Methylmalonic Acidemia – Cause of Recurrent Neonatal Death and It ’ s Social Implications

Mr and Mrs R, non-consanguineous couple had history of all their children during neonatal period. First two neonates were normal at birth, then presented with lethargy, vomiting and decreased acceptance of feeds. Both the babies expired after birth without being investigated for cause of death. The third neonate was investigated for inborn error of metabolism and found to be affected with methylmalonic acidemia. The couple departed away inspite of extensive counselling. In the fourth pregnancy antenatally fetus was diagnosed as carrier case of methylmalonic acidemia and short chain fatty acid oxidase deficiency. The fourth baby was normal and was in follow up till one year age.


Introduction
E stablishing diagnosis of Methylmalonic Acidemia (MMA) in the infant is important for providing accurate pa ent educa on, gene c counselling and es ma on of recurrence risk and off ering prenatal diagnosis.Parents can be provided with an cipatory guidelines regarding poten al problems as well as management and therapeu c op ons.In this case report, we present a couple who had recurrent neonatal death because of MMA and when it was diagnosed in third infant, couple got separated and the carrier mother had normal carrier neonate with new partner.

The Case
Mr and Mrs R (fi c ous names for pa ent confi den ality), third gravida, a non-consanguineous couple reported to our gene c clinic at 28 weeks of gesta on with a history of three neonatal deaths.In her fi rst pregnancy, she had uneven ul antenatal period.A male baby was delivered at term gesta on with birth weight of 2.8 kg through uneven ul vaginal delivery.Baby cried immediately a er birth with Apgar score at 1 min, 5 min and 10 min were 8, 8 and 9 respec vely.Baby was started on breast feeding soon a er birth.On day three of life, baby developed lethargy, vomi ng and decrease acceptance of feeds.The infant was admi ed to NICU but infant expired on day fi ve of life.No metabolic workup was done.She had similar history during her second pregnancy and the infant expired on day four.The cause of death in both the neonates was not inves gated.However based on the history, we suspected metabolic disorder.
In the present pregnancy, metabolic screening and complete evalua on of the newborn was planned.She delivered a term AGA female baby with birth weight of 3 kg with Apgar scores of 8/9/9.On physical examina on there was no gross dysmorphic features and infant was ac ve and alert.The infant was started on breast feeds and in view of previous two sibling deaths, baby was kept under observa on in the hospital.On day three, she became symptoma c with lethargy, decreased ac vity and vomi ng.The infant was evaluated with sepsis screen, blood culture, electrolytes and blood sugar which were normal.ECHO and Neurosonogram were normal.Blood gas analysis revealed signifi cant metabolic acidosis (pH of 7.01, Base defi cit of -18) and increased anion gap.Baby was evaluated for inborn error of metabolism which showed diagnosis of Methylmalonic academia (very high values of methylmalonic acid, methyl citrate, proprionlygylcine, glylglycine, and 3 hydroxypropionic acid in urine).The infant expired on day 10 of life.In spite of extensive counselling that Methylmalonic Acidemia is an autosomal recessive disorder which has 25% recurrence risk in each pregnancy and prenatal diagnosis can be off ered, the couple got divorced from each other.Mrs R had come to us in her fourth pregnancy with her second husband and requested for prenatal diagnosis.Prenatal diagnosis was done and it revealed marked eleva on of butyryl carni ne and mild eleva on of branched chain (c5: isovalaryl-/α methylbutryl) -carni ne, most compa ble with benign short chain acyl -CoA dehydrogenase (SCAD) defi ciency combined with the carrier state for MMA.Since it is a benign condi on, Mrs.R con nued pregnancy and delivered a healthy girl.The child remained normal during her fi rst year of life during our follow up.

Discussion
Methylmalonic Acidemia (MMA) is an autosomal recessive inherited inborn error of metabolism with an incidence of around 1 in 50,000 live births.MMA result in increased level of acylcarni ne in blood and increased urinary excre on of methylmalonic acid.MMA group have a common defect in which ability to convert methylmalonyl-CoA into succinyl-CoA is defec ve.This defect can be either due to complete or par al defi ciency methylmalonyl-CoA mutase apoenzyme or impaired synthesis of adenosylcobalamin, the cofactor for this enzyme or defi ciency of the enzyme methylmalonyl-CoA epimerase.Methylmalonyl-CoA mutase is key enzyme for metabolism of four amino acid (isoleucine, methionine, threonine and valine) in the body 1 .The fi rst case reports dates back to 1960 with varied manifesta on like chronic metabolic acidosis, long chain ketonuria and hyperglycinenia 2,3,4 .
MMA has varied manifesta on from neonatal period to adulthood 5 .
• Neonatal period: It present with signs overlapping with neonatal sepsis including lethargy, vomi ng, truncal hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia, neonatal death.In our case all the infants had symptoms in neonatal periods and had similar features.
• Infan le period: This has two subtype on the basis of response to Vitamin B12.-Non-B12-responsive phenotype: This is the most common variant with infants who will be normal at birth but develop lethargy, vomi ng, dehydra on, hepatomegaly, truncal hypotonia with limb hypertonia, cerebral edema, coma and mul organ failure and death a er fi rst month of life.
-B12-responsive phenotype: it usually present in fi rst year of life but can rarely be symptoma c neonatal age.Usual manifesta on includes anorexia, failure to thrive, growth retarda on, truncal hypotonia, and neuro-developmental delay.
• Adult methylmalonic acidemia: It usually manifests in adulthood with secondary complica on including developmental delay; renal failure; neurological movement disorder due to basal ganglia involvement like choreoathetosis, dystonia, and para/quadriparesis; pancrea s, growth retarda on, recurrent infec ons because of immune impairment and op c nerve atrophy.
Diagnosis is confi rmed with elevated level of methylmalonic and methyl citric acid in urine, and increased level of glycine and propionylcarini ne (C3) in serum 6 .Molecular Gene c Tes ng includes genes namely MUT, MMAA, MMAB, MCEE, and MMADHC are the genes currently known to be associated with MMA 7 .The MRI fi ndings of MMA are varie d and includes ventricular dila on, cor cal atrophy periventricular white ma er abnormality, thinning of the corpus callosum, subcor cal white ma er abnormality, cerebellar atrophy, basal ganglionic calcifi ca on, periventricular leucomalacia and myelina on delay 8 .Treatment involves suppor ve care, stopping protein in diet, calories in diet provided through dextrose and lipid, supplementa on with carni ne, vitamin B12.Emergent treatment, including dialysis to quickly remove those toxins, including MMA and ammonia.N-carbamylglutamate may also be considered if available.In chronic treatment dietary intake includes protein diet which is low in isoleucine, methionine, threonine and valine amino acid content 7 .
Karimzadeh et al studied 20 pa ents of MMA over dura on of 2002 to 2012.In their study majority of pa ents (80%) were products of consanguineous marriages.The various symptoms of the pa ents were developmental delay or regression (85%), failure to thrive (50%) and refractory seizure (20%).MRI fi ndings of these babies included brain atrophy, basal ganglia involvement (o en in putamen), and periventricular leucomalacia 6 .
In non consanguineous families with no prior history of autosomal recessive disorder, the risk of serious congenital and gene c disorder is around 2.0 -2.5% whereas it increases to 4.0-4.5% in children of fi rst degree cousins.
In our experience at Fernandez hospital, out of 379 gene c disorders which were iden fi ed in infants about 84(22.1%) of them had autosomal recessive disorders.Out of these 84 children who had autosomal recessive disorders 53 (63.1 %) were born to consanguineous couples and 36.9% were born to non-consanguineous couples.
In our case report, Mrs. R had three children with MMA with her fi rst husband, though it was a non-consanguineous marriage.During her fourth pregnancy with second husband which was again a non-consanguineous, prenatal diagnosis revealed that fetus is carrier for both MMA and Short chain acyl CO A dehydrogenase defi ciency.This provides an evidence to prove that rare autosomal recessive disorders are not uncommon in non-consanguineous couples.

Conclusions
Proper diagnosis in the index child is possible with suspicion and appropriate work up.May be post-natal work up in their fi rst child followed by an appropriate prenatal diagnosis in the mother would have prevented a marital break-up and its social implica ons.Also iden fi ca on of two disorders in the fourth pregnancy is evidence to the belief that autosomal recessive disorders are not uncommon in our popula on.
Learning Points/Take Home Messages 1. Index case workup is essen al to off er counselling, predict recurrence risk and also to off er prenatal diagnosis.
2. Autosomal recessive disorders are not uncommon in non-consanguineous couples and suspicion should be kept high if a couple have recurrent unexplained neonatal or fetal death.
3. Extensive counselling is needed in cases of gene c disorders because these condi ons have serious implica ons on rela onships of the couples and when these situa ons are not handled well it can lead to very serious consequences.