Anterior lenticonus and Alport's syndrome

A case of anterior lenticonus is reported in a 26 year old man with hemorrhagic nephritis related to familial Alport's syndrome. Anterior lenticonus is seen only as a part of Alport's syndrome. The authors describe its clinical, histologic and therapeutic aspects. They also discuss the other ocular manifestations, the nephritis and the sensorineural deafness.     

Molecular cytogenetics: applications in clinical genetics

Epidural neuroblastoma xenografts in nude rats causing paraparesis were treated with intravenous injection of an anti-GD2 monoclonal antibody 3F8. Metastatic or primary epidural tumors in humans cause rapid neurologic compromise. Treatment is often unsatisfactory. An animal model was established to study antibody targeted therapy of epidural tumor. Human neuroblastoma was xenotransplanted into the thoracic epidural space of nude rats. When paraparesis developed, animals were treated intravenously with an anti-GD2 monoclonal antibody, 3F8, either alone or radiolabeled with 131Iodine. Improvement in neurologic function occurred in 2 of 20 (10%) animals receiving no treatment or control antibody, 14 of 17 (82%) animals receiving 3F8 alone and all 9 animals receiving 131I-3F8 (p < 0.0001 for 3F8 or 131I-3F8 vs. control). Six animals treated with 3F8 alone recovered normal neurologic function and remained well until sacrifice 10 days later. Four animals treated with 3F8 alone had no tumor evident on pathologic examination. The percent injected dose of 131I-3F8/g tumor in 5 samples ranged from 0.73% to 3.8%. These observations demonstrate that neoplastic epidural compression of the spinal cord in the rat can be treated successfully with intravenous unmodified monoclonal antibody and that signs of neurologic dysfunction can be reversed. The potential of this approach in treating patients with epidural tumors and other neoplasms, especially those that are not sensitive to chemotherapy or radiotherapy, deserves to be explored.     

Fragile X syndrome: clinical and molecular genetics correlations

The fragile X form of mental retardation is presently recognized as the most frequent hereditable cause of mental impairment. The estimated frequency among males is 1 in 1250, and 1 in 2000 among females. Beside mental impairment and behavioural disturbance with hyperactivity and autistic features, the patients are characterized by morphological anomalies, such as an oblong face, broad, rectangular chin, large protruding ears and macro-orchidism. A less severe clinical expression can be found among females heterozygotes of the disorder, manifesting mainly as learning disability. The disorder is associated with the expression of a fragile site at Xq27.3 under conditions of folate depletion in the chromosome culture medium. The molecular mechanism is based on the expansion of a trinucleotide repeat [CCG]n in the promoter region of the FMR1 gene resulting in methylation of the gene. The trinucleotide repeat shows variable lengths of 6 to 53 repeats in the general population, 60 to 200 repeats in carriers of a premutation and over 200 repeats in patients with fragile X syndrome.     

Huntington's chorea: clinical aspects, genetics and current diagnosis

Huntington's disease is a late manifesting autosomal dominant neurodegenerative disorder. It is characterized by motor disturbance, loss of cognitive functions and psychiatric manifestations. The disease causing mutation, an unstable DNA sequence in the coding region of the Huntington gene on chromosome 2p, has recently been identified. A trinucleotide [CAG] repeat is expanded over the normal range and can be easily detected by standard laboratory methods. Accurate genetic testing can now be offered in clinically questionable cases and to presymptomatic subjects at risk for Huntington's disease. Furthermore, there is a correlation between the size of the expanded CAG repeat and the age of onset in affected individuals. The predictive value of this correlation, however, is limited due to the range of onset ages found at a given repeat length in large series of patients. Expanded triplet repeats exhibit a marked instability especially in male meiosis with a tendency to further increase during transmission over the generations. This is likely to be the molecular mechanism explaining anticipation, as well as the occurrence of juvenile cases and new mutations.     

GENFILES: a computerized medical genetics information network. II. MEDGEN: the clinical genetics system

MEDGEN, a clinical genetics information storage and retrieval system, facilitates the handling of medical records for the central genetics clinic and satellite clinics conducted by the University of California, San Francisco. The system is part of the GENFILES genetics network, which handles all of the genetics data generated by a comprehensive medical genetics center. The clinical data stored on each patient include 1) diagnoses, which utilize McKusick catalog numbers as well as our own diagnostic codes; 2) relevant medical, gestational, and pregnancy history; 3) clinical manifestations (functional and structural); 4) karyotype information through a crosslink to the cytogenetics file; 5) ethnic origin of the patients; 6) physical status and sex of the patient; 7) laboratory studies, including results of metabolic tests; and 8) any additional remarks deemed necessary for complete understanding. The data, staff member attending, and physical location of each visit also are recorded.     

Secondary hypertension and clinical genetics: usual presentation with unusual diagnosis

A transjugular central venous catheter was inadvertently sutured to the wall of the right atrium in a 63-year-old female during coronary bypass surgery. Using two nitinol Goose Neck snares via a transfemoral and a transjugular approach the catheter was severed into two pieces and retrieved percutaneously.     

The role of clinical pharmacology in molecular genetics

PROBLEM: Discovering the causes of unusual phenotypes in human subjects is an important aspect of patient-oriented research. MATERIAL: The tools of clinical pharmacology are uniquely useful in addressing these problems. PATIENTS, SUBJECTS, OR CASE HISTORIES: We evaluated a 42-year-old patient with lifelong orthostatic hypotension and ptosis of the eyelids. He underwent a series of biochemical, physiological, and pharmacological tests outlined in this article. RESULTS: These studies indicated that sympathetic innervation was intact but that the sympathetic neurotransmitter was dopamine rather than norepinephrine. These results demonstrated that dopamine-beta-hydroxylase deficiency underlies the clinical abnormalities of this patient. CONCLUSION: In selected individuals with unusual phenotypes, the techniques of clinical chemistry and clinical pharmacology can define the nature of the defect at almost the resolution of the human genome.     

Fragile X syndrome. Diagnosis, genetics and clinical findings

The most common heritable form of mental retardation is the fragile X syndrome. It is X-linked and affects 1:1500-1:4000 boys. In Denmark 230 affected individuals are known, thereby rendering it underdiagnosed. Only minor dysmorphic traits are associated with the syndrome, more pronounced in boys, namely a long face with large, prominent ears, and macroorchidism postpubertally. The psychological manifestations are autistic features, hyperactivity and deviant behavior. Today no medical curative treatment is available but much can be gained from social and educational intervention. The syndrome is caused by a dynamic mutation on the X chromosome and displays a remarkable pattern of inheritance. Carrier diagnosis and prenatal diagnosis are feasible. This article describes the clinical, diagnostic and genetic aspects of fragile X syndrome.     

Epidemiological and clinical patterns of genital lesions

A 5-year study of 668 patients with genital lesions revealed that teenagers and those in the age group of 20 to 40 are most vunerable. The poor, the uneducated and unmarried persons are at high risk. Chancroid and syphilis are the majority of cases. Inguinal bubo, herpes pregenitalis, condylomata acuminata, erosive balanitis and traumatic ulcers were seen less frequently. Most of the genital lesions had the classic clinical features. The findings of this study suggest that the pattern of genital lesions is showing borderline changes.     

Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications

Galactocerebrosidase (GALC) is a lysosomal beta-galactosidase responsible for the hydrolysis of the galactosyl moiety from several galactolipids, including galactosylceramide and psychosine. The deficiency of this enzyme results in the autosomal recessive disorder called Krabbe disease. It is also called globoid cell leukodystrophy (GLD), because of the characteristic storage cells found around cerebral blood vessels in the white matter of affected human patients and animal models. Although most patients present with clinical symptoms before 6 months of age, older patients, including adults, have been diagnosed by their severe deficiency of GALC activity. More than 40 mutations have been identified in patients with all clinical types of GLD. While some mutations clearly result in the infantile type if found homozygous or with another severe mutation, it is difficult to predict the phenotype of novel mutations or when mutations are found in the heterozygous state. A high incidence of polymorphic changes on apparent disease-causing alleles also complicates the interpretation of the effects of mutations. The detection of mutations has greatly improved carrier identification among family members and will permit preimplantation diagnosis for some families. The molecular characterization of the naturally occurring mouse, dog, and monkey models will permit their use in trials to evaluate different modes of therapy.     

Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study

The par genes are required to establish polarity in the Caenorhabditis elegans embryo. Mutations in two of these genes, par-3 and par-6, exhibit similar phenotypes. A third gene, pkc-3, gives a similar phenotype when the protein is depleted by RNA interference. PAR-3 and PKC-3 protein are colocalized to the anterior periphery of asymmetrically dividing cells of the germline lineage and the peripheral localizations of both proteins depends upon the activity of par-6. Here we report the molecular cloning of par-6 and the immunolocalization of PAR-6 protein. We found that par-6 encodes a PDZ-domain-containing protein and has homologues in mammals and flies. Moreover, we discovered that PAR-6 colocalizes with PAR-3 and that par-3 and pkc-3 activity are required for the peripheral localization of PAR-6. The localization of both PAR-3 and PAR-6 proteins is affected identically by mutations in the par-2, par-4 and par-5 genes. The co-dependence of PAR-3, PAR-6 and PKC-3 for peripheral localization and the overlap in their distributions lead us to propose that they act in a protein complex.     

Beta thalassemia in Germany: molecular genetics and clinical phenotype in immigrant and in the native population

Dentin dysplasia, type II (MIM*125420) is an autosomal dominant disorder of dentin development. Clinically the primary dentition appears opalescent, and radiographically the pulp chambers are obliterated, resembling dentinogenesis imperfecta. However, unlike dentinogenesis imperfecta, the permanent teeth in dentin dysplasia, type II are normal in color and, on radiographs, have a thistle-tube pulp chamber configuration with pulp stones. The similarity of the primary dentition phenotype suggested that the gene for dentin dysplasia, type II is allelic with the gene for dentinogenesis imperfecta, Shields type II (DGII; MIM*125490), which has been localized to chromosome 4q13-q21. Twenty-four members of a three generation family in which ten members are affected with dentin dysplasia, type II were genotyped for microsatellite alleles specific for the area of chromosome 4q linked to DGII. Linkage was assessed by using the LINKAGE computer program, assuming autosomal dominant inheritance, a disease allele frequency of 0.0001, and complete penetrance. The maximum two-point LOD score (Zmax = 4.2 at theta = 0.0) was obtained with SPPI and D4S2691. Multipoint analysis gave a maximum LOD score of 4.33. The candidate region for dentin dysplasia, type II is approximately 14.1 cM, includes SPPI, D4S2691, D4S2690, D4S451, and D4S2456, and overlaps the most likely location of the DGII locus. A candidate gene for DGII should also be considered a candidate gene for dentin dysplasia, type II.     

Ulcerative colitis and Crohn''s disease--susceptibility genes and clinical patterns

The pET(scF11) plasmid was constructed comprising the gene of a single-chain antibody against human ferritin. This plasmid encodes the leader peptide pelB followed by the heavy chain variable V(H) domain, (Gly4Ser)3 linker peptide, and light chain variable V(L) domain. The correctly processed scF11 antibody was expressed in Escherichia coli as an insoluble protein without the leader peptide. Purified soluble scF11 was obtained after solubilization in 6 M GdnHCl followed by a sequential dialysis against decreasing urea concentrations and ion-exchange chromatography. ScF11 demonstrated only a approximately 8-fold decrease in the affinity (Ka = 5.1 x 10(8) M(-1) in RIA and 1.8 x 10(8) M(-1) in ELISA) vs. the parent IgG2a/kappa monoclonal antibody F11. The emission maximum of intrinsic fluorescence strongly suggests a compact conformation with tryptophanyl fluorophores buried in the protein interior, consistent with the functionality of the protein. However, scF11 demonstrated (i) the lack of denaturant-induced fluorescence 'dequenching' effect characteristic of the completely folded parent antibody, and (ii) prominent binding, under physiological conditions, of a hydrophobic probe 8-anilino-1-naphthalenesulfonate (ANS) recognizing partially structured states of a protein. These findings are indicative of an incomplete tertiary fold that gives ANS access to the protein hydrophobic core. This work provides the first indication that the functional single-chain antibody scF11 displays some properties of a partially structured state and therefore may possess incomplete folding.     

Prevalence, genetics and clinical presentation of chronic granulomatous disease in Sweden

To estimate the prevalence of chronic granulomatous disease (CGD) in Sweden, an inquiry asking for known and possible CGD cases was mailed to paediatric, internal medicine and infectious disease departments all over Sweden. The detected patients were characterized as to genetics and the clinical presentation. Twenty-one patients (belonging to 16 different families) were found, corresponding to a prevalence of approximately 1/450,000 individuals. The patients with X-linked disease, lacking a functional gp91phox protein (n = 12), comprised 57% and 43% of the patients had an autosomal recessive (AR) disease lacking p47phox (n = 7) or p67phox (n = 1), respectively. All unrelated patients with X-linked disease displayed different gene abnormalities such as point mutations predicting nonsense (n = 3), missense (n = 1) or splice site mutations (n = 2), but also a total deletion and a unique 40 base pair duplicature insertion. The patients with p47phox-deficiency showed a GT deletion at a GTGT tandem repeat, and the p67phox-deficient patient displayed a heterozygous in-frame deletion of AAG combined with a large deletion in the other allele. Three patients died during the study period, two from pseudomonas cepacia infections. Patients with X-linked disease had more frequent infections (mean of 1.7 per year), than the patients with AR inheritance (0.5 infections per year). The most common infections were dermal abscesses (n = 111), followed by lymphadenitis (n = 82) and pneumonias (n = 73). Inflammatory bowel disease-like symptoms, mimicking Crohn's disease of the colon, was seen in three CGD patients.     

Sociotropy and autonomy: Differential patterns of clinical presentation in unipolar depression.

We examined the relations between sociotropy and autonomy and clinical features of depression. A. T. Beck (1983) proposed that sociotropy is related to a sense of deprivation and clinical features associated with reactive depression and that autonomy is related to a sense of defeat and clinical features associated with endogenous depression. C. J. Robins et al (see record 1989-19204-001) found support for the hypothesis for sociotropy but not for autonomy, and they suggested that the autonomy scale may be problematic. We administered new measures of sociotropy and autonomy and a more comprehensive assessment of clinical features to 50 unipolar depressed inpatients. The results support the selective relations of both sociotropy and autonomy to the predicted sets of clinical features. This study adds to the growing evidence that these personality dimensions are important to the understanding of depression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropathy after cardiac catheterization: incidence, clinical patterns, and long-term outcome

PURPOSE: Neuropathy is a rare, but potentially morbid, complication of cardiac catheterization. In this study, we report the incidence of this complication and describe its clinical presentation, cause, and natural history. METHODS: Between 1988 and 1993, 9585 cardiac catheterizations were performed at this institution. Patients in whom femoral neuropathy developed were identified through a cardiology registry. Hospital and outpatient records and personal interviews were used to determine the presentation and clinical course of each of these patients. RESULTS: Peripheral neuropathy developed in 20 patients (incidence = 0.21%). Two clinical patterns emerged. In 16 patients, large retroperitoneal hematomas were documented by either computed tomography scanning or by physical examination. These patients were admitted with a lumbar plexopathy involving the femoral, obturator, or lateral femoral cutaneous nerves. Long-term follow-up revealed persistent mild sensory neuropathy in five patients and a mild motor deficit in one. In four patients a groin hematoma or false aneurysm developed which resulted, in paresthesias involving the medial and intermediate cutaneous branches of the femoral nerve. Symptoms completely resolved in all four patients, although false aneurysms were surgically repaired in two. CONCLUSIONS: Neuropathy after cardiac catheterization can be initially disabling, but it is usually completely reversible. Operation is recommended only for coexisting complications.     

Friedreich's ataxia with retained tendon reflexes: molecular genetics, clinical neurophysiology, and magnetic resonance imaging

Lower limb areflexia is generally regarded as an essential criterion for the diagnosis of Friedreich's ataxia (FRDA). We describe a family with a recessive form of early-onset ataxia in which one member had a phenotype typical of FRDA whereas another, with retained tendon reflexes in the lower limbs, did not have electrophysiologic evidence of the usual severe afferent axonal neuropathy of FRDA. In contrast, somatosensory evoked potentials, eye-movement recordings, and MRI of the head and cervical cord provided results highly suggestive of FRDA in both patients. We performed genetic linkage analysis in this family, using markers tightly linked to the FRDA locus on chromosome 9. Inheritance of identical paternal and maternal genotypes by the affected members, but not by their unaffected siblings, provided supporting evidence that this disorder may result from mutation within the FRDA gene or is tightly linked to the investigated loci on chromosome 9.     

Etiological and clinical patterns of urolithiasis in Turkish children

A beta-glucan binding protein (BGBP) was identified in both white (Penaeus vannamei) and blue shrimp (P. stylirostris) plasma. White shrimp BGBP was purified by affinity chromatography using immobilized laminarin, and its molecular and biological properties were described. White shrimp BGBP is a monomeric protein with a molecular mass of 100 kDa, similar to those described for other crustacean BGBPs. White and blue shrimp BGBPs can be detected with antisera against crayfish BGBP and brown shrimp BGBP. Both amino acid composition and N-terminal sequence are markedly similar to brown shrimp (P. californiensis) and crayfish (Pacifastacus leniusculus) BGBP, indicating that this recognition protein is present in freshwater and marine crustaceans.