Maternally Inherited Diabetes and Deafness in 4 Family Members with DNA Mutation and at Least 4 Generations with Suggestive Disease Phenotype

Résumé fourni par la source

A 55-year-old woman presented at the emergency room suffering from dyspnea. Her medical history was notable for deafness, taking metformin for 30 years to treat type 2 diabetes, and depression. An analysis of the patient revealed an increase in lactate concentration (91 mg/dL, reference levels 4–20 mg/dL) and glucose (169 mg/dL). All other measurements were typical or within the reference range, including the presence of autoantibodies and insulin concentration. A chest x-ray showed cardiomegaly, and an echocardiography revealed systolic dysfunction with a severely depressed left ventricular ejection fraction with generalized hypokinesis. From this, the cardiologist diagnosed nonischemic dilated cardiomyopathy. The patient's family history was revealing (Fig. 1, Table 1): her grandmother (I) and mother (II), both dead, suffered from deafness; the latter also had type 2 diabetes. Her brother (IIIb) had been diagnosed with type 2 diabetes at age 30 years after taking an oral glucose tolerance test. The patient has 2 children. The son (IVb) is deaf and has worn a hearing aid since age 20; he has been diagnosed with Wolff-Parkinson-White syndrome. Her daughter (IVa) has also been diagnosed with diabetes, which emerged during pregnancy after taking an oral glucose tolerance test. The family's history, therefore, reveals a pattern of diabetes, deafness, and cardiac abnormalities. All these pathologies had remained unrelated and treated as independent diseases until now. Could there be a relationship between cardiomyopathy, diabetes, and deafness? We found that alterations in the mitochondrial genome often occur with diabetes, deafness, and cardiac abnormalities. Mitochondrial diseases are characterized by maternal inheritance, and the phenotype of this family was exactly the same as that described in inherited mitochondrial alterations. Age of onset and the family's most important clinical characteristics. Index patient. DCM, dilated cardiomyopathy; WPW, Wolff-Parkinson-White syndrome; TGA, transposition of great arteries. These patients are under 18 years of age and have not been tested. Age of onset and the family's most important clinical characteristics. Index patient. DCM, dilated cardiomyopathy; WPW, Wolff-Parkinson-White syndrome; TGA, transposition of great arteries. These patients are under 18 years of age and have not been tested. Maternally inherited diabetes and deafness (MIDD)2 occurs in adulthood and is caused by a variant in the mitochondrial DNA (mtDNA), which encodes a type of transfer RNA. The most frequent variant found in this type of pathology is A3243G in the mitochondrially encoded tRNA leucine 1 (MT-TL1) gene (1). This mitochondrial disorder is characterized by the sudden onset of hearing loss and diabetes between 20 and 30 years of age. Other alterations such as ptosis, pigmentary retinopathy, heart disease, myopathy, kidney problems, and neuropsychiatric disorders may also be present. This genetic alteration presents a varied phenotype that complicates diagnosis (2). The high prevalence of this variant in the adult population makes it the most common disease in patients with mitochondrial diabetes, with it being one of the most frequent neurogenetic alterations in the adult population. The phenotype in all these patients is related to the loss of function of the mitochondrial transfer RNA leucine. The tissues most affected are those that require this transfer RNA, such as the central nervous system, and heart and muscle tissue. Clinical variability in mitochondrial diseases is considerable (3). DNA was extracted from the whole peripheral blood. Molecular analysis was initiated with the mtDNA variants most frequently associated with maternally inherited diabetes and deafness. Point mutation is the most common form in MIDD, with the A3243G variant in the MT-TL1 gene being the most frequent. Conventional PCR was used to amplify mtDNA between nucleotides 3029 and 3456, the target position of the A3243G variant. This amplification was then sequenced using the Applied Biosystems ABI 3130 automated sequencer. The sequence obtained was examined using SeqScape® v.2.5 software, and possible variations were sought in the MITOMAP database using the Anderson sequence as reference. The A3243G variant in the heteroplasmy was detected in the mitochondrial gene MT-TL1 in the sentinel patient (IIIa). After this result, we tested the patient's brother (IIIb) and 2 children (IVa, IVb) and obtained the same outcome, with the A3243G variant present in the heteroplasmy. The variant is the replacement of a guanine by adenine at position 3243. This variant is located between base pairs 3232 and 3253 of the mitochondrial DNA, containing a termination sequence transfer RNA for leucine (UUA) (1). Sanger sequencing allowed us to detect variants in the mtDNA but not the relative quantity with respect to typical mtDNA (4). Other variants in the mtDNA were not tested; this could be a limitation of the study. We have only tested the most frequent alteration, and if there is another variant in the mtDNA, we would not have detected it. The clinical characteristics of this variant, and attending to the most frequently described cases in the literature, led us to the diagnosis of a family with MIDD. The sentinel patient (IIIa) presents with diabetes, deafness, and heart-dilated cardiomyopathy. Her brother (IIIb) has type 2 diabetes only. Her son (IVb) has Wolff-Parkinson-White syndrome and deafness, and her daughter (IVa) has type 2 diabetes. The 2 previous generations of the family (I, II) could not be tested genetically, but the maternal inheritance pattern suggests that they were potential carriers of the same variant. The family carries the A3243G variant, one of the most frequent mtDNA mutations. The prevalence of this variant in the adult population is around 16.3/100000 (1). The mitochondrial genome is a double-stranded circular molecule with 16569 base pairs and can be found in 2–10 copies in each mitochondrion. This mtDNA is maternally inherited and transmitted to all offspring, which is an important factor in genetic counselling. Other mtDNA features are its high mutation rate (around 10-fold greater than nuclear DNA) and polyplasmia and mitotic segregation, which produces a random segregation of mtDNA daughter cell molecules. Another important point is the degree of heteroplasmy, which is the percentage of mutated mtDNA molecules found in a single mitochondrion (5). mtDNA encodes 13 proteins of the mitochondrial respiratory chain, which provides information for 2 rRNA and 22 tRNA (6). Both the healthy and mutated variants coexist in the mitochondrion, so the degree of heteroplasmy will relate to the heterogeneous phenotype of this disease, with it being more severe in patients with higher levels of the mutated mtDNA. The 3243 position of mtDNA is highly conserved; studies have reported that small changes in these nucleotides are critical for the stability of binding and amino acid leucine transcription termination (7). In this position, the anticodon UUA is modified enzymatically, which will produce a tRNA carrying the nonmodified uridine, and will have a strong affinity for the UUA codon and a weak affinity for the UUG codon (8). The change from A to G results in a transcription termination factor that prevents the typical expression of rRNA. Noncoding codons producing phenylalanine and a lower rate of protein synthesis in mitochondria decreases ATP production and thus lowers the body's metabolism. Thanks to genetic diagnosis, we can find different alterations in mtDNA; one of the most frequent pathogenic mutations is A3243G, but others have also been identified, such as the A325G, T3271C, A3260G, T7512C, G583A, G1642A, T3291C, and G3241A mutations; the G3241A mutation presented only with diabetes (9). In terms of the degree of heteroplasmy, mutated and native mtDNA ratios vary depending on the cells and tissues in patients affected by the A3243G mutati

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