Macular Pattern Dystrophy Research Articles

Electrophysiological Evaluation of Macular Dystrophies

Macular dystrophies are a heterogeneous group of genetic disorders that often severely threatens the bilateral central vision of the affected patient. While advances in molecular genetics have been instrumental in the understanding and diagnosis of these disorders, there remains significant phenotypical variation among patients within any particular subset of macular dystrophies. Electrophysiological testing remains a vital tool not only to characterize vision loss for differential diagnosis but also to understand the pathophysiology of these disorders and to monitor the treatment effect, potentially leading to therapeutic advances. This review summarizes the application of electrophysiological testing in macular dystrophies, including Stargardt disease, bestrophinopathies, X-linked retinoschisis, Sorsby fundus dystrophy, Doyne honeycomb retina dystrophy, autosomal dominant drusen, occult macular dystrophy, North Carolina macular dystrophy, pattern dystrophy, and central areolar choroidal dystrophy.

PRPH2-Associated Retinopathy: Novel Variants and Genotype–Phenotype Correlations

A broad spectrum of autosomal-dominant inherited retinal diseases (IRDs), ranging from mild macular pattern dystrophy to severe cone-rod degeneration, is associated with PRPH2 variants (peripherinopathies). We present detailed clinical and molecular characterization of patients affected by peripherinopathies, aiming to expand the mutational spectrum, and propose novel genotype-phenotype correlations. Observational, retrospective case series. Patients with an IRD related to a molecularly proven PRPH2 variant. Data from ophthalmic examinations and retinal imaging were collected for each follow-up visit. The standard imaging protocol included OCT, blue-light autofluorescence, near-infrared autofluorescence, and ultra-widefield fundus imaging. Genetic analysis was performed with a genomic approach by next-generation sequencing. Results of ophthalmic examination, retinal imaging, and molecular genetic analysis. Overall, a total of 19 patients with an IRD and a (likely) pathogenic PRPH2 variant were identified. Their age at presentation had a median of 48 years, whereas the symptomatic disease onset was in their 30s or 40s in 74% of cases. The median follow-up time was 4 years. Clinically, 6 patients were diagnosed with cone-rod dystrophy and 13 with pattern dystrophy. Among the 13 PRPH2 pathogenic variants identified in our cohort, 7 were missense, 3 nonsense, 2 frame shifting, and 1 splice site. Missense variants in the D2 loop were associated with cone-rod dystrophies and poor visual prognosis, whereas predicted loss-of-function alleles with pattern dystrophies and retention of a good visual function into adulthood. Overall, the following 7 variants were novel and never associated to a clinical phenotype: c.68delT, c.290G>A, c.413T>G, c.642C>G, c.702_706dupCAGTT, c.771_772delinsGA, and c.850C>G. Here, we report the findings of a retrospective case series that provided a detailed clinical and molecular characterization of 19 patients harboring 13 different PRPH2 pathogenic variants, 7 of which were previously unreported, expanding the mutational spectrum of the PRPH2 gene. Loss-of-function variants might be preferentially associated with mild-pattern dystrophies, whereas missense dominant-negative variants might be preferentially associated with severely blinding cone-rod degenerations. Further studies are needed to better define the pathogenetic mechanisms and the functional effects of most variants to allow the development of successful gene therapy. Proprietary or commercial disclosure may be found after the references.

Neuro-ophthalmic manifestations of mitochondrial disorders and their management.

The visual system has high metabolic requirements and is therefore particularly vulnerable to mitochondrial dysfunction. The most commonly affected tissues include the extraocular muscles, photoreceptors, retinal pigment epithelium, optic nerve and visual cortex. Hence, the most common manifestations of mitochondrial disorders are progressive external ophthalmoplegia, macular pattern dystrophy, pigmentary retinopathy, optic neuropathy and retrochiasmal visual field loss. With the exception of Leber hereditary optic neuropathy and stroke-like episodes seen in mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, the majority of neuro-ophthalmic manifestations have an insidious onset. As such, some patients may not recognize subtle progressive visual symptoms. When mitochondrial disorders are highly suspected, meticulous examination performed by an ophthalmologist with targeted ancillary testing can help confirm the diagnosis. Similarly, neuro-ophthalmic symptoms and signs may be the first indication of mitochondrial disease and should prompt systemic investigations for potentially life-threatening associations, such as cardiac conduction defects. Finally, the ophthalmologist can offer symptomatic treatments for some of the most disabling manifestations of these disorders.

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Clinical phenotype of mitochondrial diabetes due to rare mitochondrial DNA mutations

ObjectiveWhile the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the role of rare mtDNA mutations in the pathophysiology of diabetes. The main objective of our study was to describe the phenotypic characteristics of patients suffering from diabetes linked to rare mtDNA mutations. Research design and methodsWe performed a post-hoc analysis of a prospective multicenter cohort of 743 patients with mitochondrial disorder (previously published by the French Network of Mitochondrial Diseases), associated to a literature review of the PubMed database from 1992 to May 2016. We extracted all reported patients with diabetes and identified rare mtDNA mutations and described their clinical and metabolic phenotypes. ResultsThe 50 identified patients (10 from the princeps study; 40 from the review of the literature) showed a heterogeneous metabolic phenotype in terms of age, symptoms prior to diagnosis, treatments, and associated clinical and biological signs. However, neurological symptoms were more frequent in case of rare mtDNA mutations compared to the classical m.3243 A>G mutation (P=0.024). In contrast, deafness (65% vs. 95%, P=3.7E-5), macular pattern dystrophy (20% vs. 86%, P=1.6E-10) and nephropathy (8% vs. 28%, P=0.018) were significantly less frequent than in case of the classical m.3243 A>G mutation. ConclusionAlthough no specific metabolic phenotype could be identified suggesting or eliminating implication of rare mtDNA mutations in diabetes, clinical phenotypes featured more frequent neurological signs.

Pattern dystrophies in patients treated with deferoxamine: report of two cases and review of the literature

BackgroundDeferoxamine (DFO) is one of the most commonly used chelation treatments for transfusional hemosiderosis. Pattern dystrophies constitute a distinct entity of retinal disorders that has been occasionally identified in association with deferoxamine.Case presentationWe report two cases of bilateral macular pattern dystrophy in transfusion dependent patients undergoing chronic chelation therapy with deferoxamine due to thalassemias. Our patients were evaluated with multimodal imaging and the results are presented. Both patients had normal cone and rod responses in the full-field electroretinogram and continued the prescribed chelation therapy, after hematology consult. The patients were followed up every 3 months for 2 and 4 years respectively for possible deterioration. Their best corrected visual acuity remained stable with no anatomic change on Optical Coherence Tomography findings.ConclusionMultimodal imaging of our patients allowed a better evaluation and possibly earlier detection of the DFO-related changes. Screening and close follow up of patients under chronic chelating therapy is important in order to promptly diagnose and manage possible toxicity either with discontinuation of the offending agent or dose modification.

Pearls & Oy-sters: Maternally inherited diabetes and deafness presenting with ptosis and macular pattern dystrophy

Mitochondrial disorders can cause an array of neuro-ophthalmologic manifestations such as ptosis, external ophthalmoparesis, nystagmus, pigmentary retinopathy, and optic neuropathy.1 The …

Ptosis as an associated finding in maternally inherited diabetes and deafness

Purpose: To report ptosis as an associated finding in 2 patients with maternally inherited diabetes and deafness (MIDD).Methods: Two unrelated female patients with genetically proven MIDD are described. A complete ophthalmological examination included evaluation of levator muscle function, vertical fissure height and upper lid crease position measurements, the ice pack test and extensive imaging. In addition, pathology of the levator muscle was performed in 1 patient.Results: The first patient had an asymmetric ptosis at presentation. Levator muscle function was initially normal and decreased 3 years after, suggestive of a myogenic ptosis. Fundus examination revealed a macular pattern dystrophy. The second MIDD patient was referred for bilateral pigment alterations at the posterior pole. Gradually bilateral ptosis developed over a 3-year period. In both patients, ocular motility testing revealed a reduced upgaze.Conclusions: Myogenic ptosis has been described in association with several of the phenotypes caused by the m.3243A>G mutation, but up to now it had not been described as a finding in MIDD. MIDD has pleomorphic manifestations, and myogenic ptosis should be added to the list of associated clinical features. The additional symmetric elevation deficit in both patients may be an early sign of chronic progressive external ophthalmoplegia (CPEO). The results provide further evidence to suggest that MIDD represents only a part of a continuous spectrum of disease related to the m.3243A>G point mutation in the tRNALeu gene.

The Clinical Variability of Maternally Inherited Diabetes and Deafness Is Associated with the Degree of Heteroplasmy in Blood Leukocytes

Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA(1c) was also found and remained significant after adjustment for age at molecular sampling and gender. These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

Macular pattern dystrophy in MIDD: Long-term follow-up

A case of maternally inherited diabetes and deafness (MIDD)-associated macular pattern dystrophy with a 15-year follow-up is reported. On initial examination at age 37, visual acuity was normal, but chorioretinal atrophy at the posterior pole was already present in both eyes. At age 52, visual acuity remained normal in the right eye and was only slightly decreased in the left eye despite notable extension of the areas of chorioretinal atrophy in that eye. No evidence of diabetic retinopathy was present at any time. This case shows that visual acuity can remain stable in the long term despite extensive lesions of macular pattern dystrophy.

Maternally Inherited Diabetes with Deafness and Obesity: Body Weight Reduction Response to Treatment with Insulin Analogues

Maternally inherited diabetes with deafness (MIDD) is a rare, monogenic form of diabetes mellitus caused by mutations in the mitochondrial genome, the most frequent being the A3243G substitution of the tRNA(Leu) gene. We screened 520 individuals with type 2 diabetes mellitus and 45 probands from families with a clinical picture of maturity onset diabetes of the young (MODY) using restriction fragment length polymorphism. One carrier of the mutation being investigated was found in a proband from a MODY family. The patient was a 20 year-old woman, diagnosed at the age of 16 years as having type 1 diabetes mellitus. On entry to the study, she was treated by a multiple daily injection regimen (MDI) with regular human insulin and human NPH insulin. Typical extra-pancreatic symptoms of MIDD were present, such as macular pattern dystrophy and mild bilateral sensory hearing loss. Additionally, the patient presented abdominal obesity (BMI 32.0), an uncommon feature in monogenic insulin secretion defects, including MIDD. To facilitate weight loss, the diabetes treatment was modified. Since metformin treatment is considered to be contraindicated in MIDD because of the increased risk of lactic acidosis, we used insulin analogues (aspart and detemir) in an MDI regimen and hypocaloric diet. This resulted in a 6.3 kg weight reduction (BMI 27.4) and normalization of HbA1c level (from 7.2 to 6.1 %) during a three-month follow-up. On the basis of this case, we suggest that an MDI regimen with insulin analogues may be a preferred therapeutic option in some rare clinical situations, such as MIDD associated with obesity.

Diabetes Mellitus with Mitochondrial Gene Mutations in Japan

Abstract: Diabetes mellitus due to the mitochondrial DNA 3243(A‐G) mutation is reported to represent 0.5‐1% of the general diabetic population in Japan. To further elucidate the clinical symptoms and course of diabetes mellitus with the 3243 mutation, we undertook a nationwide cross‐sectional case‐finding study and observational study of a genetically defined subject group. One hundred sixteen Japanese diabetic patients with the mutation were registered and analyzed. The patients had a higher maternal inheritance of diabetes or deafness, short stature, thin habitus, and early middle‐aged onset of diabetes or deafness. Eighty‐six percent of the patients required insulin therapy because of progressive insulin secretory defect. Although half of the patients had the phenotype of type 1 diabetes or slowly progressive type 1 diabetes, the patients lacked the presence of autoantibodies to glutamic acid decarboxylase. Diabetes in the mothers was characterized by early middle‐aged onset, reduction in the insulin secretory capacity, early requirement of insulin therapy, and increases in the daily insulin dose. The heteroplasmic ratio of the 3243 mutation in leukocytes was low. The patients had mitochondria‐related complications such as sensorineural deafness, cardiomyopathy, cardiac conductance disorders, encephalomyopathy, macular pattern dystrophy, and mental disorders. The patients also had advanced microvascular complications. Thus, this study has revealed that (1) diabetes mellitus with the 3243 mutation is a subtype of diabetes mellitus with mitochondria‐related complications and (2) insulin secretory ability is more severely impaired in the patients whose mothers were also diabetic.

Diabetes mellitus with mitochondrial gene mutations in Japan.

Diabetes mellitus due to the mitochondrial DNA 3243(A-G) mutation is reported to represent 0.5-1% of the general diabetic population in Japan. To further elucidate the clinical symptoms and course of diabetes mellitus with the 3243 mutation, we undertook a nationwide cross-sectional case-finding study and observational study of a genetically defined subject group. One hundred sixteen Japanese diabetic patients with the mutation were registered and analyzed. The patients had a higher maternal inheritance of diabetes or deafness, short stature, thin habitus, and early middle-aged onset of diabetes or deafness. Eighty-six percent of the patients required insulin therapy because of progressive insulin secretory defect. Although half of the patients had the phenotype of type 1 diabetes or slowly progressive type 1 diabetes, the patients lacked the presence of autoantibodies to glutamic acid decarboxylase. Diabetes in the mothers was characterized by early middle-aged onset, reduction in the insulin secretory capacity, early requirement of insulin therapy, and increases in the daily insulin dose. The heteroplasmic ratio of the 3243 mutation in leukocytes was low. The patients had mitochondria-related complications such as sensorineural deafness, cardiomyopathy, cardiac conductance disorders, encephalomyopathy, macular pattern dystrophy, and mental disorders. The patients also had advanced microvascular complications. Thus, this study has revealed that (1) diabetes mellitus with the 3243 mutation is a subtype of diabetes mellitus with mitochondria-related complications and (2) insulin secretory ability is more severely impaired in the patients whose mothers were also diabetic.

Clinical features of diabetes mellitus with the mitochondrial DNA 3243 (A–G) mutation in Japanese: Maternal inheritance and mitochondria-related complications

Diabetes mellitus with the mitochondrial DNA 3243(A–G) mutation is reported to represent 0.5–2.8% of the general diabetic population. Since the characterization of diabetes with the mutation is still incomplete, we undertook a nation-wide case-finding study of genetically defined patients using questionnaires in Japan. One hundred and thirteen Japanese diabetic patients with the mutation were registered and analyzed. The patients had a high prevalence of maternal inheritance of diabetes and deafness, short and thin stature, and showed an early middle-aged onset of diabetes and deafness. Eighty-six percent of the patients required insulin therapy due to the progressive insulin secretory defect. Glucose intolerance of the mothers was associated with an early middle-aged onset of diabetes, reduction in the insulin secretory capacity, early requirement of insulin therapy, and increases in the daily insulin dose. The heteroplasmic concentrations of the 3243 mutation in leukocytes were low and declined with aging. The patients had advanced microvascular complications, and mitochondria-related complications such as cardiomyopathy, cardiac conductance disorders, neuromuscular symptoms, neuropsychiatric disturbance, and macular pattern dystrophy. Thus, this study has revealed that: (1) diabetes mellitus with the 3243 mutation is a subtype of diabetes mellitus with mitochondria-related complications; and (2) insulin secretory ability is more severely impaired in the patients whose mothers were glucose intolerance.

Maternally Inherited Diabetes and Deafness: A Multicenter Study

Maternally inherited diabetes and deafness (MIDD), which is seen in 0.5% to 2.8% of patients with type 2 diabetes mellitus, is related to a point mutation at position 3243 of mitochondrial (mt) DNA. Its clinical description is incomplete. To study the clinical presentation and complications of diabetes in patients with MIDD and to identify clinical characteristics that may help select diabetic patients for mtDNA mutation screening. Multicenter prospective descriptive study. 16 French departments of internal medicine, diabetes and metabolic diseases, or both. 54 patients with type 2 diabetes mellitus and the mtDNA 3243 mutation. Characteristics of diabetes, metabolic control (glycosylated hemoglobin level), complications of diabetes, and involvement of other organs. On average, patients with MIDD were young at diabetes onset and presented with a normal or low body mass index. None were obese. Seventy-three percent of probands had a maternal family history of diabetes. Diabetes was non-insulin-dependent at onset in 87% of patients; however, 46% of patients had non-insulin-dependent disease at onset but progressed to insulin therapy after a mean duration of approximately 10 years. Neurosensory hearing loss was present in almost all patients. Eighty-six percent of patients who received an ophthalmologic examination had macular pattern dystrophy (a specific retinal lesion). Forty-three percent of patients had myopathy, 15% had cardiomyopathy, and 18% (9 of 51) had neuropsychiatric symptoms. Although the prevalence of diabetic retinopathy was 8% among patients who received an ophthalmologic examination, lower than expected after a mean 12-year duration of diabetes, prevalence of kidney disease was 28%. This suggests that a specific renal involvement was the result of mitochondrial disease. Maternally inherited diabetes and deafness has a specific clinical profile that may help identify diabetic patients for mtDNA testing.

Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness

Objective To evaluate the prevalence of macular pattern dystrophy (MPD) in maternally inherited diabetes and deafness (MIDD), a new subtype of diabetes mellitus that cosegregates with a mutation of mitochondrial DNA (i.e., the substitution of guanine for adenine at position 3243 of leucine transfer RNA) and to report the clinical characteristics of MPD. Design Prospective cohort study. Participants Forty-six patients from 29 families with an adenine-to-guanine mutation of mitochondrial DNA were recruited from a French collaborative multicenter study. Thirty-five patients had MIDD, 8 were asymptomatic children of MIDD patients, and 3 had MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). The 33 MIDD patients with diabetes were matched for diabetes duration and gender with 33 patients with “common” type-2 diabetes to compare the prevalence of diabetic retinopathy (DR) in both series. Methods All patients had a full ophthalmologic examination and fundus photographs. Main outcome measures The presence and severity of MPD and DR were assessed in each patient. Results Thirty MIDD patients (85.7%) of 35 exhibited bilateral MPD characterized by linear pigmentation surrounding the macula and optic disc. In 24 of these 30 patients, visual acuity was 20/25 or more in both eyes. The prevalence of DR was 6% in MIDD patients with diabetes versus 15% for patients with common type-2 diabetes (a difference that was not significant, P = 0.23). The fundus of each of the eight asymptomatic children was normal. MPD was present in one of the three cases of MELAS. Conclusion The prevalence of MPD in MIDD is high. Its detection may be helpful for the diagnosis of this new subtype of diabetes, for which specific treatments may be proposed.

Macular Pattern Dystrophy Associated With a Mutation of Mitochondrial DNA

To establish association of a macular pattern dystrophy with maternally inherited diabetes and deafness, a new subtype of diabetes mellitus caused by a mutation of mitochondrial DNA (mtDNA). Two probands of two different families with maternally inherited diabetes and deafness were examined. Both probands exhibited a macular pattern dystrophy, maternally inherited in one patient. The association of a macular pattern dystrophy with diabetes should lead to screening for a mutation of mtDNA.

Electrophysiological analysis of Best's macular dystrophy and retinal pigment epithelial pattern dystrophy

Best's macular dystrophy (BMD) and pattern dystrophy of the retinal pigment epithelium were studied by our electrophysiological test for the cone receptor cell and retinal pigment epithelium (RPE). Cone activity was evaluated by the electroretinographic rapid off-response which is mainly composed of the decay of the late receptor potential of cones. RPE activity was assessed by change in the EOG amplitude in response to hyperosmolarity and to Diamox (hyperosmolarity response and Diamox response, respectively).The L/D and the hyperosmolarity response were abnormal in both eyes of a patient with BMD. Both fundi of a daughter of this patient were ophthalmoscopically normal. The L/D and the hyperosmolarity response, however, were abnormal bilaterally in the daughter, who was thought to be a carrier of the pathological gene for Bmd. The abnormal hyperosmolarity response indicated pigment epitheliopathy in the patient with BMD and in his daughter, who had no visible fundus lesion.In both a familial case and an ...