Renal Involvement in Methylmalonic Aciduria

Alkhunaizi, Ahmed M.; Al‐Sannaa, Nouriya

doi:10.1016/j.ekir.2017.04.007

Cited by 13 publications

(13 citation statements)

References 27 publications

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“…Acute brain alterations are promoted by concurring hyperammonemia, acidosis, brain edema, and hypoperfusion [7], causing permanent learning and developmental disturbances. When the brain damage becomes chronic, this affects the basal ganglia particularly, leading to movement and tone alterations [7,8]. Nonetheless, the mechanisms underlying the brain damage are still unknown.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the renal function is commonly compromised in MMA patients, even the pathogenesis of kidney injury is not clear. Renal insufficiency and chronic kidney disease are partially resolved after kidney transplantation [1,8]. Actually, general organ metabolic alterations are thought to be caused by the breakdown of branched-chain amino acids that lead to the accumulation of circulating toxic acidic metabolites.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, metabolic acidosis induces a drop in bicarbonate levels. Lactic acidosis and hyperammonemia were shown to be important metabolic alterations of MMA [7,8]. Sadly, no efficient therapy exists for MMA, thus a dietary restriction of propiogenic amino acids is mandatory to reduce the substrate of deficient MUT, concomitant to supplementation with L-carnitine and vitamins [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress

Costanzo

Caterino

Cevenini

et al. 2020

IJMS

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Methylmalonic acidemia (MMA) is a rare inborn error of metabolism caused by deficiency of the methylmalonyl-CoA mutase (MUT) enzyme. Downstream MUT deficiency, methylmalonic acid accumulates together with toxic metabolites from propionyl-CoA and other compounds upstream of the block in the enzyme pathway. The presentation is with life-threatening acidosis, respiratory distress, brain disturbance, hyperammonemia, and ketosis. Survivors develop poorly understood multi-organ damage, notably to the brain and kidneys. The HEK 293 cell line was engineered by CRISPR/Cas9 technology to knock out the MUT gene (MUT-KO). Shotgun label-free quantitative proteomics and bioinformatics analyses revealed potential damaging biological processes in MUT-deficient cells. MUT-KO induced alteration of cellular architecture and morphology, and ROS overproduction. We found the alteration of proteins involved in cytoskeleton and cell adhesion organization, cell trafficking, mitochondrial, and oxidative processes, as validated by the regulation of VIM, EXT2, SDC2, FN1, GLUL, and CHD1. Additionally, a cell model of MUT-rescuing was developed in order to control the specificity of MUT-KO effects. Globally, the proteomic landscape of MUT-KO suggests the cell model to have an increased susceptibility to propionate- and H2O2-induced stress through an impairment of the mitochondrial functionality and unbalances in the oxidation-reduction processes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress

Costanzo

Caterino

Cevenini

et al. 2020

IJMS

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“…We have identified 3 missense mutations in the MMAB gene which were all previously reported missense mutations: c.571C>T (p.R191W), c.557G>A (p.R186Q) and c.577G>A (p.E193K) [4,36,37].…”

Section: Discussionmentioning

confidence: 83%

Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia

et al. 2021

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Background/Aim: Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 or mut-enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA) or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort. Materials and Methods: The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT, MMAA, MMAB, MMADHC, MCEE genes. Mutation screening identified 30 different types of mutations. Results: While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure. Conclusions: We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long term complications.

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“…Despite several therapeutic improvements in the past 20 years, the overall outcome of patients with MMA remains unsatisfactory [ 1 , 4 – 6 ]. Long-term prognosis is worsened by chronic organ damage: neurological impairment and intellectual deficiency [ 5 , 7 – 10 ], chronic kidney disease (CKD) [ 4 , 5 , 9 , 11 – 16 ], optic neuropathy [ 17 , 18 ], chronic pancreatitis [ 7 , 9 , 19 ] and osteopenia [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Long-term renal outcome in methylmalonic acidemia in adolescents and adults

Dao

Arnoux

Bienaimé

et al. 2021

Orphanet J Rare Dis

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Background Chronic kidney disease (CKD) is one of the main long-term prognosis factors in methylmalonic acidemia (MMA), a rare disease of propionate catabolism. Our objective was to precisely address the clinical and biological characteristics of long-term CKD in MMA adolescent and adult patients. Patients and methods In this retrospective study, we included MMA patients older than 13 years who had not received kidney and/or liver transplantation. We explored tubular functions, with special attention to proximal tubular function. We measured glomerular filtration rate (mGFR) by iohexol clearance and compared it to estimated glomerular filtration rate (eGFR) by Schwartz formula and CKD-EPI. Results Thirteen patients were included (M/F = 5/8). Median age was 24 years (13 to 32). Median mGFR was 57 mL/min/1.73 m2 (23.3 to 105 mL/min/1.73 m2). Ten out of 13 patients had mGFR below 90 mL/min/1.73 m2. No patient had significant glomerular proteinuria. No patient had complete Fanconi syndrome. Only one patient had biological signs suggestive of incomplete proximal tubulopathy. Four out of 13 patients had isolated potassium loss, related to a non-reabsorbable anion effect of urinary methylmalonate. Both Schwartz formula and CKD-EPI significantly overestimated GFR. Bias were respectively 16 ± 15 mL/min/1.73 m2 and 37 ± 22 mL/min/1.73 m2. Conclusion CKD is a common complication of the MMA. Usual equations overestimate GFR. Therefore, mGFR should be performed to inform therapeutic decisions such as dialysis and/or transplantation. Mild evidence of proximal tubular dysfunction was found in only one patient, suggesting that other mechanisms are involved.

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Renal Involvement in Methylmalonic Aciduria

Cited by 13 publications

References 27 publications

Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress

Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress

Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia

Long-term renal outcome in methylmalonic acidemia in adolescents and adults

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