- Email: [email protected]
Kearns Sayre syndrome: an unusual form of mitochondrial diabetes
SHORT
R E P O R T
Kearns Sayre syndrome: an unusual form of mitochondrial diabetes M Laloi-Michelin1, M Virally1, C Jardel2, T Meas1, I Ingster-Moati3, A Lombès2, P Massin4, H Chabriat5, A Tielmans1, J Mikol6, PJ Guillausseau1
SUMMARY
RÉSUMÉ
Kearns Sayre syndrome (KSS) is a mitochondrial disorder characterized by the emergence before age 20 of progressive external ophthalmoplegia, pigmentary retinopathy, together with other heterogeneous clinical manifestations, including cardiac conduction defects, muscle abnormalities and endocrinopathies. KSS is associated with large heteroplasmic deletions in mitochondrial DNA. We report the case of a 43-year-old woman, with diabetes mellitus as a first manifestation at age 19. Later, she exhibited bilateral ptosis and external ophthalmoplegia with progressive worsening. DNA analysis identified a large mitochondrial DNA (mtDNA) deletion, which confirmed the diagnosis of KSS. By reporting this case with diabetes mellitus as first manifestation,we aim at emphasizing problems of diagnosis in these subtypes of mitochondrial diabetes.
Le syndrome de Kearns Sayre : une forme inhabituelle de diabète
Key-words: Kearns Sayre syndrome · Mitochondrial DNA Mitochondrial diabetes · Monogenic diabetes.
Le syndrome de Kearns Sayre est une cytopathie mitochondriale caractérisée par l’apparition avant l’âge de 20 ans d’une ophtalmoplégie externe progressive associée à une rétinite pigmentaire. Des anomalies de la conduction cardiaque et une myopathie sont également fréquentes. Ce syndrome est lié à une délétion de l’ADN mitochondrial. Nous rapportons ici le cas d’une patiente de 43 ans dont la maladie a débuté à l’âge de 19 ans par un diabète. Plus tard sont apparues l’ophtalmoplégie d’aggravation progressive et la rétinite pigmentaire. L’analyse génétique a mis en évidence une délétion de l’ADN mitochondrial confirmant ainsi le diagnostic de KSS. Nous rapportons cette observation afin d’attirer l’attention des cliniciens sur le diagnostique étiologique de ces diabètes de présentation atypique qui peuvent entrer dans le cadre de maladies mitochondriales.
·
Laloi-Michelin M, Virally M, Jardel C, Meas T, Ingster-Moati I, Lombès A, Massin P, Chabriat H, Tielmans A, Mikol J, Guillausseau PJ. Kearns Sayre syndrome: an unusual form of mitochondrial diabetes Diabetes Metab 2006;32:182-186
Mots-clés : Syndrome de Kearns Sayre · ADN mitochondrial Diabète mitochondrial · Diabète monogénique.
·
1
Department of Internal Medicine-Diabetes and Metabolic Diseases, Hôpital Lariboisière, AP-HP, 2, rue Ambroise-Paré, 75010 Paris, France. INSERM U582, Groupe Hospitalier Pitié-Salpétrière, 75013 Paris, France. 3 Department of Biophysics, 4 Department of Ophthalmology, 5 Department of Neurology, 6 Department of Pathology, Hôpital Lariboisière, 2, rue Ambroise-Paré, 75010 Paris, France. 2
182
Diabetes Metab 2006;32:182-186 • www.masson.fr/revues/dm
Address correspondence and reprint requests to: M Laloi-Michelin. Department of Internal Medicine-Diabetes and Metabolic Diseases, Hôpital Lariboisière, AP-HP, 2, rue Ambroise-Paré, 75010 Paris, France. [email protected] Received: October 18th, 2005; accepted: December 18th, 2005.
Kearns Sayre syndrome and diabetes
I
n 1958, Kearns and Sayre described a multisystemic syndrome now known as Kearns Sayre Syndrome (KSS) [1]. KSS is a rare, severe mitochondrial disorder. It is characterized by the emergence before the age 20 of progressive external ophthalmoplegia and pigmentary retinopathy, with a series of other heterogeneous clinical manifestations, including cardiac conduction defects and muscle abnormalities [1,2]. KSS is associated with large heteroplasmic mitochondrial DNA deletions [3]. By reporting on this case of KSS with diabetes mellitus as a first manifestation, we want to draw attention on the problems of diagnosis in these subtypes of mitochondrial diabetes.
Case report A 43-year-old Caribbean woman was referred to the Department of Neurology for worsening of a ptosis and external ophthalmoplegia. She was the product of a normal pregnancy, from normal non-consanguineous parents. Diabetes mellitus (fasting plasma glucose at 8.9 mmol/) was diagnosed at age 19 at systematic screening before oral contraception. The patient had no family history of diabetes. Morphotype was normal with 1.64 m height, 55 kg weight and normal body mass index (BMI: 20.4 kg/m2). Diabetes was treated with diet, later associated with sulphonylurea and metformin. At age 21, bilateral ptosis was noted. External ophthalmoplegia appeared at age 25 and progressively worsened. The patient was pregnant at age 31, and delivered a 2.3 kg normal son by caesarean section at 7 months and 3 weeks of gestation. Insulin therapy had been given during pregnancy. Depression occurred after delivery. The patient was hospitalised in emergency at age 32 for an episode of persecution delirium and visual hallucinations. Neurological examination found bilateral ptosis, complete external ophthalmoplegia, proximal muscle weakness and a moderate reduction in cognitive performances (MMS 26/30). BMI was 22.6 kg/m2. Blood pressure was normal (100/72 mm Hg). Insulin was required, as diabetes was not controlled by maximal dosage of combination of antidiabetic oral agents (sulfonylureas + metformine) (HbA1c: 9.4%, normal value: 5.5 ± 1%). No diabetic retinopathy, nor nephropathy (creatinine plasma level 73 µmol/l, urinary albumin excretion 2 mg/24h) or macrovascular complications were observed. Electrocardiogram was normal with defect in neither auriculoventricular nor intraventricular conduction. Twenty-four hours ECG recording revealed ventricular extrasystoles. Echocardiography was normal. Cerebral IRM showed only vermian atrophy. Endocrine evaluation, including plasma concentration of free T4, T3, TSHus, estradiol, progesterone, FSH, LH,
and prolactin were within the normal range. Plasma calcium and PTH1-84 concentrations were normal excluding hypoparathyroidism. A salt and pepper retinitis was noticed at ophthalmologic examination, without any macular pattern dystrophy (figure 1). Optic disk and retinal vessel calibre were normal. Electroretinogram and flashes visual evoked potentials disclosed severe functional retinal disorders of the photoreceptors and the inner retinal layers. Audiogram was normal. Auditive evoked potentials showed slight conduction abnormalities, predominating on the left side. High concentration of serum pyruvate was measured (131 µmol/l, normal range: 41-67 µmol/l), serum lactate was normal. Histological analysis of the deltoid skeletal muscle revealed the presence of a typical mitochondrial myopathy associating scattered ragged red fibers on the Gomori trichome staining (figure 2). Numerous muscle fibers with a defective cytochrome C oxidative activity and normal or increased succinate dehydrogenase activity were observed at histochemistry (figure 2). Ultrastructural analysis of muscle revealed numerous mitochondria with heterogeneous size and shape. Normal organelles were mixed with strikingly abnormal mitochondria containing paracrystalline inclusion bodies (figure 3). The A3243G point mutation was absent. Southern blot analysis of muscle mitochondrial DNA (mtDNA) disclosed a unique large deletion of the mtDNA, representing 60% of total mtDNA molecules.
Discussion Phenotype of our patient includes several features, which characterises KSS, as progressive external ophthalmoplegia and pigmentary retinopathy. Ocular motor palsy is sometime present in patients carrying the A→G 3243 mutation (Maternally Inherited Diabetes and deafness, MIDD), but maternal transmission is then suggestive [4]. The salt and pepper retinitis observed in our patient is characteristic of Kearns Sayre syndrome, and differs from the macular pattern dystrophy observed in MIDD. Indeed, in the Kearns Sayre syndrome, the “salt and pepper” retinopathy involves the entire retina, including the peripheral retina. While, in MIDD, the pigmentary changes are localized to the macular area, and are combined with localized subretinal macular and peripapillary deposits ; in addition, in MIDD, the peripheral retina is normal. Ptosis, muscle weakness and moderate cognitive deficits are usual in patients with KSS. However, cardiac conduction defects, which have been frequently reported in this disease, were absent in our patient [1,2,3]. Asymptomatic diabetes mellitus was the first sign of the disease in our patient. Diabetes mellitus is reported in 10% of patients with KSS, half of them being insulin requiring [3]. Diabetes appears to be secondary to a failure in insulin Diabetes Metab 2006;32:182-186 • © 2006 Masson, all rights reserved
183
M Laloi-Michelin et al.
production. First, the histological appearance of the islets in a patient with KSS shows a complete absence of β-cells concomitant with lack of C-peptide secretion. Mutations in mtDNA are likely to contribute to islet development and function in the foetus, which would result in lower numbers of islet cells in patients with abnormalities of mtDNA [5]. In the second hand, alteration in mitochondrial function is likely to impair insulin secretion since glucose-stimulated insulin secretion is mediated by closure of ATP dependent potassium channels in the β-cell membrane. Thus insulin secretion is dependent of oxidative phosphorylation and intracellular ATP production [6]. Diabetic patients carrying mitochondrial gene mutations are negative for islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies (GAD65) [7], although low titers of ICA have been described in a few cases [8]. This case illustrates the diagnosis problem in these subtypes of mitochondrial diabetes. Clinical characteristics, which should draw attention, include young age at onset, absence of obesity, and of family history of diabetes, excluding common type 2 diabetes. Heterogeneous clinical presentation and multisystemic involvement should lead diagnosis toward a “particular” subtype of diabetes [9]. Others endocrinopathies are common in KSS, including growth hormone deficiency (37%), hypogonadism (20%), hypoparathyroidism (7-8%) and thyroid disease (3%) [10]. One case of non-autoimmune Addison disease has been described [11]. Hypomagnesaemia, bone, tooth and calcification abnormalities are uncommon [12]. Standard biological profile is usually normal. Metabolic acidosis, high serum pyruvate or lactate levels, due to respiratory chain dysfunction, can be observed, as it is the case for this patient. Computed tomography shows nonspecific findings such as white matter and basal ganglia hypoden-
Figure 1 Salt and pepper retinitis.
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Diabetes Metab 2006;32:182-186 • www.masson.fr/revues/dm
sity, calcifications of cortex and basal ganglia, atrophy of the pons and cerebellum [9,13]. The most frequent brain Magnetic Resonance abnormalities are widespread white matter hyperintensity, supratentorial cortical and cerebellar atrophy. The absence of basal ganglia hyperintensity is well correlated with KSS [14]. Muscle sample biopsy confirms the diagnosis and shows cytochrome C oxydase-negative ragged red fibbers on mod-
Figure 2 Muscle biopsy. A: Ragged red fibers on Gomori staining. (Original magnification x 150). B and C: Muscle fibres with a defective cytochrome C oxidative (cox) activity and normal or increased succinate dehydrogenase (SDH) activity. One fiber is cox negative and SDH negative. (Original magnification B x 60, C x 150).
Kearns Sayre syndrome and diabetes
Figure 3 Electron micrograph of deltoid muscle: numerous mitochondria with heterogeneous sizes and shapes. Normal organelles were mixed with strikingly abnormal mitochondria containing paracrystalline inclusion bodies. (Uranylacetate-lead citrate staining. Original magnification A x 7000, B x 9800).
ified Gomori stain. Electron microscopy reveals subsarcolemmal accumulation of abnormal mitochondria with paracrystalline inclusion bodies [3,15,16]. Molecular basis of KSS is the existence of deletion in the mitochondrial DNA varying in location, size and percentage [3,4,8,9]. A large variety of mitochondrial DNA deletions have been described [8], approximately one third of KSS patients harbour the same kind of deletion, extending over 4,977 bp within the region 8470-13459 [2,3]. In subjects carrying mitochondrial gene defects, cells possess a variable number of mitochondria containing either normal or abnormal mitochondrial DNA, defining the level of heteroplasmy [16]. Mitochondrial DNA deletion leads to generalize defects in mitochondrial polypeptides synthesis, and finally impairs oxidative phosphorylation and energy metabolism in the respiratory chain. Biochemical analysis shows a various combination of decreased activities of the four enzymes of the mitochondrial respiratory chain containing subunits encoded by mitochondrial DNA: cytochrome C oxidase I, III, IV, V [10]. The quantitative relationship between deleted mitochondrial DNA and the clinical course of KSS remains poorly understood. No correlation has been observed between the size and the place of the deletion, biochemical abnormality, mitochondrial enzymes or clinical severity [15,17]. The differential expression of mitochondrial DNA deletions in multiple tissue, and individual tissue dependence on mitochondrial energy
production, explains the heterogenicity of clinical manifestations [16]. Typically, mitochondrial DNA deletion is a sporadic event [15], but it can exhibit maternal transmission, as in other mitochondriopathies [18]. Prognosis is poor, and there is no specific treatment. Coenzyme Q 10 (cofactor of the respiratory chain) replacement therapy has been reported to be effective in some patients with KSS [19]. Its effects seem to be due to antioxidant properties and action of coenzyme Q 10 as an electron transfer mediator, circumventing the reduced activity of the complex of the respiratory chain [19]. Aknowledgements – We wish to thank Pr Bernard Vialettes (Marseille) for his help in discussing this observation.
References 1.
Kearns TP, Sayre GP. Retinitis pigmentosa, external ophtalmoplegia and complete heart block. Arch Ophthalmology 1958;60:280-9
2.
Moraes CT, DiMauro S, Zeviani M, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 1989;320:1293-9
3.
Marin-Garcia J, Goldenthal MJ, Flores-Sarnat L, Sarnat HB. Severe mitochondrial cytopathy with complete A-V block, PEO, and mtDNA deletions. Pediatr Neurol 2002;2:213-6
4.
Hammans SR, Sweeney MG, Hanna MG, Brockington M, Morgan-Hughes JA, Harding AE. The mitochondrial DNA transfer Diabetes Metab 2006;32:182-186 • © 2006 Masson, all rights reserved
185
M Laloi-Michelin et al.
RNALeu (UUR) A→G (3243) mutation. A clinical and genetic study. Brain 1995;118:721-34 5.
Poulton J, O’Rahilly S, Morten KJ, Clarck A. Mitochondrial DNA, diabetes and pancreatic pathology in Kearns-Sayre syndrom. Diabetologia 1995;38:868-871
6.
Ashcroft E, Ashcroft S. Mechanism of insulin secretion. In: Ashcroft E, Ashcroft S (eds). Insulin: molecular biology to pathology.1992. Oxford University Press Oxford: 97-150
7.
8.
9.
186
Kishimoto M, Hashiramoto M, Araki S, Ishida Y, Kazumi T, Kanda F. Diabetes mellitus carrying a mutation in the mitochondrial t RNA gene. Diabetologia 1995;38:193-200 Oka Y, Katagiri H, Yakazi Y, Murase Y, Kobayashi T. Mitochondrial gene mutation in islet antibody positive patients who were initially non insulin dependent diabetics. Lancet 1993;342:527-8 Rubi-Palomares I, Martinez-Leon MI, Vera-Medialdea R, Delgado-Marques MP, Lopez-Ruiz P. Kearns-Sayre syndrome: pediatric neuroradiologic findings in computed tomography and magnetic resonance imaging. An Esp Pediatr 2002;56:180-4
12. De Block CE, De Leeuw IH, Maassen JA, Ballaux D, Martin JJ. A novel 7301-bp deletion in mitochondrial DNA in a patient with Kearns-Sayre syndrome, diabetes mellitus, and primary amenorrhoea. Exp Clin Endocrinol Diabetes 2004;112:80-3 13. Robertson WC, Viseskul C, Lee YE, Lloyd RV. Basal ganglia calcification in Kearns Sayre Syndrome. Arch Neurol 1979;36:711-3 14. Barragan-Campos HM, Vallée JN, Lo D, et al. Brain Magnetic Resonance imaging findings in patients with mitochondrial cytopathies. Arch Neurol 2005;62:737-42 15. Shanske S, Moraes CT, Lombes A, et al. Widespread tissue distribution of mitochondrial DNA deletions in Kearns-Sayre syndrome. Neurology 1990;40:24-8 16. Moraes CT, Ricci E, Petruzella V, Shanskse S, DiMauro S, Schon EA. Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions. Nat Genet 1992;1:359-67 17. Reichmann H, Degoul F, Gold R, et al. Histological, enzymatic and mitochondrial DNA studies in patients with Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia. Eur Neurol 1991;31:108-13
10. Harvey JN, Barnett D. Endocrine dysfunction in Kearns-Sayre syndrome. Clin Endocrinol (Oxf) 1992;37:97-103
18. Schnitzler ER, Robertson WC Jr. Familial Kearns-Sayre syndrome. Neurology 1979;29:1172-4
11. Boles RG, Roe T, Senadheera D, Mahnovski V, Wong LJ. Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison disease. Eur J Pediatr 1998;157:643-7
19. Choi C, Sunwoo IN, Kim HS, Kim DI. Transient improvement of pyruvate metabolism after coenzyme Q therapy in Kearns-Sayre syndrome: MRS study. Yonsei Med J 2000;41:676-9
Diabetes Metab 2006;32:182-186 • www.masson.fr/revues/dm
R E P O R T
Kearns Sayre syndrome: an unusual form of mitochondrial diabetes M Laloi-Michelin1, M Virally1, C Jardel2, T Meas1, I Ingster-Moati3, A Lombès2, P Massin4, H Chabriat5, A Tielmans1, J Mikol6, PJ Guillausseau1
SUMMARY
RÉSUMÉ
Kearns Sayre syndrome (KSS) is a mitochondrial disorder characterized by the emergence before age 20 of progressive external ophthalmoplegia, pigmentary retinopathy, together with other heterogeneous clinical manifestations, including cardiac conduction defects, muscle abnormalities and endocrinopathies. KSS is associated with large heteroplasmic deletions in mitochondrial DNA. We report the case of a 43-year-old woman, with diabetes mellitus as a first manifestation at age 19. Later, she exhibited bilateral ptosis and external ophthalmoplegia with progressive worsening. DNA analysis identified a large mitochondrial DNA (mtDNA) deletion, which confirmed the diagnosis of KSS. By reporting this case with diabetes mellitus as first manifestation,we aim at emphasizing problems of diagnosis in these subtypes of mitochondrial diabetes.
Le syndrome de Kearns Sayre : une forme inhabituelle de diabète
Key-words: Kearns Sayre syndrome · Mitochondrial DNA Mitochondrial diabetes · Monogenic diabetes.
Le syndrome de Kearns Sayre est une cytopathie mitochondriale caractérisée par l’apparition avant l’âge de 20 ans d’une ophtalmoplégie externe progressive associée à une rétinite pigmentaire. Des anomalies de la conduction cardiaque et une myopathie sont également fréquentes. Ce syndrome est lié à une délétion de l’ADN mitochondrial. Nous rapportons ici le cas d’une patiente de 43 ans dont la maladie a débuté à l’âge de 19 ans par un diabète. Plus tard sont apparues l’ophtalmoplégie d’aggravation progressive et la rétinite pigmentaire. L’analyse génétique a mis en évidence une délétion de l’ADN mitochondrial confirmant ainsi le diagnostic de KSS. Nous rapportons cette observation afin d’attirer l’attention des cliniciens sur le diagnostique étiologique de ces diabètes de présentation atypique qui peuvent entrer dans le cadre de maladies mitochondriales.
·
Laloi-Michelin M, Virally M, Jardel C, Meas T, Ingster-Moati I, Lombès A, Massin P, Chabriat H, Tielmans A, Mikol J, Guillausseau PJ. Kearns Sayre syndrome: an unusual form of mitochondrial diabetes Diabetes Metab 2006;32:182-186
Mots-clés : Syndrome de Kearns Sayre · ADN mitochondrial Diabète mitochondrial · Diabète monogénique.
·
1
Department of Internal Medicine-Diabetes and Metabolic Diseases, Hôpital Lariboisière, AP-HP, 2, rue Ambroise-Paré, 75010 Paris, France. INSERM U582, Groupe Hospitalier Pitié-Salpétrière, 75013 Paris, France. 3 Department of Biophysics, 4 Department of Ophthalmology, 5 Department of Neurology, 6 Department of Pathology, Hôpital Lariboisière, 2, rue Ambroise-Paré, 75010 Paris, France. 2
182
Diabetes Metab 2006;32:182-186 • www.masson.fr/revues/dm
Address correspondence and reprint requests to: M Laloi-Michelin. Department of Internal Medicine-Diabetes and Metabolic Diseases, Hôpital Lariboisière, AP-HP, 2, rue Ambroise-Paré, 75010 Paris, France. [email protected] Received: October 18th, 2005; accepted: December 18th, 2005.
Kearns Sayre syndrome and diabetes
I
n 1958, Kearns and Sayre described a multisystemic syndrome now known as Kearns Sayre Syndrome (KSS) [1]. KSS is a rare, severe mitochondrial disorder. It is characterized by the emergence before the age 20 of progressive external ophthalmoplegia and pigmentary retinopathy, with a series of other heterogeneous clinical manifestations, including cardiac conduction defects and muscle abnormalities [1,2]. KSS is associated with large heteroplasmic mitochondrial DNA deletions [3]. By reporting on this case of KSS with diabetes mellitus as a first manifestation, we want to draw attention on the problems of diagnosis in these subtypes of mitochondrial diabetes.
Case report A 43-year-old Caribbean woman was referred to the Department of Neurology for worsening of a ptosis and external ophthalmoplegia. She was the product of a normal pregnancy, from normal non-consanguineous parents. Diabetes mellitus (fasting plasma glucose at 8.9 mmol/) was diagnosed at age 19 at systematic screening before oral contraception. The patient had no family history of diabetes. Morphotype was normal with 1.64 m height, 55 kg weight and normal body mass index (BMI: 20.4 kg/m2). Diabetes was treated with diet, later associated with sulphonylurea and metformin. At age 21, bilateral ptosis was noted. External ophthalmoplegia appeared at age 25 and progressively worsened. The patient was pregnant at age 31, and delivered a 2.3 kg normal son by caesarean section at 7 months and 3 weeks of gestation. Insulin therapy had been given during pregnancy. Depression occurred after delivery. The patient was hospitalised in emergency at age 32 for an episode of persecution delirium and visual hallucinations. Neurological examination found bilateral ptosis, complete external ophthalmoplegia, proximal muscle weakness and a moderate reduction in cognitive performances (MMS 26/30). BMI was 22.6 kg/m2. Blood pressure was normal (100/72 mm Hg). Insulin was required, as diabetes was not controlled by maximal dosage of combination of antidiabetic oral agents (sulfonylureas + metformine) (HbA1c: 9.4%, normal value: 5.5 ± 1%). No diabetic retinopathy, nor nephropathy (creatinine plasma level 73 µmol/l, urinary albumin excretion 2 mg/24h) or macrovascular complications were observed. Electrocardiogram was normal with defect in neither auriculoventricular nor intraventricular conduction. Twenty-four hours ECG recording revealed ventricular extrasystoles. Echocardiography was normal. Cerebral IRM showed only vermian atrophy. Endocrine evaluation, including plasma concentration of free T4, T3, TSHus, estradiol, progesterone, FSH, LH,
and prolactin were within the normal range. Plasma calcium and PTH1-84 concentrations were normal excluding hypoparathyroidism. A salt and pepper retinitis was noticed at ophthalmologic examination, without any macular pattern dystrophy (figure 1). Optic disk and retinal vessel calibre were normal. Electroretinogram and flashes visual evoked potentials disclosed severe functional retinal disorders of the photoreceptors and the inner retinal layers. Audiogram was normal. Auditive evoked potentials showed slight conduction abnormalities, predominating on the left side. High concentration of serum pyruvate was measured (131 µmol/l, normal range: 41-67 µmol/l), serum lactate was normal. Histological analysis of the deltoid skeletal muscle revealed the presence of a typical mitochondrial myopathy associating scattered ragged red fibers on the Gomori trichome staining (figure 2). Numerous muscle fibers with a defective cytochrome C oxidative activity and normal or increased succinate dehydrogenase activity were observed at histochemistry (figure 2). Ultrastructural analysis of muscle revealed numerous mitochondria with heterogeneous size and shape. Normal organelles were mixed with strikingly abnormal mitochondria containing paracrystalline inclusion bodies (figure 3). The A3243G point mutation was absent. Southern blot analysis of muscle mitochondrial DNA (mtDNA) disclosed a unique large deletion of the mtDNA, representing 60% of total mtDNA molecules.
Discussion Phenotype of our patient includes several features, which characterises KSS, as progressive external ophthalmoplegia and pigmentary retinopathy. Ocular motor palsy is sometime present in patients carrying the A→G 3243 mutation (Maternally Inherited Diabetes and deafness, MIDD), but maternal transmission is then suggestive [4]. The salt and pepper retinitis observed in our patient is characteristic of Kearns Sayre syndrome, and differs from the macular pattern dystrophy observed in MIDD. Indeed, in the Kearns Sayre syndrome, the “salt and pepper” retinopathy involves the entire retina, including the peripheral retina. While, in MIDD, the pigmentary changes are localized to the macular area, and are combined with localized subretinal macular and peripapillary deposits ; in addition, in MIDD, the peripheral retina is normal. Ptosis, muscle weakness and moderate cognitive deficits are usual in patients with KSS. However, cardiac conduction defects, which have been frequently reported in this disease, were absent in our patient [1,2,3]. Asymptomatic diabetes mellitus was the first sign of the disease in our patient. Diabetes mellitus is reported in 10% of patients with KSS, half of them being insulin requiring [3]. Diabetes appears to be secondary to a failure in insulin Diabetes Metab 2006;32:182-186 • © 2006 Masson, all rights reserved
183
M Laloi-Michelin et al.
production. First, the histological appearance of the islets in a patient with KSS shows a complete absence of β-cells concomitant with lack of C-peptide secretion. Mutations in mtDNA are likely to contribute to islet development and function in the foetus, which would result in lower numbers of islet cells in patients with abnormalities of mtDNA [5]. In the second hand, alteration in mitochondrial function is likely to impair insulin secretion since glucose-stimulated insulin secretion is mediated by closure of ATP dependent potassium channels in the β-cell membrane. Thus insulin secretion is dependent of oxidative phosphorylation and intracellular ATP production [6]. Diabetic patients carrying mitochondrial gene mutations are negative for islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies (GAD65) [7], although low titers of ICA have been described in a few cases [8]. This case illustrates the diagnosis problem in these subtypes of mitochondrial diabetes. Clinical characteristics, which should draw attention, include young age at onset, absence of obesity, and of family history of diabetes, excluding common type 2 diabetes. Heterogeneous clinical presentation and multisystemic involvement should lead diagnosis toward a “particular” subtype of diabetes [9]. Others endocrinopathies are common in KSS, including growth hormone deficiency (37%), hypogonadism (20%), hypoparathyroidism (7-8%) and thyroid disease (3%) [10]. One case of non-autoimmune Addison disease has been described [11]. Hypomagnesaemia, bone, tooth and calcification abnormalities are uncommon [12]. Standard biological profile is usually normal. Metabolic acidosis, high serum pyruvate or lactate levels, due to respiratory chain dysfunction, can be observed, as it is the case for this patient. Computed tomography shows nonspecific findings such as white matter and basal ganglia hypoden-
Figure 1 Salt and pepper retinitis.
184
Diabetes Metab 2006;32:182-186 • www.masson.fr/revues/dm
sity, calcifications of cortex and basal ganglia, atrophy of the pons and cerebellum [9,13]. The most frequent brain Magnetic Resonance abnormalities are widespread white matter hyperintensity, supratentorial cortical and cerebellar atrophy. The absence of basal ganglia hyperintensity is well correlated with KSS [14]. Muscle sample biopsy confirms the diagnosis and shows cytochrome C oxydase-negative ragged red fibbers on mod-
Figure 2 Muscle biopsy. A: Ragged red fibers on Gomori staining. (Original magnification x 150). B and C: Muscle fibres with a defective cytochrome C oxidative (cox) activity and normal or increased succinate dehydrogenase (SDH) activity. One fiber is cox negative and SDH negative. (Original magnification B x 60, C x 150).
Kearns Sayre syndrome and diabetes
Figure 3 Electron micrograph of deltoid muscle: numerous mitochondria with heterogeneous sizes and shapes. Normal organelles were mixed with strikingly abnormal mitochondria containing paracrystalline inclusion bodies. (Uranylacetate-lead citrate staining. Original magnification A x 7000, B x 9800).
ified Gomori stain. Electron microscopy reveals subsarcolemmal accumulation of abnormal mitochondria with paracrystalline inclusion bodies [3,15,16]. Molecular basis of KSS is the existence of deletion in the mitochondrial DNA varying in location, size and percentage [3,4,8,9]. A large variety of mitochondrial DNA deletions have been described [8], approximately one third of KSS patients harbour the same kind of deletion, extending over 4,977 bp within the region 8470-13459 [2,3]. In subjects carrying mitochondrial gene defects, cells possess a variable number of mitochondria containing either normal or abnormal mitochondrial DNA, defining the level of heteroplasmy [16]. Mitochondrial DNA deletion leads to generalize defects in mitochondrial polypeptides synthesis, and finally impairs oxidative phosphorylation and energy metabolism in the respiratory chain. Biochemical analysis shows a various combination of decreased activities of the four enzymes of the mitochondrial respiratory chain containing subunits encoded by mitochondrial DNA: cytochrome C oxidase I, III, IV, V [10]. The quantitative relationship between deleted mitochondrial DNA and the clinical course of KSS remains poorly understood. No correlation has been observed between the size and the place of the deletion, biochemical abnormality, mitochondrial enzymes or clinical severity [15,17]. The differential expression of mitochondrial DNA deletions in multiple tissue, and individual tissue dependence on mitochondrial energy
production, explains the heterogenicity of clinical manifestations [16]. Typically, mitochondrial DNA deletion is a sporadic event [15], but it can exhibit maternal transmission, as in other mitochondriopathies [18]. Prognosis is poor, and there is no specific treatment. Coenzyme Q 10 (cofactor of the respiratory chain) replacement therapy has been reported to be effective in some patients with KSS [19]. Its effects seem to be due to antioxidant properties and action of coenzyme Q 10 as an electron transfer mediator, circumventing the reduced activity of the complex of the respiratory chain [19]. Aknowledgements – We wish to thank Pr Bernard Vialettes (Marseille) for his help in discussing this observation.
References 1.
Kearns TP, Sayre GP. Retinitis pigmentosa, external ophtalmoplegia and complete heart block. Arch Ophthalmology 1958;60:280-9
2.
Moraes CT, DiMauro S, Zeviani M, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 1989;320:1293-9
3.
Marin-Garcia J, Goldenthal MJ, Flores-Sarnat L, Sarnat HB. Severe mitochondrial cytopathy with complete A-V block, PEO, and mtDNA deletions. Pediatr Neurol 2002;2:213-6
4.
Hammans SR, Sweeney MG, Hanna MG, Brockington M, Morgan-Hughes JA, Harding AE. The mitochondrial DNA transfer Diabetes Metab 2006;32:182-186 • © 2006 Masson, all rights reserved
185
M Laloi-Michelin et al.
RNALeu (UUR) A→G (3243) mutation. A clinical and genetic study. Brain 1995;118:721-34 5.
Poulton J, O’Rahilly S, Morten KJ, Clarck A. Mitochondrial DNA, diabetes and pancreatic pathology in Kearns-Sayre syndrom. Diabetologia 1995;38:868-871
6.
Ashcroft E, Ashcroft S. Mechanism of insulin secretion. In: Ashcroft E, Ashcroft S (eds). Insulin: molecular biology to pathology.1992. Oxford University Press Oxford: 97-150
7.
8.
9.
186
Kishimoto M, Hashiramoto M, Araki S, Ishida Y, Kazumi T, Kanda F. Diabetes mellitus carrying a mutation in the mitochondrial t RNA gene. Diabetologia 1995;38:193-200 Oka Y, Katagiri H, Yakazi Y, Murase Y, Kobayashi T. Mitochondrial gene mutation in islet antibody positive patients who were initially non insulin dependent diabetics. Lancet 1993;342:527-8 Rubi-Palomares I, Martinez-Leon MI, Vera-Medialdea R, Delgado-Marques MP, Lopez-Ruiz P. Kearns-Sayre syndrome: pediatric neuroradiologic findings in computed tomography and magnetic resonance imaging. An Esp Pediatr 2002;56:180-4
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