Autosomal Dominant Mode Of Transmission Research Articles

Rehabilitation for Marfan Syndrome

Abstract: Marfan syndrome is a spectrum of disorders caused by a heritable genetic defect of connective tissue that has an autosomal dominant mode of transmission. The defect itself has been isolated to the FBN1 gene on chromosome 15, which codes for the connective tissue protein fibrillin. Abnormalities in this protein cause a myriad of distinct clinical problems, of which the musculoskeletal, cardiac, and ocular system problems predominate. The skeleton of patients with Marfan syndrome typically displays multiple deformities. Mitral valve prolapses that requires valve replacement can occur as well. Given the variable expressivity of Marfan Syndrome, no single sign is pathognomonic; the diagnosis is made on clinical grounds on the basis of typical abnormalities. We reported a boy, 12 years old, referred from surgeon with diagnosis pectus carinatum pro brace. Chest protusion appeared since age 6, getting bigger without any complaint but cosmetic. Other complaints on feet which looked flat, sometimes ankle sore after long distance running or futsal. He was the first child and no family history had a condition like him. His hobby was playing futsal, and daily activities were independent without assistive devices. General appearance and vital signs were normal, cardiorespiratory assessment was normal, BMI on percentile 10-25, arm span to height ratio 1.09, lens subluxation of left eye, lens dislocation of right eye, poor standing balance, inadequate toe off, thoracic hyperkyphotic, positive wrist sign, true leg length discrepancy of 1 cm (left>right), bilateral ankle ROM limitation, rigid flat feet suspected bilateral vertical talus, left hallux valgus, Marfan syndrome score 9, and normal echocardiography. In this patient, we gave semi rigid thoraco-lumbo-sacral orthosis (TLSO) with 3 points pressure system and rigid bar on protution area (custom molded). resistance exercise (F: 3x/week, I: moderate fatigue, Borg scale 13-15/20, T: 8-15 reps/ set, 2-3 set/ session, T: major muscle group upper and lower extremities aerobic exercise (F: 3x/week, I: moderate to vigorous, borg scale 13-15/20, T: ≥60 min/session, @5-10 min warming up and cooling down (stretching), T: sport (swimming, running, cycling). The patient was referred to a surgeon for a brace. In conclusion, this case report highlights the multidisciplinary management of patients with Marfan syndrome. Keywords: Marfan syndrome; typical abnormalities; multiple deformities

Genetic Insights from Consanguineous Cardiomyopathy Families.

Inherited cardiomyopathies are a prevalent cause of heart failure and sudden cardiac death. Both hypertrophic (HCM) and dilated cardiomyopathy (DCM) are genetically heterogeneous and typically present with an autosomal dominant mode of transmission. Whole exome sequencing and autozygosity mapping was carried out in eight un-related probands from consanguineous Middle Eastern families presenting with HCM/DCM followed by bioinformatic and co-segregation analysis to predict the potential pathogenicity of candidate variants. We identified homozygous missense variants in TNNI3K, DSP, and RBCK1 linked with a dilated phenotype, in NRAP linked with a mixed phenotype of dilated/hypertrophic, and in KLHL24 linked with a mixed phenotype of dilated/hypertrophic and non-compaction features. Co-segregation analysis in family members confirmed autosomal recessive inheritance presenting in early childhood/early adulthood. Our findings add to the mutational spectrum of recessive cardiomyopathies, supporting inclusion of KLHL24, NRAP and RBCK1 as disease-causing genes. We also provide evidence for novel (recessive) modes of inheritance of a well-established gene TNNI3K and expand our knowledge of the clinical heterogeneity of cardiomyopathies. A greater understanding of the genetic causes of recessive cardiomyopathies has major implications for diagnosis and screening, particularly in underrepresented populations, such as those of the Middle East.

Differences Between the Two Most Common Forms of Neurofibromatosis and the Importance of their Exact Diagnosis- a case report

Neurofi bromatosis type 2 is a rare genetic disease with an autosomal dominant mode of transmission. It is characterized by manytumors in the central nervous system, where meningiomas and schwannomas are the most common. The hallmark of this diseaseis bilateral vestibulocochlear schwannomas. Although certain similarities with neurofi bromatosis type 1 exist, neurofi bromatosistype 2 is caused by a completely diff erent gene mutation, producing a distinct clinical presentation and is monitored and treateddiff erently. This paper will present the case of a 17-year-old boy misdiagnosed with neurofi bromatosis type 1 at the beginning of hisclinical workup. After taking a detailed patient history and an additional radiological examination, the correct diagnosis of neurofi -bromatosis type 2 was reached. The patient was operated on multiple times by experienced surgeons, which was thoroughly discussed at the pediatric oncology board. Neurofi bromatoses come in many forms and are diff erent diseases. Every diagnosis of neurofi bromatosis should be made using defi ned diagnostic criteria to enable the correct treatment of the patient and preserve thepatient’s quality of life as much as possible.

Pregnancy in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (AC) is a rare heart muscle disease with a genetic background and autosomal dominant mode of transmission. The clinical manifestation is characterized by ventricular arrhythmias (VA), heart failure (HF) and the risk of sudden cardiac death (SCD). Pregnancy in young female patients with AC represents a challenging condition for the life and family planning of young affected women. In addition to genetic mechanisms that influence the complex pathophysiology of AC, experimental and clinical data have confirmed the pathogenetic role of strenuous exercise and competitive sports in the early onset and rapid progression of AC symptoms and complications. Pregnancy and exercise share a number of physiological aspects of adaptation. In AC, both result in ventricular volume overload and myocardial stretch. Therefore, pregnancy has been postulated as a potential risk factor for HF, VA, SCD, and pregnancy-related obstetric complications in patients with AC. However, the available evidence on pregnancy in AC does not confirm this hypothesis. In most women with AC, pregnancies are well tolerated, uneventful, and follow a benign course. Pregnancy-related symptoms (VA, syncope, HF) and mortality, as well as obstetric complications, are uncommon in AC patients and range in the order of background populations and cohorts with AC and no pregnancy. The number of completed pregnancies is not associated with an acceleration of AC pathology or an increased risk of VA or HF during pregnancy and follow-up. Accordingly, there is no medical indication to advise against pregnancy in patients with AC. Preconditions include stability of rhythm and hemodynamics at baseline, as well as clinical follow-ups and the availability of multidisciplinary expert consultation during pregnancy and postpartum. Genetic counseling is recommended prior to pregnancy for all couples and their families affected by AC.Supplementary InformationThe online version of this article (10.1007/s00399-021-00770-7) contains supplementary material, which is available to authorized users.

Prevalence and clinical characteristics of isolated forms of central precocious puberty: a cohort study at a single academic center.

Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP. This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years. In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance. These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.

Spectrophotometric Determination of Zolmitriptan in Pure Form and in Tablets Through Charge Transfer Complex Reaction

Apert syndrome (AS) a type of acrocephalosyndactyly is a rare congenital disorder with autosomal dominant mode of transmission that consists of craniofacial synostosis, midfacial hypoplasia and bilateral limb syndactyly. Patients present in early childhood for multiple surgeries which make it imperative to know about various anaesthetic implications like difficult airway ventilation, airway hyper reactivity, associated congenital anomalies, increased airway secretions and deranged temperature thermoregulation associated with this syndrome. The patient should be thoroughly evaluated preoperatively and managed accordingly. We discuss the successful management of a three and a half years old male child two simple, rapid and selective colorimetric methods were developed for the determination of zolmitriptan (ZMT) in pure form and pharmaceutical preparations. These methods are based on the directly formation of charge-transfer complexes between ZMT and m-nitrophenol (MNP) in aqueous medium (ZMT: MNP, 1:1) and 2,4-dinitrophenol (DNP) in ethanol:water (80:20). The developed method involves formation of coloured complexes (1:1) of ZMT with MNP and DNP. The yellow formed complexes were quantitatively measured at 400 and 440 nm for ZMT-MNP and ZMT-DNP, respectively. Beer's law was obeyed in the concentration ranges of 3.0–260 μg/mL for MNP and 3.5–120 μg/mL for DNP. Limit of detection and limit of quantitation for MNP were calculated as 0.58 and 1.75 μg/mL, respectively, and for DNP were 0.32 and 0.97 μg/mL, respectively. The method was validated with respect to accuracy, robustness and selectivity. The proposed method has been successfully applied for the determination of ZMT in tablets.

Anaesthesia Concerns in Apert Syndrome - A Case Report

Apert syndrome (AS) a type of acrocephalosyndactyly is a rare congenital disorder with autosomal dominant mode of transmission that consists of craniofacial synostosis, midfacial hypoplasia and bilateral limb syndactyly. Patients present in early childhood for multiple surgeries which make it imperative to know about various anaesthetic implications like difficult airway ventilation, airway hyper reactivity, associated congenital anomalies, increased airway secretions and deranged temperature thermoregulation associated with this syndrome. The patient should be thoroughly evaluated preoperatively and managed accordingly. We discuss the successful management of a three and a half years old male child with Apert syndrome.

A Monoallelic Two-Hit Mechanism in PLCD1 Explains the Genetic Pathogenesis of Hereditary Trichilemmal Cyst Formation

Trichilemmal cysts are common hair follicle-derived intradermal cysts. The trait shows an autosomal dominant mode of transmission with incomplete penetrance. Here, we describe the pathogenetic mechanism for the development of hereditary trichilemmal cysts. By whole-exome sequencing of DNA from the blood samples of 5 affected individuals and subsequent Sanger sequencing of a family cohort including 35 affected individuals, this study identified a combination of the Phospholipase C Delta 1 germline variants c.903A>G, p.(Pro301Pro) and c.1379C>T, p.(Ser460Leu) as a high-risk factor for trichilemmal cyst development. Allele-specific PCRs and cloning experiments showed that these two variants are present on the same allele. The analysis of tissue from several cysts revealed that an additional somatic Phospholipase C Delta 1 mutation on the same allele is required for cyst formation. In two different functional invitro assays, this study showed that the protein function of the cyst-specific 1-phosphatidylinositol 4, 5-bisphosphate phosphodiesterase delta-1 protein variant is modified. This pathologic mechanism defines a monoallelic model of the two-hit mechanism proposed for tumor development and other hereditary cyst diseases.

3T MRI study discloses high intrafamilial variability in CADASIL due to a novel NOTCH3 mutation

In order to evaluate the usefulness of presymptomatic MRI, we performed 3T brain MRI and Sanger gene sequencing in a proband with suspected but not confirmed CADASIL and her apparently asymptomatic father. The 35-year-old proband presented with migraine with visual aura. Brain MRI showed diffuse leukoencephalopathy, suggesting CADASIL. NOTCH3 gene sequencing (exons 3–6) was negative. Family history was unclear. The MRI study of the father documented severe, diffuse leukoencephalopathy, with involvement of the temporal poles and external capsules (not observed in the proband), and lacunar infarcts in the absence of cardiac disease or risk factors. The MRI findings were in favour of an autosomal dominant mode of transmission and reinforced the hypothesis of CADASIL. Full NOTCH3 gene sequencing uncovered a novel exon 8 mutation (c.1337G>A; p.Cys446Tyr) outside the most commonly mutated region of NOTCH3.The novel mutation leads to a typical MRI pattern but a variable overall phenotype. The study underlines the usefulness of combining full gene sequencing with familial MRI studies.

Exome Sequencing Identifies Two Variants of the Alkylglycerol Monooxygenase Gene as a Cause of Relapses in Visceral Leishmaniasis in Children, in Sudan.

Visceral leishmaniasis (kala-azar, KA) is the most severe form of leishmaniasis, characterized by fever, weight loss, hepatosplenomegaly, and lymphadenopathy. During an outbreak of KA in Babar El Fugara (Sudan), 5.7% of cured patients displayed relapses, with familial clustering in half the cases. We performed whole-exome sequencing on 10 relapsing individuals and 11 controls from 5 nuclear families. Rare homozygous and compound-heterozygous nonsense (c.1213C > T, rs139309795, p.Arg405*) and missense (c.701A > G, rs143439626, p.Lys234Arg) mutations of the alkylglycerol monooxygenase (AGMO) gene were associated with KA relapse in 3 families. Sequencing in additional family members confirmed the segregation of these mutations with relapse and revealed an autosomal dominant mode of transmission. These mutations were detected heterozygous in 2 subjects among 100 unrelated individuals with KA who never relapsed after cure, suggesting incomplete penetrance of AGMO deficiency. AGMO is expressed in hematopoietic cells, and is strongly expressed in the liver. AGMO modulates PAF production by mouse macrophages, suggesting that it may act through the PAF/PAF receptor pathway previously shown to have anti-Leishmania activity. This is the first demonstration that relapses after a first episode of KA are due to differences in human genetic susceptibility and not to modifications of parasite pathogenicity.

Familial early puberty: presentation and inheritance pattern in 139 families.

BackgroundThe mechanism that initiates the onset of puberty is largely unknown but the age of onset is mainly under genetic control and influenced by environmental factors including nutrition. The coexistence in the same family of central precocious puberty and advanced puberty, both representing early puberty, suggests that they may represent a clinical spectrum of the same trait due to early activation of the GnRH pulse generator. We therefore evaluated the mode of inheritance of early puberty in a large series of familial cases.MethodsA retrospective, single center study was carried out on 154 probands (116 girls and 38 boys), from 139 families seen for idiopathic central precocious puberty (onset before 8 years in girls and 9–10 years in boys, n = 93) and/or advanced puberty (onset between 8 and 10 years in girls and 10 and 11 years in boys, n = 61) seen over a period of 8 years.ResultsOf the 139 families, 111 (80.4 %) had at least one affected 1st degree relatives, 17 (12 %) had only 2nd, 5 (3.6 %) only 3rd and 3 (2.2 %) had both 2nd and 3rd degree affected individuals. In the two remaining families, the unaffected mother had affected girls from two unaffected fathers. In the majority of families the inheritance of the phenotype was consistent with autosomal dominant mode of transmission with incomplete penetrance. An exclusively maternal mode of transmission could be observed or inferred in 83 families, paternal in only 2 families (p < 0.0001) and both maternal and paternal modes in 15 families.In the 139 families, 374 cases of early puberty were identified of whom 315 (84.2 %) were affected females and 59 (15.8 %) affected males (p < 0.0001). Twenty one percent of families had exclusively precocious puberty, 25 % had exclusively advanced puberty and 54 % had combinations of both.ConclusionsThe data confirm the high incidence of affected girls with familial early puberty. The mode of inheritance of the phenotype is predominantly maternal. More than half of the families included both precocious and advanced puberty suggesting similar genetic factors.

The Brugada Syndrome: A Rare Arrhythmia Disorder with Complex Inheritance.

For the last 10 years, applying new sequencing technologies to thousands of whole exomes has revealed the high variability of the human genome. Extreme caution should thus be taken to avoid misinterpretation when associating rare genetic variants to disease susceptibility. The Brugada syndrome (BrS) is a rare inherited arrhythmia disease associated with high risk of sudden cardiac death in the young adult. Familial inheritance has long been described as Mendelian, with autosomal dominant mode of transmission and incomplete penetrance. However, all except 1 of the 23 genes previously associated with the disease have been identified through a candidate gene approach. To date, only rare coding variants in the SCN5A gene have been significantly associated with the syndrome. However, the genotype/phenotype studies conducted in families with SCN5A mutations illustrate the complex mode of inheritance of BrS. This genetic complexity has recently been confirmed by the identification of common polymorphic alleles strongly associated with disease risk. The implication of both rare and common variants in BrS susceptibility implies that one should first define a proper genetic model for BrS predisposition prior to applying molecular diagnosis. Although long remains the way to personalized medicine against BrS, the high phenotype variability encountered in familial forms of the disease may partly find an explanation into this specific genetic architecture.

The NOTCH3ECD cascade hypothesis of cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease

AbstractBackgroundCerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, with an autosomal dominant mode of transmission, is an archetypal small vessel disease of the brain that has emerged as the most common heritable cause of stroke and vascular dementia worldwide.Aims and methodsHere we review the current knowledge on the pathogenesis of this disease.ResultsThe disease is caused by highly stereotyped missense mutations that alter the number of cysteine residues in the extracellular domain of NOTCH3, a transmembrane receptor that undergoes a series of proteolytic cleavages on ligand binding that release the extracellular domain, and ultimately enable the intracellular domain to translocate to the nucleus, where it acts as a transcriptional activator. NOTCH3 is predominantly expressed in vascular smooth muscle cells, and is critical for the structure and function of small vessels of the brain. Mutations differentially affect NOTCH3 transcriptional activity; however, it is still debated whether a reduction in NOTCH3 activity might contribute to the disease process. In contrast, all disease associated NOTCH3 mutations are associated with an early accumulation, aggregation and deposition of the extracellular domain at the plasma membrane of smooth muscle cells, in extracellular deposits called granular osmiophilic material. Importantly, recent work identified a novel mechanism in which excess of the extracellular domain of NOTCH3 promotes the abnormal recruitment of proteins of the extracellular matrix that might cause multifactorial toxicity in the brain vessels.ConclusionRecent studies lend support to a NOTCH3ECD cascade hypothesis in in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy that posits that the deposition of NOTCH3 extracellular domain in the brain vessels initiates a sequence of events that ultimately lead to stroke and dementia.

Epigenetic Mechanisms of Rubinstein–Taybi Syndrome

Rubinstein-Taybi syndrome (RTS) is an incurable genetic disorder with combination of mental retardation and physical features including broad thumbs and toes, craniofacial abnormalities, and growth deficiency. While the autosomal dominant mode of transmission is limitedly known, the majority of cases are attributable to de novo mutations in RTS. The first identified gene associated with RTS is CREB-binding protein (CREBBP/CBP). Alterations of the epigenetic 'histone code' due to dysfunction of the CBP histone acetyltransferase activity deregulate gene transcriptions that are prominently linked to RTS pathogenesis. In this review, we discuss how CBP mutation contributes to modifications of histone and how histone deacetylase inhibitors are therapeutically applicable to epigenetic conditioning in RTS. Since most genetic mutations are irreversible and therapeutic approaches are limited, therapeutic targeting of reversible epigenetic components altered in RTS may be an ideal strategy. Expeditious further study on the role of the epigenetic mechanisms in RTS is encouraged to identify novel epigenetic markers and therapeutic targets to treat RTS.

Apert′s syndrome: Report of a rare case

Apert's syndrome (AS), a form of acrocephalosyndactyly, is a rare congenital disorder with autosomal dominant mode of transmission; characterized by craniosynostosis, midface hypoplasia, and syndactyly of hands and feet. The rarity of the syndrome and similarity of features with other craniosynostosis syndromes makes it a diagnostic dilemma. Genetic counseling and early intervention form an essential part of treatment. Because of the paucity of reported cases in Indian literature and typical features in oral cavity, a dentist should be competent to diagnose and form a part of the multidisciplinary management team. Here, we report a case of a 14-year-old boy with AS.

Síndrome de Waardenburg: aspectos oftalmológicos e critérios de diagnóstico: relatos de casos

To describe the clinical and imaginological features of two families with Waardenburg syndrome: type I and II, with emphasis on ophthalmic manifestations, as well as the pattern of genetic inheritance. We conducted a clinical study involving two families affected by Waardenburg syndrome, and through the pedigree, determined the present pattern of genetic inheritance. Analyses were performed including the measurement of visual acuity, the presence of dystopia cantorum (telecanthus), evaluation of iris color and retinal mapping, as well as dermatological and otological examinations. The pedigree of the family affected by the Waardenburg syndrome type I showed an autosomal dominant mode of transmission. The syndrome was present at 85.71% of patients. The dystopia cantorum was the most frequent feature, followed by the white streak on the skin of the forehead, hypopigmentation of the iris and retina and deafness. The Waardenburg syndrome family type II had 33.33% of family members affected by the syndrome. No member had dystopia cantorum and hypopigmentation of the iris. Three patients had sensorineural hearing loss (12.5%), associated with white forelock and achromatic spots confluent by the body. This study shows the importance of the ophthalmologist in aiding the diagnosis of this rare genetic condition, since it includes ocular disorders such as telecanthus, hypopigmentation of the iris and retina. The cantorum dystopia is the main diagnostic criterion to differentiate type I and II syndrome and should be done by a trained ophthalmologist. The families are in medical monitoring, receiving genetic guidelines and care related to eye protection.

Cleidocranial dysplasia: a case report of a rare anomaly

Cleidocranial dysplasia (CCD) is a rare hereditary disease of unknown etiology which was previously known as cleidocranial dysotosis. It usually follows an autosomal dominant mode of transmission. The phenotype is characterized by general dysplastic bone formation manifested by abnormalities in the shoulder girdle, skull, jaw and dentition. We report a case of a six year old female child presenting with classical features of CCD. An outstanding feature of this case is that it did not follow a familial pattern of inheritance since the patient is the only member in the family suffering from such disorder. The clinician should be aware of the characteristic features of CCD for early diagnosis and initiating the appropriate treatment. The clinical, radiological findings and its embryological cause are discussed. DOI: http://dx.doi.org/10.3126/njms.v1i2.6615 Nepal Journal of Medical Sciences. 2012;1(2): 135-7

A case of porokeratosis plantaris palmaris et disseminata and literature review

Porokeratosis plantaris palmaris et disseminata (PPPD) is a quite rare variant of porokeratosis. We report a 56-year-old male patient. He first noted brownish, asymptomatic, annular macules scattered on the trunk and extremities at about age 31 and these skin lesions, continued to increase in number. Ten years prior to presentation, similar lesions appeared on the palms. About one to two years ago, the patient noted painful wart-like, keratotic punctuate papules 2-3 mm in diameter on the soles, which disturbed walking. Histological examination showed the characteristic feature of the cornoid lamella. The family tree of this patient showed an autosomal dominant mode of transmission. We review sixteen typical cases of PPPD previously reported in the English literature.

Superimposed segmental vitiligo should not be categorized as “type 2 mosaicism”

To the Editor: I read with interest the excellent article of Drs Ezzedine and coworkers1Ezzedine K. Gauthier Y. Léauté-Labrèze C. Marquez S. Bouchtnei S. Jouary T. et al.Segmental vitiligo associated with generalized vitiligo (mixed vitiligo): a retrospective case series of 19 patients.J Am Acad Dermatol. 2011; 65: 965-971Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar presenting a series of 19 patients with segmental vitiligo superimposed on nonsegmental vitiligo (“mixed vitiligo”). I fully agree that this particular disorder has so far been neglected and that a thorough study of such cases may yield new insight into the polygenic basis of vitiligo.2Happle R. Superimposed segmental manifestation of polygenic skin disorders.J Am Acad Dermatol. 2007; 57: 690-699Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Regarding one point, however, I do not concur with the authors. They state that “our data would fit type II mosaicism in most patients versus type I in patients 7 and 8.” Firstly, the fact that in two of their patients the ultraviolet B treatment was successful in both nonsegmental and segmental lesions does not exclude, in my view, a diagnosis of superimposed segmental vitiligo. Secondly, a distinction between type 1 and type 2 mosaicism can only be made in monogenic disorders with an autosomal dominant mode of transmission.2Happle R. Superimposed segmental manifestation of polygenic skin disorders.J Am Acad Dermatol. 2007; 57: 690-699Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar By contrast, in a case of isolated segmental vitiligo we can never be sure that the patient will not develop, later in life, additional nonsegmental lesions of this polygenic disease.3Happle R. Superimposed segmental manifestation of both rare and common cutaneous disorders: a new paradigm.Actas Dermo-Sif. 2009; 100: 77-85Crossref PubMed Scopus (29) Google Scholar Moreover, a type 2 segmental manifestation of a monogenic skin disorder can plausibly be explained by an early event of loss of heterozygosity, whereas in polygenic disorders the superimposed mosaic involvement may also be caused by an early postzygotic new mutation resulting in heterozygosity at an additional predisposing gene locus.3Happle R. Superimposed segmental manifestation of both rare and common cutaneous disorders: a new paradigm.Actas Dermo-Sif. 2009; 100: 77-85Crossref PubMed Scopus (29) Google Scholar For all of these reasons, I recommend the more descriptive terms “isolated” versus “superimposed” segmental manifestation.2Happle R. Superimposed segmental manifestation of polygenic skin disorders.J Am Acad Dermatol. 2007; 57: 690-699Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar However that may be, let us hope that the ingenious group from Bordeaux1Ezzedine K. Gauthier Y. Léauté-Labrèze C. Marquez S. Bouchtnei S. Jouary T. et al.Segmental vitiligo associated with generalized vitiligo (mixed vitiligo): a retrospective case series of 19 patients.J Am Acad Dermatol. 2011; 65: 965-971Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar will have the opportunity to analyze their impressively large series of “mixed vitiligo” at the molecular level.4Taïeb A. Morice-Picard F. Jouary T. Ezzedine K. Cario-André M. Gauthier Y. Segmental vitiligo as the possible expression of cutaneous somatic mosaicism: implications for common non-segmental vitiligo.Pigment Cell Melanoma Res. 2008; 21: 646-652Crossref PubMed Scopus (52) Google Scholar Segmental vitiligo associated with generalized vitiligo (mixed vitiligo): A retrospective case series of 19 patientsJournal of the American Academy of DermatologyVol. 65Issue 5PreviewMixed vitiligo (MV), the association of segmental vitiligo (SV) and nonsegmental vitiligo, has been rarely reported. Full-Text PDF

Phenocopies in families with essential tremor and restless legs syndrome challenge Mendelian laws. Epigenetics might provide answers

Essential Tremor (ET) and Restless Legs Syndrome (RLS) are both highly heritable neurological disorders. The frequent occurrence of multi-incident families suggests the existence of highly penetrant alleles. However, linkage analyses and positional cloning approaches performed within the last 10 years essentially failed to identify responsible mutations. Several loci were found, but their relevance was questioned given the occurrence of suspected phenocopies in many of those families. Remarkably, in some ET and RLS families with an apparent autosomal dominant mode of transmission, the proportion of affected individuals was higher than the expected 50% and therefore suggests a non-mendelian inheritance in some cases. In fact, there is increasing evidence that epigenetic modifications, which refer to changes in gene expression without changes in DNA sequence, can be transmitted to the next generation. Moreover, epigenetic information can be transferred from one allele of a gene to the other allele of the same gene; if then inherited to the next generation, the offspring consequently presents phenotypic properties related to the untransmitted allele. This phenomenon known as paramutation is well documented in plants and has recently been shown to occur also in mammals. Here, I explore the possibility that it is the epigenetic and not only the genetic state which confers disease risk in families. Inheritance of epigenetic mutations along with paramutational events have the potential to explain the non-mendelian features in the genetics of both diseases.