Small abnormality of the middle ear--a genetically-induced defect?

Conductive and sensorineural hearing losses are of genetic origin in 20% to 60% of cases. In general, genetic abnormalities are more often expressed as a sensorineural hearing loss than as a conductive hearing loss. At present several genes for sensorineural hearing loss have been isolated. The most common genetically transmitted forms for isolated conductive hearing losses are otosclerosis and small malformations of the ossicles. To date no genes responsible for these deformations have been isolated. We present a family with four siblings having conductive hearing losses caused by ossification of the stapedial tendon. This finding is suggestive of an autosomal recessive inheritance. The early diagnosis of an hereditary conductive hearing loss contains the possibility for permitting normal development of speech.     

HIV-1 viral load: comparative evaluation of three commercially available assays in Argentina

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of hereditary hearing impairment (HHI). To date, 16 different loci have been reported, making ARNSHL an extremely heterogeneous disorder. One of these loci, DFNB4, was mapped to a 5-cM interval of 7q31 in a large Middle-Eastern Druze family. This interval also includes the gene for Pendred syndrome. We report on three new families with HHI from the Madras region of southern India that demonstrate linkage to 7q. Their pedigrees are compatible with autosomal recessive inheritance. Furthermore, the largest family identifies a novel locus (DFNB17) telomeric to the DFNB4 and Pendred intervals. A 3-cM region of homozygosity by descent between markers D7S486 and D7S2529 is present in all affected individuals in this family and generates a multipoint LOD score of 4.24. The two other families map to the previously reported DFNB4 region but have insufficient power to attain significant LOD scores. However, mutations in the Pendred syndrome gene are present in one of these families.     

Familial Mondini dysplasia

OBJECTIVES/HYPOTHESIS: To determine the mode of inheritance of familial nonsyndromic Mondini dysplasia. Study Design: Correlative clinical genetic analysis of a single kindred. METHODS: Clinical history, physical examination, audiologic analysis, computed tomography of the temporal bones, and cytogenetic analysis. RESULTS: The male proband, three affected sisters, and an affected brother are offspring of unaffected parents. The mother and an unaffected brother have audiologic findings suggestive of heterozygous carrier status for a recessive hearing loss gene. CONCLUSIONS: Pedigree analysis indicates autosomal recessive inheritance in this family. The observed inheritance and clinical, audiologic, and radiologic findings are different from those previously described for another family with nonsyndromic Mondini dysplasia. The phenotype in this study family therefore represents a distinct subtype, indicating clinical and genetic heterogeneity of this disorder. This information should facilitate future molecular linkage analyses and genetic counselling of patients with inner ear malformations.     

Patterns of inheritance of ovarian cancer. An analysis from an ovarian cancer screening program

BACKGROUND: A variety of inheritance patterns for familial ovarian cancer have been proposed including an autosomal dominant inheritance, a breast-ovary cancer syndrome and Lynch Cancer Family Syndrome (involving breast, bowel, ovary, and endometrial cancers). METHODS: Women participating in an ovarian cancer screening study completed a questionnaire concerning their family history of ovarian and other malignancies (in particular breast, bowel, and endometrial cancer). Confirmation of the diagnosis was sought when there was uncertainty. RESULTS: Two hundred forty women with a first-degree relative with ovarian cancer participated in the study. Nine percent of these women (representing 13 families) gave a definite history of two or more affected first-degree relatives. Two families had a pedigree consistent with an autosomal dominant inheritance. A breast-ovary cancer family and a Lynch cancer family syndrome were suspected in one family each, although 34% of all women gave a history of at least one other first-degree relative with either breast, bowel, or endometrial cancer. CONCLUSIONS: Only a small number of women with a family history of ovarian cancer fit into the recognized hereditary patterns. Difficulty in recognizing the inheritance patterns and the lack of definitive genetic markers poses problems in providing adequate counseling regarding screening and prophylactic oophorectomy.     

Independent constitutional germline mutations occurring in the RB1 gene in cousins with bilateral retinoblastoma

The inheritance of a genetic susceptibility to the development of retinoblastoma generally follows an autosomal mode of inheritance with high penetrance. Rare families, however, show evidence of incomplete penetrance where individuals can transmit the mutant gene without being affected themselves. In these families formal proof of this dogma requires the identification of the predisposing mutation. In this study we have identified the mutations in cousins with bilateral (hereditary) disease. Using SSCP and DNA sequencing, different constitutional mutations were detected in the affected cousins in this pedigree. One cousin carries a C-->T mutation in exon 8 generating a stop codon directly which was also present in his affected mother whereas the other cousin carries an 8 base pair deletion in exon 20. Neither half of the family carried the same mutation as the other. The mother of the patient with the 8 bp deletion carried neither of the mutations. Thus, we have demonstrated that the retinoblastomas in this family have developed as a result of independent, sporadic genetic events which occurred coincidentally in the same extended family rather than being due to a common mutation which manifests as incompletely penetrant. These observations have important implications for genetic counselling in this type of family.     

Mutations in the COCH gene are a frequent cause of autosomal dominant progressive cochleo-vestibular dysfunction, but not of Meniere's disease

The COCH gene is the only gene identified in man that causes autosomal dominantly inherited hearing loss associated with vestibular dysfunction. The condition is rare and only five mutations have been reported worldwide. All affected families showed a similar progressive hearing loss and vestibular dysfunction. Since Meniere's disease-like symptoms have also been described in some families, it was suggested that COCH mutations might be present in some patients diagnosed with Meniere's disease. In this study, using a Japanese population, we performed a COCH mutation analysis in 23 patients from independent families with autosomal dominant hearing impairment, four of whom reported vestibular symptoms, and also in 20 Meniere's patients. While a new point mutation, A119 T, was found in a patient with autosomal dominant hearing loss and vestibular symptoms, no mutations were found in the Meniere's patients. Like all other previously identified COCH mutations, the mutation identified here is a missense mutation located in the FCH domain of the protein. The current mutation is located in close spatial proximity to W117, in which a mutation (W117R) had previously been associated with autosomal dominant hearing loss. Model building suggests that, like the W117R mutation, the A119 T mutation does not affect the structural integrity of the FCH domain, but may interfere with the interaction with a yet unknown binding partner. We conclude that mutations in the COCH gene are responsible for a significant fraction of patients with autosomal dominantly inherited hearing loss accompanied by vestibular symptoms, but not for dominant hearing loss without vestibular dysfunction, or sporadic Meniere's disease.     

Automatic activation and strategic avoidance of threat-relevant information in social phobia

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi-generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease-causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.     

Frequency of familial inheritance among 488 index patients with idiopathic focal dystonia and clinical variability in a large family

Idiopathic torsion dystonia is characterized by involuntary twisting movements and postures. One molecularly defined form with generalized dystonia has been shown to be autosomal dominantly inherited with reduced penetrance in chromosome 9q34.1, especially in Ashkenazi Jewish families, while other generalized families from Europe and families with other subtypes of dystonia have been excluded from linkage to this locus. Genealogical studies suggest that the much more frequent focal dystonia follows an autosomal dominant inheritance with reduced penetrance as well. For our study, 488 patients with focal dystonia, without a tendency for generalization, were interviewed for their family history. Evidence for hereditary disposition was found in 88 individuals. In a second step, all available family members of 17 of the 488 index patients (chosen for cooperation) were clinically examined. Objective diagnosis of affected relative was established in 13 families, whereas only 4 of the 17 index patients had previously admitted a positive family history. Furthermore, a large three-generation family with focal dystonia linked to chromosome 18p (linkage data described elsewhere) was identified. The familial pattern of all reported families is compatible with autosomal dominant inheritance with reduced penetrance. Assessment only on patients' report leads to underestimation of the frequency of familial idiopathic focal dystonia.     

Identification of normal hearing carriers of genes for deafness

The dominant and sex-linked forms of hereditary hearing loss, which have long been recognized, are readily identified on the basis of the family history and routine hearing tests. The mode of inheritance of the recessive forms of hereditary deafness, on the other hand, has been extremely difficult to determine. The research of the last few years, however, has disclosed that carriers of genes for recessive deafness can be identified by audiometric recording of certain peculiarities in the hearing function. This is an important advance, not only as regards diagnositc work, but also in the research into the genetics of deafness.     

Genetic heterogeneity of autosomal dominant cerebellar ataxia type 1: clinical and genetic analysis of 10 French families

We performed linkage analysis between the gene responsible for spinal cerebellar ataxia 1 (SCA1) and the highly polymorphic chromosome 6 locus, D6S89, in 10 French families with autosomal dominant cerebellar ataxia (ADCA) type 1. These families were clinically indistinguishable except for one family with loss of hearing and vision. Very close linkage was observed in four families, with no evidence of recombination between SCA1 and D6S89. Linkage with D6S89 was excluded in the six others, thus demonstrating genetic heterogeneity for ADCA type 1. The D6S89 marker, which is very closely linked to the disease locus, can be used to identify SCA1 families and will lead to predictive testing.     

Investigation of the actions and antagonist activity of some polyamine analogues in vivo

Complete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development.     

Genetic heterogeneity of autosomal dominant amelogenesis imperfecta demonstrated by its exclusion from the AIH2 region on human chromosome 4Q

Amelogenesis imperfecta (AI) is a group of hereditary enamel defects, characterized by large clinical diversity. On the basis of differences in clinical manifestation and inheritance pattern, 14 different subtypes have been recognized. A locus for autosomal dominant AI (ADAI) of local hypoplastic type was recently mapped to the region between D4S392 and D4S395 on the long arm of chromosome 4. To test whether the chromosome 4 locus is responsible for other forms of AI as well, a linkage study was carried out with 17 families representing at least five clinical forms of ADAI. Admixture tests for heterogeneity performed with the marker D4S2456 gave statistical support for genetic heterogeneity of ADAI with the odds 78:1. Linkage to the ADAI locus on chromosome 4q (AIH2) could only be demonstrated with families expressing the local hypoplastic type, and there was no support for heterogeneity within that group of families. Furthermore, linkage could be excluded for five families with other clinical forms of ADAI. The data therefore demonstrated that ADAI is genetically heterogeneous, and that at least two loci for it exist.     

Complex screening of family members at risk for familial adenomatous polyposis

151 members of 10 affected families with FAP have been registered at the authors' regional polyposis registry, among them 51 FAP patients were verified histologically. The disorder is autosomal dominant thus the chance for the inheritance of the mutated allele is fifty percent in the offspring of an affected patient. Because of the high risk the registration and regular control of family members is recommended. They can be divided into high risk and low risk group based on presymptomatic tests. The examination of retina pigmentepithel was the only possibility for presymptomatic diagnosis earlier. After localization and identification of APC gene responsible for the disease molecular genetic methods have been introduced for presymptomatic diagnosis. The authors performed presymptomatic tests based on ophthalmologic and molecular genetic methods among family members at risk. Ophthalmologic examination was done in 53 while molecular genetic investigation in 54 cases. All the results of endoscopic, ophthalmological and molecular genetic examinations were available in 35 persons, among them 19 FAP have been found. Ophthalmological examination were informative in 33 out 35 cases (unequivocal positive or negative) while results of molecular genetic methods and sigmoidoscopy were correlated in every case. Authors stress the significance of complex screening of affected families with FAP in the prevention of colorectal cancer and extracolonic malignant processes.     

Bilateral transscapholunate dislocations

Irreversible hearing loss is a catastrophic complication of treatment with aminoglycoside antibiotics such as streptomycin, gentamycin, and kanamycin. Many kindreds showing a matrilineal pattern of inheritance of this trait have been described in China where the widespread use of aminoglycoside antibiotics accounts for approximately 25% of profound deafness in some districts. Because of the characteristic inheritance pattern, mitochondrial DNA (mtDNA) mutations were postulated to be the cause of the deafness in these pedigrees. In 1993 it was shown that an A to G substitution at base pair 1555 of the mitochondrial 12S ribosomal RNA gene was the only mutation common to all the families with aminoglycoside ototoxicity. We ascertained three Mongolian pedigrees from the School for the Deaf and Blind in Ulaanbaatar, all of which contained multiple affected subjects with streptomycin induced deafness in a pattern consistent with matrilineal transmission. Amplified mtDNA, obtained from transformed lymphoblastoid cell lines using previously described primers, showed the A to G point mutation in the 12S rRNA gene in two of the three families by restriction analysis as well as direct sequencing. No other example of this substitution was found among 400 control samples from Mongolians with normal hearing. We have thus confirmed the clinical relevance of the 1555 A to G mitochondrial mutation in the 12S rRNA gene by identifying it in affected subjects with familial aminoglycoside ototoxicity in another ethnic group. In countries where aminoglycosides are widely used, genetic counselling and screening of high risk families before the use of these drugs could have a dramatic effect on the incidence of deafness.     

A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA13, maps to chromosome 6p

Nonsyndromic hearing loss (NSHL) is the most common type of hearing impairment in the elderly. Environmental and hereditary factors play an etiologic role, although the relative contribution of each is unknown. To date, 39 NSHL genes have been localized. Twelve produce autosomal dominant hearing loss, most frequently postlingual in onset and progressive in nature. We have ascertained a large, multigenerational family in which a gene for autosomal dominant NSHL is segregating. Affected individuals experience progressive hearing loss beginning in the 2d-4th decades, eventually making the use of amplification mandatory. A novel locus, DFNA13, was identified on chromosome 6p; the disease gene maps to a 4-cM interval flanked by D6S1663 and D6S1691, with a maximum two-point LOD score of 6.409 at D6S299.     

High prevalence of mitochondrial diabetes mellitus in Japanese patients with major risk factors

To identify diabetes mellitus caused by the mitochondrial gene substitution at genomic nucleotide pair 3243 (M3243A-->G) we selected 87 diabetic patients with high risk factors such as maternal inheritance and hearing loss. Total DNA was extracted from peripheral leukocytes, and mitochondrial DNA fragments containing M3243A-->G were amplified by polymerase chain reaction (PCR). The amplified fragments were digested with a restriction endonuclease Apa1 and analyzed by agarose gel electrophoresis. The incidence of the M3243A-->G mutation was 4.6% (four of 87) in diabetic patients with maternal inheritance and/or hearing loss. In a subgroup with both maternal inheritance and hearing loss, the incidence of the mutation was as high as 21.4% (three of 14). Cardiac disorders were also present in all four diabetic patients with the mutation. This study suggests that maternal inheritance and hearing loss are useful clinical findings to identify diabetic patients with the mutation, and that cardiac involvement is a high risk factor for the M3243A-->G mutation.     

Chiari Type I malformation and syringomyelia in unrelated patients with blepharophimosis. Report of two cases

Syringomyelia is a rare, mainly sporadic disease of the spinal cord, which is associated with 80% of cases in which a Chiari Type I malformation is also present. A mendelian transmission of syringomyelia (autosomal dominant or recessive) has been proposed in approximately 2% of reported cases. The association of syringomyelia with hereditary diseases (Noonan's syndrome, phacomatoses) has been mentioned frequently in the literature. The authors report the presence of a Chiari Type I malformation accompanied by syringomyelia in two unrelated patients affected by a familial Type II blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The first patient was a 35-year-old woman who presented with a right C-8 root paresia. The second case involved a 20-year-old man who complained of cervical radicular pain. Both belong to families in which BPES was segregated in an autosomal dominant modality, but other family members had no known neurological symptoms. To the authors' knowledge, such a combination has never been described. Perhaps the possible involvement of a genetic component in some cases of Chiari Type I-associated syringomyelia will someday be debated.     

Hereditary occurrence of the mesotelesystolic click syndrome: a study of 9 families (author's transl)

Nine families affected by the mid-systolic click syndrome were studied. Of the one hundred and forty-four first-degree relatives, 117 of whom were living, eighty-four were examined. Thirty-five were found to be affected by the syndrome. Twenty-six were females and nine were males. Auscultatory and phonocardiographic findings consisted either of isolated mis-systolic clicks or systolic murmurs or a combination of the two. Electrocardiograms revealed changes of various types, most commonly of the ST-T segment. About seventy per cent of the patients were symptomatic. Nine members, not examined by the authors, had died suddenly; all had a previous history of "cardiopathy". Progressivity of mitral valve disease with age is not confirmed by the present study. It is suggested that the mode of inheritance of the defect might be that of an autosomal dominant form of Mendelian type with delayed expression of the defect. An alternatove hypothesis of a multifactorial inheritance mechanism, which is more stimulating for future studies on the cause of the syndrome, is also taken into consideration.     

Two families with Alport's syndrome

Alport's syndrome is a hereditary disease striking cochlea, eye and kidney. The diseased women usually have a nonlethal degree of the kidney disease, but the prognosis for the men is worse. They often die from renal failure before the age of 35. Most cases of hearing loss occurs in men. The hearing loss is progressive after the age of 10. Audiological tests are characteristic for a cochlear lesion. The debut of the disease usually appears in the post natal period giving microscopic haematuria. It can, however, occur later with haematuria and proteinuria. The hearing loss may be the first symptom, which is an observandum to otologists. Two families with Alport's syndrome are described. The patients have been examined concerning kidney disease, audiological and vestibular pathology. The hereditary pattern is described.