- Email: [email protected]
Two sisters with macular dystrophy caused by the 3243A>G mitochondrial DNA mutation
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(5):240–244
ARCHIVOS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGÍA www.elsevier.es/oftalmologia
Short communication
Two sisters with macular dystrophy caused by the 3243A>G mitochondrial DNA mutation夽,夽夽 ˜ V. Sánchez-Gutiérrez ∗ , J. García-Montesinos, A. Pardo-Munoz Departamento de Oftalmología, Hospital Universitario Ramón y Cajal, Madrid, Spain
a r t i c l e
i n f o
a b s t r a c t
Article history:
Case report: Two sisters, 54 and 60 years old, with a history of diabetes and deafness, con-
Received 8 November 2015
sulted for decreased visual acuity (VA). Funduscopic examination revealed patchy areas of
Accepted 12 January 2016
chorioretinal atrophy with annular arrangement around the fovea. Genetic study identified
Available online 29 March 2016
the heteroplasmic mutation 3243A>G in mitochondrial DNA, which supports the syndrome
Keywords:
Discussion: The finding of such macular disorders, especially in the presence of diabetes
maternally inherited diabetes and deafness (MIDD) or Ballinger-Wallace disease. Macular dystrophy
mellitus and deafness, should suggest the performing of a mitochondrial genome screening
Diabetes
to identify this unusual syndrome.
Deafness
˜ de Oftalmología. Published by Elsevier España, S.L.U. All rights © 2016 Sociedad Espanola reserved.
Mitochondrial DNA Mitochondrial disease Ballinger-Wallace syndrome
Dos hermanas con distrofia macular causada por la mutación 3243A>G del ADN mitocondrial r e s u m e n Palabras clave:
˜ Caso clínico: Dos hermanas de 54 y 60 anos, con antecedentes de diabetes y sordera, con-
Distrofia macular
sultaron por disminución de la agudeza visual (AV). En la funduscopia se observaban áreas
Diabetes
parcheadas de atrofia coriorretiniana con disposición anular alrededor de la fóvea. El estudio
Sordera
genético identificó la mutación heteroplásmica 3243A>G en el ADN mitocondrial, com-
ADN mitocondrial
patible con el síndrome Maternally Inherited Diabetes and Deafness (MIDD) o enfermedad de
Enfermedad mitocondrial
Ballinger-Wallace.
Síndrome de Ballinger-Wallace
Discusión: El hallazgo de tales alteraciones maculares características, especialmente si se ˜ de diabetes mellitus y sordera, nos debe indicar la realización de un cribado del acompana genoma mitocondrial para identificar este inusual síndrome. ˜ © 2016 Sociedad Espanola de Oftalmología. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.
夽 ˜ Please cite this article as: Sánchez-Gutiérrez V, García-Montesinos J, Pardo-Munoz A. Dos hermanas con distrofia macular causada por la mutación 3243A>G del ADN mitocondrial. Arch Soc Esp Oftalmol. 2016;91:240–244. 夽夽 Paper presented at the 90th Congress of the Ophthalmology Society of Spain held in Bilbao, October 1–4, 2014. ∗ Corresponding author. E-mail address: [email protected] (V. Sánchez-Gutiérrez). ˜ 2173-5794/© 2016 Sociedad Espanola de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(5):240–244
Introduction Mitochondrial inheritance diseases include the maternal inheritance diabetes and deafness syndrome (MIDD) or Ballinger-Wallace disease, caused by the mutation of the mitochondrial DNA at the 3243A>G position. This mutation can give rise to a broad range of clinical expressions, including macular dystrophy.
Clinic case report Two sisters, 54 and 60 years old, visited the hospital to discard a diabetic retinopathy after referring for diminished visual acuity (VA). They exhibited diabetes mellitus with over 10 years evolution and both had also been diagnosed with neurosensory deafness. Family history included their mother and one aunt diagnosed with diabetes mellitus and bilateral neurosensory deafness, without genetic assessment. The youngest sister, 54 years, exhibited VA of 0.6 in the right eye and 0.9 in the left eye. Ocular fundus exploration reveals the presence of large retina pigment epithelium (RPE) atrophy areas in the posterior pole, similar in both eyes. These areas exhibited patch hypoautofluorescence, mainly in the posterior pole and the peripapillary area (Fig. 1). A multifocal electroretinogram (MF ERG) exhibited alterations with amplitude reduction in the central and perifoveal areas (Fig. 2). Family history and the associated disease of the patient prompted the request for a genetic assessment which identified the presence of 3243A>G heteroplasmic mutation in the tRNALeu (UUR) gene of mitochondrial DNA, compatible with the MIDD syndrome. The apparent heteroplasmic mutation was of 71–79%,
241
quantified by means of PCR-RLFP direct sequencing with micro-fluid separation in the BioAnalyzer Agilent device. The second sister, 60 years, exhibited a VA of 0.5 in the right eye and 0.8 in the left eye. The ophthalmological assessment produced findings similar to those of her sister. The ocular fundus exhibited large patch areas of RPE atrophy arranged as a ring around the fovea. As with the sister, said areas exhibited hypoautofluorescence and showed hyperfluorescent dots surrounding the periphery of the atrophy areas (Fig. 3). MF ERG revealed sensitivity reductions matching the ocular fundus findings (Fig. 4). Genetic analysis also showed the presence of a 3243A>G mutation in the mitochondrial DNA, with an apparent mutant heteroplasmy level of 17–25%. During the 3-year follow-up, VA remained stable in both patients with very similar ocular fundus and autofluorescence appearance found during checkups. To date, none of the 2 sisters have developed diabetic retinopathy signs.
Discussion The presence of maternal inheritance diabetes and neurosensory deafness, to which macular dystrophy is frequently associated, constitutes the MIDD syndrome, generally produced by a 3243A>G mutation in mitochondrial DNA.1 This mutation can also give rise to different clinical phenotypes such as the mitochondrial encephalomyopathy syndrome with lactic acidosis and episodes of cerebrovascular accidents (MELAS).2 The MIDD syndrome accounts for approximately 1.5% of all diabetes cases.1,3 The first expressions can appear at any age although the disease is generally diagnosed in young adults.3 In the majority of cases, said patients exhibit diabetes
Fig. 1 – Funduscopic findings and autofluorescence of the first sister. (a) Large chorioretinal atrophy area in the posterior pole of both eyes. (b) Confluent hypoautofluorescence patches in the posterior pole.
242
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(5):240–244
Ring analyse
Ring analyse
1.00µV/div
1 2
Ring
Amp.P1 nV/deg2
Normal
1.00µV/div
Ring
Amp.P1 Normal nV/deg2
1
57.1
66.6–130.8
2
20.8
30.9–77.8
21.7–59
3
18.7
21.7–59
12.9–37.1
4
17.2
12.9–37.1
5
14.2
10–28.2
1
77.1
66.6–130.8
2
20.4
30.9–77.8
3
23.1
4
17.6
5
15.7
10–28.2
1 2
3
3
4
4
5
5 20.0ms/div
20.0ms/div
130
nV/deg2
0
OD
OS
Fig. 2 – Multifocal electroretinogram (MF ERG) of the first patient: diminished sensitivity of the fovea and perifoveal rings in both eyes.
Fig. 3 – Retinography and autofluorescence of the second sister. (a) Areas of perifoveal chorioretinal atrophy. (b) Areas of atrophy with hypoautofluorescence peripherally surrounded by hyperfluorescent dots.
243
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(5):240–244
Ring analyse
Ring analyse Ring Amp.P1 Normal nV/deg2
500nV/div
1 2
500nV/div
Ring
Amp.P1 Normal nV/deg2
1
66.2
66.6–130.8
1
154.9
66.6–130.8
2
43.9
30.9–77.8
2
24.3
30.9–77.8
3
29.3
21.7–59
3
31.7
21.7–59
4
18
12.9–37.1
4
23
12.9–37.1
5
15.1
10–28.2
5
19.2
10–28.2
1 2
3
3
4
4
5
5
20.0ms/div
20.0ms/div 130
nV/deg2
0
OD
OS
Fig. 4 – Multifocal electroretinogram (MF ERG) of the second patient. RE: diminished foveal sensitivity with a relative preservation of perifoveal rings; LE: diminished perifoveal rings with preserved foveal peak.
similar to type II. However, it has been described that diabetic retinopathy is less frequent than in the classic form of diabetes.1,4 In over 80% of cases, MIDD patients develop bilateral macular dystrophy,4 the severity of which varies between patients. It is believed that this variability is due to the proportion of the mutated mitochondrial DNA in the retinal tissue, a factor which is impossible to assess.1 The most frequent macular dystrophy phenotype in this syndrome is the presence of perifoveal patched atrophy, coalescing in time in an atrophy ring similar to that found in the present patients. The literature has also described a phenotype consisting in a pattern dystrophy appearance.2 Autofluorescence findings associated to the 3243A>G mutation are quite characteristic and can be differentiated from other dystrophies on which the differential diagnostic should be based, such as in the Stargardt disease, geographic atrophy of age-related macular degeneration or maculopathy caused by the R172W mutation.2 The main characteristics that differentiate the MIDD syndrome are diffuse dotted hyperautofluorescence — particularly surrounding the atrophy areas — and the fact that the atrophy changes involve the macular and peripapillary area, generally without exceeding the vascular arches.2 Cellular division can give rise to cellular lines with normal as well as mutated mitochondria, the combination of which is known as heteroplasmy. The present patients exhibited a very different heteroplasmy percentage. This is because mitochondrial DNA is highly heterogeneous due to its different tissue distribution and the different proportion that can be found, depending on the sample extraction time. Even so, the MIDD syndrome diagnostic confirmation is based on the identification of the mutation in
the mitochondrial genome, regardless of the heteroplasmy level.1,3 In conclusion, patients with 3243A>G mutation in the mitochondrial DNA should be studied to discard the presence of maculopathy, even when asymptomatic. The same applies to the findings of characteristic macular alterations, particularly when diabetes mellitus and deafness are associated. A mitochondrial genome1 screening is indicated in these cases in order to diagnose this syndrome, because these patients could benefit from genetic counseling.
Funding The authors state they have not received financial aid for this paper.
Conflicts of interest No conflict of interests was declared by the authors.
references
1. Massin P, Virally-Monod M, Vialettes B, Paques M, Gin H, Porokhov B, et al. Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. Ophthalmology. 1999;106:1821–7. 2. Rath PP, Jenkins S, Michaelides M, Smith A, Sweeny MG, Davis MB, et al. Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation
244
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(5):240–244
with fundus autofluorescence. Br J Ophthalmol. 2008;92: 623–9. 3. Smith PR, Bain SC, Good PA, Hattersley AT, Barnett AH, Gibson JM, et al. Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness caused by the
mitochondrial DNA 3243 tRNA(Leu) A to G mutation. Ophthalmology. 1999;106:1101–8. 4. Sampedro A, Barbón JJ, Ávarez JA, Andrés MA, Baldó C. Diabetes de herencia materna y sordera. Arch Soc Esp Oftalmol. 2009;84:359–62.
ARCHIVOS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGÍA www.elsevier.es/oftalmologia
Short communication
Two sisters with macular dystrophy caused by the 3243A>G mitochondrial DNA mutation夽,夽夽 ˜ V. Sánchez-Gutiérrez ∗ , J. García-Montesinos, A. Pardo-Munoz Departamento de Oftalmología, Hospital Universitario Ramón y Cajal, Madrid, Spain
a r t i c l e
i n f o
a b s t r a c t
Article history:
Case report: Two sisters, 54 and 60 years old, with a history of diabetes and deafness, con-
Received 8 November 2015
sulted for decreased visual acuity (VA). Funduscopic examination revealed patchy areas of
Accepted 12 January 2016
chorioretinal atrophy with annular arrangement around the fovea. Genetic study identified
Available online 29 March 2016
the heteroplasmic mutation 3243A>G in mitochondrial DNA, which supports the syndrome
Keywords:
Discussion: The finding of such macular disorders, especially in the presence of diabetes
maternally inherited diabetes and deafness (MIDD) or Ballinger-Wallace disease. Macular dystrophy
mellitus and deafness, should suggest the performing of a mitochondrial genome screening
Diabetes
to identify this unusual syndrome.
Deafness
˜ de Oftalmología. Published by Elsevier España, S.L.U. All rights © 2016 Sociedad Espanola reserved.
Mitochondrial DNA Mitochondrial disease Ballinger-Wallace syndrome
Dos hermanas con distrofia macular causada por la mutación 3243A>G del ADN mitocondrial r e s u m e n Palabras clave:
˜ Caso clínico: Dos hermanas de 54 y 60 anos, con antecedentes de diabetes y sordera, con-
Distrofia macular
sultaron por disminución de la agudeza visual (AV). En la funduscopia se observaban áreas
Diabetes
parcheadas de atrofia coriorretiniana con disposición anular alrededor de la fóvea. El estudio
Sordera
genético identificó la mutación heteroplásmica 3243A>G en el ADN mitocondrial, com-
ADN mitocondrial
patible con el síndrome Maternally Inherited Diabetes and Deafness (MIDD) o enfermedad de
Enfermedad mitocondrial
Ballinger-Wallace.
Síndrome de Ballinger-Wallace
Discusión: El hallazgo de tales alteraciones maculares características, especialmente si se ˜ de diabetes mellitus y sordera, nos debe indicar la realización de un cribado del acompana genoma mitocondrial para identificar este inusual síndrome. ˜ © 2016 Sociedad Espanola de Oftalmología. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.
夽 ˜ Please cite this article as: Sánchez-Gutiérrez V, García-Montesinos J, Pardo-Munoz A. Dos hermanas con distrofia macular causada por la mutación 3243A>G del ADN mitocondrial. Arch Soc Esp Oftalmol. 2016;91:240–244. 夽夽 Paper presented at the 90th Congress of the Ophthalmology Society of Spain held in Bilbao, October 1–4, 2014. ∗ Corresponding author. E-mail address: [email protected] (V. Sánchez-Gutiérrez). ˜ 2173-5794/© 2016 Sociedad Espanola de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(5):240–244
Introduction Mitochondrial inheritance diseases include the maternal inheritance diabetes and deafness syndrome (MIDD) or Ballinger-Wallace disease, caused by the mutation of the mitochondrial DNA at the 3243A>G position. This mutation can give rise to a broad range of clinical expressions, including macular dystrophy.
Clinic case report Two sisters, 54 and 60 years old, visited the hospital to discard a diabetic retinopathy after referring for diminished visual acuity (VA). They exhibited diabetes mellitus with over 10 years evolution and both had also been diagnosed with neurosensory deafness. Family history included their mother and one aunt diagnosed with diabetes mellitus and bilateral neurosensory deafness, without genetic assessment. The youngest sister, 54 years, exhibited VA of 0.6 in the right eye and 0.9 in the left eye. Ocular fundus exploration reveals the presence of large retina pigment epithelium (RPE) atrophy areas in the posterior pole, similar in both eyes. These areas exhibited patch hypoautofluorescence, mainly in the posterior pole and the peripapillary area (Fig. 1). A multifocal electroretinogram (MF ERG) exhibited alterations with amplitude reduction in the central and perifoveal areas (Fig. 2). Family history and the associated disease of the patient prompted the request for a genetic assessment which identified the presence of 3243A>G heteroplasmic mutation in the tRNALeu (UUR) gene of mitochondrial DNA, compatible with the MIDD syndrome. The apparent heteroplasmic mutation was of 71–79%,
241
quantified by means of PCR-RLFP direct sequencing with micro-fluid separation in the BioAnalyzer Agilent device. The second sister, 60 years, exhibited a VA of 0.5 in the right eye and 0.8 in the left eye. The ophthalmological assessment produced findings similar to those of her sister. The ocular fundus exhibited large patch areas of RPE atrophy arranged as a ring around the fovea. As with the sister, said areas exhibited hypoautofluorescence and showed hyperfluorescent dots surrounding the periphery of the atrophy areas (Fig. 3). MF ERG revealed sensitivity reductions matching the ocular fundus findings (Fig. 4). Genetic analysis also showed the presence of a 3243A>G mutation in the mitochondrial DNA, with an apparent mutant heteroplasmy level of 17–25%. During the 3-year follow-up, VA remained stable in both patients with very similar ocular fundus and autofluorescence appearance found during checkups. To date, none of the 2 sisters have developed diabetic retinopathy signs.
Discussion The presence of maternal inheritance diabetes and neurosensory deafness, to which macular dystrophy is frequently associated, constitutes the MIDD syndrome, generally produced by a 3243A>G mutation in mitochondrial DNA.1 This mutation can also give rise to different clinical phenotypes such as the mitochondrial encephalomyopathy syndrome with lactic acidosis and episodes of cerebrovascular accidents (MELAS).2 The MIDD syndrome accounts for approximately 1.5% of all diabetes cases.1,3 The first expressions can appear at any age although the disease is generally diagnosed in young adults.3 In the majority of cases, said patients exhibit diabetes
Fig. 1 – Funduscopic findings and autofluorescence of the first sister. (a) Large chorioretinal atrophy area in the posterior pole of both eyes. (b) Confluent hypoautofluorescence patches in the posterior pole.
242
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(5):240–244
Ring analyse
Ring analyse
1.00µV/div
1 2
Ring
Amp.P1 nV/deg2
Normal
1.00µV/div
Ring
Amp.P1 Normal nV/deg2
1
57.1
66.6–130.8
2
20.8
30.9–77.8
21.7–59
3
18.7
21.7–59
12.9–37.1
4
17.2
12.9–37.1
5
14.2
10–28.2
1
77.1
66.6–130.8
2
20.4
30.9–77.8
3
23.1
4
17.6
5
15.7
10–28.2
1 2
3
3
4
4
5
5 20.0ms/div
20.0ms/div
130
nV/deg2
0
OD
OS
Fig. 2 – Multifocal electroretinogram (MF ERG) of the first patient: diminished sensitivity of the fovea and perifoveal rings in both eyes.
Fig. 3 – Retinography and autofluorescence of the second sister. (a) Areas of perifoveal chorioretinal atrophy. (b) Areas of atrophy with hypoautofluorescence peripherally surrounded by hyperfluorescent dots.
243
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(5):240–244
Ring analyse
Ring analyse Ring Amp.P1 Normal nV/deg2
500nV/div
1 2
500nV/div
Ring
Amp.P1 Normal nV/deg2
1
66.2
66.6–130.8
1
154.9
66.6–130.8
2
43.9
30.9–77.8
2
24.3
30.9–77.8
3
29.3
21.7–59
3
31.7
21.7–59
4
18
12.9–37.1
4
23
12.9–37.1
5
15.1
10–28.2
5
19.2
10–28.2
1 2
3
3
4
4
5
5
20.0ms/div
20.0ms/div 130
nV/deg2
0
OD
OS
Fig. 4 – Multifocal electroretinogram (MF ERG) of the second patient. RE: diminished foveal sensitivity with a relative preservation of perifoveal rings; LE: diminished perifoveal rings with preserved foveal peak.
similar to type II. However, it has been described that diabetic retinopathy is less frequent than in the classic form of diabetes.1,4 In over 80% of cases, MIDD patients develop bilateral macular dystrophy,4 the severity of which varies between patients. It is believed that this variability is due to the proportion of the mutated mitochondrial DNA in the retinal tissue, a factor which is impossible to assess.1 The most frequent macular dystrophy phenotype in this syndrome is the presence of perifoveal patched atrophy, coalescing in time in an atrophy ring similar to that found in the present patients. The literature has also described a phenotype consisting in a pattern dystrophy appearance.2 Autofluorescence findings associated to the 3243A>G mutation are quite characteristic and can be differentiated from other dystrophies on which the differential diagnostic should be based, such as in the Stargardt disease, geographic atrophy of age-related macular degeneration or maculopathy caused by the R172W mutation.2 The main characteristics that differentiate the MIDD syndrome are diffuse dotted hyperautofluorescence — particularly surrounding the atrophy areas — and the fact that the atrophy changes involve the macular and peripapillary area, generally without exceeding the vascular arches.2 Cellular division can give rise to cellular lines with normal as well as mutated mitochondria, the combination of which is known as heteroplasmy. The present patients exhibited a very different heteroplasmy percentage. This is because mitochondrial DNA is highly heterogeneous due to its different tissue distribution and the different proportion that can be found, depending on the sample extraction time. Even so, the MIDD syndrome diagnostic confirmation is based on the identification of the mutation in
the mitochondrial genome, regardless of the heteroplasmy level.1,3 In conclusion, patients with 3243A>G mutation in the mitochondrial DNA should be studied to discard the presence of maculopathy, even when asymptomatic. The same applies to the findings of characteristic macular alterations, particularly when diabetes mellitus and deafness are associated. A mitochondrial genome1 screening is indicated in these cases in order to diagnose this syndrome, because these patients could benefit from genetic counseling.
Funding The authors state they have not received financial aid for this paper.
Conflicts of interest No conflict of interests was declared by the authors.
references
1. Massin P, Virally-Monod M, Vialettes B, Paques M, Gin H, Porokhov B, et al. Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. Ophthalmology. 1999;106:1821–7. 2. Rath PP, Jenkins S, Michaelides M, Smith A, Sweeny MG, Davis MB, et al. Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation
244
a r c h s o c e s p o f t a l m o l . 2 0 1 6;9 1(5):240–244
with fundus autofluorescence. Br J Ophthalmol. 2008;92: 623–9. 3. Smith PR, Bain SC, Good PA, Hattersley AT, Barnett AH, Gibson JM, et al. Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness caused by the
mitochondrial DNA 3243 tRNA(Leu) A to G mutation. Ophthalmology. 1999;106:1101–8. 4. Sampedro A, Barbón JJ, Ávarez JA, Andrés MA, Baldó C. Diabetes de herencia materna y sordera. Arch Soc Esp Oftalmol. 2009;84:359–62.