Indian Journal of Pathology and Microbiology

: 2013  |  Volume : 56  |  Issue : 3  |  Page : 272--275

Focal segmental glomerulosclerosis associated with maternally inherited diabetes and deafness: Clinical pathological analysis

Xue-Ying Cao, Ri-Bao Wei, Yuan-Da Wang, Xue-Guang Zhang, Li Tang, Xiang-Mei Chen 
 State Discipline and State Key Laboratory of Kidney Disease (Chinese PLA General Hospital, 2011DAV00088), Beijing 100853, PR China

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


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.

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;56:272-275

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 2022 Dec 6 ];56:272-275
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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


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}


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}{Figure 2}

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.


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.


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).


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