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Home , Diabetes and deafness

RESUMO Recebido: 07dejaneiro de2017- Aceite: 27demarço2017 |  2. ServiçodeNeurologia.CentroHospitalar e UniversitáriodeCoimbra.Portugal. 1. ServiçodeMedicinaInterna.Hospital Amato Lusitano.CasteloBranco. Portugal. Acta MedPort2017Jul-Aug;30(7-8):581-585 Daniela ALVES ABSTRACT eut fo te rsne f n ised f G n the in G a of instead A an of presence the from MIDD results in mutation common most The DM. of form rare a dysfunction ofthemitochondrialrespiratorychain. that pathologies of group a encompasses disorders. genetic of result a as INTRODUCTION Mitocondrial A3243G no ADN Mutação Heterogeneidade FenotípicadeumaFamíliaCausadapela Mutation DNAA3243G Family PhenotypicHeterogeneityCausedbyMitochondrial 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES Autor correspondente:Daniela Alves. [email protected] Palavras-chave: aconselhamento família, da genético etriagemdecomorbilidadesassociadas. avaliação a considerada ser deve doentes Nestes mitocondrial. patologia da importante característica considerado sempre que há história de associada a surdez e história familiar de diabetes. ser A Deve cardiomiopatia diagnóstico. hipertrófica desafio é um uma é mellitus diabetes de monogénicas formas com pessoas A3243G de mutação mitocondrial. Aidentificação do ADN da portadores Todossão maternal. herança de doença uma sugere padrão Este surdez. e diabetes apresentam que irmãs, duas e irmãos dois seus os e mãe a destaca-se familiar, história Da surdez. e mellitus diabetes de antecedentes possui doente hipertrófica. A cardiomiopatia por admitida idade, de anos 55 feminino, sexo do doente uma de caso o Expõe-se tocondrial. mi ADN do A3243G mutação da resulta que diabetes de rara forma uma é materna transmissão de surdez e diabetes síndrome A Keywords: identify thisaetiology, familyscreening,geneticcounsellingandscreeningofassociatedcomorbiditiesareencouraged. to order In . mitochondrial of feature important an be to known also is history.Cardiopathy family relevant a and loss hearing diabetes mellitus is a diagnostic challenge. This condition should be considered whenever there is a history of of diabetes forms associated with monogenic with people of identification The mutation. DNA mitochondrial A3243G the carried siblings disorder.All inherited maternally a suggests pattern loss. This hearing and diabetes of history a had also patient’ssisters mother,The two and brothers two loss. hearing and mellitus diabetes of history a is had case .She hypertrophic index with The admitted was mutation. DNAwho woman mitochondrial 55-year-old a a by caused diabetes of form rare a is deafness and diabetes inherited Maternally Diabetes mellitus (DM) and its clinical features may arise Adult onset Still’s disease: experience in 23 patients and literature review A difficultdiagnosis?ClinRheumatol.2012;31:49–53. origin. unknown of fever with presenting disease Still’s adult-onset with and outcomein62patients.Medicine.1991;70:118–36. Sternbach M, et al. Adult Still’s disease: manifestations, disease course, disease. JRheumatol.1992;19:424–30. Still’s adult of classification for criteria Preliminary al. et H, Kashiwagi Rheumatol. J China. from cases 61 2009;36:1026–31. disease: still’s adult-onset of disease. CurrOpinPulmMed.1999;5:305–9. onset Still’s disease. Ann RheumDis.2006;65:564–72. 33. aenly neie daee ad efes MD) is (MIDD) deafness and diabetes inherited Maternally J. Ferreiros CR, O’Connor DG, Baker HR, Schumacher AJ, Reginato patients 22 of series AN. Akritidis G, T,Tzimas Pappas G, Baxevanos F,Salusinsky- Décary S, F,Carette Beaudet JS, Sampalis J, Pouchot Y, Mizushima R, Kasukawa T, Tsunematsu A, Ohta M, Yamaguchi prognosis and features Clinical CD. Yang MF, Wu YQ, Zou T, Zeng Cheema GS, Quismorio FP. Pulmonary involvement in adult-onset Still’s adult of management and Diagnosis L. Bielory PK, Paik P, Efthimiou Bywaters EG. Still’s disease in the adult. Ann Rheum Dis. 1971;30:121– Child;Deafness/genetics;DiabetesMellitus/genetics;DNA,Mitochondrial/genetics;Mutation Alves D,etal.Phenotypicheterogeneityofinheriteddiabetesanddeafness,  Criança;DiabetesMellitus/genética;DNA Mitocondrial/genética;Mutação;Surdez/genética 1 , MariaEufémiaCALMEIRO ica da Ordem dos Médicos www m o c . a s e u g u t r o p a c i d e m a t c a w. w w s o c i d é M s o d m e d r O a d a c fi í t n e i C a t s i v e R 1 iohnra diabetes Mitochondrial are caused are ▪ Copyright ©Ordemdos Médicos2017

https://doi.org/10.20344/amp.8638 1 , CarmoMACÁRIO 2 by a by 581 15. 14. 13. 12. 11. 10. 9. ahpyilgcl ehnss ht a la to lead may that . mechanisms from derived pathophysiological only practically is DNA extremely rare. have mutations point DNA mitochondrial Other tRNA. for gene the encodes that DNAmitochondrial the of (A3243G) 3243 position (mtDNA) Int. 2011;31:923–7. Rheumatol disease. Still’s adult-onset of feature pathologic a is organs as pneumonia:twocasereports. Acta ReumatolPort.2011;36:413–7. adult-onset Still’s disease.RheumatolInt.2012;32:1291–8. China. ClinRheumatol.2012;31:175–81. in origin unknown of fever with admitted disease Still’s adult-onset with Rheumatol. Exp Clin 2011;29:331–6. cases. 41 of review disease: Still’s onset Adult Adult-onset Still’s disease. patients. JRheumatol.1990;17:1058–63. Kashiwagi H, et al. Adult Still’s disease: a multicenter survey of Japanese with emphasis on organ failure. Semin Arthritis Rheum. 1987;17:39–57. Zhao DB, Dai SM, Liu XP, Xu H. Interstitial inflammation in visceral in inflammation Interstitial H. Xu XP, Liu SM, Dai DB, Zhao Huang X, Y,Ding H, Nie S. Hu Still’smisdiagnosed Adult-onset disease in prognosis and responses Therapeutic CH. Suh JM, Sung HA, Kim Chen PD, Yu SL, Chen S, Weng XH. Retrospective study of 61 patients al. et L, Mateo P, Santo S, Holgado J, Narváez A, Olivé E, Riera al. et M, Inanc A, Karadeniz S, Kamali A, Cagatay A, Y,Gul Cagatay H, Mizushima R, Kasukawa T, Tsunematsu M, Yamaguchi A, Ohta h cniin s aenly neie a mitochondrial as inherited maternally is condition The 2 , RosaSILVA Acta MedPort2017Jul-Aug;30(7-8):581-585 2 1 been associated been Int JClinPract.2009;63:1050–5.

with MIDD, 3 but are but Some -

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red in Table Table in A3243G to genetic 7. (23) for counselling, ragged and showed showed and involvement Diabetes Deafness 5. (53) 6. (26) be closely followed is represented is calcification of basal leukocytes multiorgan were referred Manifestation definitions to the patients and their first- revealed in in none of them shows signs of the 5. (29) was offered 4. (55) (SDHase) and COX-negatives (COX), Currently, in the family tree in Fig. 1. in Fig. family tree in the was performed was . Acta Med Port 2017 Jul-Aug;30(7-8):581-585 Port 2017 Acta Med 4. 2. (H-E) that were simultaneously active to succinate Family phenotypic heterogeneity phenotypic Family Monogenic forms of DM are difficult to diagnose. After The presence of diabetes, deafness and a relevant One of the index case’s sisters (II.5) presented signs The index case (II.4) and her sister (II.5) underwent Moreover, a muscular biopsy showed After a detailed family history study and 3. genetic testing degree relatives. The III.1, III.2 and III.3 cases, who were all under 30 years old, agreed screening, and to the result participate was in a positive genetic test They mutation. mitochondrial DNA counselling disease. 1. This family is an example of the of mitochondrial . DISCUSSION being diagnosed, patients because of should distinctive management issues and associated represented family history prompted an investigation test genetic for MIDD. The A3243G mitochondrial DNA mutation. The (II.4) index siblings carried A3243G mitochondrial case’s DNA mutation levels. with different of depression and cognitive impairment. A brain magnetic resonance imaging (MRI) ganglia and diffuse of the cerebellum. These are mitochondrial disorders (Fig.s 2, 3). common features of an ophthalmologic examination, which revealed macular dystrophy (Fig. 4). Moreover, their hearing tests showed sensorineural deafness proteinuria showed tests urine and blood Their frequencies. with preponderance with preserved renal function. to high fibres dehydrogenase (Fig. 5). which is specific to mitochondrial disorders 1. 3. (57)

582 5 . is was onset, dyspnoea 2. She her diabetes. showed that

unrecognised and macular Surprisingly, the et al 5 loss 1. 2. (58) follow-up the hospital. A cross- to because of an associated . was diagnosed.

2 and her four siblings shared a R e v i s ta C i e n tífi c a d a Or d e m d o s M é d i c o s w w w.a c ta m e d i c a p o r tu g u e s a .c o m mother 1. (60) was admitted was admitted a history of depression, cognitive impairment Alves D, et al. Phenotypic heterogeneity of inherited diabetes and deafness, and deafness, diabetes of inherited heterogeneity et al. Phenotypic Alves D, , sensorineural hearing and suffered from progressive sensorineural to the internal medicine department because Unfortunately, MIDD often goes often MIDD Unfortunately, 4 5-7 Index case family tree III II I – earlier, 7 also had While recording the patient’s family history, it became The patient The index case (II.4) is a 55-year-old woman who went The present clinical report describes a case of a person a of case a describes report clinical present The First described in 1992, MIDD affects 0.5% to 2.8% of A multicentre study by Guilasseau Figure 1 history of diabetes and progressive deafness. Her family and progressive loss of motor skills. evident that she, her then referred of multisystem comorbidities and to She sectional echocardiography showed hypertrophy of the left ventricle, with a left ventricular ejection fraction Hypertrophic of cardiomyopathy 42%. . Diabetes was non- dependent at dependent non-insulin was Diabetes loss. hearing but 11 years later she started insulin mass index (BMI) was 21 kg/m therapy. Her body to the emergency room because of chest pain, and fatigue. She had been diagnosed years with diabetes 12 CASE REPORT comorbidity. comorbidity. A thorough clinical and family history suggested the diagnosis of MIDD, which was subsequently study confirmed. (8%) while the prevalence of disease was as high as high as was disease kidney of prevalence the while (8%) 28%. with diabetes who all patients with MIDD experienced neurosensory hearing loss and 86% had macular expected than lower was retinopathy dystrophy. diabetic of prevalence insulinopenia dystrophy. resistance. people with diabetes. Patients typically have progressive mitochondrial mitochondrial diabetes include impaired insulin secretion, glucose toxicity with loss of pancreatic cells, and insulin

CASO CLÍNICO like episodes. clinical manifestations of MELAS — or stroke- index case (II.4) and her family did not present the landmark important. very stroke), is diagnosis differential its and thus, and, (mitochondrial acidosis MELAS lactic — encephalopathy, syndrome , severe more a in MIDD phenotype’s severity. determine potentially can levels heteroplasmy hand, other the On MIDD. of expressions phenotypic different in result from cellularenergydeficiency. may features diagnostic accompanied main The rate. metabolic comorbidities. minerals suchascalciumandblood(hyposignal) namely susceptibility, magnetic with material to sensitive very is 2 Figure Figure 4 srn fmla cutrn o daee sol raise should diabetes of clustering familial strong A tissues different in mtDNA mutated of levels Diverse higher a with organs in itself manifests usually MIDD – – Macular dystrophypresentinindex case eune 2 E n h ail ln. hs sequence This plane. axial the in GE T2 Sequence Alves D,etal.Phenotypicheterogeneityofinheriteddiabetesanddeafness, by a wide range of manifestations that result that manifestations of range wide a by 6,8 ica da Ordem dos Médicos www m o c . a s e u g u t r o p a c i d e m a t c a w. w w s o c i d é M s o d m e d r O a d a c fi í t n e i C a t s i v e R 9,10 This mutation can also result 2 9 The be 583

ment of the of ment 3 Figure than expectedfortheagegroup dystrophy, which affects 86% of cases. MIDD’s most common ophthalmic feature is macular retinal BMI: the lower the BMI, the higher the heteroplasmy levels. correlation had also She BMI. normal a had and 33 of age the at diabetes with diagnosed was (II.4) case index The old. years 40 and 30 onset of diabetes, which is usually insidious, ranges 85%. between is estimated diabetes of The penetrance release. insulin reduced and dysfunction distinguishes dystrophy mitochondrial diabetesfromMODY. macular or impairment with hearing together transmission maternal also of presence the may the of but It diabetes onset diabetes. (maturity MODY mitochondrial indicate of suspicion the sin Figure 5 (H-E) Persistent – – – high heteroplasmy levels. A significant negative significant A levels. heteroplasmy high Sequence T1 SE in the sagittal plane, showing enlarge showing plane, sagittal Sequence the in SE T1 Muscular biopsy with folia Acta MedPort2017Jul-Aug;30(7-8):581-585 a found was of the cerebellum, which presents a lower volume lower a presents which cerebellum, the of hyperglycaemia ewe htrpam lvl and levels heteroplasmy between ragged red leads to both mitochondrial both to leads 2 The average age for the for age average The 8 5

The index case (II.4) fibres , hematoxylin eo young), - 9 -

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------Unknown whenever Proteinuria Proteinuria Nephropathy mitochondrial - - - - block Cardiac Unknown disorders be considered left anterior Hypertrophic Hypertrophic Hypertrophic Left fascicular fascicular block cardiomyopathy cardiomyopathy cardiomyopathy; . The diagnosis of - - - - - birth Unknown Cognitive symptoms Depression Depression dysfunction; Developmental counselling Neuropsychiatric Neuropsychiatric cognitive delay from

Acta Med Port 2017 Jul-Aug;30(7-8):581-585 Port 2017 Acta Med 13,14 - - - - - Yes Yes Yes All authors report no conflict of interest. This research received no specific grant from any The identification of monogenic forms of DM is difficult. The authors declare that the procedures were followed use in protocols the followed having declare authors The Macular Unknown dystrophy CONFLICTS OF INTEREST FUNDING SOURCES funding agency in the public, commercial, or not-for-profit sectors. attention has focused on prevention through of germline gene replacement transmission of therapy. CONCLUSION However, this condition should there is a history of diabetes associated with both hearing loss and relevant provided and mutation the family for screened be should members history. All first-degree family with genetic for diabetes. disorder can influence treatment options PROTECTION OF AND ANIMALS HUMANS according to the regulations established Research by the and Clinical Ethics Association. Medical Declaration of the World Committee and to the Helsinki CONFIDENTIALITY DATA data publication. at their working center regarding patients’

584 , 12 - - - is Yes Yes Yes Yes and Insulin Insulin therapy therapy Diabetes and show - - - valproate remodelling Yes Yes Yes Yes Yes Yes Deafness function; however function; be conducted regularly conducted be depression Both II.5 and II.1 have 2 11% 44% 51% 58% 21% 52% 43% < 5% mtDNA mtDNA Unknown % A3243G R e v i s ta C i e n tífi c a d a Or d e m d o s M é d i c o s w w w.a c ta m e d i c a p o r tu g u e s a .c o m Heteroplasmy 55 53 29 26 23 60 58 57 Age at 82 Dead disease. Hypertrophic disorders with disease, occurring in up to 40% of patients. Alves D, et al. Phenotypic heterogeneity of inherited diabetes and deafness, and deafness, diabetes of inherited heterogeneity et al. Phenotypic Alves D, F F F F F F F M M Blood pressure control and early treatment with 7 Gender 11 - Family phenotypic heterogeneity - Family phenotypic mitochondrial There is no curative treatment for patients with Some drugs such as tetracyclines, Cardiopathy is known as another important feature Nephropathy is more common in people with MIDD, Brain changes (i.e., bilateral subcortical and basal I.1 II.5 II.1 II.2 II.3 II.4 III.3 III.1 III.2 the limitations of prenatal and preimplantation diagnosis, increased risk of lactic acidosis. mitochondrial disease. Given the lack of treatments and metformin may deteriorate mitochondrial deteriorate may metformin Metformin well-known. not are patients MIDD in effects their is less effective and may be harmful because of the abnormalities and must failure heart and abnormalities from an early stage. the dominant pattern of cardiomyopathy mitochondrial in all forms of Follow-up and screening of both cardiac conduction nephroprotective agents may be beneficial to prevent renal failure. of suggesting a specific involvement of mitochondrial kidney disease. respiratory function impairment. neuropsychiatric birth. progressive cognitive dysfunction since ganglia high-signal lesions on T2-weighted images) appear ganglia high-signal lesions on in the MRI of case II.5. These changes probably reflect a hypometabolic state in neurons caused by mitochondrial images show pigmented lesions in the retina and atrophy of the choroid pigment epithelium, with “salt and pepper” appearance, as can be seen in Fig. 4. complained of visual loss and night blindness. Macular test Table 1 Table

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