Clinical picture and therapy of hypertrophic cardiomyopathy

Although central vision in Stargardt's disease is impaired relatively early, peripheral function is usually little affected and patients do not lose all vision. We report 4 patients with bull's-eye macular dystrophy that is indistinguishable from Stargardt's disease/fundus flavimaculatus, but with very depressed peripheral retinal function. One patient had bull's-eye maculopathy with a dark choroid on the fluorescein angiogram with a normal peripheral fundus and good retinal function initially. Sixteen years later, however, peripheral bone corpuscle pigmentation and optic disc atrophy developed and the electroretinogram became nonrecordable. Three patients from another family also had peripheral pigment degeneration besides macular degeneration. These cases may represent a rare combination of Stargardt's disease and retinitis pigmentosa. However, there was no clinical sign or even suggestion of retinitis pigmentosa at the initial examination in 1 patient. The mode of inheritance in 3 of our patients is probably autosomal recessive.     

Autosomal dominant medullary cystic kidney disease: evidence of gene locus heterogeneity

Autosomal dominant medullary cystic kidney disease (ADMCKD; synonym: medullary cystic disease, MCD) is an autosomal dominant kidney disorder, sharing morphological and clinical features with recessive juvenile nephronophthisis (NPH), such as reduced urinary concentration ability and multiple renal cysts at the corticomedullary junction. While in NPH end-stage renal disease (ESRD) occurs in adolescence, ADMCKD leads to ESRD in adulthood. Recently a gene locus for ADMCKD has been localized to chromosome 1q21 in two large Cypriot families. This prompted us to examine linkage in three ADMCKD-families, using the same set of polymorphic microsatellite markers spanning the critical region on chromosome 1q21. Haplotype analysis revealed that none of the three families showed linkage to this locus, thus demonstrating evidence for genetic locus heterogeneity. Additional linkage analysis studies need to be performed in order to identify further gene loci cosegregating with this autosomal dominant kidney disorder.     

Study on treatment of retinitis pigmentosa with traditional Chinese medicine by Flicker electroretinogram

Study on treatment of 54 patients (106 eyes) of retinitis pigmentosa (RP) with traditional Chinese medicine was conducted by using modified method of electroretinography. Results showed: (1) Flicker response of electroretinogram was the most sensitive-criterion in examination, it was more effective when combined with infrared spectrogram. (2) The 30 Hz flicker index, response time were improved after TCM therapy in different hereditary types of RP, the improvement was significant in patients with Yang-Deficiency of Spleen-Kidney Syndrome and those of autosomal dominant inheritance type (P < 0.01). (3) Decrease of phase angle (phi) under different frequency of flicker after treatment was also significant statistically. The results suggested that flicker responses, which represents mainly retinal cone activity of patients, could be improved to a certain extent by TCM treatment, even in those with advanced retinal degeneration. TCM treatment could also enhance the bioactivity of nerve network and therefore have a definite significance in retarding the progression of disease and keeping the central vision. The flicker ERG, especially its flicker index, is an effective, sensitive and useful parameter for detection of visual function in patient with retinitis pigmentosa.     

Current concepts and controversies in imaging of renal cystic diseases

Renal cystic disease compromises a diverse group of inherited and acquired entities. This article reviews the clinical, pathologic, and radiologic findings of eight renal cystic diseases. For each entity, the current concepts of pathogenesis and pathophysiology are discussed. When appropriate, controversies concerning terminology, management, and malignant potentials are addressed. Renal cystic diseases that are discussed include autosomal dominant and autosomal recessive polycystic kidney disease, medullary sponge kidney, medullary cystic disease, multicystic, dysplastic kidney, von Hippel-Lindau disease, acquired cystic kidney disease, and tuberous sclerosis.     

Autosomal dominant medullary cystic disease: a disorder with variable clinical pictures and exclusion of linkage with the NPH1 locus

BACKGROUND: The nephronophthisis-medullary cystic disease (NPH/MCD) complex represents a heterogeneous group of hereditary tubulointerstitial nephritis. The most common variant is juvenile recessive NPH, for which a gene locus (NPH1) has been mapped on chromosome 2q13. MCD is a less common dominant condition usually recognized later in life, which resembles NPH in many aspects, still presenting remarkable clinical differences. Nothing is known about the chromosome locus of MCD. METHODS: Five MCD families were studied. Diagnosis was made by inference from family history, type of inheritance, clinical signs and histology. Multipoint linkage analysis was performed by markers D2S293, D2S340 and D2S160 spanning the entire NPH1 locus. RESULTS: Diagnosis of MCD was made in 28 affected members (16 males; 12 females), belonging to five families. Histological diagnosis was available in 10 patients; clinical diagnosis in 11; seven deceased relatives had diagnosis of chronic nephritis. The age at diagnosis ranged from 8 to 65 years. Renal medullary cysts were found in a minority of patients. In family 1, the disease was associated with hyperuricaemia and gouty arthritis. Progression of renal disease presented intra- and extra-family variability with members of the same family showing mild elevation of creatinine or terminal renal failure. The NPH1 locus associated to recessive NPH was excluded from linkage to the dominant MCD. CONCLUSIONS: MCD might be more common than previously assumed. Variability in clinical presentation and absence of histopathological hallmarks contribute to make the diagnosis uncommon. The most remarkable clinical difference with NPH is the age of onset in some kindreds and a delayed progression towards renal failure. The exclusion of linkage to the NPH1 locus suggests the existence of an MCD responsible locus, still to be mapped.     

Relative morbidity of abdominal hysterectomy and myomectomy for management of uterine leiomyomas

Inheritance of idiopathic torsion dystonia (ITD) was studied in 41 Russian families including 41 probands with generalized, focal, and segmental dystonia and 140 recurred cases. Affected relatives appeared in two or more generations in 31 families analyzed. It was shown that in 76% of segregated cases, ITD was inherited as an autosomal dominant trait with a penetrance of 40% and varying expression. An autosomal recessive type was observed in 24% of the cases. Approximately 10% of the cases of disease could be caused by a new mutation and 14.6% by a nongenetic phenotype similar to genetic forms in its clinical symptoms. ITD with the X-linked recessive type of inheritance did not occur in the families studied. The recurrence risk was 20% in autosomal dominant forms. The risk correlated with age the relative's: clinical symptoms developed in 98.4% of patients by the age of 30.     

Progressive retinal atrophy in miniature longhaired dachshund dogs

A form of generalized progressive retinal atrophy unlike other previously recorded canine retinal dystrophies has been investigated in Miniature Longhaired Dachshund dogs. Segregation patterns in litters from matings involving affected individuals were consistent with simple autosomal recessive inheritance. The earliest ophthalmoscopic signs, appearing at approximately 6 months of age and coinciding in some cases with the onset of nyctalopia, included changes in the granular appearance of the tapetal fundus followed by generalized tapetal hyper-reflectivity and retinal vascular attenuation; later there was irregular loss of pigment in the non-tapetal fundus and optic atrophy. However, there was marked variation in the age of onset and progression of the disease, even within a single litter. The electroretinogram was normal in waveform and latency in four affected littermates at 10 weeks of age but by 9 months was markedly reduced in amplitude in two pups and virtually extinguished in the others. Significant histological changes at 10.5 weeks of age included thinning of the outer nuclear layer, irregularity and attenuation of the rod photoreceptor outer segments and early disorganization of the rod outer segment disc lamellae. By 25 weeks the photoreceptors were grossly degenerate with short rounded inner segments and only residual amounts of outer segment material remaining. This condition in the Miniature Longhaired Dachshund is later in onset than rod-cone dysplasia in Irish Setters but significantly earlier than progressive retinal atrophy in Tibetan Terriers and progressive rod-cone degeneration in, for example, Miniature Poodles. The condition could therefore serve as a potentially useful model for retinitis pigmentosa in man.     

Hereditary tubulo-interstitial nephropathy

Most of the hereditary tubulointerstitial nephropathy see the cyst formation in the kidney. Among them, juvenile nephronophthisis and medullary sponge kidney, which primarily involve the tubule structures of the renal medulla, are associated with variable enlargement of the distal tubules and collecting ducts and with interstitial fibrosis and inflammation of a variable extent. Juvenile nephronophthisis features sodium wasting, anemia, and renal failure. Eighty % of juvenile nephronophthisis is an autosomal recessive disorder, and it also has a variant form which is an autosomal dominant disease. A gene for autosomal recessive juvenile nephronophthisis is now mapped to 2q13, although no linkage has been observed in autosomal dominant variant to this region. Thus genetic heterogeneity between autosomal recessive variant and autosomal dominant variant of juvenile nephronophthisis is suggested. Juvenile nephronophthisis progress to end-stage renal failure. In contrast, medullary sponge kidney, which features nephrocalcinosis and urinary stones, is a relatively benign condition and occurs occasionally in the same family.     

A new codon 15 rhodopsin gene mutation in autosomal dominant retinitis pigmentosa is associated with sectorial disease

OBJECTIVE: To ascertain and characterize rhodopsin gene mutations in autosomal dominant retinitis pigmentosa and to correlate these mutations with the clinical phenotypes. METHODS: DNA was extracted from leukocytes, and the rhodopsin gene was amplified and analyzed using molecular-biological methods. Clinical and electrophysiological data were collected from patient charts. RESULTS: We found a disease-causing mutation that was previously undescribed, to our knowledge, for autosomal dominant retinitis pigmentosa within codon 15 of exon 1 of the rhodopsin gene. It was a single base-pair transversion (AAT to AGT) leading to a serine-for-asparagine substitution. This altered a glycosylation site in the intradiscal portion of the rhodopsin molecule. The pedigree examined demonstrated an inferior distribution of retinal pigmentary changes and predominantly superior visual field loss with relative preservation of electroretinographic amplitudes and good vision, which is consistent with sectorial or sectorial-like retinitis pigmentosa. CONCLUSIONS: A codon 15 rhodopsin gene mutation caused retinitis pigmentosa in the pedigree studied. There may be an association between intradiscal rhodopsin gene mutations and sectorial forms of retinitis pigmentosa.     

A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping

A novel type of infantile nephronophthisis was identified in an extended Bedouin family from Israel. This disease has an autosomal recessive mode of inheritance, with the phenotypic presentation ranging from a Potter-like syndrome to hyperechogenic kidneys, renal insufficiency, hypertension, and hyperkalemia. Affected individuals show rapid deterioration of kidney function, leading to end-stage renal failure within 3 years. Histopathologic examination of renal tissue revealed variable findings, ranging from infantile polycystic kidneys to chronic tubulointerstitial nephritis, fibrosis, and cortical microcysts. A known familial juvenile nephronophthisis locus on chromosome 2q13 and autosomal recessive polycystic kidney disease on chromosome 6p21.1-p12 were excluded by genetic linkage analysis. A genomewide screen for linkage was conducted by searching for a locus inherited by descent in all affected individuals. Pooled DNA samples from parents and unaffected siblings and individual DNA samples from four affected individuals were used as PCR templates with trinucleotide- and tetranucleotide-repeat polymorphic markers. Using this approach, we identified linkage to infantile nephronophthisis for markers on chromosome 9q22-31. The disorder maps to a 12.9-cM region flanked by markers D9S280 and GGAT3G09.     

Recent advances in understanding the spectrum of canine generalised progressive retinal atrophy

Canine generalised progressive retinal atrophy (gPRA) is a large and ever-increasing collection of naturally occurring, heterogeneous, progressive disorders. Most are inherited in an autosomal recessive manner and new, breed-specific forms continue to be described. The gPRAs cause photoreceptor cell death and subsequent retinal degeneration, culminating in blindness. In humans, similar inherited retinal dystrophies are recognised as retinitis pigmentosa and macular dystrophy. Molecular biological studies have revealed disease-causing mutations in several genes in humans and also in mice with retinal dystrophies. Recently, molecular genetic techniques have identified the cause of one form of gPRA in Irish setters while important candidate genes have been investigated in other breeds. Identification of mutations responsible for different forms of gPRA allows carrier and predegenerate animals to be detected using DNA-based tests. Such genetic tests will greatly facilitate the eradication of these diseases in different breeds.     

Late occurrence of cysts in autosomal dominant medullary cystic kidney disease

Medullary cystic kidney disease (MCD) is characterized by multiple renal cysts at the corticomedullary boundary area, by autosomal dominant inheritance, and by onset of chronic renal failure in the third decade of life. We report on a family with three affected individuals of both sexes in two generations presenting with end-stage renal failure at age 22-31 years. Primarily diagnoses considered included unclassified hereditary nephropathy and autosomal dominant polycystic kidney disease. Careful evaluation of all findings, initiated after investigation of renal morphology with CT, revealed features characteristic for MCD and led to the final diagnosis of MCD. We conclude that MCD is an important differential diagnosis for polycystic kidney disease in young adults with end-stage renal failure. Establishing the correct diagnosis has considerable impact for genetic counselling.     

X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60

OBJECTIVE: This study describes the ophthalmic findings in two unrelated white families with X-linked retinitis pigmentosa (XLRP) caused by a missense mutation in the retinitis pigmentosa GTPase regulator (RPGR) gene. DESIGN: Genetic screening and clinical correlation. PARTICIPANTS: Thirty-six families with XLRP seen by the authors were screened for a possible mutation in the RPGR gene to identify three affected hemizygotes with retinitis pigmentosa and four heterozygote carriers in one family and one hemizygote and one carrier in a second family. INTERVENTION: All nine patients underwent a routine ocular examination, including slit-lamp biomicroscopy and a dilated fundus examination. Goldmann visual field kinetic perimetry, static threshold perimetry, and electroretinography also were obtained. The DNA screening was performed on the three affected male patients and four obligate carriers examined from one family and the two examined patients, plus an additional male and obligate carrier, from the second family to determine the presence of any causative mutation in the RPGR gene. MAIN OUTCOME MEASURES: Findings on fundus examination, static threshold and kinetic perimetry, and electroretinography testing were the main outcome measures. RESULTS: A G-->T nucleotide change at position 238 in exon 3 of the RPGR gene resulting in a putative substitute of Gly-->Val at codon 60 was shown to segregate with RP in affected males and the carrier state in female heterozygotes in these two families. The ophthalmologic findings in hemizygotes as well as the carriers in this family were within the spectrum of findings characteristically noted in XLRP families. A tapetal-like reflex was not observed in any of the five female carriers. Psychophysical and electrophysiologic testing on the carriers indicated that cone and rod functions were impaired equivalently. When present in the carriers, visual field restriction was most apparent in, or limited to, the superotemporal quadrant, which corresponded to the retinal pigmentary changes that tended to occur in the inferonasal retina. CONCLUSIONS: A mutation in exon 3 of the RPGR gene, which would result in a putative glycine to valine substitution at codon 60, is associated with a severe clinical phenotype in male patients and a patchy retinopathy without a tapetal-like reflex in carrier females. In these families, heterozygote carriers showed equivalent impairment of their cone and rod function.     

Extraction of RNA from single frozen sections

PURPOSE: Recently, mutations in several genes have been identified as being responsible for the pathogenesis of autosomal recessive retinitis pigmentosa (arRP). These genes include rhodopsin, beta-subunit of rod cGMP phosphodiesterase (PDEB), alpha-subunit of rod cGMP phosphodiesterase (PDEA), and alpha-subunit of rod cGMP-gated channel. We here attempted to identify a novel mutation in the PDEB gene in Japanese arRP patients. METHODS: Using the PCR-SSCP method, sequencing analysis, and restriction endonuclease digestion assay, we analyzed the PDEB gene in 17 Japanese families with non-dominant retinitis pigmentosa. RESULTS: A novel Ile535Asn mutation was identified in two patients in a single family and the mutation cosegregated with RP in this family. Among 90 unrelated healthy individuals, no one was identified as homozygous for this mutation, except for one individual who was found to be heterozygous. CONCLUSIONS: Isoleucine at codon 535 in the PDEB gene is conserved among various mammals. Missense mutations of the PDEB gene causing arRP have been reported in a limited region (codon 527-codon 699) in which codon 535 is located. Thus, the Ile535Asn mutation is an additional missense mutation which is responsible for the pathogenesis of arRP.     

Ferrochelatase activities in patients with erythropoietic protoporphyria and their families

Ferrochelatase, estimated as zinc chelatase, was measured in the lymphocytes of 30 patients with erythropoietic protoporphyria (EPP), in 35 first- or second-degree relatives of patients with EPP, and in 50 healthy controls. In 30 EPP patients the zinc chelatase level (mean +/- standard deviation, SD) was 0.45 +/- 0.10 nmol of zinc protoporphyrin per hour per milligram of protein, in 14 EPP carriers the zinc chelatase level (mean +/- SD) was 0.42 +/- 0.09 and in 50 healthy controls the zinc chelatase level (mean +/- SD) was 0.84 +/- 0.27. All patients with EPP were also demonstrated to have an elevated protoporphyrin level in their red blood cells: the erythrocyte protoporphyrin levels were as follows EPP patients (mean +/- SD) 1300 +/- 758 nmol protoporphyrin/dl, EPP carriers (mean +/- SD) 60 +/- 24, and healthy controls (mean +/- SD) 50 +/- 25 (P < 0.001 for EPP patients compared to controls and EPP carriers). The families of 12 out of 15 EPP patients were examined with respect to the mode of inheritance of the disorder. Of 35 relatives, 14 were carriers of EPP, as characterized by reduced zinc chelatase activity in lymphocytes and by a normal protoporphyrin level in red blood cells. None of the 14 EPP carriers had presented with clinical symptoms of EPP. The mod of inheritance was autosomal dominant in seven of the 12 examined families, and autosomal recessive in two. In two families only one parent could be investigated, but we nevertheless concluded that the inheritance was autosomal dominant. Inheritance in one EPP family could not be elucidated as both parents showed normal zinc chelatase levels and did not demonstrate abnormal erythrocyte protoporphyrin levels.     

Ocular manifestations of autosomal recessive Alport syndrome

Ocular abnormalities are common in X-linked Alport syndrome, but they have not been studied in patients with the rarer autosomal recessive disease. We have examined the eyes of a family with autosomal recessive Alport syndrome. Four of the eight offspring of a consanguineous marriage had renal failure and deafness by the age of 20 years. The diagnosis of Alport syndrome was confirmed on the ultrastructural demonstration of a lamellated glomerular basement membrane (GBM) in one affected family member. Autosomal recessive inheritance was suggested by the lack of linkage to the COL4A5/COL4A6 locus, and by linkage to the COL4A3/COL4A4 locus. All four affected family members had anterior lenticonus (or had had a lens replacement for this) and the three who were examined had a dot-and-fleck retinopathy. Neither of the two unaffected offspring who were examined nor the father had these abnormalities. The ocular manifestations of autosomal recessive Alport syndrome are probably identical to those for the X-linked form. Although the mutations in these diseases affect genes for different type IV collagen chains, these chains occur together in the basement membranes of the kidney, eye and ear, and abnormalities in any one may result in the same clinical phenotype.     

Histopathology of the human retina in retinitis pigmentosa

The term, 'retinitis pigmentosa', refers to a heterogeneous group of inherited diseases that cause degeneration of rod and cone photoreceptors in the human retina. Loss of photoreceptor cells is usually followed by alterations in the retinal pigment epithelium and retinal glia. Ultimately, degenerative changes occur in the inner retinal neurons, blood vessels, and optic nerve head. This chapter provides background information on the genetics of retinitis pigmentosa and a summary of the histopathologic alterations in human retinas caused by this disease. Detailed information is provided on the effects of the primary disease process on the rod photoreceptors and changes in the other retinal components, all of which are important considerations for understanding and developing therapies for retinitis pigmentosa.     

A Jordanian view about cancer knowledge and attitudes

Inherited polycystic kidney disease (PKD) in children is a disorder characterized by diffuse cystic involvement of both kidneys, without evidence of dysplasia. Both forms, autosomal recessive (ARPKD) and autosomal dominant (ADPKD) have considerable overlap in clinical presentation and radiographic features in the pediatric population. At present, a prenatal diagnosis is possible with ultrasound examination. A brief review of the literature is here reported. The knowledge of pathophysiological and clinical data is requested, since PKD represents a major cause of renal failure in pediatrics.     

Restoration of serum albumin levels in nagase analbuminemic rats by hepatocyte transplantation

More than 100 mutations within the rhodopsin gene have been found to be responsible for some forms of retinitis pigmentosa, a progressive retinal degeneration characterized by night blindness and subsequent disturbance of day vision that may eventually result in total blindness. Congenital stationary night blindness (CSNB) is an uncommon inherited retinal dysfunction in which patients complain of night vision difficulties of a nonprogressive nature only and in which generally there is no involvement of day vision. We report the results of molecular genetic analysis of an Irish family segregating an autosomal dominant form of CSNB in which a previously unreported threonine-to-isoleucine substitution at codon 94 in the rhodopsin gene was found to segregate with the disease. Computer modeling suggests that constitutive activation of transducin by the altered rhodopsin protein may be a mechanism for disease causation in this family. Only two mutations within the rhodopsin gene have been previously reported in patients with congenital stationary night blindness, constitutive activation also having been proposed as a possible disease mechanism.