The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy

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Abstract

Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient’s skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

Highlights

► We reported a patient with Wolfram syndrome and dilated cardiomyopathy. ► We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). ► Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. ► The deletions remove several tRNA and protein-coding genes.

Introduction

First described in 1938, Wolfram syndrome (WFS) (MIM 222300) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) [1], [2]. This is a progressive, neurodegenerative disorder, with diabetes mellitus and optic atrophy presenting in the first decade, cranial diabetes insipidus, and sensorineural deafness in the second, and neuropathic bladder in the third, followed by neurological complications in the fourth decade [3], [4].

Nevertheless, such manifestations are not always present and we can note the association with other diverse neurological and psychiatric features, including ataxia, peripheral neuropathy, dementia and depression. Thus, Wolfram syndrome seems to be a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult because, with the exception of a few series, the number of patients in most reports is small. The pathogenesis of the disease is still unknown.

Diagnosis is usually established in one or several siblings from unaffected parents suggesting an autosomal recessive mode of transmission [5]. In fact, one candidate gene WFS1 (wolframin) has been mapped to chromosome 4p and was recently cloned and localized [6], [7], [8]. It was shown to encode a transmembrane protein called wolframin whose function is not yet determined.

Nevertheless, the wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. This hypothesis was confirmed in sporadic cases that showed a loss of mitochondrial function and the presence of heteroplasmic deletion in mtDNA [9], [10], [11]. In addition, authors suggested that mtDNA variants (4216 and 11,251) may predispose to Wolfram syndrome [12].

In the present study, we report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. His brother was died from a typical Wolfram syndrome since he suffered from diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. The mitochondrial DNA genetic study in the alive patient revealed the presence of the ND1 m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle) but also multiple mitochondrial deletions in the DNA extracted from the skeletal muscle.

Section snippets

Patient

The proband is a 36 years-old men presented with type II diabetes, neurological complications and dilated cardiomyopathy. He had steppage gait and his Magnetic Resonance Imaging (MRI) showed localized dilatation of the left occipital horn with hyperintense white matter on T2 but without any abnormalities on the brainstem and the cerebellum. His eye fundus examination did not show optic atrophy or retinitis pigmentosa and his audiogram was normal.

His brother died from a typical Wolfram syndrome

Results

In the present study, we reported a 36-years-old men patient with type II diabetes, neurological complications and dilated cardiomyopathy. He presented steppage gait and his MRI showed hyperintense white matter on T2. His brother was died from a typical Wolfram syndrome.

We started the genetic study by a mutational screening of the mitochondrial genes associated to diabetes. In fact, we screened the tRNALeu(UUR) and the tRNAGlu genes, but no reported mutations were found, especially the

Discussion

We reported a 36 years-old men presenting with type II diabetes, neurological complications, dilated cardiomyopathy and an MRI showing localized dilatation of the left occipital horn with hyperintense white matter on T2 but without any abnormalities on the brainstem and the cerebellum. His brother was died from a typical Wolfram syndrome suggesting that the studied patient presents a moderate form of Wolfram syndrome.

A study of the mitochondrial DNA showed the presence of the ND1 m.3337G>A

Acknowledgments

We thank the patient and his family for their cooperation in the present study. This work was supported by The Ministry of Higher Education and Scientific Research in Tunisia.

References (20)

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