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Year : 2013  |  Volume : 56  |  Issue : 3  |  Page : 272-275
Focal segmental glomerulosclerosis associated with maternally inherited diabetes and deafness: Clinical pathological analysis

State Discipline and State Key Laboratory of Kidney Disease (Chinese PLA General Hospital, 2011DAV00088), Beijing 100853, PR China

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Date of Web Publication24-Oct-2013


Maternally inherited diabetes and deafness (MIDD), which is caused by an A to G substitution at position 3243 (m.3243A>G) in the transfer ribonucleic acid leucine gene, is characterized by diabetes and hearing loss. Patients with MIDD frequently have renal disease, which may precede the diagnosis of either diabetes or deafness or may be the sole manifestation of the m.3243A>G mutation. Recently, progressive renal failure was reported in adults, and a number of childhood cases of focal segmental glomerulosclerosis (FSGS) of MIDD have been reported. However, little is known about the glomerular lesions in FSGS in MIDD. In the present study, we reported two cases of FSGS associated with MIDD and studied the clinical features of the proband and her mother.

Keywords: Clinical pathology, focal segmental glomerulosclerosis, maternally inherited diabetes and deafness

How to cite this article:
Cao XY, Wei RB, Wang YD, Zhang XG, Tang L, Chen XM. Focal segmental glomerulosclerosis associated with maternally inherited diabetes and deafness: Clinical pathological analysis . Indian J Pathol Microbiol 2013;56:272-5

How to cite this URL:
Cao XY, Wei RB, Wang YD, Zhang XG, Tang L, Chen XM. Focal segmental glomerulosclerosis associated with maternally inherited diabetes and deafness: Clinical pathological analysis . Indian J Pathol Microbiol [serial online] 2013 [cited 2023 Jan 30];56:272-5. Available from:

   Introduction Top

Maternally inherited diabetes and deafness (MIDD) is a subtype of diabetes which accounts for 1-2% of people with diabetes world-wide. [1],[2] MIDD is a genetic disorder caused by a mitochondrial gene mutation with clinical features of diabetes and sensorineural hearing loss, progressive insulin secretory defect, absence of islet-cell antibodies and absence of obesity. [3],[4] Mitochondrial deoxyribonucleic acid (mtDNA) is exclusively inherited maternally, so all offspring of an affected mother inherit the genetic defect. Molecular investigation of mtDNA has verified MIDD is caused by an A to G substitution at position 3243 (m.3243A>G) in the mitochondrial transfer ribonucleic acid (tRNA) leucine gene. [5],[6] It has been reported that MIDD patients exhibit a high prevalence of kidney disease, which may precede the diagnosis of either diabetes or deafness or may be the sole manifestation of the m.3243A>G mutation. [7] The renal disease commonly manifests as proteinuria in early adulthood, particularly in women and occasionally in children. Recently, progressive renal failure was reported in adults, and a number of childhood cases of focal segmental glomerulosclerosis (FSGS) of MIDD have been reported. [8],[9] However, little is known about the glomerular lesions in FSGS in MIDD patients. In the present study, we report two cases of FSGS associated with MIDD. The clinical features and mtDNA abnormalities for the proband and her mother were investigated.

   Patients and Methods Top


The patients, the proband (case 1) and her mother (case 2), were referred to our nephrology unit with a clinical history of chronic glomerulopathy.

Case 1: The proband

A 14-year-old female was admitted because of poor blood glucose control and proteinuria. She had a history of diabetes mellitus beginning from 12 years old, and the blood glucose was controlled by oral hypoglycemic agents. She had no history of seizures, myoclonus, migraines, or mental deficits, except for progressive hearing loss and mild hypothyroidism beginning from 5 years ago to 1 year ago, respectively. In 2004, she was found to have persistently high proteinuria and 1 year later, she was found to have growth retardation and progressive hearing loss. After diagnosed with symmetrical high-frequency hearing loss by pure tone audiometry, she underwent cochlear implantation and was given growth hormone (3 μl/day, subcutaneous injection) for 1 year. And then her height increased from 127 cm to 133 cm.

The eye examination revealed a visual acuity of 0.4 in the left eye and 0.5 in the right. Both irises were depigmented with diffuse choroidal sclerosis. The fundus examination showed that the binocular color plate boundary was clear and the eyes were round with retinitis pigmentosa, part of the disorder in the macular area, and an equivocal (±) central light reflex. She had mild left-limb weakness, but no Babinski sign. Brain computed tomography (CT) revealed an abnormal signal over the basal ganglia bilaterally. The serum glycohemoglobin was 11.3% (normal <6.1%) while the serum immunoreactive insulin and C peptide levels were low. Insulin autoantibodies, anti-insulin receptor antibodies, and the glutamic acid decarboxylase autoantibody were negative.

Case 2: The mother

The 39-year-old mother had a 9-year history of hearing loss, occasional tinnitus and visual object rotation, but without treatment. Ten days before her admission, laboratory examination showed the urinary protein was 500 mg/dl with 0-2 red blood cells per high power field and the fasting blood glucose was 14.29 mM. Her blood glucose level was controlled well with regular insulin injections. Eye examination showed a mottled retinal pigment distribution.


The renal tissues obtained from the proband and her mother by renal biopsy were fixed in DUBOSCQ-BRAZIL FLUID and then subjected to histological and pathological studies. DNA was analyzed using blood samples from patients and relatives who agreed to be tested. The high frequency of diabetes in the pedigree focused attention on the mtDNA tRNA Leu gene.

Qualitative polymerase chain reaction (PCR)

All regions of the mitochondrial genome were amplified by PCR with the GeneAmp PCR 9600 System (Perkin-Elmer, Norwalk, CT, USA). PCR amplifications were performed with 200 μM of dNTPs, 0.5 μM of forward and reverse primers, 1 U of ExTaq polymerase (Takara Biomedical, Ohtsu, Japan), 5 μl of 10× PCR reaction buffer (Takara Biomedical), and 200 ng of DNA template, for a total of 50 μl. The primers used in this study are shown in [Table 1]. The amplification consisted of an initial 1 min at 94°C, followed by 35 cycles of 94°C for 30 s, 53-62°C for 60 s, and 72°C for 10 min. The amplified fragments were digested with restriction endonucleases (ApaI, AflII, BglI, or HpaII; Takara Biomedical) and separated on 8% polyacrylamide gels, which were stained with SYBR Green I nucleic acid stain (Takara Biomedical).
Table 1: Primers used in this study

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   Results Top

Renal pathology examination

Light microscopic examination of 12 glomeruli showed mild mesangial widening due to an increase in the mesangial matrix, except one glomerulus, which had been obliterated by global sclerosis. Deposition of periodic acid-Schiff (PAS)-positive material was noted in some glomeruli [Figure 1]a. One glomerulus showed segmental sclerosis with the proliferation of visceral epithelial cells [Figure 1]a. Focal tubular atrophy and interstitial fibrosis were observed. Interstitial inflammatory infiltrates were generally minimal. Periodic acid methenamine silver revealed no deposition of Immunoglobulin or C1q along the glomerular basement membrane or in the mesangial area [Figure 1]b. Electron microscopy revealed an increase in the mesangial matrix and the presence of scattered mesangial electron-dense deposits [Figure 2]. No obvious changes in the glomerular basement membrane were observed. Fused foot processes were only occasionally observed and no morphologically abnormal mitochondria were observed. A renal pathological diagnosis of FSGS for the proband was reached based on the above information.
Figure 1: The representative pictures of the histological analysis of the renal tissues. (a) Periodic acid-Schiff staining (×400); (b) Periodic acid methenamine silver staining (×400)

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Figure 2: The representati ve pictures of electron microscopic analysis of the renal tissues. (a) (×4000); (b) (×8000)

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Screening for mtDNA point mutations

The molecular genetic analysis of the patient and available relatives showed a heteroplasmic point mutation at position 3243 (A3243G) of the mtDNA in the parents and her sister, which confirmed the diagnosis of MIDD.

   Discussion Top

MIDD is caused by mitochondrial respiratory chain dysfunction induced by mtDNA mutations. MIDD can occur at any age, but it is more common in adolescents and adults, and its diagnosis depends on genetic analysis. Although rare, it is important to diagnose MIDD correctly as it may affect the therapeutic strategy, screening of associated manifestations, and family screening.

In 1992, van den Ouweland et al. [6] first reported MIDD syndrome, known as mitochondrial diabetes, which is often accompanied by myopathy, mental disorders, short stature, epilepsy, and endocrine disorders. Initially, this syndrome was considered as part of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke syndrome. Genetic testing indicated that the mitochondrial gene tRNA Leu (UUR) A3243G mutation was the most common pathogenic mutation, followed by C12258A. [6] Approximately 0.5-2.8% of patients with diabetes have been found to have this mutation, and an estimated 90% of hearing loss is associated with this mutation. In addition, age, genetic background, and environmental stress also play important roles in MIDD. [10] It is hypothesized that mtDNA could be an obvious candidate for genetic susceptibility of MIDD since mitochondria play a central role in glucose homeostasis. [6],[11] Indeed, Oxidative mitochondrial metabolism is extremely important in the regulation of insulin production, in the pancreatic beta cell. The A3243G mutation affects the structure of the mitochondrial tRNA, leading to mitochondria with reduced function as reflected by a ~70% reduction in oxygen consumption in mitochondria. [12],[13] An accurate diagnosis of MIDD is helpful in the treatment of diabetes mellitus because the most common hypoglycemic agent, metformin, has been reported to be able to promote liver mitochondria liver mitochondria injury predisposing to cell death. [14] In the present study, although the characteristics of the proband, including juvenile diabetes, deafness, short stature, and endocrine disorders, matched the clinical manifestations of MIDD, the diagnosis had not been made before genetic analysis.

Mitochondrial mutation leads to a severe disruption of oxidative mitochondrial function, which affects cellular functions throughout the body, and tends to affect most severely those cells with high oxygen consumption such as neurons, myocytes, and endocrine cells. [15] Interesting, diabetes is also reported to accelerate the accumulation of the A3243G mutation in mtDNA. [16] Chinnery and Schon [10] considered that the multiple organ dysfunctions are associated with the number of mtDNA mutations. Patients with MIDD have a higher prevalence of end-stage renal disease. A renal biopsy might occasionally indicate diabetic kidney damage, but it more often shows FSGS. [17] Proteinuria is the main clinical manifestation of MIDD. Japanese researchers have reported that 0.9-5.9% [18] of patients undergoing dialysis have an A3243G mutation of the mitochondrial tRNA (Leu (UUR)) gene. However, some patients with chronic kidney disease and deafness are often misdiagnosed with Alport syndrome. [9],[17],[19] Females without microscopic hematuria and macular dystrophy are occasionally diagnosed with X-linked Alport syndrome, [20] but more likely with MIDD. Some patients with MIDD may have pathological manifestations of tubulointerstitial injury and renal cysts. [20] In the present study, the mesangial widening and deposition of PAS were noted in the glomeruli, and increased mesangial matrix and scattered mesangial electron-dense deposits were observed by electron microscopy. Therefore, the diagnosis of FSGS was achieved. It is possible that the abnormal mitochondria in the epithelial cells gradually induce epithelial cell dysfunction, which leads to FSGS. [21]

In summary, in the adult patients with clinical manifestations of renal disease, particular the proteinuria, if deafness, diabetes mellitus, macular dystrophy and hypertrophic cardiomyopathy are presenting in the course of the disease, MIDD should be differentiated when treating patients by genetic counseling.

   Acknowledgments Top

This work was supported by grants from the "Significant creation of new drugs" of National Science and Major Project (2010ZX09102-204), National Natural Sciences Foundation of China (81072914 and 30901573), and Medicine and Health Foundation of PLA (06MA265, and 10ZYZ255).

   References Top

1.Maassen JA, Kadowaki T. Maternally inherited diabetes and deafness: A new diabetes subtype. Diabetologia 1996;39:375-82.  Back to cited text no. 1
2.Kadowaki T, Sakura H, Otabe S, Yasuda K, Kadowaki H, Mori Y, et al. A subtype of diabetes mellitus associated with a mutation in the mitochondrial gene. Muscle Nerve Suppl 1995;3:S137-41.  Back to cited text no. 2
3.Hosszúfalusi N, Karcagi V, Horváth R, Palik E, Várkonyi J, Rajczy K, et al. A detailed investigation of maternally inherited diabetes and deafness (MIDD) including clinical characteristics, C-peptide secretion, HLA-DR and -DQ status and autoantibody pattern. Diabetes Metab Res Rev 2009;25:127-35.  Back to cited text no. 3
4.van den Ouweland JM, Lemkes HH, Gerbitz KD, Maassen JA. Maternally inherited diabetes and deafness (MIDD): A distinct subtype of diabetes associated with a mitochondrial tRNA(Leu)(UUR) gene point mutation. Muscle Nerve Suppl 1995;3:S124-30.  Back to cited text no. 4
5.Fukao T, Kondo M, Yamamoto T, Orii KE, Kondo N. Comparison of mitochondrial A3243G mutation loads in easily accessible samples from a family with maternally inherited diabetes and deafness. Mol Med Rep 2009;2:69-72.  Back to cited text no. 5
6.van den Ouweland JM, Lemkes HH, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PA, et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet 1992;1:368-71.  Back to cited text no. 6
7.Massin P, Dubois-Laforgue D, Meas T, Laloi-Michelin M, Gin H, Bauduceau B, et al. Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case-control study. Diabetologia 2008;51:1664-70.  Back to cited text no. 7
8.Dinour D, Mini S, Polak-Charcon S, Lotan D, Holtzman EJ. Progressive nephropathy associated with mitochondrial tRNA gene mutation. Clin Nephrol 2004;62:149-54.  Back to cited text no. 8
9.Jansen JJ, Maassen JA, van der Woude FJ, Lemmink HA, van den Ouweland JM, t' Hart LM, et al. Mutation in mitochondrial tRNA(Leu(UUR)) gene associated with progressive kidney disease. J Am Soc Nephrol 1997;8:1118-24.  Back to cited text no. 9
10.Chinnery PF, Schon EA. Mitochondria. J Neurol Neurosurg Psychiatry 2003;74:1188-99.  Back to cited text no. 10
11.Ballinger SW, Shoffner JM, Hedaya EV, Trounce I, Polak MA, Koontz DA, et al. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nat Genet 1992;1:11-5.  Back to cited text no. 11
12.Janssen GM, Maassen JA, van Den Ouweland JM. The diabetes-associated 3243 mutation in the mitochondrial tRNA(Leu(UUR)) gene causes severe mitochondrial dysfunction without a strong decrease in protein synthesis rate. J Biol Chem 1999;274:29744-8.  Back to cited text no. 12
13.Maassen JA. Mitochondrial diabetes: Pathophysiology, clinical presentation, and genetic analysis. Am J Med Genet 2002;115:66-70.  Back to cited text no. 13
14.Carvalho C, Correia S, Santos MS, Seiça R, Oliveira CR, Moreira PI. Metformin promotes isolated rat liver mitochondria impairment. Mol Cell Biochem 2008;308:75-83.  Back to cited text no. 14
15.Ogawa D, Shikata K, Matsuda M, Wada J, Uchida H, Asada M, et al. Pelvic lymphocyst infection associated with maternally inherited diabetes mellitus. Diabetes Res Clin Pract 2003;61:137-41.  Back to cited text no. 15
16.Nomiyama T, Tanaka Y, Piao L, Hattori N, Uchino H, Watada H, et al. Accumulation of somatic mutation in mitochondrial DNA and atherosclerosis in diabetic patients. Ann N Y Acad Sci 2004;1011:193-204.  Back to cited text no. 16
17.Guillausseau PJ, Massin P, Dubois-LaForgue D, Timsit J, Virally M, Gin H, et al. Maternally inherited diabetes and deafness: A multicenter study. Ann Intern Med 2001;134:721-8.  Back to cited text no. 17
18.Iwasaki N, Babazono T, Tsuchiya K, Tomonaga O, Suzuki A, Togashi M, et al. Prevalence of A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene in Japanese patients with diabetes mellitus and end stage renal disease. J Hum Genet 2001;46:330-4.  Back to cited text no. 18
19.Cheong HI, Chae JH, Kim JS, Park HW, Ha IS, Hwang YS, et al. Hereditary glomerulopathy associated with a mitochondrial tRNA(Leu) gene mutation. Pediatr Nephrol 1999;13:477-80.  Back to cited text no. 19
20.Guéry B, Choukroun G, Noël LH, Clavel P, Rötig A, Lebon S, et al. The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation. J Am Soc Nephrol 2003;14:2099-108.  Back to cited text no. 20
21.Yamagata K, Muro K, Usui J, Hagiwara M, Kai H, Arakawa Y, et al. Mitochondrial DNA mutations in focal segmental glomerulosclerosis lesions. J Am Soc Nephrol 2002;13:1816-23.  Back to cited text no. 21

Correspondence Address:
Ri-Bao Wei
State Discipline and State Key Laboratory of Kidney Disease, (Chinese PLA General Hospital, 2011DAV00088), Beijing 100853, PR China

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.120392

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