbesserte das Befinden der Patientin. Schlussfolgerung: Das azelluläre Hautmatrixtransplantat kann als eine Alternative in der Behandlung von EB betrachtet werden, um die Breite der fest angewachsenen Gingiva zu vergrößern und zur Möglichkeit der Erhaltung der Dentition beizutragen. Résumé La bullose épidermolysie (EB) est une maladie contractée ou héritée qui peut être aussi bien autosomale dominante que récessive avec une fréquence de 1/50,000. La caractéristique clinique importante de la maladie est le développement de bulles ou de vésicules au niveau de la muqueuse ou de la peau comme réponse à un traumatisme mineur. Une femme avec un type dystrophique de EB a été placée dans un régime de maintenance après la fin de la phase initiale du traitement parodontal et suivie durant sept années. Le but de ce rapport est de documenter le placement d'un allographe de la matrice dermique acellulaire visant à augmenter la largeur de la gencive attachée chez cette patiente qui avait des problèmes aux niveaux masticatoire et du contrôle de la plaque dentaire vu la perte dramatique de la gencive attachée après sept années de maintenance parodontale. Sous anesthésie locale et sous couverture antibiotique, l'allographe de la matrice dermique acellulaire a été placé dans la région antérieure de la mâchoire supérieure pour augmenter la largeur de la gencive attachée afin d'améliorer le confort de la patiente. La guérison s'est déroulée sans problème et un gain significatif de gencive attachée a été observé neuf mois après la chirurgie parodontale. Ce processus chirurgical élimine la nécessité d'avoir un site donneur, apporte des résultats satisfaisants du point de vue esthétique et améliore le confort du patient. L'allographe de la matrice dermique acellulaire peut donc être considéré comme une alternative dans le traitement des cas de EB afin d'augmenter la largeur de la gencive attachée et faciliter le maintien de la dentition. [source] Parkinson's disease in Arabs: A systematic reviewMOVEMENT DISORDERS, Issue 9 2008FRCP, Hani T.S. Benamer PhD Abstract Studies of specific populations have provided invaluable knowledge about Parkinson's disease (PD), especially in the field of genetics. The present report systematically reviews the medical literature on PD in Arabs. Medline and Embase were searched, and 24 article were identified: genetic (n = 17), epidemiological (n = 3), and clinical series (n = 5). Both autosomal dominant and recessive forms of inherited PD are described, associated with four genes (Parkin, PINK1, LRRK2, and PARK9). The G2019S LRRK2 mutation is more common in both familial (37,42%) and apparently sporadic PD (41%) in North African Arabs than in Europeans and North Americans (2,3%). The incidence of PD is reported at 4.5 per 100,000 person-years and reported prevalence at 27 to 43 per 100,000 persons. Hospital-based clinical series suggest that parkinsonism is the commonest movement disorder. Clinical features of PD in Arabs are not significantly different from those reported elsewhere. PD was reported as the cause of dementia in around 7% of Arabs. The majority of studies relate to the role of genes in the etiology of PD in North African Arabs. Further genetic, epidemiological and clinical studies from the majority of Arabic countries may enhance our understanding of PD. © 2008 Movement Disorder Society. [source] Familial essential tremor with apparent autosomal dominant inheritance: Should we also consider other inheritance modes?MOVEMENT DISORDERS, Issue 9 2006Shaochun Ma MD Abstract A positive family history is present in many patients with essential tremor (ET), but twin studies and segregation analysis have suggested that ET is not entirely a genetic disorder. Two genetic loci have been identified in autosomal dominant (AD) ET and polymorphisms in the DRD3 and HS1-BP3 genes have been proposed as the possible susceptibility factors for ET. There is also evidence for further genetic heterogeneity. We evaluated 4 unrelated large kindreds with ET with an apparent AD mode of transmission. Each kindred spanned at least 3 generations and contained at least 13 living affected subjects who met criteria for definitive ET. None of the pedigrees had evidence for inheritance of ET from both parents. Known genetic ET loci were excluded in these families. We detected a preferential transmission of ET in every kindred and the proportion of affected offspring varied from 75% to 90% (P < 0.05) in the generations with complete ascertainment. Our data indicate that non-Mendelian preferential transmission of an affected allele is a feature in many ET kindreds with multiple affected members and an apparent AD mode of inheritance. ET may have a complex etiology. Additional genetic models need to be considered, including an interaction of susceptibility genes and environmental risk factors. © 2006 Movement Disorder Society [source] Restless legs syndrome: Epidemiological and clinicogenetic study in a South Tyrolean population isolateMOVEMENT DISORDERS, Issue 8 2006Florian D. Vogl MSc Abstract Genetic contributions to restless legs syndrome (RLS) have been consistently recognized from population and family studies. To determine the clinical and genetic features of RLS in a population isolate and explore linkage to three previously described susceptibility loci on chromosomes 12q, 14q, and 9p, respectively, an isolated population in the South Tyrolean Alps was identified and 530 adults participated in the study. Using a two-step strategy, 47 patients with idiopathic RLS were ascertained. The prevalence in the population was 8.9%. Twenty-eight patients (59.6%) had at least one affected first-degree relative and were classified as hereditary cases. In a single extended pedigree, linkage to known RLS loci was investigated specifying autosomal dominant and recessive models; parametric and nonparametric multipoint linkage scores were computed. None of the calculated linkage scores was suggestive of linkage between RLS and any of the three investigated loci. This study was conducted in a population isolate providing for a homogeneous genetic and environmental background. The absence of a suggestive linkage signal at the three known RLS susceptibility loci is indicative of further locus heterogeneity of this frequent disorder and encourages further studies to unveil the genetic causes of RLS. © 2006 Movement Disorder Society [source] Phenotypic characterization of DYT13 primary torsion dystonia,MOVEMENT DISORDERS, Issue 2 2004Anna Rita Bentivoglio MD Abstract We describe the phenotype of DYT13 primary torsion dystonia (PTD) in a family first examined in 1994. A complete neurological evaluation was performed on all available family members: 8 individuals were definitely affected by dystonia. The family was re-evaluated in March 2000: at that time, 3 more individuals had developed symptoms of dystonia. Inheritance of PTD was autosomal dominant, with affected individuals spanning three consecutive generations and male-to-male transmission. Age at onset ranged from 5 to 43 years. Onset occurred either in the craniocervical region or in upper limbs. Progression was mild, and the disease course was benign in most affected individuals; generalization occurred only in 2 cases. We did not find anticipation of age at onset or of disease severity through generations. Most subjects presented with jerky, myoclonic-like dystonic movements of the neck or shoulders. DYT13-PTD is an autosomal dominant disease, with incomplete penetrance (58%). Clinical presentation and age at onset were more variable than in DYT1-PTD, and the neck was involved in most of those affected. Moreover, the individuals with generalised dystonia were not severely disabled and were able to lead independent lives. To date, this is the only family with DYT13-PTD. © 2003 Movement Disorder Society [source] Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complexNEUROPATHOLOGY, Issue 6 2008Karin Boer Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. In the present study we discuss the neuropathological findings of a 32-year-old patient with a germ-line mutation in the TSC2 gene. Post mortem MRI combined with histology and immunocytochemical analysis was applied to demonstrate widespread anatomical abnormalities of gray and white matter structure. TSC brain lesions were analyzed for loss of heterozygosity (LOH) on chromosome 16p13. The neuropathological supratentorial abnormalities were represented by multiple subependymal nodules (SENs) and cortical tubers. In addition to cerebral cortical lesions, cerebellar lesions and hippocampal sclerosis were also observed. LOH was not found in the cortical tubers and SENs of this patient. Immunocytochemical analysis of the TSC brain lesions confirmed the cell-specific activation of the mTOR pathway in cortical tubers, SENs and cerebellum, as well as differential cellular localization of hamartin and tuberin, the TSC1 and TSC2 gene products. Examination of the pathological brain regions revealed activated microglial cells and disruption of blood-brain barrier permeability. Predominant intralesional cell-specific distribution was also detected for the multidrug transporter protein P-gp, possibly explaining the mechanisms underlying the pharmacoresistance to antiepileptic drugs. Autopsy findings confirm the complexity of the brain abnormalities encountered in TSC patients and proved useful in clarifying certain aspects of the pathogenesis, epileptogenesis and pharmacoresistance of TSC lesions. [source] Liver and kidney disease in ciliopathies,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 4 2009Meral Gunay-Aygun§ Abstract Hepatorenal fibrocystic diseases (HRFCDs) are among the most common inherited human disorders. The discovery that proteins defective in the autosomal dominant and recessive polycystic kidney diseases (ADPKD and ARPKD) localize to the primary cilia and the recognition of the role these organelles play in the pathogenesis of HRFCDs led to the term "ciliopathies." While ADPKD and ARPKD are the most common ciliopathies associated with both liver and kidney disease, variable degrees of renal and/or hepatic involvement occur in many other ciliopathies, including Joubert, Bardet,Biedl, Meckel,Gruber, and oral,facial,digital syndromes. The ductal plate malformation (DPM), a developmental abnormality of the portobiliary system, is the basis of the liver disease in ciliopathies that manifest congenital hepatic fibrosis (CHF), Caroli syndrome (CS), and polycystic liver disease (PLD). Hepatocellular function remains relatively preserved in ciliopathy-associated liver diseases. The major morbidity associated with CHF is portal hypertension (PH), often leading to esophageal varices and hypersplenism. In addition, CD predisposes to recurrent cholangitis. PLD is not typically associated with PH, but may result in complications due to mass effects. The kidney pathology in ciliopathies ranges from non-functional cystic dysplastic kidneys to an isolated urinary concentration defect; the disorders contributing to this pathology, in addition to ADPKD and ARPKD, include nephronophithisis (NPHP), glomerulocystic kidney disease and medullary sponge kidneys. Decreased urinary concentration ability, resulting in polyuria and polydypsia, is the first and most common renal symptom in ciliopathies. While the majority of ADPKD, ARPKD, and NPHP patients require renal transplantation, the frequency and rate of progression to renal failure varies considerably in other ciliopathies. This review focuses on the kidney and liver disease found in the different ciliopathies. Published 2009 Wiley-Liss, Inc. [source] Perinatal imaging findings of inherited Sotos syndromePRENATAL DIAGNOSIS, Issue 10 2002Chih-Ping Chen Abstract Objectives Although most cases of Sotos syndrome are sporadic, familial cases have been described. In familial cases, the most likely mode of inheritance is autosomal dominant with variable expressivity. We present the perinatal imaging findings of an inherited case. Case This was the second pregnancy of a 32-year-old woman with Sotos syndrome. She had given birth to her first child with macrocephaly, ventriculomegaly, macrocisterna magna and neonatal death at 28 weeks' gestation. During this pregnancy, prenatal ultrasonography at 18 weeks' gestation showed only mild dilatation of lateral ventricles. The pregnancy was uneventful until 31 weeks' gestation when fetal macrocephaly, right hydronephrosis, and polyhydramnios began to develop. At 33 weeks' gestation, dilatation of the third ventricle and fetal overgrowth were obvious. At 34 weeks' gestation, macrodolichocephaly, hypoplasia of the corpus callosum, enlargement of the lateral ventricles with prominent occipital horns, and macrocisterna magna were noted. At 36 weeks' gestation, a male baby was delivered with macrodolichocephaly, frontal bossing and a facial gestalt of Sotos syndrome. Birth weight was 3822 g, length 55 cm, and occipitofrontal head circumference 41 cm (all > 97th centile). The magnetic resonance imaging (MRI) scans demonstrated enlargement of the lateral ventricles, the trigones, and the occipital horns, hypoplasia of the corpus callosum, a persistent cavum septum pellucidum and cavum vergae, and macrocisterna magna. Conclusions Fetuses at risk for Sotos syndrome may present abnormal sonographic findings of the brain and the skull in association with overgrowth, unilateral hydronephrosis and polyhydramnios in the third trimester. Perinatal MRI studies aid in confirmation of the diagnosis. Copyright © 2002 John Wiley & Sons, Ltd. [source] Dysregulation of human bestrophin-1 by ceramide-induced dephosphorylationTHE JOURNAL OF PHYSIOLOGY, Issue 18 2009Qinghuan Xiao Best vitelliform macular dystrophy is an inherited autosomal dominant, juvenile onset form of macular degeneration caused by mutations in a chloride ion channel, human bestrophin-1 (hBest1). Mutations in Best1 have also been linked to several other forms of retinopathy. In addition to mutations, hBest1 dysfunction might come about by disruption of other processes that regulate Best1 function. Here we show that hBest1 chloride channel activity is regulated by ceramide and phosphorylation. We have identified a protein kinase C (PKC) phosphorylation site (serine 358) in hBest1 that is important for sustained channel function. Channel activity is maintained by PKC activators, protein phosphatase inhibitors, or pseudo-phosphorylation by substitution of glutamic acid for serine 358. When ceramide levels are elevated by exogenous addition of ceramide to the bath, by addition of bacterial sphingomyelinase, or by hypertonic stress, S358 is rapidly dephosphorylated. The dephosphorylation is mediated by protein phosphatase 2A. Hypertonic stress-induced dephosphorylation is blocked by a dihydroceramide, an inactive form of ceramide, and manumycin, an inhibitor of neutral sphingomyelinase. Our results support a model in which ceramide accumulation during early stages of retinopathy inhibits hBest1 function, leading to abnormal fluid transport across the retina, and enhanced inflammation. [source] Are children of older fathers at risk for genetic disorders?ANDROLOGIA, Issue 4 2003A. Jung Summary. Genetic risks related to paternal age should be of interest to clinical andrologists counselling older men who wish to father a child. Theoretically, the number of (pre-meiotic) mitotic cell divisions during spermatogenesis and their remarkable increase with ageing compared with oogenesis would be in favour of genetic risks for the offspring of older men. But for numerical and structural chromosomal anomalies, such an influence of paternal age has not been found. However, in several autosomal dominant disorders affecting three specific genes (fibroblast growth factor receptor 2 and 3, RET proto-oncogene) the risk for a child to be affected increases with paternal age at time of birth. For other autosomal dominant ,X chromosomal dominant or recessive disorders, the available data are sufficient to support the concept of a positive relationship between paternal age and de novo gene mutations. Studies analysing gene sequences of affected children and their parents would allow further evaluation of this topic. The impact of paternal age on disorders with a complex genetic background, however, is a matter of debate. A significant effect of paternal age could not be shown for nonfamilial Alzheimer's disease, congenital heart defects, nonfamilial schizophrenia, acute lymphoblastic leukaemia or prostate cancer. [source] Huntington's disease,like 2 (HDL2) in North America and JapanANNALS OF NEUROLOGY, Issue 5 2004Russell L. Margolis MD Huntington's Disease,like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of 33 triplets. A younger age of onset is correlated with a longer repeat length (r2 = 0.29, p = 0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype. Ann Neurol 2004 An Erratum has been published for this article in Ann Neurol 56: 911, 2004. [source] Tibial muscular dystrophy in a Belgian familyANNALS OF NEUROLOGY, Issue 2 2003Peter Y. K. Van den Bergh We report a Belgian family with autosomal dominant, late-onset, distal myopathy with selective foot extensor muscle involvement of the lower legs. Linkage to the tibial muscular dystrophy (TMD) locus 2q31 was not evident at first because of incomplete disease penetrance in a 50-year-old asymptomatic family member. An abnormal tibialis anterior muscle biopsy established her subclinical status and linkage of the family to the TMD locus. Mutation analysis showed a disease-specific, heterozygous point mutation in the last exon, Mex6, of the titin gene. This is the third mutation found in TMD and the second European family with TMD outside the Finnish population, suggesting that titinopathies may occur in various populations. Ann Neurol 2003 [source] Loose anagen syndrome: A prospective study of three familiesAUSTRALASIAN JOURNAL OF DERMATOLOGY, Issue 2 2002Alvin H Chong SUMMARY Loose anagen syndrome (LAS) is an autosomal dominant, age-related disorder characterized by the ability to easily and painlessly extract unsheathed anagen hairs from the scalp with a gentle hair pull. The phenotype is heterogeneous with three distinct clinical presentations. To further characterize the phenotype of loose anagen syndrome and its fluctuations over time, a prospective study of eight cases from three families was conducted over a period of 18 months. Patients were examined using standardized hair-pull and hair-pluck protocols. Each of the three different phenotypes of LAS were found to be present in one family. This implies that these phenotypes are variants of a single genotype, modified by environmental or age-related factors. The hair-pluck trichogram from LAS cases consistently showed a high proportion of loose anagen (LA) hairs. In contrast the hair-pull test was found to vary over time with regards to the number of LA hairs that could be extracted. Periods where no hairs could be obtained on hair pull were found. These findings have important implications in the diagnosis of LAS. A single negative hair-pull test does not exclude the diagnosis. If LAS is suspected on clinical grounds, then either a hair-pluck trichogram or serial re-examination by hair pull would be required to exclude the diagnosis. [source] Dystrophic epidermolysis bullosa pruriginosa is not associated with frequent FLG gene mutationsBRITISH JOURNAL OF DERMATOLOGY, Issue 2 2008H. Schumann Summary Background, Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr; OMIM 604129) is a rare manifestation of dystrophic epidermolysis bullosa (DEB), characterized by pruritus, nodular prurigo-like lesions and fragility of the skin mainly in the extremities. Fewer than 40 patients with autosomal dominant or recessive inheritance, or sporadic DEB-Pr, have been described in the literature. Objectives, To disclose mutations in DEB-Pr and to elucidate the role of other pathogenic factors which may influence the pruriginous phenotype. Methods, Seven patients with typical clinical features of DEB-Pr were studied. Results, In all patients, mutations in the gene encoding collagen VII (COL7A1) were disclosed, two of them novel (p.G2623V, p.E2736K). Three mutations were dominant, three recessive and one de novo. In the families with dominant DEB there were one or more members with DEB-Pr, but also at least one affected sibling who did not develop DEB-Pr. In six of seven patients, the clinical history revealed factors that initially induced pruritus, such as atopy, pregnancy, thyroid hormone imbalance, diabetes, infections and contact sensitization. Common filaggrin mutations were ruled out in all patients and normal filaggrin staining was found in the skin samples. Conclusions, DEB-Pr develops as a result of COL7A1 gene mutations and acquired phenotype-modifying factors. Filaggrin mutations did not contribute to the pruriginous phenotype in the present patient cohort. [source] Novel SPG3A and SPG4 mutations in dominant spastic paraplegia familiesACTA NEUROLOGICA SCANDINAVICA, Issue 2 2009J. L. Loureiro Objectives,,, The hereditary spastic paraplegias (HSP) are a genetically and clinically heterogeneous group of neurodegenerative disorders, mainly characterized by a progressive spasticity and weakness of the lower limbs. Mutations in the SPG4 and SPG3A genes are responsible for approximately 50% of autosomal dominant HSP. To genetically diagnose the Portuguese families with HSP, mutation analysis was performed for the SPG4 and SPG3A genes. Patients and methods,,, Analysis was performed by polymerase chain reaction, followed by denaturing high performance liquid chromatography (DHPLC), in 61 autosomal dominant (AD)-HSP families and 19 unrelated patients without family history. Results,,, Ten novel mutations were identified: one in the SPG3A and nine in the SPG4 genes; three known mutations in the SPG4 were also found. Most of the novel mutations were frameshift or nonsense (80%), resulting in a dysfunctional protein. Conclusions,,, The SPG4 and SPG3A analysis allowed the identification of 10 novel mutations and the genetic diagnosis of approximately a quarter of our AD-HSP families. [source] Persistent hyperplastic primary vitreous: congenital malformation of the eyeCLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 9 2009Barkur S Shastry PhD Abstract Persistent hyperplastic primary vitreous (PHPV), also known as persistent fetal vasculature, is a rare congenital developmental malformation of the eye, caused by the failure of regression of the primary vitreous. It is divided into anterior and posterior types and is characterized by the presence of a vascular membrane located behind the lens. The condition can be of an isolated type or can occur with other ocular disorders. Most cases of PHPV are sporadic, but it can be inherited as an autosomal dominant or recessive trait. Inherited PHPV also occurs in several breeds of dogs and cats. In a limited number of cases, Norrie disease and FZD4 genes are found to be mutated in unilateral and bilateral PHPV. These genes when mutated also cause Norrie disease pseudoglioma and familial exudative vitreoretinopathy that share some of the clinical features with PHPV. Mice lacking arf and p53 tumour suppressor genes as well as Norrie disease pseudoglioma and LRP5 genes suggest that these genes are needed for hyaloid vascular regression. These experiments also indicate that abnormalities in normal apoptosis and defects in Wnt signalling pathway may be responsible for the pathogenesis of PHPV. Identification of other candidate genes in the future may provide a better understanding of the pathogenesis of the condition that may lead to a better therapeutic approach and better management. [source] Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutationsCLINICAL GENETICS, Issue 1 2004NV Whittock Spondylocostal dysostoses (SCD) are a heterogeneous group of disorders of axial skeletal malformation characterized by multiple vertebral segmentation defects and rib anomalies. Sporadic cases with diverse phenotypes, sometimes including multiple organ abnormalities, are relatively common, and monogenic forms demonstrating autosomal recessive (AR) and, more rarely, autosomal dominant (AD) inheritance have been reported. We previously showed that mutations in delta-like 3 (DLL3), a somitogenesis gene that encodes a ligand for the notch signaling pathway, cause AR SCD with a consistent pattern of abnormal segmentation. We studied an SCD family previously reported to show AD inheritance, in which the phenotype is similar to that in AR cases. Direct DLL3 sequencing of individuals in two generations identified the affected father as homozygous for a novel frameshift mutation, 1440delG. His two affected children were compound heterozygotes for this mutation and a novel missense mutation, G504D, the first putative missense mutation reported in the transmembrane domain of DLL3. Their two unaffected siblings were heterozygotes for the 1440delG mutation. Pseudodominant inheritance has been confirmed, and the findings raise potential consequences for genetic counseling in relation to the SCD disorders. [source] | |||||||||||||||||||||||||