| Abstract|| |
Methylmalonic acidemia (MMA) is an inborn error of metabolism that results in the accumulation in blood, and increased excretion in the urine of, methylmalonic acid. It may present either as an acute, often fatal, condition in infancy, or in a more chronic intermittent form in older children. Organ involvement including kidneys has been described. We report here the presentation and management of a ten-year-old boy who had MMA and chronic renal failure.
Keywords: Methylmalonic acid, Renal failure, Metabolic acidosis.
|How to cite this article:|
Srinivas K V, Want MA, Freigoun OS, Balakrishna N. Methylmalonic Acidemia with Renal Involvement: A Case Report and Review of Literature. Saudi J Kidney Dis Transpl 2001;12:49-53
|How to cite this URL:|
Srinivas K V, Want MA, Freigoun OS, Balakrishna N. Methylmalonic Acidemia with Renal Involvement: A Case Report and Review of Literature. Saudi J Kidney Dis Transpl [serial online] 2001 [cited 2020 Jun 2];12:49-53. Available from: http://www.sjkdt.org/text.asp?2001/12/1/49/33886
| Introduction|| |
Organic acidemia should be suspected in any infant or child with an unexplained metabolic acidosis with a base deficit. Methylmalonic acidemia (MMA) appears to be more common than other organic acidemias perhaps because it has several underlying causes.  MMA can present in the neonatal period. Affected infants present in the first few days of life with vomiting, respiratory distress, feeding intolerance, lethargy and severe keto-acidosis, which, if not aggressively treated, often progresses rapidly to coma and death. , A benign variant of MMA is a more frequent form of the disease. It occurs in older children who usually have low levels of methylmalanoic acid in blood and urine and have normal growth and development. , These children present intermittently with acidotic crises and are otherwise normal during crisis-free periods. Increased levels of organic acids including methylmalonic acid can be toxic to various cell types in the body.  Involvement of different organs including central nervous system, bone marrow and the kidneys has been described. 
| Case Report|| |
A ten-year-old boy was admitted from the emergency room with complaints of fever and vomiting for three days and sudden onset of breathlessness since the evening prior to admission. There was no history of sore throat, joint pain, chest pain, palpitations, or exertional shortness of breath. There was no history of hematuria, dysuria or oliguria. Past history was suggestive of having similar episodic crises of breathlessness. History was not suggestive of childhood bronchial asthma. During infancy, the patient was said to have gone through times of difficulty to thrive, irritability and lethargy. He was the first child, born to consanguineous parents after full-term normal pregnancy. Milestones were slightly delayed, but he picked up with growth and development. At school, he performed well. He lost two of his siblings in infancy; they apparently suffered from a similar problem. His other two surviving siblings, although apparently normal, are undergoing further investigations. His maternal cousin died because of a similar problem. Physical examination revealed an active pale child with stable vital signs, acidotic breathing, dehydration, and grossly normal systemic examination.
Laboratory investigations showed hemoglobin 88 gm/L, leukocytes 13,200/Cu mm, blood urea 30.9 mmol/L and serum creatinine 184 µmol/L. Arterial blood gases showed pH 7.0 and bicarbonate 6 mmol/L. Urine examination showed pH 5.0 with +2 ketone bodies. Ultrasound examination showed normal sized kidneys with increased echogenicity. Magnetic resonance imaging of the brain showed changes in the basal ganglia.
A working diagnosis of acute on chronic renal failure, probably due to chronic interstitial nephritis, secondary to some hereditary causes was considered. Infection and dehydration were considered as precipitating risk factors. Renal tubular acidosis was also considered in the differential diagnosis. The patient improved with the administration of fluids and alkali. He was discharged after clinical and biochemical stabilization.
He was admitted after one month for the second time with a similar acidotic crisis precipitated by acute bronchitis. He was on regular oral Shohl's solution, L-carnitine and intramuscular vitamin B 12 therapy, prescribed for him while the family was in the USA.
During this admission, the past medical records, which became available to us, revealed that the boy was diagnosed during infancy to have MMA in the USA and was carrying the protocol of management, which helped us in managing this patient successfully. During a crisis, the management protocol included generous amounts of fluid intake, as much as 150-200 ml/kg/day. L-Carnitine was given at a dose of 20 ml (4 grams) per day intravenously in four equally divided doses, administered slowly over ten minutes. Injections of one mg doses of vitamin B 12 were given intramuscularly twice daily. Alkali supplements in the form of intravenous sodium bicarbonate were given according to the calculated deficit. The patient was continued on maintenance oral medications of Shohl's solution 90 mmol in three equally divided doses, L-Carnitine 12 ml daily along with one mg of vitamin B12 given intramuscular every alternative day. No attempt was made to measure methylmalonic acid since the clinical picture and response to therapy seemed highly supportive of the diagnosis.
| Discussion|| |
MMA is an autosomal recessively inherited, inborn error of metabolism. Genetic mutations in the chromosomal regions GP 12-P21.2 has been identified. MMA can result from deficiency of various enzymes, and accordingly three sub-types have been recognized. MMA type 1 is due to the deficiency of methylmalonyl coenzyme A mutase. In type 2 MMA, there is a deficiency of adenosyl-B 12 . Type 3 MMA results when there is deficiency of racemace enzyme.  A further metabolic complication ensues from the role of reduced hydroxyB 12 in the biosynthesis of methyl-B 12 , which is an enzyme involved in remethylation of homocysteine to methionine. Thus, some of these patients present with both methylmalonic aciduria and homocysteinuria. 
About half the patients with MMA are responsive to vitamin-B12 therapy. Many of those who are unresponsive to vitamin-B 12 develop symptoms in the newborn period and have an intrinsic mutase defect.  Many of the cobalamine B12 responsive patients present later in infancy or during the first year. Symptoms include failure to thrive, vomiting, lethargy and developmental delay.  Most of these children are not anemic and their bone marrow is normal.
Patients can also present with fatal acute ketoacidotic episode. Increased levels of organic acids are known to cause cell toxicity. Metabolic disorders are well known to initiate this response by altering normal cell functions.  During acidotic crises methylmalonic acid suppresses bone marrow resulting in anemia, leukopenia and thrombocytopenia. Involvement of other organ systems including central nervous system (cerebellum and basal ganglia) and renal disorders in the form of tubulo-interstitial nephritis,  several types of tubular dysfunction, including various types of renal tubular acidosis, and progressive renal insufficiency resulting in end-stage renal disease, have been reported.  In one study, approximately 10% of patients with MMA had tubulointerstitial nephritis and was an important cause of renal failure in these patients. 
When discovered, these patients may give a history of polydypsia, nocturia, weight loss or fatigue. These patients are frequently mildly volume depleted due to impairment of water reabsorption. Patients with chronic tubulointerstitial nephritis have no clinical evidence of disease until late in the course. Hypertension is usually a late finding and edema is typically absent. If discovered late in the course of the disease, children may present with chronic renal failure associated with marked hypertension, hypertensive retinopathy, and cardiac failure. A positive family history may point to the hereditary cause of chronic tubulointerstitial nephritis.
Laboratory diagnosis of MMA involves estimation of methylmalonic acid in the blood or its excretion in 24-hours urinary specimen after an oral dose of 10 grams of Lvaline or of an equimolar amount of isoleucine. Colorimetric methods do not readily differentiate other weak organic acids from methylmalonic acid and hence, are unreliable. Gas chromatography after ether extraction is the analytical method of choice. The excretion is related to the degree of vitamin B 12 deficiency. Definitive diagnosis involves measuring the activity of the enzyme in white blood cells or cultured fibroblasts.
Managing these patients during crisis requires intravenous administration of generous amount of alkali and L-carnitine supplements  along with high doses of vitamin B 12 . Patients are maintained after stabilization on regular oral supplements of alkali, L-carnitine and vitamin B 12 . They should be prescribed a diet low in the amino-acids leucine, isoleucine and valine and rich in vitamins particularly vitamin B 12 .  These patients should avoid dehydration. In addition, printed instructions regarding the crisis management have to be given to these patients, which can be of help to any treating physician to manage the crisis effectively.
If metabolic acidosis does not respond to conservative therapy, the patients should be managed by either peritoneal or hemodialysis. Patients with renal failure can be maintained on regular hemodialysis or continuous ambulatory peritoneal dialysis.  Patients with end-stage renal disease can be offered renal transplantation. Cure of the disease may require single organ or multiple organ transplantation. Van Calcar et al  reported a patient who had successful renal transplant, while the patient reported by Van't Hoff et al  underwent combined liver kidney transplantation. A number of studies suggest that children transplanted for inherited metabolic disease have a less difficult course after transplantation than those with primary organ failure. 
Genetic counseling should be offered to the parents of such patients. Prenatal diagnosis is possible by measuring methyl malonic acid in amniotic fluid, in maternal urine and by estimating enzyme activity in the fetal while blood cells and cultured fibroblasts. Attempts to treat this condition during intra-uterine life with vitamin B 12 injections has had little success.
The rapid expansion of the field molecular genetics and the development of effective gene therapy may well displace organ transplantation as appropriate treatment for these disorders in the future. 
| Acknowledgment|| |
I express my heart felt gratitude to Dr. Pinar T. Ozand for his guidance and encouragement to publish this article and my sincere thanks to Mr. Moncy Varghese for his excellent secretarial help in typing this manuscript.
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K V Srinivas
Department of Nephrology, King Fahd Central Hospital, Gizan