Methylmalonic Acidemia: An Unusual Cause of Chronic Renal Disease in Adults

Background: Methylmalonic aciduria (MMA) is a genetic disorder of aminoacid metabolism, due to mutations in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonic acid in body fluids. Patients typically present at the age of 1 month to 1 year with dehydration, renal impairment as well as neurologic manifestations viz. seizure, encephalopathy, strokes and disease in the globus pallidi. The case: a 26-year-old man presented with severe acute on top of chronic renal disease with serum creatinine at 590 umol/L and bilateral 8 cm kidneys with thin and echogenic cortex. He had: (a) hypernatremic dehydration, metabolic acidosis and high ammonia level with (b) a history of multiple similar attacks since the age of 8 months. Diagnosis of MMA was confirmed by high serum and urine enzymatic levels as well as genetic testing. His initial management included support with replacements of fluids, electrolytes, and bicarbonates as well as intravenous dextrose, vitamin B12 and broad-spectrum antibiotic (Meropenem) for his chest infection. Subsequently, he received 1) CARBAGLU (carglumic acid) for 7 days to lower his ammonia level to Conclusion: Untreated homozygous MMA variants, can achieve adulthood with significant renal disease yet their morbidity and mortality can be ameliorated with diet and specific therapy.

Clinical features and MUT gene mutation spectrum in Chinese patients with isolated methylmalonic acidemia:identification of ten novel allelic variants

Background: This study aims to study MUT gene mutation spectrum in Chinese patients with isolated methylmalonic academia (MMA) and their clinical features for the potential genotype-phenotype correlation. Methods: Forty-three patients were diagnosed with isolated MMA by elevated blood propionylcarnitine, propionylcarnitine to acetylcarnitine ratio, and urine methylmalonate without hyperhomocysteinemia. The MUT gene was amplifi ed by polymerase chain reaction and directly sequenced. Those patients with at least one variant allele were included. The novel missense mutations were assessed by bioinformatic analysis and screened against alleles sequenced from 50 control participants. Results: Among the 43 patients, 38 had typical clinical presentations, and the majority (30/38) experienced early-onset MMA. Eight patients died and seven were lost to follow-up. Twenty patients had poor outcomes and eight showed normal development. The 43 identified MUT gene mutations had at least one variant allele, whereas 35 had two mutant alleles. Of the 33 mutations reported before, eight recurrent mutations were identified in 32 patients, and c.729_730insTT (p.D244Lfs*39) was the most common (12/78) in the mutant alleles. Of the 10 novel mutations, six were missense mutations and four were premature termination codon mutations. The six novel missense mutations seemed to be pathogenic. Conclusions: A total of 10 novelMUT mutations were detected in the Chinese population. c.729_730insTT (p.D244Lfs*39) was the most frequent mutation. A genotype-phenotype correlation could not be found, but the genotypic characterization indicated the need of genetic counseling for MMA patients and early prenatal diagnoses for high-risk families.

Fractional anisotropy for assessment of white matter tracts injury in methylmalonic acidemia

Background Methylmalonic acidemia （MMA） is a multifactorial autosomal recessive inborn error of organic acid metabolism, often presenting with neurological symptoms. As neurological disorders are often related to white matter injury, diffusion tensor imaging （DTI） is an excellent tool for assessment of white matter injury and possibly for diagnosing this disorder. Methods We retrospectively analyzed DTI images of 12 patients with MMA （7 males, 5 females, age range： 7-12 months, mean age： 9.25±1.70 months） with negative MRI findings. And another 12 age-matched and gender-matched infants were enrolled as control subjects. Fractional anisotropy （FA） of different white matter tracts of the brain was measured in both groups. Results For patients with negative MRI findings, compared with healthy infants, a statistically significant reduction in DTI FA value of the frontal white matter, temporal white matter, and occipital white matter was observed （P〈0.01）. Conclusions In addition to conventional TlW and T2W MR Image, Brain DTI presents a useful, sensitive and complementary tool for the assessment of brain damage in patients with MMA.

Long-term clinical outcomes and health-related quality of life in patients with isolated methylmalonic acidemia after liver transplantation:experience from the largest cohort study in China

Background Liver transplantation(LT)has been proposed as a viable treatment option for selected methylmalonic acidemia(MMA)patients.However,there are still controversies regarding the therapeutic value of LT for MMA.The systematic assessment of health-related quality of life(HRQoL)-targeted MMA children before and after LT is also undetermined.This study aimed to comprehensively assess the long-term impact of LT on MMA,including multiorgan sequelae and HRQoL in children and families.Methods We retrospectively evaluated 15 isolated MMA patients undergoing LT at our institution between June 2013 and March 2022.Pre-and post-transplant data were compared,including metabolic profiles,neurologic consequences,growth parameters,and HRQoL.To further assess the characteristics of the HRQoL outcomes in MMA,we compared the results with those of children with biliary atresia(BA).Results All patients had early onset MMA,and underwent LT at a mean age of 4.3 years.During 1.3–8.2 years of follow-up,the patient and graft survival rates were 100%.Metabolic stability was achieved in all patients with liberalized dietary protein intake.There was a significant overall improvement in height Z scores(P=0.0047),and some preexisting neurological complications remained stable or even improved after LT.On the Pediatric Quality of Life Inventory(PedsQL™)generic core scales,the mean total,physical health,and psychosocial health scores improved significantly posttransplant(P<0.05).In the family impact module,higher mean scores were noted for all subscales post-LT,especially family function and daily activities(P<0.01).However,the total scores on the generic core scales and transplant module were significantly lower(Cohen’s d=0.57–1.17)when compared with BA recipients.In particular,social and school functioning(Cohen’s d=0.86–1.76),treatment anxiety,and communication(Cohen’s d=0.99–1.81)were far behind,with a large effect size.Conclusions This large single-center study of the mainland of China showed an overall favorable impact of LT on isolated MMA in terms of long-term survival,metabolic control,and HRQoL in children and families.The potential for persistent neurocognitive impairment and inherent metabolic fragility requires long-term special care.