2. Methylmalonic acidemia & Kidney
Dr. Alaleh Gheissari,
Professor of Paediatrics
Paediatric Nephrologist
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3. Incidence & Genetic
• Incidence:
• AR 1/50000-1/100000 (cystinosis 1/150000)
• Heterogeneous group of disorders
– (Ranging from fatal to asymptomatic) leading to the accumulation of methylmalonic acid
and its by-products in biological fluids.
• Different genetic defects:
– Deficiency of methylmalonyl-CoA mutase (mut0 or mut– enzymatic subtype)
• mut(0):no detectable enzymatic activity; mut- phenotypes: residual cobalamin-dependent activity
– Disorders of intracellular cobalamin metabolism
• a defect in the synthesis or transport of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA),
– Deficiency of the enzyme methylmalonyl-CoA epimerase.
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5. Symptoms Continue
• Kidney failure
• Dehydration
• Failure to thrive
• Acidosis
• Repeated Yeast infections
• Secondary hyperammonemia
• Secondary inhibition of the urea cycle is caused by abnormalities that
reduce the activity of other enzymes involved in amino acid processing.
• Respiratory distress
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7. MMUT Gene
• The MMUT gene responsible for making methylmalonyl CoA mutase.
• This enzyme is active in mitochondria.
• Methylmalonyl CoA mutase is responsible for
– breakdown of several protein building blocks (amino acids),
– break down certain types of fats (lipids) and cholesterol.
• First converts the amino acids, lipids, or cholesterol to methylmalonyl CoA.
• Then, working with a compound called adenosylcobalamin (AdoCbl), converts
methylmalonyl CoA to succinyl-CoA.
• Other enzymes break down succinyl-CoA into molecules that are later used for
energy(KREBS cycle)
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8. Pathogenesis
• Methylmalonyl CoA requires vitamin B12 to form succinyl-CoA.
• Insufficient B12 leads to buildup of unused methylmalonyl-CoA eventually
leads to MMA.
• the body is unable to break down the aminoacids
methionine, threonine, isoleucine and valine.
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10. Methylmalonyl CoA mutase
• MUT mutation: 60%
– Encodes the protein Methylmalonyl CoA mutase
– MM CoA mutase digests toxic derivatives of the breakdown of
methionine, threonine, isoleucine and valine and odd chain FA
– MMCOA mutase converts methylmalonyl-CoA into succinyl-CoA
– Mutations in the MMAA, MMAB, and MMADHC genes
– Dysfunction in encoding a protein required for normal functioning of
methylmalonyl CoA mutase.
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11. Methylmalonyl CoA Epimerase
• MCEE gene:
• Encodes the methylmalonyl CoA epimerase
protein(methylmalonyl racemase)
• Causes mild form of the disorder.
• It functions like the mutase in breaking down the same
substances, but to a lesser extent.
• The phenotypic differences sometimes are so mild(even a
disorder or clinical syndrome?)
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12. Adenosylcobalamin (VIT B12)
• A required cofactor of methylmalonyl CoA mutase.
– Even with a functional version of the enzyme at physiologically normal
levels, if B12 cannot be converted to this active form, the mutase will
be unable to function.
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13. Kidney AND MMA
• Kidney involvement is very common(esp. in isolated MMA)
• Chronic tubulointerstitial disease: 20-60% of adolescents.
• Chronic kidney disease more common in:
– Vitamin B12 nonresponsive forms of MMA
– Individuals with the mut0 enzymatic subtype (61%)
– Individuals with cblB enzymatic subtype (66%)
– occurs less frequently in those with the cblA enzymatic
subtype (21%)
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14. Pathogenesis of Kidney Injury
• Metabolic acidosis Increased ammonia-
genesis in the PT.
• Nitrogen nucleophiles such as ammonia are injurious to
the kidney and stimulate chronic tubulointerstitial
inflammation through activation of the alternative
complement pathway.
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15. Pathogenesis of Kidney Injury
• Metabolic acidosis Increase endothelin
production promoted progressive decline of
renal function in rats.
• Metabolic Acidosis Activation of the
reninangiotensin system.
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16. Pathogenesis of Kidney Injury
• Involvement of dicarboxylic acid transport
– A possible mechanism of renal injury in patients with
MMA.
• Mitochondrial dysfunction in the proximal renal
tubule.
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17. Renal Tubules & MMA
• The majority of patients are able to lower the urinary
PH even during metabolic decompensation.
• The low urine PH in the setting of hyperchloremic
metabolic acidosis observed in patients with MMA
suggests:
– Proximal RTA
– Type 4 RTA
– Type 1 (distal RTA is less common)
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18. Pathogenesis of Kidney Injury
• Excretion of large quantities of MA in the urine may also
contribute to the low urinary PH.
• Overt proteinuria is not common.
• Ultrastructural examination of glomeruli:
– Relatively well-preserved foot processes of the visceral epithelial
cells.
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19. Renal Length in MMA
• Renal length reflective of kidney growth, significantly
decreased in MMA
• Cystatin- C and serum MMA concentrations are
highly correlated with smaller kidneys and decreased
renal function.
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20. Diagnosis
Urine:
I. Elevated serum glycine
II. Raised methylmalonic acid,
III. Methylcitrate and propionic acid
Enzymology:
I. Fibroblasts and DNA analysis.
Prenatal testing:
I. Enzyme assay on chorionic villus(CVS)
II. DNA analysis
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21. Management of Hyperammonemia
• Discontinue all oral feeds and provide adequate calories
• Use nitrogen-scavenging agents (such as sodium benzoate and sodium phenylacetate)
• Use urea cycle intermediates (such as l-arginine and l-citrulline)
• Intravenous l-carnitine
– All variants respond to the levo isomer of carnitine
– The improper breakdown of the affected substances results in developing a carnitine deficiency.
– The carnitine also assists in the removal of acyl-CoA
• Oral phenylbutyrate
• Vit B12 & Biotin
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22. Kidney Replacement Therapy
• Rapidly deteriorating neurological status, coma, or cerebral oedema with blood
ammonia level >150μmol/l.
• Presence of either moderate or severe encephalopathy.
• High-dose CVVHD, is the recommended first-line treatment for hyperammonaemia
when possible.
• Step-down CKRT can follow HD or high-dose CKRT when the blood ammonia level
is <200μmol/l.
• PD is recommended when other modalities of KRT are unavailable.
• Rigid peritoneal catheters are not recommended as they are associated with
increased rates of complications such as clotting and infections.
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23. Outcome
• With proper medical care, most patients can survive
into adulthood.
• Liver transplantation is curative.
• Patients with advanced renal failure may benefit
from combined liver and kidney transplantation.
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24. Liver- Kidney TX
• Quantitative systematic review:
• Favorable survival outcomes and metabolic stability
• Low risks of transplant-related complications
• CLKT is preferred method for patients with abnormal
kidney function.
– The improvement of neurodevelopmental status and
liberalization of protein intake were not promising.
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