Familial cutaneous collagenomas resulting from a novel mutation in LEMD3.
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Chromosome Disorders↗
Biomedical subjects
E Sprecher
Publications and source records attributed to E Sprecher.
Cerebral hemodynamics in symptomatic and asymptomatic patients with severe unilateral carotid stenosis before and after carotid endarterectomy.
BACKGROUND: Data concerning hemodynamic status prior to and after carotid endarterectomy (CEA) in symptomatic and asymptomatic patients is insufficient. Transcranial Doppler (TCD) provides information regarding compensatory collateral flow as well as mechanisms of cerebral autoregulation in patients with carotid stenosis. PATIENTS AND METHODS: Forty eight symptomatic and 81 asymptomatic patients with unilateral severe carotid stenosis were examined by TCD before and in early postoperative period after CEA. RESULTS: Cigarette smoking was the only risk factor significantly more frequent in symptomatic patients. Preoperative anterior cerebral artery (ACA) and middle cerebral artery (MCA) asymmetry, basilar artery velocity and number of ophthalmic arteries with reversed flow, were not significantly different between the two groups. Pulsatility index, cerebrovascular reactivity and flow acceleration on the side of stenosis were significantly lower in symptomatic patients. After surgery there was a significant improvement of all TCD parameters in symptomatic as well as asymptomatic patients. CONCLUSIONS: The exhausted ability of cerebral autoregulation is an important factor differentiating between symptomatic and asymptomatic patients with severe carotid stenosis. Successful surgery provides good recovery of cerebral hemodynamics in both symptomatic and asymptomatic patients.
Aged↗
A homozygous missense mutation in PEPD encoding peptidase D causes prolidase deficiency associated with hyper-IgE syndrome.
BACKGROUND: Prolidase deficiency is a complex disease characterized by various skin manifestations accompanied by mental retardation, facial dysmorphism and susceptibility to pyogenic infections. METHODS: We assessed a patient presenting a peculiar phenotype combining manifestations of prolidase deficiency with features typical of hyper-IgE syndrome. Mutation analysis was performed using direct PCR amplification and PCR restriction fragment length polymorphism analysis. RESULTS: We identified a novel homozygous recessive mutation in the PEPD gene, which was found to segregate in the family of the patient with the disease and was not found in a panel of DNA samples representative of all major Druze families living in northern Israel. DISCUSSION: Our results suggest that prolidase deficiency associated with hyper-IgE syndrome, a rare disorder, can be caused by mutations in PEPD.
Adult↗
Molecular basis of hypotrichosis with juvenile macular dystrophy in two siblings.
BACKGROUND: Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by sparse and short scalp hair from birth, followed within a few years by progressive macular degeneration leading to blindness. HJMD was shown to result from mutations in CDH3 encoding P-cadherin. OBJECTIVES: In the present study, we attempted to identify the molecular basis of abnormal hair growth in two siblings of Arab Muslim origin with hypotrichosis but no visual symptoms. METHODS: Mutation analysis was performed using direct sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Patients displayed sparse and short hair since birth. Significant macular degenerative pigmentary changes were noticed in the face of normal visual acuity. Despite the fact that a single CDH3 mutation had previously been described in several families of Israeli Arab Muslim origin, the two affected patients were found to be homozygous carriers of a novel nonsense mutation (Y615X) predicted to result in premature termination of P-cadherin translation. CONCLUSIONS: The present results indicate that all patients with congenital hypotrichosis should undergo thorough fundus examination, which, when revealing pigmentary macular changes, can be considered as indicative of an underlying CDH3 causative mutation.
Arabs↗
Epidermolytic hyperkeratosis type PS-1 caused by aberrant splicing of KRT1.
Mutations in the keratin 1 (KRT1) gene underlie epidermolytic hyperkeratosis (EHK). This autosomal dominant disorder is characterized by phenotypic heterogeneity. In the present study, we assessed a 33-year-old individual presenting with severe palmoplantar keratoderma and histopathological findings suggestive of EHK. We analysed genomic DNA extracted from the patient's blood lymphocytes for pathogenic mutations in KRT1. A heterozygous 4-bp deletion was identified in intron 1 of the gene (591+3_+6delGAGT), suggesting the possibility that it may interfere with the normal splicing of intron 1. We detected a 66-bp deletion in KRT1 mRNA extracted from the patient's skin, predicted to result in the translation of a mutant KRT1 lacking 22 amino acids, including the conserved helix initiation motif. The identification of this unusual and novel mutation underscores the diagnostic importance of sequence analysis of keratin gene noncoding regions.
Adult↗
Quantitative measurement of pain sensation in patients with Parkinson disease.
BACKGROUND: Pain is common in patients with Parkinson disease (PD) and can precede the diagnosis of the disease. Experimental studies and clinical evidence indicate involvement of basal ganglia and dopaminergic pathways in central pain processing. OBJECTIVE: To quantitatively assess and compare pain perception in patients with unilateral PD with and without pain and in patients with response fluctuations. METHODS: Thirty-six patients with PD (mean age, 61.8 +/- 11.2 years) with predominantly unilateral disease, 15 patients with response fluctuations (mean age, 65.3 +/- 10.4 years), and 28 age-matched healthy control subjects participated in the study. Subjective pain was assessed using the visual analog scale with von Frey filaments for tactile thresholds and contact thermode for warm sensation (WS) and heat pain thresholds (HPTs). RESULTS: Tactile and WS thresholds did not differ between patients in both patient groups and control subjects nor between sides. HPT was lower in patients with PD who experienced pain (n = 21) compared with those who did not (42.6 +/- 3.0 degrees C vs 45.6 +/- 2.8 degrees C; p < 0.01) and those who experienced pain in the more affected side (41.4 +/- 2.6 degrees C vs 43.7 +/- 3.3 degrees C; p < 0.0001). In patients with fluctuations there were no side differences in WS and HPT or between "on" and "off" periods. CONCLUSION: Endogenous pain in patients with Parkinson disease is accompanied by increased sensitivity to some painful stimuli, suggesting that basal ganglia abnormality also involves pain encoding.
Aged↗
Deleterious mutations in SPINK5 in a patient with congenital ichthyosiform erythroderma: molecular testing as a helpful diagnostic tool for Netherton syndrome.
The congenital erythrodermas represent a heterogeneous group of inherited and acquired disorders often accompanied by systemic infections, impaired epidermal barrier function and concomitant life-threatening fluid and electrolyte imbalance. In the present report, we describe a patient who was considered to have congenital ichthyosiform erythroderma for 26 years until molecular testing led to the correct diagnosis of Netherton syndrome.
Adult↗
Compound heterozygosity for mutations in the hairless gene causes atrichia with papular lesions.
BACKGROUND: Congenital atrichias represent a complex and heterogeneous group of genodermatoses, which have been shown in several consanguineous families to result from homozygous mutations in the hairless gene (HR). OBJECTIVES: To identify the molecular basis of congenital atrichia in a non-consanguineous family. METHODS: Genetic analysis was carried out in a two-generation family with two children with congenital atrichia and one healthy child. RESULTS: We established a diagnosis of atrichia with papular lesions based on clinical and histopathological data. We identified a heterozygous 11-bp deletion (189-199del) in the two affected children and their mother. In addition, the two affected children and their father were shown to carry a non sense mutation (Q478X), which has previously been described in a Pakistani family. Haplotype analysis revealed that mutation Q478X occurred independently in the two families. CONCLUSIONS: We have identified the first case of compound heterozygosity for mutations in HR as well as the first instance of a recurrent mutation in this gene. These data further expand our understanding of the molecular pathomechanisms underlying congenital atrichias.
Alopecia↗
Assessment of ophthalmic artery collateral pathway in the hemispheric cerebral hemodynamics in patients with severe unilateral carotid stenosis.
The role of ophthalmic artery collateral pathway in hemispheric hemodynamics in patients with severe carotid stenosis is controversial. The aim of the present study was to address this question comparing the asymmetry of the velocity in middle and anterior cerebral arteries (MCAs and ACAs) and cerebrovascular reactivity (CVR) in MCA on stenotic side in the patients with unilateral severe stenosis of internal carotid artery (ICA) in patients with and without ophthalmic artery collateral pathway. The cohort of 118 patients with carotid stenosis was prospectively assembled. Fifty patients who had severe unilateral ICA stenosis (71%-99%) by Duplex Ultrasound (DUS) were observed by transcranial Doppler (TCD). Cerebral blood flow velocity in MCA and ACA in both sides, direction of blood flow in ophthalmic artery (OA) and CVR on the side of stenosis were determined. There were 14 patients with retrograde blood flow in OA (Group I). The remaining 36 patients with anterograde flow in OA composed Group II. The degree of interarterial asymmetry of peak and mean velocity (Vpeak and Vmean) in MCA and ACA and CVR in MCA were compared in both groups. The degree of ACA asymmetry by Vpeak was 44.0% +/- 6.9% in Group I and 38.3% +/- 3.9% in Group II (p = 0.49), by Vmean 40.3% +/- 6.7% and 36.6% +/- 3.8% (p = 0.63) respectively. The degree of MCA asymmetry by Vpeak was 24.2% +/- 2.8% in Group I and 19.5% +/- 5.0% in Group II (p = 0.42), by Vmean 23.5% +/- 2.9% and 20.6% +/- 5.1% (p = 0.63) respectively. CVR in Group I was 26.1% +/- 6.1%, in Group II 29.0% +/- 6.7% (p = 0.65). The ophthalmic collateral pathway has no influence on hemispheric cerebral hemodynamics in patients with severe unilateral carotid stenosis.
Aged↗
Stress in a case of SAPHO syndrome.
In this article, we describe a case of seemingly stress-induced SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome in a man who exhibited the central features of palmoplantar psoriasis and anterior chest involvement. We also review the etiology, pathogenesis, and treatment of SAPHO syndrome and emphasize the important differences between this syndrome and psoriatic arthritis.
Acquired Hyperostosis Syndrome↗
The nature of microemboli in patients with artificial heart valves.
Cognitive decline has recently been found to be associated with microemboli in cerebral vessels in patients with artificial heart valves. The authors sought to determine the nature of such microemboli, that is, whether they are gaseous or solid, by comparing their characteristics to those of artificially generated air emboli in patients with patent foramen ovale (PFO). Three hundred and forty-eight microemboli were recorded in 11 patients with artificial valves (all taking coumadin), and 86 microemboli were recorded in response to intravenous injection of saline agitated with air in 8 PFO patients. No difference in intensity, duration, or relative velocity of microemboli was found between groups. The authors conclude that microemboli generated from artificial heart valves are generally gaseous and not solid.
Adult↗
Immunogenetics of HLA class II in Israeli Ashkenazi Jewish, Israeli non-Ashkenazi Jewish, and in Israeli Arab IDDM patients.
The distribution of HLA class II alleles and genotypes in IDDM patients was examined in the three main Israeli ethnic groups: Ashkenazi Jews, non-Ashkenazi Jews, and Arabs. Molecular sequence specific oligonucleotide probe analysis was performed for DRB1, DQA1, and DQB1 genes. The DRB1*03011, DQA1*05 DQB1*02/DRB1*0402, DQA1*03, DQB1*0302 genotype was found to be the main susceptibility genotype in all three groups, with differences in the degree of association. In addition to DRB1*0402 (more frequent among Ashkenazi Jews), DRB1*0405, another subtype of DRB1*04, was found to be more prevalent among non-Ashkenazi Jews and Arabs. Many alleles were found to be negatively associated with insulin dependent diabetes mellitus (IDDM). This could be a result of the high frequency of susceptible alleles, or of linkage disequilibrium to a primary negatively associated allele. The strongest negative association was observed for DQB1*0301 in all three ethnic groups. The alleles DRB1*1401, DRB1*1501, DQB1*05031, DQB1*0602, and DQB1*0609 were not detected in any of the 202 IDDM patients, and are probably either strongly protective or in linkage with such alleles. Despite the differences found between the three ethnic groups, an overall analysis shows that the DRB1*04 alleles that account for susceptibility to IDDM in the Israeli population (DRB1*0402 and *0405) are the same as those responsible for susceptibility to IDDM in a number of other Mediterranean populations. In contrast, the susceptible allele in most Caucasian populations is DRB1*0401. It is noteworthy that the susceptible alleles DRB1*0402/05 for Mediterranean and DRB1*0401 for Caucasian populations are also frequent in the respective healthy populations. These findings support the results obtained in other studies, which point to a genetic relationship between the Israeli and Mediterranean populations.
Alleles↗
Simultaneous recording of late and ultra-late pain evoked potentials in fibromyalgia.
OBJECTIVE: To characterize laser evoked potentials (LEP), pain psychophysics and local tissue response in fibromyalgia patients. METHODS: LEP were recorded in 14 women with fibromyalgia in response to bilateral stimulation of tender and control points in upper limbs by 4 blocks of 20 stimuli at each point. Subsequently, heat pain thresholds were measured and supra-threshold magnitude estimations of heat pain stimuli were obtained on a visual analogue scale. Finally, the extent of the local tissue response induced by the previous stimuli was evaluated. RESULTS: Laser stimuli elicited two long latency waves: A late wave (mean latency 368.9+/-66.9 ms) in most patients (13/14) from stimuli at all points, and an ultra-late wave (mean latency 917.3+/-91.8 ms) in 78.5% of the patients at the control points and in 71.4% at the tender points. Amplitude of ultra-late waves was higher at the tender points (20.67+/-11.1 microV) than at the control points (10.47+/-4.1 microV) (P=0.016). Pain thresholds were lower in the tender (41.2+/-2.7 degrees C) than the control points (43.9+/-3.2 degrees C) (P=0.008). Local tissue response was significantly more intense at tender than control points (P=0.004). CONCLUSIONS: Ultra-late laser evoked potentials can be recorded simultaneously with late potentials. Our findings are compatible with presence of peripheral C-fiber sensitization, mostly at tender points, probably combined with generalized central sensitization of pain pathways in fibromyalgia.
Arm↗
Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin.
Congenital hypotrichosis associated with juvenile macular dystrophy (HJMD; MIM601553) is an autosomal recessive disorder of unknown etiology, characterized by hair loss heralding progressive macular degeneration and early blindness. We used homozygosity mapping in four consanguineous families to localize the gene defective in HJMD to 16q22.1. This region contains CDH3, encoding P-cadherin, which is expressed in the retinal pigment epithelium and hair follicles. Mutation analysis shows in all families a common homozygous deletion in exon 8 of CDH3. These results establish the molecular etiology of HJMD and implicate for the first time a cadherin molecule in the pathogenesis of a human hair and retinal disorder.
Adolescent↗
Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.
Unraveling the molecular basis of inherited disorders of epithelial fragility has led to understanding of the complex structure and function of keratin intermediate filaments. Keratins are organized as a central alpha-helical rod domain flanked by nonhelical, variable end domains. Pathogenic mutations in 19 different keratin genes have been identified in sequences corresponding to conserved regions at the beginning and end of the rod. These areas have been recognized as zones of overlap between aligned keratin proteins and are thought to be crucial for proper assembly of keratin intermediate filaments. Consequently, all keratin disorders of skin, hair, nail, and mucous membranes caused by mutations in rod domain sequences are characterized by perinuclear clumping of fragmented keratin intermediate filaments, thus compromising mechanical strength and cell integrity. We report here the first mutation in a keratin gene (KRT1) that affects the variable tail domain (V2) and results in a profoundly different abnormality of the cytoskeletal architecture leading to a severe form of epidermal hyperkeratosis known as ichthyosis hystrix Curth-Macklin. Structural analyses disclosed a failure in keratin intermediate filament bundling, retraction of the cytoskeleton from the nucleus, and failed translocation of loricrin to the desmosomal plaques. These data provide the first in vivo evidence for the crucial role of a keratin tail domain in supramolecular keratin intermediate filament organization and barrier formation.
Amino Acid Sequence↗
The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.
The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.
Adolescent↗
Type 1 diabetes environmental factors and correspondence analysis of HLA class II genes in the Yemenite Jewish community in Israel.
OBJECTIVE: The Israeli Yemenite Jewish community has displayed an exceptionally rapid increase in the frequency of type 1 diabetes, having the highest rate of all Israeli ethnic groups. We studied the role of the environment, in relation to the nature and frequency of HLA class II genes, to evaluate its possible involvement in the development of diabetes. RESEARCH DESIGN AND METHODS: We interviewed 196 elderly Yemenite women, who had immigrated to Israel as adults, in programmed encounters about signs and symptoms of type 1 diabetes, infant feeding customs, and infectious diseases in Yemen. We also performed HLA oligotyping of DRB1, DQA1, and DQB1 genes in 120 unrelated Yemenite Jews, including 44 type 1 diabetic patients and 76 healthy control subjects, and used these data in correspondence analysis comparing Yemenites with different Israeli ethnic groups. RESULTS: Interviews indicated that early exposure to cow's milk was very common in Yemen. However, none of the women could recall classical presentations of diabetes. HLA oligotyping showed that gene frequencies of non-Asp-57 (of the HLA-DQB chain) in the patients (0.94) and control subjects (0.6) were similar to those of other populations with a known high incidence of type 1 diabetes. Correspondence analysis revealed that Yemenite Jews are genetically distinct from other ethnic groups in Israel. CONCLUSIONS: The genetic distinctiveness of Yemenite Jews may explain their unusually high incidence of type 1 diabetes in Israel. Despite the presence of highly susceptible diabetogenic HL4 class II genes in this community, early exposure to cow's milk did not cause phenotypic expression of diabetes in Yemen. This finding suggests that in this population, either cow's milk does not play a crucial role in triggering diabetes, or environmentally conferred protection, such as frequent infectious disease in Yemen, was dominant.
Adult↗
Normative values for female genital sensation.
OBJECTIVES: Neurologic disorders might be responsible for many cases of female sexual dysfunction. Yet, they are currently undiagnosed because of the lack of measurement tools to assess genital neural function. Therefore, our objective is to provide norms for sensory thresholds in the vagina and clitoris, for a wide range of patient ages. METHODS: Vaginal and clitoral warm, cold, and vibratory sensory thresholds were measured in 89 healthy paid volunteers by the method of limits. Normograms were derived from this group of healthy volunteers. An additional 61 patients were also tested, for a total of 150 individuals. Sixty-two individuals (42 healthy volunteers and 20 patients) from the total group were tested twice to provide test-to-test repeatability data across the range of clinical (normal and abnormal) responses. RESULTS: Normograms are presented, providing age-corrected upper and lower normal values, expressed as 95% confidence limits for warm, cold, and vibratory thresholds. Intertest repeatability is also reported. CONCLUSIONS: Thermal and vibratory thresholds of both the vaginal and clitoral region are clinically feasible, valid, and repeatable. These can be applied as a valuable diagnostic tool to assess neural dysfunction through sensory assessment of the female genitalia.
Adolescent↗