A young male with kidney damage from genetic mitochondrial disease: case report and literature review

Abstract

Background

The most familiar ear and kidney syndrome is Alport syndrome for a nephrologist. Mutations in the mitochondrial gene MT-TL1, which encodes UUR, can also cause renal dysfunction and hearing loss. In this study, we reported a young Chinese male presented with proteinuria and renal dysfunction with a morphological presentation of focal segmental glomerulosclerosis (FSGS) with m.3243 A > G mutation in the mitochondria in the mitochondrial gene MT-TL1. We conducted a systematic literature review to summarize previously reported cases.

Case presentation

A 17-year-old male was admitted to our hospital due to foamy urine that had persisted for three months after an upper respiratory tract infection. He also complained of weakness in both lower extremities, particularly the calves. He had progressive hearing loss and body hair growth in the last two years.His urinalysis revealed 2 + proteinuria and 24-hour urine protein of 0.85 g.His blood tests revealed increased serum creatinine of 2.1 mg/dl, blood urea nitrogen of 36.1 mg/dl, and uric acid of 12.5 mg/dl. His fasting blood glucose was within the normal range of 99 mg/dl. Renal biopsy pathology revealed changes consistent with FSGS.High-power microscopy demonstrated swollen podocytes and an increased number of dysmorphic mitochondria within renal tubular epithelial cells. Consequently, whole-exome sequencing was performed, confirming that both the patient and her mother harbor the m.3243 A > G mutation in the mitochondrial MT-TL1gene.We provide patients with treatments to improve mitochondrial energy synthesis, reduce creatinine production, promote creatinine excretion, and lower uric acid levels.After a 23-month follow-up, renal function remained stable.

Conclusion

The UUR gene is an important tRNA gene in mtDNA. Its mutation can lead to mitochondrial dysfunction and cause a variety of diseases.The family history of patients with concurrent ear and renal diseases should be assessed in detail.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12882-026-05238-9.

Background

The most familiar ear and kidney syndrome is Alport syndrome for a nephrologist. We would like to call attention to another syndrome associated with hearing loss and renal disease. Mutations in the mitochondrial gene MT-TL1, which encodes tRNA Leu (UUR), can also cause renal dysfunction and hearing loss. In the most severe form, mutations in this gene cause MELAS syndrome (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke), which is a multisystem disorder that can present with cerebral vascular accidents, seizures, hearing loss, cardiomyopathy, diabetes, and nephropathy. Besides, there is another form of syndrome of MIDD (maternally inherited diabetes and deafness) caused by the mutations in the mitochondrial gene MT-TL1. In this study, we reported a young Chinese male presented with proteinuria and renal dysfunction with a morphological presentation of FSGS with the m.3243 A > G variant in the mitochondrial gene MT-TL1.We conducted a systematic literature review to summarize previously reported cases.

Case presentation

A 17-year-old male was admitted to our hospital for foamy urine after catching a cold for three months. He also complained of weakness in both lower extremities, particularly the calves. He had progressive hearing loss and body hair growth in the last two years. He denied a history of diabetes mellitus or hypertension. He had a height of 155 cm and a body weight of 43 kg. Standardized height SDS and age- and sex-matched percentile evaluation were performed based on the Chinese national growth standard WS/T 612–2018 using the LMS method. The calculated height SDS was approximately − 2.35, corresponding to a stature below the 3rd percentile for age-matched males, consistent with short stature screening criteria.He had normal blood pressure (125/75 mmHg). Consistent with his chief complaint, decreased muscle strength was detected in bilateral lower limbs (especially the calves). According to the MRC 5-point muscle strength grading scale, muscle strength of the bilateral lower limbs were grade 4. Pain, temperature and light touch sensation of all four limbs were normal; proprioception was intact. No abnormal gait such as lameness or foot dragging was nosted. Physiological tendon reflexes including biceps, triceps, knee and ankle jerks were brisk.This neurological evaluation was purely qualitative; standardized quantitative neuromuscular scoring and formal neurophysiological examinations were not completed due to clinical constraints.He presented with thick hair on the four limbs, rear neck, and hip (Fig. 1). He would actively use his right ear to approach the examiner when talking. He was the only son and his mother also had a short stature for an adult Chinese woman with height of 145 cm(height <3rd percentile, SDS = − 2.42), weight of 40 kg, and body mass index of 19.0 kg/m²) and progressive hearing impairment in her teenage. However, his mother’s urinalysis and renal function were normal.

Fig. 1.

Clinical manifestation of hirsutism. (A) Thick hair distributed over the upper limbs; (B) Marked hirsutism on the lower limbs; (C) Excessive hair growth on the posterior neck and hip

His urinalysis revealed 2 + proteinuria and 24-hour urine protein of 0.85 g (mainly characterized by glomerular proteinuria), with no red blood cells by microscopy in the urine dipstick. His blood tests revealed increased serum creatinine of 2.1 mg/dl, blood urea nitrogen of 36.1 mg/dl, and uric acid of 12.5 mg/dl. His fasting blood glucose was within the normal range of 99 mg/dl. Other blood tests were unremarkable.Serum creatine kinase was 133.2U/L.Serum calcium, phosphate, and magnesium levels were 2.24 mmol/L, 1.56 mmol/L, and 0.90 mmol/L, respectively, indicating no obvious renal tubular dysfunction. Glycated hemoglobin (HbA1c) was 5.8%. The levels of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were 4.84 pmol/L, 15.11 pmol/L, and 1.66 mIU/L, respectively. In addition, the serum levels of sex hormones were detected as follows: estradiol, 18.6 pg/mL; follicle-stimulating hormone (FSH), 8.5 IU/L; luteinizing hormone (LH), 2.5 IU/L; prolactin, 10.3 ng/mL; testosterone, 5.4 ng/mL; and progesterone, 0.12 ng/mL. These laboratory findings ruled out common endocrine disorders associated with hirsutism and metabolic lithiasis. Renal ultrasonography revealed normal-sized bilateral kidneys (right kidney 8.9 × 4.6 × 4.1 cm and left kidney 9.2 × 4.9 × 4.1 cm) with increased cortical echogenicity, and multiple stones in his bilateral kidneys (the right largest one measuring approximately 5 mm in length and the left largest one measuring approximately 4 mm in length) without hydronephrosis, masses or cysts. Electrocardiography revealed normal sinus rhythm, type A pre-excitation syndrome (Wolff-Parkinson-White Syndrome, WPW), and left ventricular high voltage with ST-T changes, while echocardiography revealed unremarkable. Ophthalmic examination showed no obvious abnormalities in both eyes. However, an audiometry screen revealed a severe hearing loss at full frequencies in the left ear, and a moderate hearing loss at high frequencies in the right ear with normal acoustic conductance, suggesting the presence of sensorineural hearing loss.

A kidney biopsy was ordered which revealed that 3 of 9 glomeruli were globally and 2 were with focal segmental glomerulosclerosis (Fig. 2A). The remaining glomeruli were unremarkable except for mild mesangial proliferation in some glomerular segments. Renal tubular epithelial cell granule and vacuolar degeneration and some protein casts in the lumen were observed. According to the Columbia classification of FSGS, this case is classified as FSGS NOS (not otherwise specified). Two distinct segmental lesions were identified: one perihilar sclerosis (Fig. 2A) and one FSGS-NOS lesion (Fig S.1). Though a perihilar lesion was present, the patient had no classic adaptive risk factors (reduced nephron mass, glomerular hyperfiltration, obesity, or hypertension) and the absence of arteriolosclerosis. No tip-domain lesions, diffuse endocapillary hypercellularity, or glomerular collapse with podocyte hyperplasia were identified to meet criteria for tip, cellular, or collapsing variants. Given the mixed sclerotic patterns and absence of diagnostic hallmarks for the four specific subtypes, the lesion was categorized as FSGS NOS. The limited number of sampled glomeruli (9 total) also creates inherent sampling bias that precludes definitive assignment to pure perihilar variant.Electron microscopy showed no diffuse foot process fusion, excluding primary podocytopathy. There were mild (10% of the cortical area) tubular atrophy and interstitial fibrosis with associated interstitial inflammation, without acid crystal deposits or cysts in the sample (Fig. 2B). There was no arteriosclerosis. Immunofluorescence intensity was trace for IgM, and negative for IgG, IgA, C1q, C3, and fibrin. Immunostaining for type IV collagen chains showed normal α3 expression along glomerular basement membrane (GBM), with segmentally reduced α3 deposition in tubular basement membrane (TBM). Glomerular α5 expression was preserved, whereas segmental loss of α5 was noted in Bowman’s capsule and TBM. α1 staining served as positive control and displayed intact expression throughout all basement membranes (FigS.2).Electron microscopy revealed a distinctive feature of an increased number of dysmorphic mitochondria within swollen podocytes and renal tubular epithelial cells at high magnification (Fig. 2CDE). The glomerular basement membrane presented segmental thickening and splitting of the lamina densa, incomplete inner and outer edges(Fig. 2F). Glomeruli revealed about 60% of fusion of podocyte foot processes.Scattered virus-like particles with uneven distribution were observed within the glomerular basement membrane. Given the lack of clinical, serological and molecular evidence of viral infection, we interpret these structures with extreme caution as non-specific degenerative ultrastructural changes rather than authentic viral particles. They most likely represent autophagic vacuoles or damaged mitochondrial debris secondary to long-term podocyte mitochondrial dysfunction, or minor artifacts generated during electron microscopy specimen processing, with no confirmed causal link to the MT-TL1 m.3243 A > G variant.

Fig. 2.

Renal pathological and ultrastructural findings. (A) Light microscopy (PASM stain, ×200 magnification): Segmental glomerulosclerosis (white arrowheads). Scale bar: 50 μm. (B) Light microscopy (PAS stain, ×100 magnification): Globally sclerotic glomerulus (white arrowhead). Scale bar: 50 μm.(C–E) Electron microscopy: Abnormally increased, swollen and dysmorphic mitochondria are visible within podocytes(white arrowheads) and renal tubular epithelial cells(white short arrowheads). (C, D: ×25000 magnification; E: ×4000 magnification). Scale bars: 500 nm for C, D and 2 μm for E.(F) Electron microscopy (×25000 magnification): Scattered virus-like particles with uneven distribution within the glomerular basement membrane(white arrowheads). Scale bar: 500 nm

Whole exome sequencing (WES) based on next-generation sequencing (NGS) was performed on an Illumina platform for genetic screening. The average sequencing depth was ≥ 150× for nuclear genes and ≥ 1000× for mitochondrial DNA (mtDNA), achieving full coverage of the entire mtDNA genome. Raw sequencing data were processed using standard bioinformatic pipelines, including quality control, sequence alignment, variant filtering and variant annotation, to screen pathogenic variants associated with mitochondrial disorders and other hereditary diseases.Putative pathogenic variants identified by WES were further validated by conventional Sanger sequencing. Segregation analysis was conducted using peripheral blood DNA samples from the patient and his mother. No disease-related somatic variant was identified. The m.3243 A > G variant in MT-TL1 was detected in both the proband and his mother. The heteroplasmy levels of this variant in peripheral blood were quantitatively determined via NGS: 55.5% in the patient and 21.9% in his mother, respectively (Fig. 3). MT-TL1 m.3243 A > G heteroplasmy was quantified via Sanger sequencing combined with peak height quantification of sequencing chromatograms using proprietary software; genomic DNA was extracted from peripheral blood leukocytes of the proband and his mother. The mutant/wild-type peak area ratio was calculated to determine heteroplasmy percentage, tested in duplicate to guarantee data reliability.Although Sanger sequencing with chromatogram peak-area comparison was used to qualitatively verify the presence of the MT-TL1 m.3243 A > G variant, we acknowledge that this method only provides semi-quantitative data with narrow linear range and low accuracy for heteroplasmy measurement. To obtain precise mutant load values, high-depth NGS (mtDNA coverage ≥ 1000×) was applied to quantify heteroplasmy levels at 55.5% and 21.9% in peripheral blood of the proband and his mother, respectively.Quantitative NGS revealed distinct heteroplasmy levels of the pathogenic mtDNA variant between the proband and his asymptomatic mother. The proband exhibited a markedly higher mutant load in peripheral blood, consistent with his severe multi-system phenotype featuring both progressive glomerular injury and bilateral sensorineural hearing loss; in contrast, the mother harbored a lower heteroplasmy level and only manifested mild isolated hearing dysfunction without renal impairment. Notably, heteroplasmy measured from peripheral blood cannot precisely reflect the actual variant burden in disease-vulnerable organs such as renal tubular epithelial cells and inner ear hair cells, as tissue-specific heteroplasmic mosaicism is a well-documented hallmark of maternally inherited mitochondrial disorders.

Fig. 3.

Genomic analysis. WES results indicate that our patient and his mother have m.3243 A > G mutation in the mitochondrial gene MT-TL1

The patient’s disease characteristics are as follows: renal pathology revealed non-specific segmental glomerulosclerosis, accompanied by focal capsular adhesion and focal hyalinosis at sclerotic segments, presenting with proteinuria, no hematuria, and renal insufficiency; electron microscopy revealed swollen podocytes and renal tubular epithelial cells with an increased number of abnormal mitochondria, segmental thickening of the GBM with lamellation of the dense layer, incomplete inner and outer margins, and unevenly distributed virus-like particles within the GBM. Nephrolithiasis was noted with a maximum stone diameter of 5 mm on the right side and 4 mm on the left side. The patient also exhibited severe hearing loss at all frequencies in the left ear and moderate hearing loss at high frequencies in the right ear, a mild decrease in muscle strength in the bilateral lower limbs, thick hair distributed over the four limbs, posterior neck, and hip, and short stature with a height of 155 cm and weight of 43 kg (body mass index 17.9 kg/m²). Cardiac findings included type A pre-excitation syndrome and left ventricular high voltage with ST-T changes, while liver function was normal. The patient’s mother presented with short stature and hearing loss.

The patient was highly suspected to have a maternally inherited mitochondrial disorder complicated by renal injury, focal segmental glomerulosclerosis, chronic renal insufficiency, stage 3 chronic kidney disease, and bilateral sensorineural hearing loss.The patient was treated with medications to improve mitochondrial energy metabolism, reduce creatinine production, facilitate creatinine excretion and lower serum uric acid levels.Coenzyme Q10 capsules 20 mg, 3 times a day, 2 capsules each time, orally; compound vitamin B tablets 3 times a day, 1 tablet each time, orally; febuxostat tablets 40 mg, once a day, 1 tablet each time, to lower uric acid; low-protein diet combined with compound α-keto acid tablets 3 times a day, 4 tablets each time, to reduce creatinine production; Jinshuibao tablets 0.42 g, 3 times a day, 4 tablets each time, to delay renal fibrosis; Shenshuaining tablets 0.36 g, 3 times a day, 2 tablets each time, to promote intestinal detoxification.Standard supportive regimens for mitochondrial nephropathy include renin-angiotensin system (RAS) blockade and sodium-glucose cotransporter 2 (SGLT2) inhibitors, which exert renoprotective effects via reducing proteinuria and alleviating renal interstitial injury. These two agents were not administered to this patient for the following reasons. First, the patient had mild renal insufficiency with normal blood pressure, and there was no progressive proteinuria or hypertension to indicate an urgent need for RAS blockade. Second, considering the patient’s young age, potential risk of hypovolemia and electrolyte disturbances associated with SGLT2 inhibitors, as well as limited clinical experience of these drugs in pediatric mitochondrial nephropathy, we did not initiate SGLT2 inhibitor therapy. After a 23-month follow-up, renal function remained stable.Upon re-examination in March 2026, serum creatinine level was 2.2 mg/dl, blood urea nitrogen was 39.8 mg/dl, uric acid was 7.21 mg/dl, and 24-hour urine protein was 0.97 g. No symptomatic arrhythmias occurred.

Discussion and conclusions

Mitochondrial diseases, among the most complex of all inherited genetic diseases, are involved in both the mitochondrial genome of maternal inheritance and the nuclear genome of Mendelian inheritance [1]. Abnormalities in mitochondrial structure and function caused by genetic defects can lead to energy metabolism disorders in multiple systems, often affecting the brain, skeletal muscle, eyes, ears, digestive system, endocrine system, cardiovascular, hematologic systems, and kidneys [1]. The most common disease associated with UUR gene mutations is MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). Other diseases include diabetes, deafness, cardiomyopathy, and kidney disease.The kidneys affected by mitochondrial dysfunction either genetic defects in multiple mitochondrial genes or nuclear genes presented with proteinuria, renal insufficiency, and renal tubular dysfunction which mainly presented with Fanconi syndrome, while hematuria was rare.

The common pathological manifestations of mitochondrial nephropathy are FSGS in the light microscope, and an increased dysmorphological mitochondria within podocyte and renal tubular epithelial cells in the electron microscope. A study demonstrated that granular swollen epithelial cells were characteristic manifestations, while not found in this case [2]. In addition, no arteriolosclerosis was identified in the present case.The absence of arteriolosclerosis is mainly attributed to the patient’s young age, persistent normal blood pressure and no history of hypertension or dyslipidemia. Though mitochondrial damage causes glomerular injury, it scarcely induces vascular sclerosis in early disease stage. Limited by only two cortical tissue strips from sampling, small arterioles in medulla were unavailable for observation. Otherwise, we found uneven distribution of virus-like particles within the basement membrane. This is an isolated finding with undetermined significance. We don’t know whether these particles are directly related to mitochondrial disease. We interpret the intramembranous virus-like particles conservatively and avoid drawing causal conclusions. This isolated ultrastructural change lacks disease specificity for m.3243 A > G-related mitochondrial nephropathy, and no supportive evidence indicates systemic viral involvement in this patient. Morphologically analogous microvesicles are well-documented in renal disorders characterized by mitochondrial dysfunction and elevated oxidative stress, arising from disordered mitophagy and cellular degradation. At present, we cannot confirm that these particles contribute to glomerular injury; they are regarded as a secondary, incidental morphological epiphenomenon rather than a primary pathogenic lesion.The lamellation and irregular thickening of GBM are considered secondary ultrastructural changes induced by long-term mitochondrial dysfunction and podocyte injury, rather than a direct pathogenic outcome of MT-TL1 mutation itself. The sporadic virus-like particles within GBM are an incidental isolated ultrastructural finding; no clinical or serologic evidence supports systemic viral infection. To date, the exact origin remains unclear and is not correlated with MT-TL1 variant.The observed virus-like particles are considered non-specific ultrastructural alterations rather than authentic viral particles, and they may also be attributed to specimen preparation artifacts. Accumulated evidence indicates that mitochondrial dysfunction and excessive oxidative stress can induce aberrant formation of autophagic vesicles, damaged mitochondrial debris and clathrin-coated vesicles, which morphologically mimic virus-like particles under electron microscopy. Similar ultrastructural changes have been documented in multiple renal disorders characterized by mitochondrial injury and cellular metabolic disturbance. No serological or molecular evidence confirmed viral infection in this patient. Collectively, these particles are regarded as secondary manifestations of podocyte and tubular cell damage caused by underlying mitochondrial defect, rather than a disease-specific feature [3–6].

FSGS is the most common renal pathology in patients with m.3243 A > G mitochondrial disease. Published cases mainly involve adolescents with proteinuria, renal insufficiency and hyperuricemia, without obvious hematuria. Abnormal mitochondria in podocytes and renal tubules are the typical ultrastructural changes, and most lesions are classified as FSGS-NOS. Most cases are accompanied by hearing loss and diabetes, following maternal inheritance with 20%–60% blood heteroplasmy.The biopsy revealed two segmental sclerotic lesions with mixed morphological patterns: one perihilar-type sclerosis and one FSGS-NOS lesion. Electron microscopy showed no diffuse foot process fusion, excluding typical primary podocytopathic FSGS.We propose that mixed mechanisms underlie this dual morphological phenotype. The focal perihilar sclerotic lesion may reflect mild local hemodynamic alteration, whereas the NOS-type lesion is predominantly driven by mitochondrial dysfunction-induced podocyte injury. Clinically, the patient had no typical predisposing factors for perihilar FSGS, such as reduced nephron mass or chronic glomerular hyperdynamic stress, further arguing against a classic adaptive perihilar subtype. Collectively, the absence of clinical adaptive triggers together with the mixed morphological features supports classifying this lesion as FSGS NOS. Notably, the present renal biopsy harbored a total of 9 glomeruli, including 3 globally sclerotic and 2 segmentally sclerotic glomeruli. Such limited sampled glomeruli pose an inherent sampling constraint, which may compromise the precision and reliability of FSGS subtyping.

Our case differs from prior reports in three key aspects: no glucose metabolic disorders, rare combination of WPW syndrome, hirsutism and nephrolithiasis, and high blood heteroplasmy without classic MELAS manifestations. The virus-like particles in glomerular basement membrane on electron microscopy are also a unique finding. This case broadens the atypical phenotypic spectrum of m.3243 A > G variant and provides new clinical evidence for the diagnosis of mitochondrial nephropathy.

The genetic characteristics of mitochondrial genetic defects mainly include maternal inheritance, heterocytoplasm, and threshold effect. Due to the lack of histone protection of mtDNA and the lack of an effective DNA repair system, the mutation frequency is extremely high, with point mutations being the most common. The inheritance characteristics of the UUR gene mutation are maternal inheritance, mtDNA is maternally inherited, so the UUR gene mutation will be passed on to offspring through the mother. Among these point mutations, the most common is a 3243 A > G (m.3243 A > G) mutation on the dihydrouracil ring in the conserved region. Detailed inquiry of other maternal relatives was performed, yet the patient’s maternal grandmother passed away with no available clinical data or genetic testing; the patient’s mother has no siblings, and relevant maternal cousins declined peripheral blood sampling and clinical screening due to personal reasons.

Bilateral kidney stones were found in this case. Recent evidence has demonstrated the involvement of mitochondrial dysfunction in CaOx crystal retention and aggregation as well as Randall’s plaque formation, all of which are the essential mechanisms for kidney stone formation [7].

Besides renal involvement, extrarenal involvement includes almost all systems, such as hearing, nervous system, muscle strength, heart, and almost all other systems.Hearing impairment is the most common, with an incidence of 40.8% [8], which requires differentiation from classic Alport syndrome. Our patient had decreased hearing, decreased left upper limb muscle strength, heart development abnormalities (type A preexcitation syndrome, left ventricular high voltage and ST-T changes) and growth retardation (short stature). WPW syndrome is increasingly recognized as a cardiac manifestation of mitochondrial disease. The MT-TL1 m.3243 A > G mutation can cause diverse cardiac complications. Mitochondrial energy deficiency and oxidative stress in cardiomyocytes may disrupt cardiac conduction development and trigger accessory pathways, resulting in pre-excitation syndrome [9]. Different from sporadic isolated WPW, this arrhythmia in MT-TL1 mutation carriers usually presents alongside multisystem mitochondrial lesions, which matches our patient’s clinical features. The abnormal electrocardiographic changes in this case were also attributed to impaired myocardial energy metabolism. Regular cardiac monitoring is therefore recommended for such patients to prevent arrhythmia-related risks.

In addition, our patient had hirsutism. Mitochondrial abnormalities and hirsutism are rarely described.The direct mechanistic link between mitochondrial dysfunction and hirsutism is indeed poorly characterized in the literature, with hirsutism typically discussed as a clinical sign of hyperandrogenism rather than as a direct consequence of mitochondrial pathology. The available evidence connects the two only indirectly, primarily through the shared pathophysiological platform of polycystic ovary syndrome (PCOS) [10].Available literature suggests a plausible link between mitochondrial dysfunction and hirsutism, though robust clinical evidence remains scarce. MtDNA variants impair oxidative phosphorylation and trigger excess reactive oxygen species, which facilitates insulin resistance and excessive androgen synthesis via disrupted steroidogenic function of endocrine tissues; elevated free androgens then convert vellus hairs into terminal hairs to cause hirsutism [11]. In addition, compromised follicular ATP metabolism activates proliferative signaling such as mTOR and ERK, prolonging the anagen phase of hair follicles and aggravating hypertrichosis. Isolated hypertrichosis has been occasionally documented in sporadic MELAS case reports, indirectly supporting this correlation [12, 13]. Nevertheless, we acknowledge that hirsutism is still an uncanonical phenotype of MT-TL1 mutation, and large-cohort studies are required to further validate the causal relevance.

Several limitations of this study need to be addressed. First, serum lactate and pyruvate, the core biomarkers for mitochondrial disease, were not detected because our institution lacks the corresponding testing capacity. Additionally, due to the lack of these baseline laboratory indicators, we could not dynamically monitor the changes of these metabolites following coenzyme Q10 and B-vitamin supplementary treatment. Second, brain MRI was not performed owing to the patient’s refusal. Although no neurological symptoms or stroke-like episodes occurred during hospitalization and the 23-month follow-up period, subtle subclinical CNS mitochondrial lesions cannot be entirely excluded. Long-term annual neurological surveillance is therefore recommended to monitor for potential delayed cerebral manifestations.The patient suffered from multisystem impairments including renal damage, FSGS, sensorineural hearing loss, WPW syndrome, myasthenia and short stature. The coexistence of multiple organ lesions strongly suggested a hereditary mitochondrial disorder, which was the main reason for us to perform whole-exome sequencing and mitochondrial gene analysis.Third, Sanger sequencing cannot accurately quantify mtDNA heteroplasmy and only acts as a qualitative validation tool. Even high-depth NGS using peripheral blood samples fails to reflect tissue-specific heteroplasmy loads in energy-intensive organs (kidney, myocardium, inner ear and skeletal muscle), which partially explains the divergent clinical phenotypes between the proband and his mother carrying identical mtDNA variants with different blood heteroplasmy fractions.Another notable limitation lies in incomplete quantitative neurological evaluation of the patient. Only qualitative assessment of limb muscle strength, sensation and tendon reflexes was performed, without standardized quantitative neurological scoring or neurophysiological testing. Additionally, multiple clinical indicators including neuromuscular manifestations and ultrastructural renal lesions were described solely via qualitative morphological observation lacking quantitative metrics. Combined with the absence of serum lactic acid/pyruvate detection and brain MRI, these gaps restrict the robustness of definitive mitochondrial disease diagnosis. Above all, current evidence remains suggestive rather than definitive, further standardized biochemical and neuroimaging assessments are therefore required to reach a conclusive diagnosis.

mtDNA mutations differ from nuclear DNA (nDNA) mutations in heterogeneity. Mutant and wild-type mtDNA may coexist, and the higher the mutation ratio, the more severe the symptoms are usually. The mutation ratio (heteroplasmy level) is correlated with the severity of the disease. Since there are hundreds of thousands of mtDNA copies in the cells, mutant mtDNA copies coexist with normal mtDNA in different proportions, and whether mutated mtDNA presents phenotypic effects or not in some organs depends on the relative ratio of mutated to normal mtDNA, and the degree of the organ dependent on ATP produced by mitochondria [14]. It is noteworthy that Sanger sequencing is unable to accurately quantify mtDNA heteroplasmy, thus NGS was adopted for quantitative analysis in this study. In addition, heteroplasmy levels show prominent tissue-specific differences in mtDNA-related diseases. The heteroplasmy data obtained from peripheral blood cannot fully reflect the mutant load in affected organs such as kidney, heart and skeletal muscle. This tissue heterogeneity is one of the key reasons for the diverse clinical manifestations and variable disease severity among m.3243 A > G carriers.The patient’s blood heteroplasmy (55.5%) was markedly higher than his mother’s (21.9%). Consistent with mitochondrial threshold effect theory, higher mutant mtDNA load exceeds the energy supply threshold in high ATP-demand organs (kidney, inner ear, myocardium) in the offspring, triggering obvious nephropathy, severe hearing loss and cardiac abnormalities. In contrast, the mother’s low heteroplasmy only induced short stature and mild hearing impairment without renal damage, explaining their distinct clinical phenotypes.

The m.3243 A > G MT-TL1 variant is classically linked to two major phenotypes: MELAS syndrome and MIDD. Notably, the proband in this study has a relatively high blood heteroplasmy level of 55.5%, but lacks the hallmark features of these two classic disorders, including recurrent stroke-like episodes, seizures, lactic acidosis, and insulin-dependent diabetes. This phenotype discrepancy is a common phenomenon in mtDNA-related disorders and can be explained by several key mechanisms. First, heteroplasmy levels detected in peripheral blood cannot represent the mutant load in metabolically active organs such as the brain, pancreas, kidney and heart. Even with high heteroplasmy in blood, the proportion of mutant mtDNA may remain below the pathogenic threshold in the central nervous system and pancreatic β-cells, which prevents the occurrence of typical MELAS or MIDD. Second, different tissues have distinct energy demands and different pathogenic thresholds for mutant mtDNA. Renal tissue, cardiac conduction system, inner ear and skeletal muscle are more vulnerable in this patient, while the brain and pancreas are relatively spared. Third, the clinical spectrum of m.3243 A > G is highly heterogeneous. Beyond classic MELAS and MIDD, this variant can also cause pure renal disease, isolated cardiomyopathy, hearing loss or multisystem atypical mitochondrial syndrome, which has been widely reported in previous cohorts.Interpretation of heteroplasmy data requires comprehensive consideration beyond simple comparisons of blood mutant loads. Although the gradient of heteroplasmy partly explains the phenotypic discrepancy between the proband and his mother, exclusive reliance on heteroplasmy differences oversimplifies the complex pathogenic mechanism underlying mitochondrial disease. Multiple critical modifiers jointly shape clinical presentations, including tissue-specific pathogenic thresholds for mtDNA variants, organ-specific mitochondrial functional reserve, nuclear genetic modifiers, and long-term accumulation of oxidative damage. For the present family, variable tissue heteroplasmy distribution between kidney and auditory tissue further decouples peripheral blood heteroplasmy from organ-specific disease severity, reinforcing the need for cautious, case-specific inference when correlating heteroplasmy measurements with clinical phenotypes.

In this case, the patient presents an atypical multisystem phenotype dominated by FSGS-related renal injury, sensorineural hearing loss, WPW syndrome, myasthenia, short stature and hirsutism, accompanied by nephrolithiasis and abnormal electrocardiographic changes. These manifestations, rather than classic MELAS/MIDD features, constitute the main clinical profile. During long-term follow-up, no new typical MELAS or MIDD symptoms emerged, yet we cannot exclude potential subclinical lesions. For instance, subtle myocardial electrical instability and early renal tubular damage are already present, indicating ongoing mitochondrial dysfunction at the cellular level.Combined with the family history (the patient’s mother also has hearing loss and short stature with detectable m.3243 A > G variant), the co-segregation of genotype and clinical phenotypes further verifies the pathogenicity of m.3243 A > G in this pedigree. This case expands the phenotypic spectrum of the m.3243 A > G variant, and reminds clinicians that high heteroplasmy does not always lead to classic MELAS or MIDD; atypical multisystem manifestations should also raise suspicion for this common mtDNA mutation.The atypical phenotype of this patient also suggests that blood heteroplasmy alone is insufficient to predict clinical subtypes of m.3243 A > G carriers. Long-term follow-up is required to monitor potential progression or new-onset subclinical symptoms.

Literature retrieval was performed on PubMed databases from database inception to March 2026. Search keywords: MT-TL1, m.3243 A > G, mitochondrial nephropathy, FSGS, hearing loss. Inclusion criteria: original human case reports/clinical researches confirming m.3243 A > G mutation with renal impairment and hearing impairment; exclusion criteria: animal experiments, review-only articles, duplicated publications and cases lacking definite gene verification. Two authors independently screened literatures according to preset criteria, with disagreements resolved via discussion. A total of 121 eligible articles were finally enrolled for summary analysis. Mitochondrial dysfunction caused by genetic defects in multiple mitochondrial or nuclear genes can affect the kidney, known as mitochondrial associated nephropathy (supplemental Tables 1,2,3).

How to detect UUR gene mutation༟Whether UUR gene mutation exists can be determined by whole genome sequencing of mtDNA or specific gene site detection.Among mutations in the UUR gene, m.3243 A > G is the most common mutation type [15, 16].

The mDNA 3243 A > G variant usually causes a slowly progressive disease. In a follow-up cohort study with 151 carriers of the mDNA 3243 A > G variant scored the disease severity using the Newcastle Mitochondrial Disease Adult Scale, clinical phenotype was the only determinant of disease progression, with the MELAS the worst compared to MIDD, other, and dormant carriers, with kidney impairment included in other group [17]. In addition, what is the prognosis for the kidney and the effect of kidney transplantation? Research has found that half of patients with m.3243 A > G mutations enter end-stage renal disease, and 25% die (median follow-up time of 11 and 12 years, respectively) [18].The prognosis depends on renal pathologic diagnosis and the time of onset of renal manifestations.Patients with end-stage renal disease can undergo dialysis. Most cases of kidney transplantation perform well [19, 20].The main risk of graft loss does not come from recurrence of the disease in situ, but rather from the aforementioned systemic complications and drug toxicity.

The UUR gene is an important tRNA gene in mtDNA. Its mutation can lead to mitochondrial dysfunction and cause a variety of diseases. Understanding the function and mutation mechanism of this gene is of great significance for the diagnosis and treatment of mitochondrial-related diseases.

The therapeutic regimen in this case complies with standard treatments for mitochondrial nephropathy. Coenzyme Q10 and B vitamins were used to improve mitochondrial energy metabolism and reduce oxidative damage. Febuxostat targeted hyperuricemia to avoid further renal injury. Low-protein diet plus α-keto acids, together with renal-protective herbal preparations, were applied to reduce renal burden and retard interstitial fibrosis.During the 23-month follow-up, renal function remained stable, serum uric acid returned to normal, and no deterioration of hearing loss, myasthenia or arrhythmia was observed. For mitochondrial nephropathy, treatment is mainly supportive and symptomatic. Long-term combined intervention and regular multi-system monitoring are necessary to delay renal function decline and prevent severe systemic complications.

Alport syndrome is the most well-known ear-kidney syndrome for nephrologists.To differentiate this mitochondrial ear-kidney phenotype from classic Alport syndrome, immunofluorescence staining for type IV collagen α3 and α5 chains was performed, showing intact α3 deposition on glomerular basement membrane and preserved glomerular α5 expression, without the complete or mosaic loss characteristic of COL4A3/COL4A4/COL4A5 pathogenic variants. Whole-exome sequencing further confirmed no pathogenic variants in COL4A3, COL4A4, and COL4A5, only identifying the maternal transmitted mitochondrial MT-TL1 m.3243 A > G heteroplasmic mutation as the causal genetic defect.This article aims to raise clinicians’ awareness of another syndrome complicated by concurrent hearing loss and renal disorders. We describe a young Chinese male presenting with proteinuria and renal dysfunction, whose renal biopsy revealed focal segmental glomerulosclerosis accompanied by the pathogenic m.3243 A > G variant in the mitochondrial MT-TL1 gene. The patient lacked hallmark manifestations of MELAS as well as diabetes typical of MIDD. These findings indicate an atypical mitochondrial disorder secondary to MT-TL1 mutation predominantly involving the kidney, inner ear, skeletal muscle, heart and physical development.The patient presented with unexplained generalized hirsutism, a rarely documented phenotype linked to MT-TL1 mutation, which expands the clinical phenotypic spectrum of this variant.Irregular glomerular basement membrane lamellation and incidental intrabasement-membrane virus-like particles were observed under electron microscopy, an unreported ultrastructural feature in classic mitochondrial nephropathy.These original clinical and pathological observations provide new complementary information for future recognition of mitochondrial-related kidney disease.Given the incomplete neurological quantitative workup and lack of core mitochondrial biochemical biomarkers, we cannot establish an absolute definitive diagnosis of systemic mitochondrial disease; our clinical inference is limited to the evidence acquired in this single case.

Supplementary Information

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Author contributions

Miao Jia wrote the main manuscript text, Qian Wu prepared all figures, Jun Zou did manuscript editing, Donghua Jin supervised throughout the study.All authors reviewed the manuscript.

Funding

This work was supported by the Medical Education and Research Collaborative Innovation Fund of Jiangsu University [JDYY2023129] 、the Scientific Innovation Fund of The People’s Hospital of Suzhou New District(SGY2023C01)、the Talent Research Project of Suzhou Gusu Health Talent Plan [GSWS2022133]、the Suzhou Municipal Health Commission “Science and Technology for Health” General Projects [MSXM2025095]; Suzhou Municipal Bureau of Science and Technology: Suzhou Science and Technology Breakthrough Program (Medical and Health Innovation)(SYWD2025082).

Data availability

The datasets utilized in this study are available on ClinVar，accession number SCV007592065.

Declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of the People’s Hospital of Suzhou New District. Written informed consent was obtained from all of the participants in the study.This research was conducted in accordance with the Declaration of Helsinki.

Consent for publication

The authors of this study have read and approved the submitted form of this manuscript and declare that it is not under consideration for publication elsewhere.Written informed consent for publication of clinical details and clinical images was obtained from the parents of the patient.

Competing interests

The authors declare no competing interests.