BACKGROUND: Methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in propionyl-CoA (P-CoA) catabolism; of note, liver neoplasms rarely occur as a long-term complication of the disorder. Herein, we report the case of a patient with MMA and hepatocellular carcinoma (HCC) who was successfully treated with a living-donor liver transplant (LDLT) following prior kidney transplantation.
METHODS: A 25-year-old male patient with MMA underwent LDLT with a left lobe graft because of metabolic instability and liver neoplasms. He had presented with chronic symptoms of MMA, which had been diagnosed by genetic testing. Additionally, he had undergone living-donor kidney transplantation with his father as the donor due to end-stage kidney disease 6 years before the LDLT. He had an episode of metabolic decompensation triggered by coronavirus disease in 2019. Imaging studies revealed an intrahepatic neoplasm in the right hepatic lobe. Due to concerns about metabolic decompensation after hepatectomy, LDLT was performed using a left lobe graft obtained from the patient\'s mother. Pathological findings were consistent with the characteristics of well-to-moderately differentiated HCC. The postoperative course was uneventful, and the patient was discharged 48 days after the LDLT without any complications. At the 9-month follow-up, the patient\'s condition was satisfactory, with sufficient liver graft function and without metabolic decompensation.
CONCLUSIONS: This case indicates that although HCC is a rare complication in patients with MMA, clinicians should be aware of hepatic malignancies during long-term follow-up.

BACKGROUND: Persistent pulmonary hypertension of the newborn manifesting with refractory and severe cyanosis is the consequence of high pulmonary vascular resistance causing extrapulmonary right-to-left shunt. Acidosis and hypoxemia produce pulmonary vasoconstriction. Persistent pulmonary hypertension of the newborn occurs due to numerous disorders and has been rarely reported as a manifestation of methylmalonic acidemia. We report a newborn with methylmalonic acidemia who presented with persistent pulmonary hypertension of the newborn.
METHODS: A 1-day-old Iranian girl presented with respiratory distress and refractory metabolic acidosis. She was born at 39 + 5 weeks gestational age with Apgar scores of 8 and 9 in the 1st and 5th minutes, respectively, and was in good condition up to 10 hours of life. After that, she presented with cyanosis, tachypnea, retraction, and hypotonia. Despite receiving oxygen, she had low oxygen saturation. Echocardiography revealed severe pulmonary hypertension and right-to-left shunt through patent ductus arteriosus and foramen ovale. Her acidosis worsened despite receiving full support and medical therapy. So, she was started on peritoneal dialysis. Unfortunately, she did not respond to treatment, and after she had died, biochemical tests confirmed methylmalonic acidemia.
CONCLUSIONS: Persistent pulmonary hypertension of the newborn is a very rare manifestation of methylmalonic acidemia. Severe inborn errors of metabolism may cause irreversible damage with adverse lifelong morbidity, and early diagnosis may help to prevent such complications. Furthermore, diagnosis of these disorders aids in prenatal diagnosis through the use of cultured amniocytes or chorionic villi to detect gene mutations, as well as biochemical analyses of amniotic fluid for subsequent pregnancies.

Background: Methylmalonic acidemia (MMA) can display many clinical manifestations, among which acute lymphoblastic leukemia (ALL) has not been reported, and congenital heart disease (CHD) is also rare. Case presentation: We report an MMA case with ALL and CHD in a 5.5-year-old girl. With developmental delay and local brain atrophy in MRI, she was diagnosed with cerebral palsy at 9 months old. Rehabilitation was performed since then. This time she was admitted to hospital because of weakness and widespread bleeding spots. ALL-L2 (pre-B-cell) was confirmed by bone marrow morphology and immunophenotyping. Echocardiography showed patent foramen ovale. The girl was treated with VDLD and CAML chemotherapy, during which she developed seizures, edema and renal insufficiency. Decrease of muscle strength was also found in physical examination. Screening for inherited metabolic disorders showed significantly elevated levels of methylmalonate-2, acetylcarnitine (C2), propionylcarnitine (C3), C3/C2 and homocysteine. Gene analysis revealed a compound heterozygous mutaion in MMACHC (NM_015,560): c.80A > G (p.Gln27Arg) and c.609G > A (p.Trp203*). CblC type MMA was diagnosed. Intramuscular injection of cyanocobalamin and intravenous L-carnitine treatment were applied. The edema vanished gradually, and chemotherapy of small dosage of vindesine was given intermittently when condition permitted. 2 months later, muscle strength of both lower limbs were significantly improved to nearly grade 5. The levels of methylmalonic acid and homocysteine were improved. Conclusion: Metabolic disease screening and gene analysis are very necessary for diseases with complex clinical symptoms. ALL can be a rare manifestation for MMA. Synopsis: We report a case of methylmalonic acidemia with acute lymphoblastic leukemia and congenital heart disease, which uncovered the importance of genetic testing and metabolic diseases screening in patients with multiple systemic organ involvement.

Methylmalonic acidemia (MMA) due to methylmalonyl-CoA mutase deficiency (OMIM #251,000) is an autosomal recessive disorder of organic acid metabolism associated with life-threatening acute metabolic decompensations and significant neuropsychological deficits. \"Isolated\" MMA refers to the presence of excess methylmalonic acid without homocysteine elevation. Belonging to this class of disorders are those that involve complete deficiency (mut0) and partial deficiency (mut-) of the methylmalonyl-CoA mutase enzyme and other disorders causing excess methylmalonic acid excretion. These other disorders include enzymatic subtypes related to cobalamin A defect (cblA) (OMIM #25,110), cobalamin B defect (cblB) (OMIM #251,110) and related conditions. Neuropsychological attributes associated with isolated MMA have become more relevant as survival rates increased following improved diagnostic and treatment strategies. Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning. Mean IQ for all types apart from cblA defect enzymatic subtype is rarely above 85 and much lower for mut0 enzymatic subtype. Identifying psychological domains responsive to improvements in biochemical status is important. This review suggests that processing speed, working memory, language, attention, and quality of life may be sensitive to fluctuations in metabolite levels while IQ and motor skills may be less amenable to change. Due to slower developmental trajectories, Growth Scale Values, Projected Retained Ability Scores and other indices of change need to be incorporated into clinical trial study protocols. Neuropsychologists are uniquely qualified to provide a differentiated picture of cognitive, behavioral and emotional consequences of MMA and analyze benefits or shortcomings of novel treatments.

Cobalamin C disease is the most common complementation class of cobalamin disorders. Here, we present a case of a 14-yr-old male with early-onset cblC disease and autism spectrum disorder (ASD) admitted to our inpatient medical service for behavioral decompensation. We use this case to highlight key aspects of the neurodevelopmental and neuropsychiatric disorders associated with cblC disease. By incorporating a comprehensive review of existing literature, we highlight salient domains of psychological impairment in cblC disease, discuss the full range of neuropsychiatric presentations, and review clinical management implications unique to cblC disease.

BACKGROUND: actual literature suggests that children of methylmalonic acidemia patients are mostly healthy, but data are only partial, especially regarding long-term outcome. Therefore, our aim was to evaluate the possible long-term neurological effects of fetal exposure to high levels of methylmalonic acid in a child of a renal transplant recipient.
METHODS: we retrospectively evaluated the clinical and neurological records of a girl whose mother is a kidney transplant recipient affected by methylmalonic acidemia. Subsequently, we compared our results with the ones already published.
RESULTS: the girl\'s weight and stature were within the normal range in the first years of life but, starting from 4 years of age, she became progressively overweight. Regarding the neurodevelopment aspects, for the first time we performed a complete and seriated neuropsychological evaluation, highlighting a mild but significant weakness in the verbal domain, with a worsening trend at three-year revaluation.
CONCLUSIONS: since children of MMA patients are exposed to methylmalonic acid, the efforts of the physicians caring for these children should be directed on careful evaluation of growth, prevention of obesity and regular neurological examination together with structured neuropsychological tests to achieve a better insight in possible complications of pregnancy in patients suffering from this condition.

Background-objectives: Liver transplantation (LT) and combined liver and kidney transplantation (CLKT) have been proposed as enzyme replacement therapies for methylmalonic aciduria (MMA). We aimed to synthesize the available evidence on their safety and efficacy.
Medline, Embase and Cochrane library were searched to identify studies that reported post-LT/CLKT clinical outcomes of MMA from their inception to February 1, 2020. The pooled rate was calculated using random-effects model with Freeman-Tukey double arcsine transformation method.
Thirty-two studies involving 109 patients were included. The pooled estimate rates were 99.9% (95% CI 95.3-100.0) for patient survival, 98.5% (95% CI 91.5-100.0) for graft survival after LT/CLKT. The combined incidence of biliary, vascular complications and rejection were 0.2% (95% CI 0.0-6.6), 7.7% (95% CI 0.1-22.1) and 18.4% (95% CI 4.6-36.3), respectively. The pooled estimate rates were 100.0% (95% CI 99.4-100.0) for metabolic eradication, 61.5% (95% CI: 33.4-87.0) for normalization of kidney function. Chronic kidney disease (CKD) remission is more promising after CLKT (70.3% VS 37.6% in LT group). The pooled estimate rates for neurodevelopmental status improvement and protein intake liberalization were 52.0% (95% CI 2.8-98.8) and 36.3% (95% CI 6.3-71.7), respectively.
This first quantitative systematic review confirms favorable survival outcomes and partially improved disease-related complications in transplanted MMA patients, although some results should be interpreted with caution. Future studies with detailed description of long-term outcomes and consensus on neurodevelopmental evaluation method can help provide a more accurate picture.

Liver transplantation is recognised as a treatment option for patients with propionic acidemia (PA) and those with methylmalonic acidemia (MMA) without renal impairment. In patients with MMA and moderate-to-severe renal impairment, combined liver-kidney transplantation is indicated. However, clinical experience of these transplantation options in patients with PA and MMA remains limited and fragmented. We undertook an overview of post-transplantation outcomes in patients with PA and MMA using the current available evidence.
A literature search identified publications on the use of transplantation in patients with PA and MMA. Publications were considered if they presented adequate demographic and outcome data from patients with PA or MMA. Publications that did not report any specific outcomes for patients or provided insufficient data were excluded.
Seventy publications were identified of which 38 were full papers. A total of 373 patients underwent liver/kidney/combined liver-kidney transplantation for PA or MMA. The most typical reason for transplantation was recurrent metabolic decompensation. A total of 27 post-transplant deaths were reported in patients with PA [14.0% (27/194)]. For patients with MMA, 18 post-transplant deaths were reported [11% (18/167)]. A total of 62 complications were reported in 115 patients with PA (54%) with cardiomyopathy (n = 12), hepatic arterial thrombosis (HAT; n = 14) and viral infections (n = 12) being the most commonly reported. A total of 52 complications were reported in 106 patients with MMA (49%) with viral infections (n = 14) and renal failure/impairment (n = 10) being the most commonly reported.
Liver transplantation and combined liver-kidney transplantation appears to benefit some patients with PA or MMA, respectively, but this approach does not provide complete correction of the metabolic defect and some patients remain at risk from disease-related and transplantation-related complications, including death. Thus, all treatment avenues should be exhausted before consideration of organ transplantation and the benefits of this approach must be weighed against the risk of perioperative complications on an individual basis.

BACKGROUND: New neurological symptoms in methylmalonic acidemia (MMA) patients after liver and/or kidney transplantation (LKT) are often described as metabolic stroke-like-events. Since calcineurin inhibitors (CNIs) are a well-known cause of new neurological symptoms in non-MMA transplanted patients, we investigated the incidence of CNI-induced neurotoxicity including posterior reversible encephalopathy syndrome (PRES) in post-transplanted MMA patients.
METHODS: We report the two MMA patients treated with LKT in our center. Additionally, we performed a systematic review of case reports/series of post-transplanted MMA patients and determined if CNI-induced neurotoxicity/PRES was a likely cause of new neurological symptoms. Definite CNI-induced neurotoxicity was defined as new neurological symptoms during CNI treatment with symptom improvement after CNI dose reduction/discontinuation. PRES was defined as CNI-induced neurotoxicity with signs of vasogenic edema on brain magnetic resonance imaging (MRI)-scan post-transplantation.
RESULTS: Our two MMA patients both developed CNI-induced neurotoxicity, one had PRES. In literature, 230 transplanted MMA patients were identified. Neurological follow-up was reported in 54 of them, of which 24 were excluded from analysis since no anti-rejection medication was reported. Thirty patients, all using CNI, were included. Sixteen patients (53%) had no new neurological symptoms post-transplantation and five patients (17%) had definite CNI neurotoxicity of whom two had PRES. Including our cases this results in a pooled incidence of 22% (7/32) definite CNI neurotoxicity and 9% PRES (3/32) in post-transplanted MMA patients on CNI.
CONCLUSIONS: In MMA post-transplanted patients with new neurological symptoms CNI-induced neurotoxicity/PRES should be considered. Early recognition of CNI-induced neurotoxicity is essential to initiate dose reduction/discontinuation of CNI to minimize persistent neurologic damage and improve outcome.
UNASSIGNED: In all post-transplanted MMA patients with new neurological symptoms CNI-induced neurotoxicity/PRES should be considered, and directly reducing the dose/discontinuation of CNI is essential.

Organic acidemias, especially propionic acidemia (PA) and methylmalonic acidemia (MMA), may manifest clinically within the first few hours to days of life. The classic presentation in the newborn period includes metabolic acidosis, hyperlactatemia, and hyperammonemia that is precipitated by unrestricted protein intake. Implementation of newborn screening to diagnose and initiate early treatment has facilitated a reduction in neonatal mortality and improved survival. Despite early diagnosis and appropriate management, these individuals are prone to have recurrent episodes of metabolic acidosis and hyperammonemia resulting in frequent hospitalizations. Liver transplantation (LT) has been proposed as a treatment modality to reduce metabolic decompensations which are not controlled by medical management. Published reports on the outcome of LT show heterogeneous results regarding clinical and biochemical features in the post transplantation period. As a result, we evaluated the outcomes of LT in our institution and compared it to the previously published data.
We performed a retrospective chart review of nine individuals with PA or MMA who underwent LT and two individuals with MMA who underwent LT and kidney transplantation (KT). Data including number of hospitalizations, laboratory measures, cardiac and neurological outcomes, dietary protein intake, and growth parameters were collected.
The median age of transplantation for subjects with MMA was 7.2 years with a median follow up of 4.3 years. The median age of transplantation for subjects with PA was 1.9 years with a median follow up of 5.4 years. The survival rate at 1 year and 5 years post-LT was 100%. Most of our subjects did not have any episodes of hyperammonemia or pancreatitis post-LT. There was significant reduction in plasma glycine post-LT. One subject developed mild elevation in ammonia post-LT on an unrestricted protein diet, suggesting that protein restriction may be indicated even after LT.
In a large single center study of LT in MMA and PA, we show that LT may reduce the incidence of metabolic decompensation. Moreover, our data suggest that LT may be associated with reduced number of hospitalizations and improved linear growth in individuals with PA and MMA.