ABSTRACTS/ESTUDIOS PUBLICADOS

http://www.cocmed.sld.cu/no124/pdf/n124ori11.pdf

Trabajo original

Facultad de Ciencias Médicas “Mariana Grajales”

Estudio de una familia de la Policlínica “Máximo Gómez” donde tres miembros padecen enfermedad de Stargardt.

A Study of a Family with Stargardt`s Disease. Máximo Gómez. Polyclinic. Holguín.2006.

Luís Borrego Díaz (1), Elena Díaz Santos (2), Marlen Orges Ramírez (3), Kariné González Sapsin (4)

1. Especialista de Primer Grado en MGI. Máster en Urgencias médicas. Profesor Instructor. Policlínica Docente “Máximo Gómez”. Holguín.
2. Especialista de Primer Grado en Oftalmología. Máster en Enfermedades Infecciosas. Profesor Instructor. Centro Provincial de Retinosis Pigmentaria- Holguín.
3. Especialista de Primer Grado en Oftalmología. Profesor Asistente. Hospital Doc. “V.I.Lenin”. Holguín.
4. Especialista de Primer Grado en MGI. Máster en Urgencias Médicas. Profesor Instructor. Policlínica Docente “Máximo Gómez”. Holguín.

RESUMEN

Se realizó un estudio descriptivo de una familia en la cual hay un miembro afectado con la enfermedad de Stargardt en el área de salud de la Policlínica “Máximo Gómez”, en la etapa comprendida noviembre 2004 a mayo 2006. Fueron examinados 14 familiares y 5 de ellos ínterconsultados con el grupo multidisciplinario del Centro de Retinosis Pigmentaria donde fueron diagnosticados dos enfermos más, de 8 y 12 años. El enfermo estuvo desvinculado de la consulta cuatro años y se logró su reincorporación. Se demostró una vez más la importancia que juega el médico de la familia en el diagnóstico precoz de las enfermedades, así como la vinculación estrecha entre atención secundaria y primaria en la labor de pesquisa de las enfermedades oculares.

Palabra clave: enfermedad de Stargardt, déficit visual, grupo multidisciplinario.

ABSTRACT

A descriptive study on Stargart`s disease at Màximo Gòmez Polyclinic area from November 2004 and May 2006, due to the visual deficit that this illness produces was carried out . The study was done in a patient with this diagnosis. 14 relatives were examinated and 5 of them were attended by the integrated multidisciplinary group at Retinitis Pigmentosa Center to confirm the diagnosis. The patient had been away from the consultation during 4 years. Two of them who were 8 and 12 years were diagnosed with this disease. The importance of the family

1

doctor in the early diagnosis of the diseases was also proved, as well as the close relation between primary care and secondary care for the study of new cases.

Key words: Stargart`s disease, visual deficit, multisdisciplinary group.

INTRODUCCIÓN

La enfermedad de Stargardt es hereditaria autosómica recesiva (1) (2) (3), que consiste en la afectación de la retina (afectación de los conos del polo posterior). Produce una disminución de la visión central (escotoma central), no se asocia a enfermedades generales (4) (5) (6).

De conjunto con los especialistas del Centro de Retinosis hemos realizado varias investigaciones de pesquisa (1) (3), lo que facilitó como Especialista de M.G.I. de la Policlínica “Máximo Gómez” identificar los problemas visuales de nuestra población. Como parte de la actividad investigativa que desarrollamos, nos motivó un joven con el diagnóstico de enfermedad de Stargardt, que su familia no había sido estudiada y no asistía a consulta desde hacía cuatro años, conociendo la repercusión que este hecho podría traer tanto para el joven, como para familiares, nos dedicamos a la tarea de realizar el estudio familiar para detectar si existían nuevos enfermos y brindarles el adecuado seguimiento.

MÉTODO

Se realizó un estudio descriptivo de una familia en la cual hay un miembro afectado con la enfermedad de Stargardt, en el área de salud de la Policlínica “Máximo Gómez” del municipio Holguín en la etapa comprendida de noviembre 2004 a mayo 2006, con la finalidad de hacer una pesquisa y diagnóstico precoz de nuevos enfermos, además de conocer el patrón genético-

clínico del comportamiento de la enfermedad en esa familia.

Se examinaron 14 familiares, distribuidos en tres generaciones (árbol genealógico), a los que se les aplicó una encuesta, se le realizó examen oftalmológico completo, a los pacientes que presentaron disminución de la agudeza visual fueron explorados con la cartilla de Snellen, los posibles enfermos fueron enviados al C.R.P. donde se le realizaron el resto de los exámenes para confirmar diagnóstico.

RESULTADO Y DISCUSIÓN

Representamos la estrategia creada para el desarrollo del estudio lo que permitió llevar a cabo la investigación (gráfico 1). De los 14 pacientes examinados encontramos cinco posibles enfermos, con diagnóstico positivo de la enfermedad tres, de ellos dos niños en los cuales logramos un diagnóstico precoz, por todos es conocido lo invalidante que es esta afección (1) (7) (8), la importancia que revierte para el enfermo y la sociedad su diagnóstico temprano, ya que nos permitió dar un seguimiento y tratamiento adecuado. El tercer paciente de 31 años de edad, se había desvinculado de la consulta desde hacía cuatro años, por lo que tenía un mayor deterioro de su visión (gráfico 2).

Representamos una ficha familiar (cuadro 1), donde aparecen distribuidos los pacientes por generaciones con una forma típica de presentación y con manifestaciones de la enfermedad por

2

debajo de los diez años. En los tres pacientes fallecidos no fue posible recoger estos datos, al

igual que en los dos enfermos referidos. La ficha familiar abarcó una serie de información

importante en el análisis sobre el comportamiento de la enfermedad en la familia en estudio (3, 4, 8).

Al realizar este estudio evidenciamos ventajas (cuadro 2), pues pudimos definir el patrón de transmisión hereditaria, realizar la pesquisa de nuevos enfermos, el diagnóstico precoz en dos niños, así como su seguimiento. Además confeccionamos el árbol genealógico (gráfico 3), con su patrón de herencia autonómica recesiva. Todo esto fue posible por la vinculación estrecha entre atención primaria y secundaria.

page3image6560
page3image6832

Fuente: modelo de encuesta.

3

Gráfico 2

page4image2968

Fuente: modelo de encuesta.

Cuadro 1. Ficha familiar:

No Nombre Generacional

I ESC

I MSC

I CSC

III RSC

III SSB

III RSB

III EST

III LST Fuente: modelo de encuesta.

Lugar de Año de Color

de la

Edad de comienzo.

———-

———-

———-

18

10

8

———-

———-

F Clínica.

———-

———-

———-

Típica

Típica

Típica.

nacimiento nacido.

piel.

M

M

M

B

M

M

M

M

page4image21720

page4image21880

page4image22416

page4image22576

page4image23112

page4image23272

page4image23808
page4image24080
page4image24352
page4image24624
page4image24896
page4image25168
page4image25440
page4image25712
page4image25984
page4image26256
page4image26528
page4image26800
page4image27072
page4image27344

C García.

C García.

C García

C García

Holguín

Holguín

Gibara

Gibara.

1929

1930

1938

1963

1988

1993

page4image32272

page4image73768

page4image74304
page4image74576
page4image74848

Cuadro 2. Definición del patrón de Herencia.

No de diagnosticados.

Antes del estudio 1

Después del estudio. 3 Fuente: modelo de encuesta.

pacientes

Patrón de herencia.

No definido

page4image78344 page4image78768 page4image79360

page4image79896
page4image80168
page4image84024

page4image84184

page4image84888
page4image85160
page4image85432

page4image86608

Autosómica recesiva.

page4image87744

4

page5image776

Fuente: modelo de encuesta.

CONCLUSIONES

Logramos el diagnóstico precoz en dos miembros de la familia, así como la mejoría del estado de salud del enfermo. Reafirmamos una vez más la importancia que tiene la acción del médico de familia en el diagnóstico precoz de las enfermedades, así como la vinculación estrecha entre la atención primaria y secundaria.

BIBLIOGRAFÍA

  1. Peláez Molina O. Retinosis Pigmentaria. Experiencia cubana. Eitorial Científico-Técnica. Habana: 1987.
  2. Muller R, Young I. Emery ́ s. Elements of Medical Genetics. 10th ed. Marban.2001
  3. Díaz S E y col. Características Clínicas-Genéticas y Epidemiológicas de la Retinosis Pigmentaria en la Provincia de Holguín. IV Congreso Nacional de Genética Médica.Diciembre 2004. La Habana, Cuba 2004
  4. Pérez G. RM .Caracterización Clínico Epidemiológica de la Retinosis Pigmentaria en laProvincia de las Tunas. [Tesis de doctorado]. Las Tunas; 2004.

5

  1. Hamel, Ch. P, et al. Genetique molecular dis retinopathies pigmentaire. Itification dis mutation dis genes. J. Fe Opphtalmolol. 2000; 23 (10): 985-995.
  2. Heredia Garcia C D. Retinitis Pigmentaria. General Review and Immunological Point of view. On Inst Barraquer 2003; 32:103-109.
  3. Heredia García C D. Tratamiento Clínico-Quirúrgico de Afecciones vítreo Retinianas. Vectorizacion de antimflamatorios no esteroideo en Oftalmología [monografía]. Laboratorio Menarines, p. 83.
  4. Mueller RYoung I. Emery ́ ́s. Elements of Medical Geneties 1ae. . Marban; 2006.

Correspondencia: Dr. Luís Borrego Díaz. Calle 20 de mayo 2. Reparto Santiestebán. Holguín. Telef. 427997. Correo electrónico: borrego@cristal.hlg.sld.cu

Indice Anterior Siguiente

page6image6488
page6image6760
page6image7032
page6image7304

6

Mutations in ABCR (ABCA4) in Patients with Stargardt Macular Degeneration or Cone-Rod Degeneration

  1. Christine E. Briggs 1 ,
  2. David Rucinski 1 ,
  3. Philip J. Rosenfeld 2 ,
  4. Tatsuo Hirose 3 ,
  5. Eliot L. Berson 4 and
  6. Thaddeus P. Dryja 1

+Author Affiliations


  1. 1From the Ocular Molecular Genetics Institute, Massachusetts Eye and Ear Infirmary, Boston; the

  2. 2Bascom Palmer Eye Institute, University of Miami School of Medicine, Florida;

  3. 3Schepens Retina Associates, Boston, Massachusetts; and the

  4. 4Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.

Abstract

PURPOSE. To determine the spectrum of ABCR mutations associated with Stargardt macular degeneration and cone–rod degeneration (CRD).

METHODS. One hundred eighteen unrelated patients with recessive Stargardt macular degeneration and eight with recessive CRD were screened for mutations in ABCR (ABCA4) by single-strand conformation polymorphism analysis. Variants were characterized by direct genomic sequencing. Segregation analysis was performed on the families of 20 patients in whom at least two or more likely pathogenic sequence changes were identified.

RESULTS. The authors found 77 sequence changes likely to be pathogenic: 21 null mutations (15 novel), 55 missense changes (26 novel), and one deletion of a consensus glycosylation site (also novel). Fifty-two patients with Stargardt macular degeneration (44% of those screened) and five with CRD each had two of these sequence changes or were homozygous for one of them. Segregation analyses in the families of 19 of these patients were informative and revealed that the index cases and all available affected siblings were compound heterozygotes or homozygotes. The authors found one instance of an apparently de novo mutation, Ile824Thr, in a patient. Thirty-seven (31%) of the 118 patients with Stargardt disease and one with CRD had only one likely pathogenic sequence change. Twenty-nine patients with Stargardt disease (25%) and two with CRD had no identified sequence changes.

CONCLUSIONS. This report of 42 novel mutations brings the growing number of identified likely pathogenic sequence changes in ABCR to approximately 250.

Stargardt macular degeneration is characterized by the onset of central vision loss, usually by 20 years of age, progressive bilateral atrophy of the retinal pigment epithelium in the macula, accumulation of a lipofuscin-like substance in the retinal pigment epithelium, and a reduced foveal cone ERG.1 2 3 4 It is recessively inherited and has an incidence of approximately 1 in 10,000. Mutations in the ABCR gene, located within chromosome 1p13, have been identified as a cause of recessive Stargardt macular degeneration.5 6 7 8 Fundus flavimaculatus is allelic and is regarded by some as the same disorder with a later onset of symptoms and slower progression.3 6 9 10 11 Unidentified loci linked to dominant forms of juvenile macular degeneration have been mapped to chromosomes, 6q11-14 (STGD3) and 4p (STGD4).12 13 14

Recessive mutations in ABCR have been found in patients with Stargardt macular degeneration, fundus flavimaculatus, cone–rod degeneration (CRD; a panretinal photoreceptor degeneration with predominant loss of cone function that affects the macula early in its course) and retinitis pigmentosa (a panretinal photoreceptor degeneration usually associated with intraretinal pigmentary deposits).5 15 16 17 18 19 20 21 2223 To date, approximately 200 mutations in ABCR have been found in patients with these diseases.

We report the results from an analysis of ABCR in 118 patients with juvenile macular degeneration and 8 with CRD.

Materials and Methods

Ascertainment of Patients

The methods used in this study conformed to the tenets of the Declaration of Helsinki and received approval from the Institutional Review Boards at the Massachusetts Eye and Ear Infirmary and Harvard Medical School. Informed consent was obtained from all patients and family members who participated in the study. Patients with Stargardt macular degeneration were recruited from the Berman-Gund Laboratory (83 patients) and the Bascom Palmer Eye Institute (35 patients). All patients with Stargardt macular degeneration had unaffected parents by history or clinical evaluation. All had reduced central visual acuity before age 30 and characteristic fundus changes of Stargardt macular degeneration. In addition, all patients had diagnostic fluorescein angiograms and/or ERGs consistent with the diagnosis of Stargardt macular degeneration. ERGs showed full-field rod responses that were normal and full-field cone responses that were either normal or slightly reduced and delayed. Foveal ERGs were abnormal in every patient in whom they were measured. Fluorescein angiography revealed a dark choroid in those patients so evaluated.

We also included eight patients with CRD in this mutation screen (five from the Berman-Gund Laboratory, two from the Bascom Palmer Eye Institute, and one from Schepens Retina Associates). Patients with CRD had unaffected parents. Ophthalmoscopy revealed panretinal degeneration affecting the macula more severely. Patients had severely reduced full-field cone ERG amplitudes (reduced 90% or more), moderately reduced cone–rod ERG amplitudes (reduced approximately 50% or more), and markedly delayed cone implicit times (≥40 msec; normal, ≤32 msec). Mixed cone–rod responses were typically 30 times larger than cone-isolated responses in young patients with this condition.

Venous blood samples were obtained from participating patients and some of their relatives after informed consent was received. Leukocyte DNA was purified according to standard methods.

Detection of Sequence Changes

DNA samples were screened with the single-strand conformation polymorphism (SSCP) technique for sequence changes in the 50 exons ofABCR (primer sequences are available at a Web site provided by the Massachusetts Eye and Ear Infirmary http://eyegene.meei.harvard.edu/OMGI/ABCR/primers.html). Each exon and 6 to 100 bp of flanking intron sequence were amplified from 20 ng of leukocyte DNA in 20 μl of a solution containing 20 μM dATP, dTTP, and dGTP; 2 μM dCTP, including 0.6 μCi[ -32P]-dCTP (3000 Ci/mmol); 20 mM tris hydrochloride (pH 8.4 or 8.6); 0.25 to 5.0 mM MgCl2; 50 mM KCl; 0.1 mg/ml bovine serum albumin; 20 pmol of each primer; 0.25 U Taqpolymerase; and 0% or 10% dimethyl sulfoxide (DMSO). Conditions for the amplification of each exon were optimized for [MgCl2], 0% or 10% DMSO, annealing temperature, and pH. In some cases, primer sets for two amplicons with a difference in size of at least 50 bp were combined in the same amplification reaction mixture. Samples were heated to 95°C for 4.5 minutes and incubated for 22 to 27 cycles of the following temperature sequence: 30 seconds at 94°C, 30 seconds at 52°C to 60°C, and 40 seconds at 72°C. Samples underwent a final incubation at 72°C for 5 minutes. After amplification, samples were diluted 1:1 with a solution of 40% formamide, 5 mM EDTA, 0.05% SDS, 0.25% bromphenol blue, 0.25% xylene cyanol, and 0.5× TBE (45 mM Tris-base, 45 mM boric acid, 1 mM disodium EDTA, pH 8.3). The amplified DNA was heat denatured (95°C for 3 minutes), and the resultant single-stranded fragments were separated by gel electrophoresis through 6% polyacrylamide TBE gels, with or without 10% glycerol or through a 5% polyacrylamide gel with TME (30 mM tris, 35 mM 2-[N-morpholino]ethanesulfonic acid, and 1 mM EDTA)24 at 8 to 16 W for 8 to 16 hours. Gels were transferred to Whatman paper (Whatman, Inc., Clifton, NJ), dried, and analyzed by autoradiography. DNA fragments that migrated at rates different from wild-type fragments were evaluated by direct genomic sequencing, according to standard methods.

Individuals without a history of retinal degeneration or blood relatives without retinal degeneration were used as control subjects. Normal control subjects were screened for every likely pathogenic sequence change found in at least 6 of the 126 patients screened.

Neutral and intron sequence changes not affecting the canonical splice-acceptor or splice-donor sites were analyzed for their likelihood of creating or destroying splice sites, by using the neural network software that is available at a Web site provided by the Berkeley Drosophila Genome Project, University of California, Berkeley (www.fruitfly.org/seq_tools/splice.html).25

Results

Sequence Changes Identified

On analyzing 118 patients with Stargardt macular degeneration and 8 with CRD, we identified a total of 118 sequence changes (Table 1) , 77 of which were likely to be pathogenic (Fig. 1) . Forty-two of these 77 likely pathogenic sequence changes have not been previously reported. Twenty-one of the changes (including 15 novel changes) were interpreted as obviously null mutations: One was a missense change affecting the initiation codon (Met1Val), four were nonsense mutations, four changed canonical splice-site donor or acceptor sites, and 12 were frameshifts caused by the insertion or deletion of one or more base pairs (Table 1) . We have categorized the splice-site mutation IVS13+2T→C as a likely null mutation, although it may only reduce splice donor function because the dinucleotide GC is occasionally found as a splice donor in some genes.

TABLE 1.

ABCR Sequence Changes Found in 118 Patients with Stargardt and 8 with CRD

Figure 1.

View larger version:

FIGURE 1.

Distribution of 77 ABCRmutations found in our patients. Numbers immediately above the bar indicate each exon number. Numbers within the boxes of the bar indicate the number of codons per exon. Numbersbelowthe bar indicate the codon number at exon boundaries.

There were a total of 61 missense changes (26 novel) and a novel in-frame deletion of a consensus glycosylation site (deletion of Lys13-Trp15). Ten missense changes were found in 6 or more patients each. From 95 to 190 normal control individuals were evaluated for the presence of these 10 missense changes. Five of these 10 changes were statistically significantly less frequent in control subjects and were thus considered likely to be pathogenic. Specifically, Leu541Pro, Pro1380Leu, Gly1961Glu, and Leu2027Phe were not identified in any of the control individuals (P < 0.04). Gly863Ala was detected in 9 of 252 patient alleles and 2 of 380 normal control alleles tested (P = 0.009), and it was also considered pathogenic. Four missense changes, Arg212His, His423Arg, Arg943Gln, and Pro1948Leu, were found at approximately equal frequency among patients and normal control subjects (P > 0.05 by Fisher’s two-tailed analysis) and were thus categorized as nonpathogenic polymorphisms. Asn1868Ile was less frequent in patients with Stargardt disease than in control subjects (42/252 patient alleles and 50/170 control alleles; P = 0.002 by Fisher’s two-tailed analysis) and was therefore considered nonpathogenic. The abundance of this allele in control subjects may reflect an unappreciated difference in the ethnic ancestry of the patients versus the control subjects in this study.

A rarely encountered missense change, Ala1637Thr, was interpreted as nonpathogenic because it was found in a patient (032-066) who also had two obviously null mutations determined to be allelic by segregation analysis, Lys356Ter and Gln1513(insC). Another change, Ala1038Val, was found in two patients (032-023 and 034-035), and in both cases segregation analysis showed that it was in cis with Leu541Pro, a combination also reported by Rivera et al.23 We interpreted Leu541Pro as pathogenic because it was found without the Ala1038Val change more frequently in patients than in control subjects. However, Sun et al.26have shown abnormal ABCR function associated with either Ala1038Val or Leu541Pro, and it is therefore possible that both these changes are pathogenic in isolation. The remaining 49 missense changes were each found in five or fewer patients with Stargardt-CRD and were categorized as likely to be pathogenic. In all, 26 of the 55 likely pathogenic missense changes were novel.

We detected 35 isocoding substitutions and intron changes. These were all interpreted as nonpathogenic. Only one of these, Val2244Val, was predicted to possibly change a splice site. This sequence change affects the first codon of exon 49. Splice-site prediction software identifies the expected splice-acceptor site at the end of intron 48 in the wild-type sequence (probability score 0.98). This changes to a predicted splice-donor site in the mutant sequence (probability score 0.70). Despite this computer-based prediction of an effect on intron splicing, the Val2244Val change was interpreted as nonpathogenic because one of the two patients who were heterozygous for this change (032-066) also had two obvious null mutations determined to be allelic by segregation analysis.

Likely Pathogenic Sequence Changes Found in 95 of 126 Patients

Forty-nine patients with Stargardt and three with CRD had at least two likely pathogenic sequence changes. An additional three with Stargardt and two with CRD were homozygotes for a likely pathogenic sequence change (Leu244Pro, Pro1380Leu, Arg1640Gln, Cys2150Tyr, or Val1973[delG]). We conducted segregation analyses in 20 of these 57 patients’ families, and the results showed that the identified sequence changes segregated as expected for pathogenic alleles (Fig. 2) .

Figure 2.

View larger version:

FIGURE 2.

Pedigrees of 20 patients in whom segregation analysis was conducted. Arrows: index cases. The ABCRalleles are indicated beneathor to the side of the symbol for each family member whose DNA was evaluated. The clinical findings of the three affected siblings in the family of the proband 032-030 with the R1640Q mutation have been previously reported.33

One family had an index member (034-045) who was heterozygous for the missense changes Ile824Thr and Gly1961Glu. The Gly1961Glu allele27 was found to have been inherited from the patient’s mother, but the Ile824Thr allele was not detected in either parent or in any sibling. The results of genotyping analysis of six microsatellite markers in the patient and her parents were consistent with the designated paternity and we interpreted the Ile824Thr allele as a de novo mutation in this patient. The markers were D13S1316 (The Genome Database [GDB] accession number 614907), D13S1325 (GDB 615130), D13S1236 (GDB 601655), D13S1275 (GDB 604479), and D19S254 (GDB 189257; RB1.20)28 (results not shown). We did not conduct further studies to determine whether the Ile824Thr and Gly1961Glu changes were allelic in this index patient.

Thirty-seven patients with Stargardt disease and one with CRD each had only one detectable sequence change that we categorized as likely to be pathogenic. There were a total of 24 unique sequence changes among these 38 patients. Five were null mutations, one was an in-frame deletion, and 18 were missense changes. Eight of the missense changes were found in at least one other index patient who was a compound heterozygote with another likely pathogenic sequence change. Of the remaining 10 missense changes, 8 affect amino acid residues that are identical in the mouse abc129 and human ABCR proteins (Table 2) . Four of these missense changes also occur in consensus sequences for functional motifs (Table 2) .

TABLE 2.

Missense Changes Found in Patients with No Other Detected ABCR Changes

Twenty-nine patients with Stargardt disease and two with CRD had no detectable sequence changes that were considered likely to be pathogenic.

Nucleotide 2588G →C (Gly863Ala) and Nucleotide 2828G→A (Arg943Gln)

One likely pathogenic missense change, Gly863Ala, was frequently associated with a presumed nonpathogenic missense change, Arg943Gln. In fact, all 9 patients who were heterozygous carriers of Gly863Ala also carried Arg943Gln. Maugeri et al.21 also found an association between the Gly863Ala and Arg943Gln changes, but they were unable to determine whether Gly863Ala by itself was pathogenic. In our study, the Arg943Gln change was present in five other patients without Gly863Ala, and it was present without Gly863Ala in 9 of 190 control alleles. In addition, a recently reported evaluation of the Gly863Ala mutant protein has shown that it has abnormal function in vitro.26 Taken together, these results indicate that Gly863Ala by itself is likely to be pathogenic and Arg943Gln by itself is not.

Seven of the nine patients with Stargardt disease who were carrying Gly863Ala heterozygously also carried another missense change. Segregation analysis was conducted in the families of four of these 7 patients and the results in all four indicated that the two changes were allelic. Two patients who were heterozygous for the Gly863Ala allele had no other detectable changes likely to be pathogenic.

Nullizygosity Associated with Panretinal Degeneration

We found putative null mutations (e.g., frameshifts, nonsense mutations, or intron splice-site alterations) in 26 (10%) of the 252 alleles screened in this study. Eleven of these patients were compound heterozygotes with one null mutation and a second missense mutation. All had Stargardt macular degeneration. Only four had two allelic null mutations and all four of these patients had the diagnosis of CRD. The ERGs recorded from three of these patients (007-014, 035-002, and 032-066 at ages 24, 21, and 19 years, respectively) showed severely reduced cone amplitudes in response to 30-Hz flickering light (0.2, 0.4, and 6.8 μV, respectively; normal, ≥50 μV) and showed moderately reduced rod-dominated amplitudes in response to single flashes of light (129, 170, and 180 μV, respectively; normal, ≥350μ V). The fourth patient (032-081) declined evaluation with an ERG. This is in contrast to patients with Stargardt disease who typically have full-field rod and cone ERG amplitudes in the normal or near-normal range at comparable ages.

Discussion

We report 118 ABCR sequence changes, including 77 categorized as pathogenic. The 77 likely pathogenic changes include 21 null mutations (15 novel), 55 missense mutations (26 novel), and one novel deletion of a consensus glycosylation site. Of the 236 mutant alleles in the 118 patients with Stargardt macular degeneration, we found mutations in 141 (assuming that all patients with two likely pathogenic mutations were compound heterozygotes). The percentage of Stargardt alleles with an identified ABCR mutation (60%) is comparable to that found in another survey of a large group of patients: Lewis et al.20 found mutations in 57% of the 300 alleles in a set of 150 unrelated subjects.

The absence of detected mutations in 29 patients with Stargardt in our survey is not strong evidence for a second recessive Stargardt disease macular degeneration gene besides ABCR. It is more likely that we missed mutations that lie outside the regions of the gene that were screened (e.g., intron sequence far from flanking exons, the promoter region and the 5′ and 3′ untranslated regions) or that the SSCP mutation screening technique failed to detect some mutations, especially large deletions or insertions that encompass one or both primer sites used for a PCR amplification. Furthermore, we conducted a search for examples of Stargardt macular degeneration not linked to the ABCR locus. Of the 29 index patients with no detected ABCRmutations, only one (032-070) had both an affected sibling who was willing to participate in our research and an informative polymorphism in the ABCR gene. The index patient and the affected sibling had identical ABCR alleles (data not shown). Thus, even in this multiplex family with Stargardt macular degeneration and no identifiedABCR mutations, segregation analysis was consistent with ABCR being the disease locus.

The criteria we and others used to classify sequence variants as“ likely” to be pathogenic are not perfect. It is possible that some of the likely pathogenic mutations, especially the missense changes, are nonpathogenic. In addition, because segregation analysis was not always possible or was not always informative, some of the patients with two likely pathogenic changes may not be compound heterozygotes but rather may have a complex allele with both changes in cis. Some of the missense mutants previously associated with Stargardt macular degeneration are reported to have abnormal adenosine triphosphatase (ATPase) activity stimulated by all-trans retinal in vitro.26 It is not yet clear whether this assay reliably distinguishes pathogenic missense variants from those that are nonpathogenic.

Of the eight patients carrying Gly863Ala reported by Maugeri et al.,21 five were compound heterozygotes with a null mutation affecting the other allele. This led to speculation that the Gly863Ala sequence change is only pathogenic when present in compound heterozygotes who also carried a null allele. However, none of our patients with this change had a detected null allele. Rather, seven had another missense change and two had no other detectable changes likely to be pathogenic.

ABCR mutations have been reported to cause a spectrum of vision disorders including Stargardt macular degeneration, CRD, and atypical retinitis pigmentosa.15 16 17 18 19 20 21 27 Maugeri et al.21 and others have proposed a model in which two ABCR alleles with severe (null) mutations result in a visual disorder with features that are more severe than typical Stargardt macular degeneration and that they have called atypical retinitis pigmentosa. According to this model, compound heterozygosity for a severe (null) and a moderately severe mutation causes CRD, whereas two moderately severe mutations or a mild and a severe allele together cause Stargardt macular degeneration. Our findings support this model because all four patients with allelic null mutations (035-002, 032-066, 032-081, and 007-014) whom we encountered had CRD, a panretinal degeneration much more severe than typical Stargardt macular degeneration. A fifth patient with CRD (032-030) was homozygous for the missense change Arg1640Gln and a sixth patient (007-009) had the missense change Gly2146Asp and no other sequence changes that we were able to detect. (The two remaining patients with CRD had no detected ABCRmutations.) Although we have determined that all six of these patients have CRD, the late stages of CRD can have fundus features and extinguished ERGs that are indistinguishable from the late stages of retinitis pigmentosa. Therefore, it may be clearer to consider together in one category both CRD and atypical retinitis pigmentosa caused by severe or null ABCR mutations.

Acknowledgments

The authors thank Ileana Cantillo, Terri McGee, and Jennifer McEvoy for technical assistance.

Footnotes

  • Supported by Grants EY08683 and EY00169 from the National Eye Institute, Bethesda, Maryland; the Foundation Fighting Blindness, Owings Mills, Maryland; The Ruth and Milton Steinbach Fund, New York, New York; the V. Kann Rasmussen Foundation, Boston, Massachusetts; and Research to Prevent Blindness, New York, New York.

  • Submitted for publication January 3, 2001; revised April 25, 2001; accepted May 25, 2001.

  • Commercial relationships policy: N.

  • The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked“ advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.

  • Corresponding author: Thaddeus P. Dryja, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.dryja@helix.mgh.harvard.edu

References

  1. Stargardt K. Uber familiare, progressive Degeneration in der Makulagegend des Auges. Graefes Arch Klin Exp Ophthalmol.1909;71:534–549.
  2. Hadden OB, Gass JD. Fundus flavimaculatus and Stargardt’s disease.Am J Ophthalmol.1976;82:527–539.
  3. Noble KG, Carr RE. Stargardt’s disease and fundus flavimaculatus.Arch Ophthalmol. 1979;97:1281–1285.
  4. Sandberg MA, Jacobson SG, Berson EL. Foveal cone electroretinograms in retinitis pigmentosa and juvenile macular degeneration. Am J Ophthalmol. 1979;88:702–707.
  5. Allikmets R, Singh N, Sun H, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15:236–246.
  6. Kaplan J, Gerber S, Larget-Piet D, et al. A gene for Stargardt’s disease (fundus flavimaculatus) maps to the short arm of chromosome 1[ published correction appears in Nat Genet.1994;6:214]. Nat Genet.1993;5:308–311.
  7. Anderson KL, Baird L, Lewis RA, et al. A YAC contig encompassing the recessive Stargardt disease gene (STGD) on chromosome 1p. Am J Hum Genet. 1995;57:1351–1363.
  8. Hoyng CB, Poppelaars F, van de Pol TJ, et al. Genetic fine mapping of the gene for recessive Stargardt disease. Hum Genet. 1996;98:500–504.
  9. Franceschetti A. Ueber tapeto-retinale Degenerationen in Kindersalter. In: Entwicklung und Fortschitt in der Augenkeilkunde.1963;107–120. Enke Verlag Stuttgart, Germany.
  10. Fishman GA. Fundus flavimaculatus: a clinical classification. Arch Ophthalmol. 1976;94:2061–2067.
  11. Gerber S, Rozet JM, Bonneau D, et al. A gene for late-onset fundus flavimaculatus with macular dystrophy maps to chromosome 1p13.Am J Hum Genet. 1995;56:396–399.
  12. Donoso LA, Frost AT, Stone EM, et al. Autosomal dominant Stargardt-like macular dystrophy. Arch Ophthalmol. 2001;119:564–570.
  13. Stone EM, Nichols BE, Kimura AE, et al. Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q. Arch Ophthalmol. 1994;112:765–772.
  14. Kniazeva M, Chiang MF, Morgan B, et al. A new locus for autosomal dominant stargardt-like disease maps to chromosome 4. Am J Hum Genet. 1999;64:1394–1399.
  15. Cremers FP, van de Pol DJ, van Driel M, et al. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt’s disease gene ABCR. Hum Mol Genet.1998;7:355–362.
  16. Gerber S, Rozet JM, van de Pol TJ, et al. Complete exon-intron structure of the retina-specific ATP binding transporter gene (ABCR) allows the identification of novel mutations underlying Stargardt disease. Genomics. 1998;48:139–142.
  17. Martinez-Mir A, Paloma E, Allikmets R, et al. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR (Letter; Comment). Nat Genet. 1998;18:11–12.
  18. Rozet JM, Gerber S, Souied E, et al. Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies. Eur J Hum Genet. 1998;6:291–295.
  19. Fishman GA, Stone EM, Grover S, et al. Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene. Arch Ophthalmol. 1999;117:504–510.
  20. Lewis RA, Shroyer NF, Singh N, et al. Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet. 1999;64:422–434.
  21. Maugeri A, van Driel MA, van de Pol DJ, et al. The 2588G→C mutation in the ABCR gene is a mild frequent founder mutation in the western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet.1999;64:1024–1035.
  22. Maugeri A, Klevering BJ, Rohrschneider K, et al. Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. Am J Hum Genet. 2000;67:960–966.
  23. Rivera A, White K, Stohr H, et al. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet.2000;67:800–813.
  24. Kukita Y, Tahira T, Sommer SS, et al. SSCP analysis of long DNA fragments in low pH gel. Hum Mutat. 1997;10:400–407.
  25. Reese MG, Eeckman FH, Kulp D, et al. Improved splice site detection in Genie. J Comput Biol.1997;4:311–323.
  26. Sun H, Smallwood PM, Nathans J. Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet.2000;26:242–246.
  27. Allikmets R, Shroyer NF, Singh N, et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science.1997;277:1805–1807.
  28. Wiggs J, Nordenskjold M, Yandell D, et al. Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med. 1988;318:151–157.
  29. Luciani MF, Chimini G. The ATP binding cassette transporter ABC1, is required for the engulfment of corpses generated by apoptotic cell death. EMBO J. 1996;15:226–235.
  30. Simonelli F, Testa F, de Crecchio G, et al. New ABCR mutations and clinical phenotype in Italian patients with Stargardt disease. Invest Ophthalmol Vis Sci. 2000;41:892–897.
  31. Nasonkin I, Illing M, Koehler MR, et al. Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21–p22.1 and identification of novel mutations in Stargardt’s disease. Hum Genet.1998;102:21–26.
  32. Papaioannou M, Ocaka L, Bessant D, et al. An analysis of ABCR mutations in British patients with recessive retinal dystrophies. Invest Ophthalmol Vis Sci. 2000;41:16–19.
  33. Suzuki R, Hirose T. Bull’s-eye macular dystrophy associated with peripheral involvement. Ophthalmologica. 1998;212:260–267.
  34. Luciani MF, Denizot F, Savary S, et al. Cloning of two novel ABC transporters mapping on human chromosome 9. Genomics.1994;21:150–159.
  35. Klugbauer N, Hofmann F. Primary structure of a novel ABC transporter with a chromosomal localization on the band encoding the multidrug resistance-associated protein. FEBS Lett.1996;391:61–65.

Facultad de Ciencias Médicas “Mariana Grajales”

Estudio de una familia de la Policlínica “Máximo Gómez” donde tres miembros padecen enfermedad de Stargardt.

A  Study of a Family with Stargardt`s Disease. Máximo Gómez.  Polyclinic. Holguín.2006.

Luís Borrego  Díaz(1), Elena Díaz Santos(2), Marlen Orges Ramírez(3), Kariné  González Sapsin(4).

1. Especialista de Primer Grado en MGI.  Máster en Urgencias médicas. Profesor Instructor. Policlínica Docente “Máximo Gómez”. Holguín.

2. Especialista de Primer Grado en Oftalmología. Máster en Enfermedades Infecciosas. Profesor Instructor. Centro Provincial de Retinosis Pigmentaria-Holguín.

3. Especialista de Primer Grado en Oftalmología. Profesor Asistente. Hospital Doc. “V.I.Lenin”. Holguín.

4. Especialista de Primer Grado en MGI.  Máster en Urgencias Médicas. Profesor Instructor. Policlínica Docente “Máximo Gómez”. Holguín.

RESUMEN

Se realizó un estudio descriptivo de una familia en la cual hay un miembro afectado con la enfermedad de Stargardt en el área de salud de la Policlínica “Máximo Gómez”, en la etapa comprendida noviembre 2004  a mayo 2006. Fueron examinados 14 familiares y 5 de ellos ínterconsultados con el grupo multidisciplinario del Centro de Retinosis Pigmentaria donde fueron diagnosticados dos enfermos más, de 8 y 12 años. El enfermo estuvo desvinculado de la consulta cuatro años y se logró su reincorporación. Se demostró una vez más la importancia que juega el médico de la familia en el diagnóstico precoz de las enfermedades, así como la vinculación estrecha entre atención secundaria y primaria en la labor de pesquisa de las enfermedades oculares.

Palabra clave: enfermedad de Stargardt, déficit visual, grupo multidisciplinario.

ABSTRACT

A descriptive study on Stargart`s disease at  Màximo Gòmez Polyclinic area from November 2004 and May 2006, due to  the visual deficit that this illness produces was carried out  . The study was done in a patient with this diagnosis.  14 relatives were examinated and 5 of them were attended by the integrated multidisciplinary group at  Retinitis Pigmentosa Center to confirm the diagnosis.  The patient had been away from the consultation during 4 years. Two of them who were  8 and 12 years  were diagnosed with this disease.  The importance of the family doctor in the early diagnosis of the diseases was also proved, as well as the close relation between  primary care and  secondary care  for the study of new cases.

Key words: Stargart`s disease, visual deficit, multisdisciplinary group.

INTRODUCCIÓN

La enfermedad de Stargardt es hereditaria autosómica recesiva (1) (2) (3), que consiste en la afectación de la retina (afectación de los conos del polo posterior). Produce una disminución de la visión central (escotoma central), no se asocia a enfermedades generales (4) (5) (6).

De conjunto con los especialistas del Centro de Retinosis hemos realizado varias investigaciones de  pesquisa (1) (3), lo que facilitó como Especialista de M.G.I.  de la Policlínica  “Máximo Gómez” identificar los problemas visuales de nuestra población. Como parte de la actividad investigativa que desarrollamos, nos motivó un joven con el diagnóstico de enfermedad de Stargardt, que su familia no había sido estudiada y no asistía a consulta desde hacía cuatro años, conociendo la repercusión que este hecho podría traer tanto  para  el joven, como para familiares, nos dedicamos a la tarea de realizar el estudio familiar para detectar si existían nuevos enfermos y brindarles el adecuado seguimiento.

MÉTODO

Se realizó un estudio descriptivo de una familia en la cual hay un miembro afectado con la  enfermedad de Stargardt, en el área de salud de la Policlínica “Máximo Gómez” del municipio Holguín en la etapa comprendida de noviembre 2004 a mayo 2006, con la finalidad de hacer una pesquisa y diagnóstico precoz  de nuevos enfermos, además de conocer el patrón genético- clínico del comportamiento de la enfermedad en esa familia.

Se examinaron 14 familiares, distribuidos en tres generaciones (árbol genealógico), a los que se les aplicó una encuesta, se le realizó examen oftalmológico completo, a los pacientes  que presentaron disminución de la agudeza visual fueron explorados con la cartilla de Snellen, los posibles enfermos fueron enviados al C.R.P. donde se le realizaron el resto de los exámenes para confirmar diagnóstico.

RESULTADO Y DISCUSIÓN

Representamos la estrategia creada para el desarrollo del estudio lo que permitió llevar a cabo la investigación (gráfico 1). De los 14 pacientes examinados encontramos cinco posibles enfermos, con diagnóstico positivo de la enfermedad tres, de ellos dos niños en los cuales logramos un diagnóstico precoz, por todos es conocido lo invalidante que es esta afección (1) (7) (8), la importancia que revierte para el enfermo y la sociedad su diagnóstico temprano, ya que nos permitió dar un seguimiento y tratamiento adecuado. El tercer paciente de 31 años  de edad, se había desvinculado de la consulta desde hacía cuatro años, por lo que tenía un mayor deterioro de su visión (gráfico 2).

Representamos una ficha familiar , donde aparecen distribuidos los pacientes por generaciones con una forma típica de presentación y con manifestaciones de la enfermedad por debajo de los diez años. En los tres pacientes fallecidos no fue posible recoger estos datos, al igual que en los dos enfermos referidos. La ficha familiar abarcó una serie de información importante en el análisis sobre el comportamiento de  la  enfermedad  en  la familia  en  estudio (3, 4, 8).

Al realizar este estudio  evidenciamos ventajas, pues pudimos definir el patrón de transmisión hereditaria, realizar la pesquisa de nuevos enfermos, el diagnóstico precoz en dos niños, así como su seguimiento. Además confeccionamos el árbol genealógico (gráfico 3), con su patrón de herencia autonómica recesiva. Todo esto fue posible por la vinculación estrecha entre atención primaria y secundaria.

Fuente: modelo de encuesta.

Cuadro 1. Ficha familiar:

No Generacional Nombre Lugar de nacimiento Año de nacido. Color de la piel. Edad de comienzo. F Clínica.
I ESC C García. 1929 M ———- ———-
I MSC C García. 1930 M ———- ———-
I CSC C García 1938 M ———- ———-
III RSC C García 1963 B 18 Típica
III SSB Holguín 1988 M 10 Típica
III RSB Holguín 1993 M 8 Típica.
III EST Gibara ———- M ———-
III LST Gibara. ———- M ———-

Fuente: modelo de encuesta.

Cuadro 2. Definición del patrón de Herencia.

No de pacientes diagnosticados. Patrón de herencia.
Antes del estudio 1 No definido
Después del estudio. 3 Autosómica recesiva.

Fuente: modelo de encuesta.

Fuente: modelo de encuesta.

CONCLUSIONES

Logramos el diagnóstico precoz en dos miembros de la familia, así como la mejoría del estado de salud del enfermo. Reafirmamos una vez más la importancia que tiene la acción del médico de familia en el diagnóstico precoz de las enfermedades, así como la vinculación estrecha entre la atención primaria y secundaria.

BIBLIOGRAFÍA

  1. Peláez Molina O. Retinosis Pigmentaria. Experiencia cubana. Eitorial Científico-Técnica. Habana: 1987.
  2. Muller R, Young I. Emery´ s. Elements of Medical Genetics. 10th ed. Marban.2001
  3. Díaz S E y col. Características Clínicas-Genéticas y Epidemiológicas de la  Retinosis Pigmentaria en la  Provincia de Holguín. IV Congreso Nacional de Genética Médica. Diciembre 2004.  La   Habana, Cuba 2004
  4. Pérez G. RM .Caracterización Clínico Epidemiológica de la Retinosis Pigmentaria en la Provincia de las Tunas. [Tesis de doctorado]. Las Tunas;2004.
  5. Hamel, Ch. P, et al. Genetique molecular dis  retinopathies pigmentaire. Itification dis mutation dis genes. J. Fe Opphtalmolol. 2000; 23 (10): 985-995.
  6. Heredia Garcia C D. Retinitis Pigmentaria. General Review and Immunological Point of view. On Inst Barraquer 2003; 32:103-109.
  7. Heredia García C D. Tratamiento Clínico-Quirúrgico de Afecciones vítreo Retinianas. Vectorizacion de antimflamatorios no esteroideo en Oftalmología [monografía]. Laboratorio Menarines,  p. 83.
  8. Mueller RYoung I. Emery´´s. Elements of Medical Geneties 1ae. . Marban; 2006.

Correspondencia: Dr. Luís Borrego Díaz. Calle 20 de mayo 2. Reparto Santiestebán. Holguín. Telef. 427997. Correo electrónico: borrego@cristal.hlg.sld.cu

———————————————————————————————————————————————————————————-

Estudio electrofisiológico
Enfermedad de Stargardt, oclusión vena central de la retina, electro-oculografía.

Índice.
Introducción 4
Enfermedad de estargardt. 5
Definición: 5
Etiología: 5
Signos y síntomas 6
Diagnóstico 6
Tratamiento 7
Calidad de vida 7
EOG y CV 7
Oclusion vena central de la retina 8
Definición: 8
Etiología: 8
Signos y Síntomas: 8
Diagnóstico: 9
Tratamiento: 9
Calidad de vida. 9
CV y EOG 10
Electro- oculografia 11
Definición. 11
Técnicas de registro y realización del examen. 11
Origen de sus componentes. 13
Patologías 13

Conclusión 14

Bibliografía 15

Introducción

El siguiente trabajo tiene como finalidad introducir conocimientos básicos de la Enfermedad de Stargardt y de la Oclusión de la vena central de la retina. Teniendo en cuenta principalmente la etiología, signos y síntomas, y los modos de los cuales disponemos para realizar su diagnostico.

Además se introduce el tema del EOG, examen quizás subvalorado, y que como veremos tiene importancia en el diagnostico de las enfermedades anteriormente mencionadas.

Enfermedad de Stargardt

Definición:

FO: Manchas amarillas paramaculares. Atrofia central.
Distrofia macular de Stargardt es una maculopatía bilateral de herencia generalmente autosomica recesiva. Caracterizada por disminución de la visión central en ambos ojos e indolora.

Algunos autores señalan que el Fundus Flavimaculatus es la misma enfermedad que la Stargardt, pero el primero un estado más avanzado. En cambio otros señalan que la distrofia macular juvenil o Stargardt y el Fundus flavimaculatus son variantes de la misma enfermedad pero que se presentan en diferentes momentos y con pronósticos distintos.

Etiología:

Microscopia electrónica de barrido.   Células de EPR ingurgitadas con lipofuscina.
El gen responsable de esta enfermedad es el ABCR, específicamente ATP-binding cassette transportes gene, subfamilia A, miembro 4 (ABCA4). Este gen de gran tamaño codifica una…(Sigue el estudio en http://www.buenastareas.com bajo suscripción)

Saffron Supplementation in Stargardt’s Disease (STARSAF02)

This study is currently recruiting participants.

Verified February 2012 by Catholic University of the Sacred Heart

First Received on January 14, 2011.   Last Updated on February 12, 2012   History of Changes

Sponsor: Catholic University of the Sacred Heart
Information provided by (Responsible Party): Benedetto Falsini, Catholic University of the Sacred Heart
ClinicalTrials.gov Identifier: NCT01278277

Purpose

The general area of research in which this project has been designed is that of retinal degeneration related to mutations in the ABCR gene, responsible of Stargardt disease/fundus flavimaculatus retinal dystrophy (STD/FF). STG/FF is one of the major causes of vision impairment in the young age. STG/FF originates typically from the dysfunction and loss of cone and rod photoreceptors, developing through a photo-oxidative mechanism. The major disease locus is the central retina, i.e. the macula, whose neurons have the highest density and underlie critical functions such as visual acuity, color vision and contrast sensitivity. There is currently no cure for STG/FF. Recent experimental findings indicate that Saffron, derived from the pistils of Crocus Sativus, may have a role as a retinal neuro-protectant against oxidative damage. The stigmata of Crocus sativus contain biologically high concentrations of chemical compounds including crocin, crocetin, whose multiple C=C bonds provide the antioxidant potential. In addition it is well known that this compound is safe and free of adverse side effects. The aim of this research is to investigate the influence of short-term Saffron supplementation on retinal function in STG/FF patients carrying ABCR mutations. The macular cone-mediated electroretinogram (ERG) in response to high-frequency flicker (focal flicker ERG) will be employed as the main outcome variable. Secondary outcome variable will be the psychophysical cone system recovery after bleaching.

Condition Intervention Phase
Retinal DegenerationGenetic Disease

Single-Gene Defects

Macular Dystrophy

Dietary Supplement: Saffron supplementationOther: placebo Phase IPhase II
Study Type: Interventional
Study Design: Allocation: RandomizedEndpoint Classification: Safety/Efficacy Study

Intervention Model: Crossover Assignment

Masking: Double Blind (Subject, Investigator)

Primary Purpose: Treatment

Official Title: A Novel Therapeutic Strategy Targeting Photoreceptor Oxidative Damage in ABCR-related Retinal Degenerations

Resource links provided by NLM:

Genetics Home Reference related topics: age-related macular degeneration Stargardt macular degeneration X-linked juvenile retinoschisis Help Me Understand Genetics

MedlinePlus related topics: Macular Degeneration

U.S. FDA Resources

Further study details as provided by Catholic University of the Sacred Heart:

Primary Outcome Measures:

  • Focal electroretinogram (FERG) [ Time Frame: six months ] [ Designated as safety issue: No ]ERGs will be elicited by the LED-generated sinusoidal luminance modulation of a circular uniform field (18° in diameter, 80 cd/m2 mean luminance, dominant wavelength: 630 nm), presented at the frequency of 41 Hz on the rear of a ganzfeld bowl, illuminated at the same mean luminance as the stimulus.

Secondary Outcome Measures:

  • Psychophysical recovery of cone system sensitivity after bleaching [ Time Frame: six months ] [ Designated as safety issue: No ]Psychophysical threshold will be determined at the paracentral visual field locations with preserved visual sensitivity, by presenting a 0.5 sec flashing light on a light adapting background of 20 cd/sqm. Following baseline assessment, the threshold intensity for the flashed light will be measured and plotted as a function of time, following 30 sec exposure to an adapting light (delivered in Maxwellian view by means of a calibrated indirect ophthalmoscope) whose intensity is estimated bleach approx 30% of the cone photopigment.
Estimated Enrollment: 30
Study Start Date: February 2011
Estimated Study Completion Date: July 2012
Estimated Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: placebo supplementationpatients will be assigned, in a cross-over design, to placebo or supplement administration Other: placeboplacebo supplementation
Active Comparator: SaffronSaffron Supplementation 20 mg/die Dietary Supplement: Saffron supplementationSaffron supplementation 20 mg

Other Name: Zaffit Special

Show Detailed Description

Eligibility

Ages Eligible for Study: 8 Years to 60 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

  • Macular and peripheral retinal degeneration with typical funduscopic lesions (retinal flecks)
  • Relatively preserved central retinal function
  • Known genotype or genotype under study

Exclusion Criteria:

  • absence of a rod-cone pattern of dysfunction
  • acuity less than 0.1
  • Unknown genotype

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01278277

Contacts

Contact: Benedetto Falsini, MD 0039063015 ext 4929 bfalsini@rm.unicatt.it

Locations

Italy
Policlinico A. Gemelli Recruiting
Rome, Italy, 00168
Contact: Benedetto Falsini, MD     0039063015 ext 4929     bfalsini@rm.unicatt.it
Sub-Investigator: Dario Marangoni, MD
Principal Investigator: Benedetto Falsini, MD
Principal Investigator: Marco Piccardi, MD

Sponsors and Collaborators

Catholic University of the Sacred Heart

Investigators

Principal Investigator: Benedetto Falsini, MD Catholic University of the Sacred Heart
Principal Investigator: Marco Piccardi, MD Catholic University of the Sacred Heart
Study Director: Silvia Bisti, PhD University of L’Aquila

pastedGraphic_4.pdf More Information

Additional Information:

web site of Catholic University of the Sacred Heart, Rome, Italy pastedGraphic_5.pdf

Publications:

Falsini B, Piccardi M, Minnella A, Savastano C, Capoluongo E, Fadda A, Balestrazzi E, Maccarone R, Bisti S. Influence of saffron supplementation on retinal flicker sensitivity in early age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6118-24. Epub 2010 Aug 4.

Responsible Party: Benedetto Falsini, Associate Professor Ophthalmology, Catholic University of the Sacred Heart
ClinicalTrials.gov Identifier: NCT01278277 History of Changes
Other Study ID Numbers: STARSAF02
Study First Received: January 14, 2011
Last Updated: February 12, 2012
Health Authority: Italy: Ethics Committee

Keywords provided by Catholic University of the Sacred Heart:

Stargardt diseasemacula

electroretinogram

saffron

Additional relevant MeSH terms:

Genetic Diseases, InbornRetinal Degeneration

Macular Degeneration

Retinal Diseases

Eye Diseases

ClinicalTrials.gov processed this record on March 07, 2012

OTROS LIBROS INTERESANTES

Allikmets R, Singh N, Shroyen SH, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular Dystrophy. Nat Genet, 1997; 15: 236-246.
Cideciyan AV, Aleman TS, Swider M, et al. Mutations in ABCA4 results in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease séquense. Hum Mol Genet, 2004; 13: 525-534.
De Laey JJ, Veroughstraete C. Hyperlipofuscinosis and subretinal fibrosis in Stargardt´s disease. Retina 1995; 15: 399-406.
Donoso LA, Edwards AO, Frost A, et al. Autosomal Dominant Stargardt-like macular dystrophy. Surv Ophthalmol 2001, 46: 149-163.
Fishman GA, Stone EM, Grover S, et al. Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene. Arch Ophthalmol,1999; 117: 504-510.
Kang DerwentJJ, Derlacki DJ, Hetling JR, et al. Dark Adaptation of rod photoreceptors in normal subjects, and in patients with Stargardt disease and an ABCA4 mutations. Invest Ophthalmol Vis Sci 2004; 45: 2447-2456.
Lachapelle P, Little JM, Roy MS. The electroretinogram in Stargardt´s disease and fundus flavimaculatus. Doc Ophthalmol, 1989; 73: 395-404.
Lois N, Holder GE, Fitzke FW, et al. Intrafamilial variation of phenotype in Stargardt Macular Dystrophy-Fundus Flavimaculatus. Invest Ophthalmol Vis Sci, 1999; 40: 2668-2675.
Mandal NA, Ambasudhan R, Wong PW, et al. Characterization of mouse orthologue of ELOVL4: genomic organization and spatial and temporal expression. Genomics 2004; 83: 626-635.
Mata NL, Weng J, Travis GH. Biosynthesis of a major lipofuscin fluorophore in mice and human retinal and macular degeneration. Proc Natl Acad Sci, 2000; 13: 7154-7159.
Pacione LR, Szego MJ, Ikeda S, et al. Progress toward understanding the genetic and biochemical mechanisms of inherited photoreceptor degenerations. Annu Rev Neurosci, 2003; 26: 657-700.
Paloma E, Coco R, Martínez-Mir A, Vilageliu L, Balcells S, González-Duarte R. Análisis of ABCA4 in mixed Spanish Familias segregating different retinal dystrophies. Hum Mutat 2002 ; 20 : 476-83.
Radu RA, Mata NL, Nusinowitz S, et al. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt´s macular degeneration. Proc Natl Acad Sci, 2003; 100: 4742-4747.
Radu RA, Mata NL, Bagla A, et al. Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt´s macular degeneration. Proc Natl Acad Sci, 2004; 101: 5928-5923.
Schwoerer J, Secretan M, Zografos L, et al. Indocyanine green angiography in Fundus Flavimaculatus. Ophthalmologica, 2000; 214: 240-245.
Shroyen NF, Lewis RA, Allikmets R, et all. The rod photoreceptor ATP-binding cassette transporter gene, ABCR and retinal disease: from monogenic to multifactorial. Vis Res 1999; 39: 2537-2544.
Van Driel MA, Maugeri A, Klevering BJ, et al. ABCR unites what ophthalmologist divide. Ophthalmic Genet, 1998; 19: 117-22.
Zhang K, Kniazeva M, Hutchinson A, et al. The ABCR gene in recessive and dominant Stargardt diseases: a genetic pathway in macular degeneration. Genomics1999; 60: 234-237.


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s