Autosomal Dominant Transmission Research Articles

Hyperimmunglobulin E Syndrome with Severe Cold Abcesses

Observation: Hyperimmunoglobulin E syndrome is an immundeficiency disease characterized by recurrent pyogenic infections and periferic eosinophilia. It may be sporadic or with autosomal dominant transmission. Cold abscesses seen in patients are pathognomonic for this disease. This paper reports a 4-year-old male patient having severe cold abscesses in inguinal region, both thighs, and below umbilicus. On examination and laboratory investigation, there were pneumonia, high IgE levels and eosinophilia. Staphylococcus aureus growth occurred in culture from wound and blood and the patient was given antibiotherapy accordingly.

Analysis of the glucokinase gene in Iranian families with maturity onset diabetes of the young

Non insulin dependent diabetes mellitus (NIDDM) as a most common form of diabetes is a major public health problem; there is a subgroup of NIDDM patients who develop the disease at an early age and show a dominant mode of inheritance. This type is nominates Maturity onset diabetes of the young (MODY). The prevalence of MODY is difficult to access, and patients with MODY genes mutations are often identified during routine screening for other purposes. MODY2 was linked to glucokinase gene (GCK) mutations, and accounted for 8% to 56% of MODY, with the highest prevalence found in the southern Europe. The aim of this study was to examine the prevalence and nature of mutations in GCK gene in Iranian paients. We have screened GCK mutations by polymerase chain reaction (PCR); single stranded conformation polymorphism (SSCP) technique in 12 Iranian families with clinical diagnosis of MODY, included 30 patients (8 males and 22 females) and their 21 family members. PCR products with abnormal mobility in denaturing gradient gel electrophoresis (DGGE) were directly sequenced. We identified 6 novel mutations in GCK gene in Iranian families (corresponding to 36.6% prevalence). Our findings and the last study on MODY1 highlight that in addition to GCK, other MODY genes such as MODY3 and MODYX may play a significant role in diabetes characterized by monogenic autosomal dominant transmission. There is an important point that the genetic recognation can be used to pre-symptomatically identify family members at risk for developing MODY.

Identification of Large Families in Early Repolarization Syndrome

The aim of this study was to identify families affected by early repolarization syndrome (ERS) and to determine the mode of transmission of the disease. Early repolarization (ER) has recently been linked to idiopathic ventricular fibrillation. Familial inheritance of the disease has been suggested but not demonstrated. We screened relatives of 4 families affected by ERS. ER was defined as a distinct J-wave in at least 2 consecutive leads and a 1-mm amplitude above baseline. The Valsalva maneuver was performed in affected and unaffected family members to decrease heart rate and thus increase or reveal an ER pattern. Twenty-two sudden cardiac deaths occurred in the 4 families including 10 before 35 years of age. In the 4 families, the prevalence of ER was 56%, 34%, 61%, and 33% of, respectively, 30, 82, 29, and 30 screened relatives. In these families, transmission of an ER pattern is compatible with an autosomal dominant mode of inheritance. All probands were screened for genes identified in ERS, and no mutation was found. The Valsalva maneuver was performed in 80 relatives, resulting in increased J-wave amplitude for 17 of 20 affected patients and revealing an ER pattern in 17 relatives in whom 5 are obligate transmitters of an ER pattern. ERS can be inherited through autosomal dominant transmission and should be considered a real inherited arrhythmia syndrome. Familial investigation can be facilitated by using the Valsalva maneuver to reveal the electrocardiographic pattern in family members. The prognosis value of this test remains to be assessed.

Novel Inheritable Caveolin-1 Mutations in Pulmonary Arterial Hypertension

Previous genetic studies of patients with idiopathic pulmonary arterial hypertension (PAH) and heritable PAH have identified mutations in several genes related to transforming growth factor-β signaling, including bone morphogenetic protein receptor type 2 (BMPR2), activin receptor-like kinase 1 (ALK1), endoglin (ENG), and mothers against decapentaplegic 9 (SMAD9). Furthermore, 25% of heritable PAH and 85% of idiopathic PAH cases have no identified genetic association. The study by Austin et al1 sought to identify additional genes responsible for idiopathic PAH and heritable PAH. Sequencing was performed on 2 cohorts. The first was a 3-generation family with autosomal dominant transmission of PAH and no identifiable mutations in BMPR2 by dideoxy sequencing or multiple ligation-dependent probe amplification and ALK1 , ENG , or SMAD9 by exon sequencing. Exon sequencing was then performed on samples from 4 of 12 family members to identify the presumed …

Hereditary trichilemmal cysts: a proposal for the assessment of diagnostic clinical criteria

Trichilemmal cysts (TCs) can occur as sporadic lesions or in hereditary-familial settings with autosomal dominant transmission. These entities have not been widely analyzed in their peculiar aspects yet. The aim of this study was to describe a cohort of patients with diagnosis of TCs through a clinical and biomolecular characterization, intended to highlight some effective diagnostic criteria for their identification. Among 149 cases of this study, 24 cases of TCs (16.1%) arose in patients with at least one first-degree relative with diagnosis of TCs. Peculiar findings concerning hereditary lesions included the multiple presentation with an early onset age. On the basis of clinical evaluation, we propose a panel of clinical and histologic criteria for the diagnosis of hereditary TCs, which includes: (i) the diagnosis of TCs in at least two first-degree relatives or in three first- or second-degree relatives in two consecutive generations; (ii) at least one of the patients with TCs diagnosed <45 years; and (iii) the diagnosis of multiple or giant (>5-cm lesions) or rare histopathologic features (proliferating and ossifying) TCs.

Autosomal dominant transmission of nevus sebaceous of Jadassohn

Nevus sebaceus of Jadassohn is a complex congenital hamartoma that has a predominant sebaceous component. It presents as waxy, well-circumscribed, yellow plaques localized to the head and neck. Its genetic etiology has more often been described as sporadic, with scattered cases featuring autosomal dominant transmission also reported. The development of benign tumors within the lesions is a well-known phenomenon and requires clinical surveillance for new growths suggesting malignant transformation. We report three cases of nevus sebaceus of Jadassohn localized to the scalp in a mother and her two daughters. This case further supports the underlying genetic association in familial cases of NSJ, specifically autosomal dominant transmission.

Hereditary gastric cancer

In 1998, Guilford et al. identified the hereditary diffuse gastric cancer (HDGC) syndrome, caused by germline alterations at the CDH1 (E-cadherin) gene. To date, 141 probands harboring more than 100 different germline CDH1 alterations, mainly point mutations and large deletions, have been described. In mutation-positive individuals prophylactic total gastrectomy is recommended. The systematic histological study of prophylactic gastrectomies shows intramucosal signet-ring cell carcinoma and pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. In 2011, a new hereditary gastric cancer syndrome was identified: gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma, characterized by the autosomal dominant transmission of fundic gland polyposis, with areas of dysplasia or intestinal-type GC, restricted to the proximal stomach, with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.

Transforming Growth factor β 2 Mutations and Familial Thoracic Aortic Aneurysms

Previous genetic studies of patients with thoracic aortic aneurysms have identified mutations in several genes involvedin some way with transforming growth factor (TGF)-β signaling: FBN1 (encoding fibrillin-1, causing Marfan syndrome), TGFBR1 and TGFBR2 (encoding transforming growth factor-β receptors I and II, causing Loeys-Dietz syndrome), and SMAD3 (encoding Mothers against decapentaplegic homolog 3, causing aneurysms-osteoarthritis syndrome). Two groups (Boileau et al, Lindsay et al) sought to identify additional genes responsible for familial thoracic aortic aneurysms. They also sought to explain an apparent paradox: mutations in the aforementioned genes that would be predicted to result in reduced activity of the TGF-β pathwayappear to cause vasculopathy via increased TGF-β signaling. Both groups started by identifying families with autosomal dominant transmission of thoracic aortic aneurysms and in whom mutations in FBN1 , TGFBR1 , TGFBR2 , and SMAD3 had been ruled out. Each used modern genetic techniques to identify the presumptive causal gene mutations responsible …

Neuropathies optiques héréditaires

Hereditary optic neuropathies are a group of heterogeneous conditions affecting both optic nerves, with an autosomal dominant, autosomal recessive, X-related or mitochondrial transmission. The two most common non-syndromic hereditary optic neuropathies (Leber's hereditary optic neuropathy and autosomal dominant optic atrophy) are very different in their clinical presentation and their genetic transmission, leading however to a common, non-specific optic nerve atrophy. Beyond the optic atrophy-related visual loss, which is the clinical hallmark of this group of diseases, other associated neurological signs are increasingly recognized.

Familial forms of nonspecific interstitial pneumonia/idiopathic pulmonary fibrosis

Familial pulmonary fibrosis has long been recognized and suggests that pulmonary fibrosis may have a genetic origin in some cases with an autosomal dominant transmission. Mutations in the telomerase complex and in the surfactant pathways have been discovered in the last decade. Almost 20% of the cases of familial pulmonary fibrosis are related to known functional mutations in one of these systems. A polymorphism in the promoter of the MUC5B gene has been associated with both sporadic and familial forms of idiopathic pulmonary fibrosis; however, the impact of this association remains to be determined. These genes point to alveolar epithelium injury and repair as a major component of the fibrotic process.

The Implications of Inheritance for Clinical Management

Since the advent of genotyping, recognition of heritable disease has been perceived as an opportunity for genetic diagnosis or new gene identification studies to advance understanding of pathogenesis. Until recently, however, clinical application of DNA-based testing was confined largely to Mendelian disorders. Even within this remit, predictive testing of relatives is cost-effective only in diseases in which the majority of families harbor mutations in known causal genes, such as adult polycystic kidney disease and hypertrophic cardiomyopathy, but not dilated cardiomyopathy. Confirmatory genetic testing of index cases with borderline clinical features may be economic in the still smaller subset of diseases with limited locus heterogeneity, such as Marfan syndrome. Furthermore, Mendelian diseases account for ≈5% of total disease burden.1 Genome-wide association studies have made headway in elucidating the genetic contribution to the more common, complex diseases, and high throughput techniques promise to facilitate integration of genetic analysis into clinical practice. Nevertheless, many genes remain to be identified and implementation of genomic profiling as a population screening tool would not be cost-effective at present. The implications of heredity, however, extend beyond serving as a platform for genetic analysis, influencing diagnosis, prognostication, and treatment of both index cases and relatives, and enabling rational targeting of genotyping resources. This review covers acquisition of a family history, evaluation of heritability and inheritance patterns, and the impact of inheritance on subsequent components of the clinical pathway. Eliciting a family history is the first step to determining whether a known diagnosis is heritable or symptoms of unknown etiology have a hereditary basis. Both narrative and diagrammatic approaches are integral to data collection, the former including questioning for diseases that recur within the family and the latter involving construction of a pedigree or family tree. Incorporation of psychosocial and interactional data, such as emotional relationships (harmony, apathy, …

Integrating Genetics and Genomics in Primary Aldosteronism

Primary aldosteronism (PA) is the most common form of secondary hypertension, with an estimated prevalence of ≈10% in referred patients and 4% in primary care1,2 but as high as 20% in patients with resistant hypertension.3,4 It is characterized by hypertension with low plasma renin and elevated aldosterone that is often seen with hypokalemia. PA occurs as a result of a dysregulation of the normal mechanisms controlling adrenal aldosterone production. The 2 major causes are aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia (BAH), also called idiopathic hyperaldosteronism. The early detection of PA has an enormous impact on clinical outcome and survival, given the major cardiovascular adverse effects of aldosterone excess, which are independent of blood pressure,5,6 and predict outcome after surgical treatment.7,8 Patients with PA have a significantly higher risk of nonfatal myocardial infarction, atrial fibrillation, and stroke compared with age-, sex-, and blood pressure–matched essential hypertensives.5 Furthermore, changes in cardiac structure and function9 and partially reversible renal dysfunction10 have been described, whereas the increased occurrence of metabolic abnormalities in patients with PA is still a matter of debate.11,12 Although the 2008 guidelines for the management of PA have been pivotal for homogenizing screening procedures and treatment among specialized centers,13 there remain a few critical issues related to diagnosis, subtype differentiation, and treatment of nonsurgically correctable forms. Reliable diagnostic and prognostic biomarkers are lacking for more sensitive and specific screening, as well as new therapeutic avenues, because medical and/or surgical treatment of PA leads to normotension in only a minority of patients. This may come from a better understanding of the pathogenic mechanisms of the disease, in particular, identification of the genetic and molecular determinants leading to the development of APA and …

Mutation in the CHAC gene in a family of autosomal dominant chorea–acanthocytosis

Writ e Click is restricted to comments about studies published in Neurology ® within the past 8 weeks. The submission below represents an exception because it addresses a genetic sequencing error published in Neurology in 2003. In addition, these Writ e Click submissions will be available as open access to all readers in an effort to further publicize the Correction. In 2003, Saiki et al.1 reported an autosomal dominant transmission of chorea-acanthocytosis (ChAc) that constituted a significant challenge to the generally …

Hypermobilité du membre supérieur (épaule exceptée)

The benign joint hypermobility syndrome (BJHS) where the joint hypermobility is the major sign will be essentially treated. The other main diseases where the joint hypermobility could be present are Marfan syndrome, Stickler syndrome and osteogenesis imperfecta. The localized hypermobility following a trauma will be excluded. BJMS is related to Ehlers-Danlos hypermobility type, previously named type III. The diagnosis is based on an association of criterion according to Brighton. Determining the Beighton'score is the first step for making the diagnosis. A score higher than 4 is required (the highest possible score is 9). The fingers and elbows localization is important reaching 6/9 of the total score. It is a connective tissue disorder, genetically determined with an autosomal dominant transmission. The abnormalities concern the synthesis of fibrillar collagens or tenascin-X (non collagenic molecule of extracellular matrix). Pain are frequent and severe with functional impairment and repercussions on day-life, sleep and quality of life.

Epileptologists in quest for the Holy Grail

The epilepsies affect around 50 million people worldwide and constitute in 2012 the second neurological group of diseases. Anyone can suffer one type of epilepsy with more or less severe repeated seizures independently of age, race, or of socioeconomic or geographic situation. In Europe, the prevalence of epilepsy is of 8.2 per 1,000 corresponding to 6 million individuals with active epilepsy and around 15 million having experienced epilepsy during their lives (see [1]). Since almost two or even three decades now, the epileptologists repeatedly claim that in spite of the scientific progress in the field of basic neurosciences on the one hand and in clinical and neuropharmacological research on the other hand, 30–40 % of their patients remain incurable or at least drug-resistant. It took a long time to recognize the extreme diversity of the epileptic syndromes and to remain concentrated on the treatment of the seizures themselves. One of the symptoms of this is the ongoing use of the term ‘‘Epilepsy’’ in the singular form. For years, this attitude was clearly justified, since the antiepileptic drugs were efficient in at least half of the patients. Therefore, from the clinical point of view, considerable efforts have been developed to better identify and classify new epileptic syndromes and sometimes diseases. Truly, the principal symptom that links the different epileptic diseases is the seizure itself, a phenomenon due to the sudden occurrence in a particular area of the cerebral cortex of an epileptogenic circuit probably starting by hypersynchronous bioelectrical discharges in a set of cortical neurons then propagating in specific parts of the brain through synaptic connections. Therefore, for years, the therapeutic efforts tended to limit excitation and/or to favour inhibition considering epilepsy (i.e. ‘‘in singular’’) as a clear imbalance between these two phenomena. Although several experimental evidences illustrated that one can produce huge epileptogenic circuits by favouring GABAergic inhibitory inputs in some circumstances, one has to observe that this ‘‘old thought’’ is still hard to tackle among the clinical and also the pharmacological world. Since 1995, positional cloning strategies in multigenerational families with autosomal dominant transmission have revealed several genes (KCNQ2, KCNQ3, CHRNA4, CHRNA2, CHRNB2, SCN1B, SCN1A, SCN2A, GABRG2, GABRA1...) and numerous loci for febrile seizures and epilepsies. Most of these genes encode neuronal ion channel or neurotransmitter receptor subunits creating a first enthusiastic hypothesis that at least idiopathic generalized epilepsies could be considered as a new group of channelopathies. However, molecular approaches have revealed great genetic heterogeneity, with most genes remaining to be identified. One of the major challenges is now to understand phenotype–genotype correlations. Following these advances, it became more and more popular to think of the antiepileptic treatment in terms of their basic mechanisms of action, i.e. acting on Na or K channels or GABA transmission, etc...., as if a specific and precise molecular mechanism of action in given epileptic syndromes (childhood absence epilepsy, medial temporal lobe epilepsy, or the Dravet syndrome, etc....) were completely elucidated. We have to admit that this probably still constitutes an illusion. Today, the effort to clarify the effectiveness of a rationale of antiepileptic treatment on a (somewhat empirical) clinical basis and multidisciplinary T. Grisar (&) CHU, Department of Neurology, GIGA Neurosciences Research Centre, University of Liege, Liege, Belgium e-mail: tgrisar@ulg.ac.be

PWE-280 Ferroportin disease—an important cause of iron overload

IntroductionFerroportin disease is a recently characterised cause of iron overload. Unlike hereditary haemochromatosis it involves genetic mutations of SLC40A1 gene, and has autosomal dominant transmission. We describe here 3 siblings...

Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy

To identify a new genetic cause of distal hereditary motor neuropathy (dHMN), which is also known as a variant of Charcot-Marie-Tooth disease (CMT), in a Chinese family. We investigated a Chinese family with dHMN clinically, electrophysiologically, and genetically. We screened for the mutations of 28 CMT or related pathogenic genes using an originally designed microarray resequencing DNA chip. Investigation of the family history revealed an autosomal dominant transmission pattern. The clinical features of the family included mild weakness and wasting of the distal muscles of the lower limb and foot deformity, without clinical sensory involvement. Electrophysiologic studies revealed motor neuropathy. MRI of the lower limbs showed accentuated fatty infiltration of the gastrocnemius and vastus lateralis muscles. All 4 affected family members had a heterozygous missense mutation c.2677G>A (p.D893N) of alanyl-tRNA synthetase (AARS), which was not found in the 4 unaffected members and control subjects. An AARS mutation caused dHMN in a Chinese family. AARS mutations result in not only a CMT phenotype but also a dHMN phenotype.

Exercise testing: the catecholaminergic polymorphic ventricular tachycardia crystal ball?

This editorial refers to ‘The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands’ by M. Hayashi et al. , on page 1344 Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a fascinating inherited arrhythmia syndrome characterized by autosomal dominant transmission of adrenergically induced ventricular tachycardia (VT) associated with syncope and sudden death. First described clinically in the late 1970s,1,2 we have discovered many interesting insights about the disease over the past three decades. Clinical diagnosis is currently based on the observation of stress-induced polymorphic or bidirectional VT in the absence of structural heart disease or a prolonged QT interval.3 Diagnosis can be confirmed by the detection of mutations in the gene encoding the cardiac ryanodine receptor channel (RyR2) or the gene encoding cardiac calsequestrin (CASQ2) in ∼60% of symptomatic patients.4–7 Catecholaminergic polymorphic ventricular tachycardia has a malignant prognosis, with a recent study reporting an overall 8-year fatal or near-fatal event rate of 13%.8 Moreover, the same study reported an alarmingly high rate of arrhythmic events in asymptomatic relatives. However, CPVT appears to be a heterogenous disease that may have an age-dependent prognosis.8,9 As is often the case, early reports of rare syndromes typically report a dramatic course of the disease, and subsequent case finding unearths a spectrum of expression, including both asymptomatic phenotype carriers, and gene carriers with little or no phenotype. Beta-blocker therapy remains the cornerstone of treatment. However, a recent meta-analysis of 403 patients with 88% beta-blocker usage still reported an estimated 8-year fatal event rate of ∼6%.10 Therefore, an …

Frontotemporal lobar degeneration: current knowledge and future challenges

Frontotemporal lobar degeneration (FTLD) is one of the most frequent neurodegenerative disorders with a presenile onset. It presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. New diagnostic criteria identified two main cognitive syndromes: behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia. Regarding bvFTD, new criteria include the use of biomarkers. According to them, bvFTD can be classified in "possible" (clinical features only), "probable" (inclusion of imaging biomarkers) and "definite" (in the presence of a known causal mutation or at autopsy). Familial aggregation is frequently reported in FTLD, and about 10 % of cases have an autosomal dominant transmission. Microtubule-associated protein tau gene mutations have been the first ones identified, and are generally associated with early onset (40-50 years) and with the bvFTD phenotype. More recently, progranulin gene mutations were recognized in association with the familial form of FTLD and a hexanucleotide repetition in C9ORF72 has been shown to be responsible for familial FTLD and amyotrophic lateral sclerosis. In addition, other genes are linked to rare cases of familiar FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified.

Autosomal recessive transmission of chorea-acanthocytosis confirmed

We would like to draw attention to new genetic data recently reported [8] on a patient previously described as suffering from chorea-acanthocytosis (ChAc) with autosomal dominant transmission [7] and for whom neuropathological findings were published in this journal in 2009 [4]. At that time we questioned the apparent inheritance, given the limitations of the molecular methodology employed, and the lack of support for this mode of transmission otherwise found [2]. A correction concerning the original publication by Saiki et al. [7] has recently been published [1] stating: “an error in sequencing occurred and the inheritance pattern should have been reported as autosomal recessive (pseudodominant)”. This erratum reflects the findings reported by Tomiyasu et al. [8] whose patient no. 22 was identified with III-3 from the pedigree originally published and is identical with the patient in whom autopsy findings had been described in this journal [4]. This subject was also reported as case 1 of a further clinical study [6]. The new molecular findings describe compound heterozygous VPS13A mutations in him and also in his affected sister: 1305G>A in exon 15 and 8035G>A in exon 57. The nomenclature of the latter mutation was corrected from 8295G>A in the original report [4, 7]. The patients’ mother (II-4) was shown to be an asymptomatic carrier of a single heterozygous 1305G>A mutation. The father of the postmortem case of Ishida et al. [4], by conclusion a carrier of the 8035G>A mutation, was said to be suffering from early onset hyperkinesia as did other family members [5]. Unfortunately, no further analyses on DNA were feasible and the presence of mutations in other genes, e.g., IT15, responsible for the supposedly dominant features observed in this man, his father, his two sisters and a sister’s son could not be investigated [7]. In addition, there is still a possibility of subclinical involvement in subjects who carry a single heterozygous VPS13A mutation although, so far, no convincing evidence has yet been put forward to support that claim [3, 9]. In summary, the suggestion of dominant transmission of a condition recognized as an autosomal recessive trait (OMIM 200150) has eventually been put to rest in the autopsy case reported in this journal in 2009 and one source of confusion has been removed.