Methylmalonic acidemia

INTRODUCTION — Methylmalonic acidemia (MMA) or methylmalonic aciduria, simply, is the elevation of methylmalonic acid in the blood and/or the urine (generally it is seen in both). This may occur alone or in combination with other biochemical abnormalities such as elevation of homocysteine and low methionine. Elevation of methylmalonic acid may be due to a defect in the metabolism of methylmalonyl-coenzyme A (CoA) or cobalamin (Cbl)/vitamin B12, which are inborn errors of metabolism that are classified as organic acidemias, or may be caused by dietary Cbl deficiency.

The genetic causes of MMA are reviewed here. An overview of the presentation, initial evaluation, diagnosis, and management of organic acidemias and discussion of other specific forms of organic acidemias are presented in greater detail separately, as is dietary vitamin B12 deficiency. (See "Organic acidemias: An overview and specific defects" and "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

ABSORPTION AND METABOLISM OF COBALAMIN — Common sources of cobalamin (Cbl) in the diet include seafood, fortified cereals, meat, poultry, eggs, and milk/dairy products. After ingestion, Cbl is released by carrier proteins and binds to haptocorrin, which is produced by the salivary glands. Formation of this complex protects Cbl from degradation by stomach acids. In the duodenum, haptocorrin is degraded, and Cbl then binds to intrinsic factor (IF), which is produced by gastric parietal cells. Next, the Cbl-IF complex binds to the cubam receptor and enters enterocytes of the distal ileum via receptor-mediated endocytosis. Cbl is released from the lysosome into the blood, where it is bound to transcobalamin (encoded by transcobalamin 2 [TCN2]).

From the blood, Cbl-transcobalamin enters cells via the transcobalamin receptor (encoded by the CD320 gene [CD320]) (figure 1). Cbl is released from transcobalamin within the lysosome, and then lysosomal Cbl transporter (encoded by KMBR1 domain-containing 1 gene [LMBRD1]) and lysosomal membrane transporter (encoded by ATP-binding cassette subfamily D member 4 gene [ABCD4]) help transport hydroxocobalamin out of the lysosome. Cbl III (Cbl³⁺) are then reduced to Cbl II (Cbl²⁺) by the cytoplasmic chaperone protein methylmalonic aciduria and homocystinuria type C (MMACHC; encoded by the gene of the same name [MMACHC]). The host cell factor C1 gene (HCFC1) encodes a transcriptional factor that upregulates MMACHC through interaction with Ronin (Thap domain containing 11 [Thap11]) [1]. Methylmalonic aciduria and homocystinuria type D (MMADHC; encoded by MMADHC]) is another chaperone protein that interacts with MMACHC.

Within the cytoplasm, Cbl II is converted to methylcobalamin by methionine synthase reductase (encoded by 5-methyltetrahydrofolate-homocystein methyltransferase reductase [MTRR]). Methylcobalamin is needed for the conversion of homocysteine to methionine by methionine synthase (encoded by 5-methyltetrahydrofolate-homocysteine methyltransferase [MTR]).

Propionyl-coenzyme A (CoA) is a byproduct of valine, isoleucine, methionine, threonine, odd-chain fatty acid, and cholesterol metabolism within the mitochondria. Propionyl-CoA is converted to D-methylmalonyl-CoA by propionyl-CoA carboxylase using biotin as a cofactor. D-methylmalonyl-CoA is then converted to L-methylmalonyl-CoA by methylmalonyl-CoA epimerase (encoded by MCEE). Cbl II is brought into the mitochondria, metabolized into adenosylcobalamin via Cbl adenosyltransferase, and then transferred to methylmalonyl-CoA mutase. L-methylmalonyl-CoA is converted to succinyl-CoA by methylmalonyl-CoA mutase (encoded by MUT) using adenosylcobalamin as a cofactor. Succinyl-CoA then enters the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle). Even defects in the first step of the TCA cycle with the conversion of succinyl-CoA to succinate by succinate-CoA ligase (encoded by succinate-CoA ligase ADP-forming beta subunit [SUCLA2] and succinate-CoA ligase alpha subunit [SUCLG1]) may lead to elevated methylmalonic acid [2-5]. Defects anywhere along this pathway will result in an elevation of methylmalonyl-CoA and propionyl-CoA. These bind with carnitine to become methylmalonyl-carnitine (C4DC) and propionylcarnitine (C3). C3 will become elevated first and is the marker for MMA and propionic acidemia on newborn screening.

The table (table 1) lists the different diseases with their genetics.

CLINICAL PRESENTATION — An infant may present symptomatically in the newborn period, or the diagnosis may be detected by newborn screening (see "Organic acidemias: An overview and specific defects", section on 'Clinical presentation'). The presentation varies with the type of defect (table 1):

●Infants with methylmalonyl-coenzyme A (CoA) mutase, cobalamin A (CblA), CblB, and CblD variant 2 may present with sepsis-like picture, including emesis, lethargy, respiratory distress, hypothermia, metabolic acidosis (due to lactate and/or ketones), ketonuria, hyperammonemia, hypoglycemia, or cytopenias [6].

●Patients with early-onset CblC may present in the first month of life with lethargy, hypotonia, poor oral intake, and failure to thrive. However, they generally do not have metabolic crises with ketosis, acidosis, and hyperammonemia [7]. Some patients with CblC present with hemolytic uremic syndrome [8]. Patients with late-onset CblC may present with lower limb weakness, psychiatric disturbances, gait instability, or brain or spinal cord changes by imaging [9].

●Patients with CblD combined type, CblF, CblJ, CblX disease, and transcobalamin II deficiency usually present with developmental regression, thrombocytopenia, megaloblastic anemia, and lethargy in the first six months of life. These patients do not generally have acute metabolic crises with ketosis, acidosis, and hyperammonemia.

INITIAL EVALUATION AND DIAGNOSIS — The diagnosis should be suspected in infants with a positive newborn screen (isolated elevation of propionylcarnitine [C3] (algorithm 1)) or lethargy and any of the other clinical features (see 'Clinical presentation' above). Of note, absence of C3 on newborn screen does not exclude one of these disorders. Cobalamin C (CblC) disease has been missed due to normal C3, probably due to low carnitine on newborn screen [10]. (See "Approach to hypoglycemia in infants and children" and "Approach to the child with metabolic acidosis" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Initial evaluation' and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Evaluation of specific critical presentations' and "Inborn errors of metabolism: Identifying the specific disorder".)

The initial evaluation in a patient with a positive newborn screen or clinical features suggestive of MMA should include:

●Complete history and physical, including development and attention to the presenting symptoms reviewed above. (See 'Clinical presentation' above.)

●Detailed family history, including infant or childhood deaths, neurologic disorders, consanguinity, and dietary restrictions such as avoidance of protein.

●Routine laboratory evaluation, including blood glucose, electrolytes, blood gas with lactate, ammonia, complete blood count (CBC) with differential, urine ketones, and liver function tests. Infants with methylmalonyl-coenzyme A (CoA) mutase, CblA, or CblB disease typically have severe metabolic acidosis with an increased anion gap, ketosis, and hyperammonemia. Other common findings include hypoglycemia and electrolyte and other abnormalities associated with volume depletion. A CBC and differential are performed to detect neutropenia, thrombocytopenia, or pancytopenia, which occur frequently because of bone marrow suppression.

●Metabolic assays for biochemical evaluation, including urine organic acids, plasma amino acids, plasma acylcarnitines, and plasma total homocysteine. Urine orotic acid should be included if there is hyperammonemia.

These laboratory results are interpreted as follows (table 1 and algorithm 1):

•Elevation of C3, the presence of methylmalonic acid in the urine and/or plasma, and normal plasma homocysteine suggest a defect in methylmalonyl-CoA mutase (either mut^- or mut⁰), CblA, CblB, or CblD variant 2.

•Elevation of C3, often with elevated C4-dicarboxylic acylcarnitine (C4DC; a marker for both methylmalonylcarnitine and succinylcarnitine, which are isobaric compounds of C4DC); the presence of methylmalonic acid in the urine and/or plasma; and elevation of plasma homocysteine suggest CblC, CblD, CblF, CblJ, CblX, transcobalamin II deficiency, transcobalamin receptor defect, or vitamin B12 deficiency [11].

•Elevation of both C3 and C4DC, the presence of methylmalonic acid in the urine and/or plasma, and normal level of plasma homocysteine may also suggest succinyl-CoA synthetase deficiency.

•Acylcarnitines and homocysteine within the normal range with normal urine organic acids suggest a false positive.

•Infants with vitamin B12 deficiency due to maternal B12 deficiency may have elevated C3 and elevated urine or plasma methylmalonic acid levels [12].

•Propionic acidemia may present similarly with elevation of C3, but propionic acid is present in the urine [11].

Confirmatory genetic testing should be performed in patients with a positive metabolic screening. This testing is available through diagnostic genetic laboratories, either for a single gene or multiple genes via a gene panel [5,6,11].

Postmortem testing — If testing is necessary after the cessation of life, a skin biopsy or blood draw to establish fibroblast or lymphocyte cell line, as well as deoxyribonucleic acid (DNA) extraction from blood and/or skin, should be performed. Biochemical testing may be performed on plasma, serum, and urine if frozen [13].

DIFFERENTIAL DIAGNOSIS — Patients presenting with ketosis, acidosis, and hyperammonemia may have MMA or another organic acidemia. Evaluation of plasma acylcarnitines and urine organic acids can help to make the diagnosis. Organic acidemias may have a similar presentation, although patients with propionic acidemia may have more severe hyperammonemia than patients with MMA. The differential diagnosis of organic acidemias is reviewed in detail separately. (See "Organic acidemias: An overview and specific defects", section on 'Differential diagnosis'.)

Other inherited metabolic disorders that cause elevated serum methylmalonic acid include combined malonic and methylmalonic aciduria, mitochondrial depletion syndrome due to autosomal recessive pathogenic variants in SUCLA2 or SUCLG1, and also vitamin B12 deficiency.

Combined malonic and methylmalonic aciduria — Combined malonic and methylmalonic aciduria (CMAMMA) is characterized by elevations of both malonic acid and methylmalonic acid in the urine and is due to pathogenic variants in the malonyl-coenzyme A (CoA) decarboxylase gene (MLYCD; MIM #248360) [14], acyl-CoA synthetase (acyl-CoA synthetase family member 3 [ACSF3]) gene (MIM #614265) [15], or zinc finger and BTB domain containing 11 gene (ZBTB11; MIM #618383) [16]. Defects in malonyl-CoA decarboxylase cause a disorder characterized by metabolic acidosis, developmental delay, seizures, and cardiomyopathy [14]. Patients with defects in acyl-CoA synthetase tend to have a more benign clinical course and higher excretion of methylmalonic acid than those with malonyl-CoA decarboxylase deficiency [15,17]. However, another small series of patients with acyl-CoA synthetase defects had a similar phenotype to the other diseases causing MMA, including failure to thrive, developmental delay, hypotonia, seizures, encephalopathy, ocular migraine, memory issues in older patients, hypoglycemia, elevated transaminases, acidosis, and T2 hyperintensities on brain magnetic resonance imaging (MRI) [18]. ZBTB11 is a transcriptional regulator of ACSF3, and mutant ZBTB11 results in decreased ACSF3 transcript [16]. Biallelic pathogenic variants in ZBTB11 result in a syndrome that is characterized by intellectual disability, regression, ataxia, spasticity, hypotonia, dystonia, and cerebellar and white matter atrophy.

Nutritional vitamin B12 deficiency — Vitamin B12 is an important cofactor for both methylmalonyl-CoA mutase and methionine synthase. Thus, a deficiency in vitamin B12 will lead to an increase in methylmalonic acid and sometimes propionic acid as well. Severe nutritional cobalamin (Cbl) deficiency (levels of 83.8±27.6 [45.6 to 114] pg/mL) can present with growth retardation, developmental delay, and hypotonia and hematologic issues such as macrocytic anemia [19] and may also be detected as elevations of propionylcarnitine (C3) on newborn screening. Vitamin B12 deficiency also leads to an increase in total homocysteine due to the decreased activity of methionine synthase. There have been cases of both infant and maternal vitamin B12 deficiency detected on newborn screening [12,20,21]. (See "Micronutrient deficiencies associated with protein-energy malnutrition in children", section on 'Vitamin B12' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

Mitochondrial DNA depletion syndrome — Mitochondrial DNA depletion syndromes 5 (MIM# 612073) and 9 (MIM #245400) are autosomal recessive diseases due to pathogenic variants in SUCLA2 or SUCLG1, respectively, which encode for subunits of succinyl-CoA ligase. Methylmalonic acid is elevated in the blood but may not reach a level where it is excreted in the urine [22]. Tricarboxylic acid (Krebs) cycle intermediates (succinate, fumarate, 2-ketoglutarate), methylcitrate, 2-methylglutaconic acid, and 3-hydroxyisovaleric acid may also be seen in the urine [22]. Patients with SUCLA2 pathogenic variants tend to have a milder phenotype than patients with SUCLG1 pathogenic variants, evidenced by later onset of symptoms and higher median survival [22], although patients with biallelic SUCLG1 pathogenic variants and milder presentations dominated by behavioral issues have been described [23]. Overall, these depletion syndromes are characterized by dystonia, hypotonia, psychomotor delay, sensorineural hearing loss, and feeding difficulties. The majority of patients have basal ganglia involvement [22]. Patients with SUCLG1 may also have hepatopathy and hypertrophic cardiomyopathy [22].

Transcobalamin receptor defect and transcobalamin II deficiency cause elevated methylmalonic acid with elevated homocysteine.

Transcobalamin receptor defect — Transcobalamin receptor defects are due to autosomal recessive pathogenic variants in CD320 (MIM #613646). These patients may present with positive newborn screen and elevated methylmalonic acid, and some may have elevated homocysteine. Vitamin B12 generally leads to normalization of levels, and normal development has been reported [24-26].

Transcobalamin II deficiency — Transcobalamin II deficiency (MIM #275350) is due to autosomal recessive pathogenic variants in TCN2 and usually results in elevation of both methylmalonic acid and homocysteine [27]. Clinically, patients may present with severe diarrhea and vomiting, recurrent infections, stomatitis, macrocytic anemia, and neutropenia [27,28]. They may also have cerebellar atrophy or autism spectrum disorder [27,28]. Treatment is with hydroxocobalamin [27].

REFERRAL — All patients with suspected or confirmed methylmalonic acidemias should be referred to a clinician specializing in biochemical genetics who is part of a multidisciplinary team that is experienced in the diagnosis and management of these disorders. This team should ideally be an integral part of a tertiary pediatric facility with access to additional subspecialists.

GENERAL MANAGEMENT ISSUES

Routine monitoring — In the first year of life, the visits should be at least every three months. As patients get older, visits may be decreased to every four to six months, based on the metabolic control of the patient. Routine evaluation by the metabolic specialist/biochemical geneticist should include the following [6]:

●History, including diet and development, to ensure adequate nutritional intake and assess the degree of developmental delay.

●Physical exam, including weight, height, head circumference, and full neurologic exam to assess for growth and any neurologic deficits.

●Laboratory evaluation, including:

•Comprehensive metabolic panel (CMP) and ammonia at every visit. The goal is for normal CMP; ammonia should be less than the upper end of normal.

•Quantitative plasma amino acids (three to four hours fasting), total homocysteine, and methylmalonic acid in the plasma and urine every visit. If plasma amino acids are not normal, this suggests an essential amino acid deficiency. Methylmalonic acid levels are expected to be elevated generally, but maintenance of a specific level in a patient may correlate with metabolic control.

•Albumin, prealbumin, and pancreatic enzymes (amylase, lipase) every visit.

•Free and total carnitine every 6 to 12 months to ensure no carnitine deficiency.

•Complete blood count (CBC) with differential to screen for cytopenias at least yearly or more frequently if symptoms.

•Micronutrient levels (zinc, selenium, ferritin, folic acid, vitamin B12) yearly or more frequently as needed in the setting of nutrient deficiencies to assess the need for supplementation.

•Assessment of bone health (calcium, phosphorus, alkaline phosphatase, magnesium, parathyroid hormone, 25-hydroxyvitamin D) yearly to assess the need for supplementation.

•Assessment of kidney function (serum creatinine, urea, electrolytes, cystatin C, uric acid; urinary electrolytes and protein loss; and glomerular filtration rate [GFR]) every 6 to 12 months. In patients with kidney disease, bone health and kidney studies are obtained more frequently as directed by nephrology.

●Imaging – Patients with isolated MMA should have dual-energy x-ray absorptiometry (DXA) scan to assess bone density after four years of age since they are at increased risk for osteopenia and osteoporosis (see 'Complications' below). If abnormal, this should be repeated yearly, and patients should be assessed by an endocrinologist. In patients with normal initial screening, DXA can be repeated every three years.

Specialist referrals — Routine specialist evaluations should include:

●Neurodevelopmental assessment by developmental pediatrics and neuropsychology should be started at four to six months of age. Formal intelligence quotient (IQ) testing should be at the recommendation of the specialist.

●Cardiology for electrocardiogram (ECG) and echocardiogram at the time of diagnosis and then as directed by cardiology.

●Ophthalmology at least annually after six years of age.

●Dental visits every six months.

Evaluation by additional specialists is based upon clinical need:

●Nephrology consult should be obtained if there are signs of kidney disease.

●Neurology consult for electroencephalogram (EEG) or brain magnetic resonance imaging (MRI) is indicated if there is concern for seizures or movement disorders.

●Referral to endocrinology for evaluation of short stature or suspected poor bone health based upon laboratory studies is suggested. Administration of growth hormone is an option in the setting of growth hormone deficiency [29,30], but biochemical parameters should be monitored closely due to increased risk for catabolism [6].

●Other potential specialty referrals include audiology for hearing screen, gastroenterology with a specialized feeding team if there are feeding difficulties, or hematology for cytopenias [6].

Vaccines — Routine vaccine administration is recommended in MMA, especially as illness may precipitate metabolic decompensation [6]. Patients should be monitored for fever after vaccination, with antipyretics administered promptly if fever develops. Hospital admission for monitoring and continuous administration of dextrose-containing intravenous fluids may be necessary in patients who have severe disease or are showing signs of loss of metabolic control. (See 'Significant catabolic event/metabolic decompensation' below.)

Pregnancy — There is sparse information about methylmalonic acidemia and pregnancy. The results from a case series and literature review of 17 pregnancies in females with isolated MMA implied an increased risk for prematurity [31], although there are case reports of pregnancies without complications in females with isolated MMA [32,33] or cobalamin C (CblC) [34]. Metabolic control should be optimized prior to pregnancy, and treatment should be continued during pregnancy [6].

There is one case report that suggests prenatal treatment may affect developmental outcome. Treatment with hydroxocobalamin (30 mg/week) and folic acid (5 mg/day) was started at 15 weeks gestational age in a patient with CblC. At 11 years old, this patient had normal IQ and mild ophthalmologic complications compared with the older sister who did not receive similar prenatal treatment and has severe intellectual disability [35]. However, another report demonstrated that maternal treatment with hydroxocobalamin in a pregnancy at risk for CblC did not appear to positively affect fetal outcome (the affected child had characteristic symptoms of the disease) [36]. Thus, more natural history studies are needed on this topic.

Surgery — Surgical procedures should be performed when the patient is well and under good metabolic control [6]. If patients require surgery, they should be admitted for dextrose-containing intravenous fluids administration prior to surgery. Nitrous oxide should be avoided in patients with CblC. It has a high affinity for Cbl II and may deplete the body of Cbl, leading to inhibition of methionine synthase (which is dependent on Cbl) [37-42].

Medications and situations to avoid — Systemic glucocorticoids should be avoided, if possible, since they increase catabolism and may place a patient at risk for metabolic decompensation. Valproic acid should be avoided as it depletes carnitine (excreted in the urine as valproylcarnitine) and thus may precipitate metabolic decompensation including hyperammonemia [43]. Nitrous oxide should also be avoided (see 'Surgery' above). Nephrotoxic medications are also typically avoided because these patients are already at increased risk for kidney disease.

Genetic counseling — The majority of these diseases (with the exception of CblX, which is an X-linked recessive disorder) are due to autosomal recessive inheritance, meaning there must be two pathogenic variants in trans to cause the disorder (table 1 and figure 1).

If a genetic defect is identified, we also recommend testing parents for the pathogenic variants to confirm carrier status. If both parents are carriers, there is a 25 percent recurrence risk in future pregnancies. Full siblings of the patient are at 50 percent risk to be an asymptomatic carrier. Genetic counseling is recommended.

Preimplantation or prenatal diagnosis — Preimplantation or prenatal diagnosis is an option for families with a previous affected child or in situations where both parents are known carriers.

Preimplantation genetic testing is possible if the variant is known. This process involves in vitro fertilization followed by targeted variant testing of the embryo. Only embryos without the pathogenic variant are implanted [44].

Prenatal diagnosis may be performed if the diagnosis is suspected by family history. Genetic testing can be performed from chorionic villus sampling or amniocentesis. Targeted testing for specific familial pathogenic variants may be performed if known [45,46]. Confirmatory genetic testing and meeting with a genetic counselor and biochemical geneticist is advised for parents considering termination of a pregnancy.

Although biochemical analysis of amniotic fluid is not routinely performed in clinical practice, one retrospective study demonstrated that biochemical analysis was diagnostic in 99.5 percent of fetuses with MMA. Diagnostic sensitivities of propionylcarnitine (C3) level, C3 to acetylcarnitine (C2) ratio (C3/C2), methylmalonic acid level, and methylcitrate level in the amniotic fluid were 95.1, 100, 100, and 82.9 percent, respectively, and diagnostic specificities were 98.7, 99.3, 97.4 and 96.7 percent, respectively [47].

Noninvasive prenatal screening is under development [48,49].

Resources for patients and caregivers — Support organizations may be helpful for patients and caregivers; however, sometimes, the information may not be accurate. Many of our patients like the Organic Acidemia Association.

ISOLATED METHYLMALONIC ACIDEMIA

Overview — Isolated elevation of methylmalonic acid is seen in patients with autosomal recessive pathogenic variants in MUT (MMA mutase type), leading to either undetectable enzyme activity (mut⁰) or decreased enzyme activity (mut^-). Isolated MMA is also seen in patients with CblA (metabolism of cobalamin associated A [MMAA]), CblB (metabolism of cobalamin associated B [MMAB]), CblD variant 2 (pathogenic variants in MMADHC leading to a stop codon near the N terminus), or MCEE pathogenic variants.

Epidemiology — The estimated prevalence of isolated MMA is between 1:50,000 and 1:100,000 [5,50,51]. The overall incidence of isolated MMA mutase type is approximately 1:120,000 in Taiwan based on newborn screening [52]. For all types of MMA, detections rates range between 0.79 to 6.04:100,000 newborns in different regions throughout the world [53].

Clinical and laboratory features — In one natural history study of patients with CblA, CblB, mut^-, or mut⁰, patients presented with lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, hypotonia, developmental delay, hepatomegaly, coma, and hyporeflexia or areflexia [54]. Other features of acute metabolic decompensation include irritability, hypothermia, poor feeding, dehydration, poor urine output, seizures, altered mental status, and encephalopathy [6]. Chronic feeding difficulties and recurrent vomiting are also common, particularly in early childhood, and often require enteral nutrition via a feeding tube [55,56].

Laboratory findings in one series of patients included methylmalonic acidemia or aciduria or both (100 percent), normal serum vitamin B12 (100 percent), metabolic acidosis (92 percent), ketonemia or ketonuria or both (81 percent), hyperammonemia (71 percent), hyperglycemia or hyperglycinuria or both (68 percent), leukopenia (60 percent), thrombocytopenia (50 percent), and anemia (33 percent) [54]. Hypoglycemia and elevated lipase can also occur with metabolic decompensation. Rarer hematologic manifestations include hemophagocytic lymphohistiocytosis [57,58], marrow hypoplasia [58], and myelodysplasia [58,59]. Symptoms may be exacerbated by concomitant vitamin B12 deficiency [60].

Acute management — Metabolic decompensation is typically precipitated by states that induce catabolism, such as illness, especially with fever; prolonged fasting or intense exercise; or medications (eg, systemic glucocorticoids) [6]. Additional etiologies include general anesthesia, acute trauma, hemorrhage, stress, or excessive protein intake. Emergency management is aimed at treating the underlying cause, stopping catabolism, and stabilizing the patient.

The European consensus guidelines published in 2014 are primarily based upon case reports, case series, and expert opinion due to the small number of patients with these disorders [6]. Our approach is consistent with these guidelines.

Mild illness — In the setting of mild illness such as common cold and mild fever where increased metabolic demand may be expected but there is minimal concern for metabolic decompensation, a home "sick day" diet may be appropriate. This "sick day diet" generally includes increased dextrose, decreased protein, and increased water to account for the illness. The patient/caregiver should consult with a clinician specializing in biochemical genetics to determine whether this is a reasonable approach or if the patient should be referred to the hospital for further evaluation.

Significant catabolic event/metabolic decompensation — These patients should be managed by a biochemical geneticist/metabolic disease specialist since different laboratory findings may necessitate nuances in treatment. Admission, and possibly transfer to a tertiary care center, may be warranted depending upon the severity of the presentation. A more general discussion of the presentation and management of metabolic emergencies is reviewed separately. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

Emergency evaluation and treatment of a significant catabolic event with metabolic decompensation should include:

●Complete history and physical exam to determine the underlying etiology of the acute decompensation.

●Laboratory evaluation:

•Point-of-care glucose for hypoglycemia.

•Comprehensive metabolic panel (CMP; for acidosis, electrolyte disturbances, liver enzymes).

•Lipase and amylase (for pancreatitis).

•Complete blood count (CBC) with differential (for cytopenias).

•Ammonia (ideally a free-flowing venous or arterial blood sample collected in a prechilled specimen tube, transported to the laboratory on ice, and separated and analyzed within 15 minutes of collection).

•Urinalysis for ketones.

●Immediate initiation of 10% dextrose-containing intravenous fluid with electrolytes (such as sodium with or without potassium) based upon age (avoid hypotonic solutions) and kidney function to target a glucose infusion rate (GIR) of approximately 8 mg/kg/min or 1.5 times maintenance fluid rate. Others use a scale based upon age [6]. Increasing the GIR while using insulin to maintain euglycemia may be required in severe cases.

Potassium should be used with caution depending on the severity of kidney disease. Sodium bicarbonate is an option to alkalinize the urine and aid in the elimination of methylmalonic acid. In patients with cardiomyopathy, fluid status should be evaluated and the fluid rate adjusted while maintaining the GIR accordingly.

●Additional treatment:

•Management of the underlying etiology of the decompensation.

•Cessation or reduction of protein intake for 24 to 48 hours, including the use of "sick day diet." Parenteral nutrition should be used if the clinical status does not allow for enteral feeding.

•Intralipid should be provided immediately for high parenteral calorie intake during the decompensation.

•Prompt use of antipyretics.

•Ongoing management of fluid and electrolytes, including normal saline bolus for dehydration, sodium bicarbonate boluses as needed to correct acidosis or added to infusion to alkalinize the urine and promote excretion of methylmalonic acid, and dextrose bolus for hypoglycemia or insulin for hyperglycemia.

•Ammonia scavengers for the treatment of hyperammonemia. Intravenous infusion of sodium phenylacetate-sodium benzoate should be started if the plasma ammonia level is three or more times higher than the reference level or in patients presenting with hyperammonemic encephalopathy. Administer 250 mg/kg of phenylacetate-sodium benzoate as a loading dose for over 90 to 120 minutes followed by 250 mg/kg/day as a maintenance dose until ammonia normalizes or the patient can tolerate oral nutrition and medications.

•Dialysis is used in neonates and children with blood ammonia levels >400 to 500 micromol/L or adolescents and adults with blood ammonia >200 micromol/L or if there is no response to medical therapy in three to six hours.

•Management of hypoglycemia by 2.5 mL/kg of 10% dextrose solution given as a slow bolus (2 to 3 mL/min). (See "Approach to hypoglycemia in infants and children", section on 'Glucose therapy'.)

•Avoidance of systemic glucocorticoids.

Emergency management letter — Patients should be provided with an emergency management letter (table 2) that contains the patient's diagnosis, common acute complications, initial management recommendations, laboratory evaluation, contraindication of systemic glucocorticoids, and the contact information for the managing clinician.

Long-term management for isolated MMA — Long-term management includes monitoring for complications, dietary modifications, and, in some patients, medications and/or supplements. The European consensus guidelines published in 2014 are primarily based upon case reports, case series, and expert opinion due to the small number of patients with these disorders [6]. Our approach is consistent with these guidelines. (See 'General management issues' above.)

Dietary modifications — The diet must be limited in methionine, odd-chain fatty acids, valine, isoleucine, and threonine since these are precursors to propionyl-coenzyme A (CoA) [6]. Propionyl-CoA is produced from the beta oxidation of odd-chain fatty acids and catabolism of branched-chain amino acids (figure 1). Propionyl-CoA is converted to methylmalonyl-CoA via propionyl-CoA carboxylase. However, protein restriction should be monitored by a metabolic dietician since it may also lead to iatrogenic essential amino acid deficiencies [61]. It is possible for infants to consume breast milk, but this must be accounted for in the complete protein intake. Patients generally cannot exclusively breastfeed. An enteral feeding tube may be warranted if there are feeding difficulties [6].

Levocarnitine deficiency — Levocarnitine deficiency with increased acylcarnitine-to-carnitine ratio is seen in organic acidurias including MMA [62,63]. It may be due to the increased excretion of propionylcarnitine (C3) species in the urine leading to an imbalance of acyl-CoA-to-CoA ratios and worsening mitochondrial dysfunction. L-carnitine supplementation at 100 to 200 mg/kg/day divided in two to four doses is recommended for deficient patients, with titration of doses as needed to normalize levels [6]. Some patients may experience mild gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea. If this occurs, we slowly increase the dose to goal.

Vitamin B12-responsive disease — Patients are considered vitamin B12 responsive if they have a >50 percent reduction in plasma methylmalonic acid, C3, and homocysteine after treatment with hydroxocobalamin [64]. There is not a specific protocol to assess vitamin B12 response [65]. We give 1 mg/day intramuscular (IM) vitamin B12 in the form of hydroxocobalamin for at least one or two weeks followed by biochemical testing. If there is no response to vitamin B12 supplementation based on decreased levels of plasma and urine MMA levels, it can be discontinued [5]. In responsive cases, combinations of parenteral/enteral treatment are also an option [6]. Patients are monitored by measurement of methylmalonic acid in the serum, plasma amino acids, and urine organic acids every three to six months.

Chronic acidemia — Sodium citrate or sodium bicarbonate supplementation is used to normalize chronic acidemia. These have equivalent effects on acid-base status when tested in healthy volunteers [66]. In addition to helping correct acid-base balance, this treatment will also alkalinize the urine and aid in the elimination of methylmalonic acid [6].

Recurrent episodes of hyperammonemia — For patients with multiple acute hyperammonemic episodes, we suggest treatment with N-carbamylglutamate (NCG; carglumic acid). NCG is a structural analog to N-acetylglutamate synthase (NAGS), an obligate allosteric activator of carbamoyl phosphate synthetase I (CPSI) that metabolizes ammonia [67]. It decreases plasma ammonia and glutamine in patients with organic acidurias [68-71]. Carglumic acid (NCG) was approved by the US Food and Drug Administration (FDA) in 2021 for acute hyperammonemia. Dosing is weight based (150 mg/kg/day if ≤15 kg; 3.3 g/m²/day if >15 kg) and is divided into two daily doses rounded up to the nearest 50 mg and given orally every 12 hours until ammonia level is <50 micromol/L (max duration of dosing seven days). In unpublished trial data submitted to the US FDA, median time to target ammonia level was 1.5 days in 42 patients randomly assigned to carglumic acid compared with two days for patients assigned to standard of care that did not include sodium benzoate [72].

One retrospective study examined long-term treatment with NCG (mean 23 months; range 3 to 51 months) in 11 patients with MMA and 10 patients with propionic acidemia [73]. Ammonia levels decreased significantly from baseline with long-term treatment (69.64±17.828 versus 55.31±13.762 micromol/L). Patients also had fewer hospitalizations for acute hyperammonemic episodes or episodes of acute decompensation [73]. Other clinical trials are ongoing in the United States and Saudi Arabia to determine the efficacy of treatment of hyperammonemia with NCG and whether this affects the long-term outcomes of patients (NCT01597440 and NCT02426775).

An alternative to carglumic acid (NCG) for management of recurrent episodes of hyperammonemia is sodium benzoate at 150 to 250 mg/kg/day orally [6]. Benzoate binds glycine and then is excreted as hippurate, leading to a decrease in the nitrogen load.

Prevention of osteopenia — Supplementation with vitamin D and calcium is important to prevent osteopenia, especially in patients with bone health issues or renal osteodystrophy.

Liver and kidney transplantation — Patients who have undergone liver transplantation live 1.5 years longer on average and have 7.9 more quality-adjusted life years, with an estimated USD $582,369 lifetime savings, compared with patients who receive nutritional management alone [74]. These patients also have shorter hospital admissions, decreased frequency of tube feedings, decreased caregiver anxiety, and an increase in the developmental quotient or intelligence quotient (IQ) [52]. Liver transplant decreases the plasma level of C3 [75] and the serum and urine levels of methylmalonic acid [76,77], resulting in fewer episodes of metabolic decompensation and acidosis [78,79]. Patients also have improvement in growth [75]. However, liver transplantation may not affect the long-term neurologic outcome, kidney failure, or risk for metabolic stroke [77,80]. Thus, patients should still continue on dietary management [75]. Kidney transplantation is helpful in end-stage kidney disease [81] and may be combined with liver transplantation [82].

Reduction of anaerobic bacteria in the gut — Previously, it was common practice to use metronidazole to kill propionate-producing bacteria in the gut because these bacteria were hypothesized to contribute to the risk of metabolic decompensation in an otherwise well-controlled patient [83-87]. However, this is no longer common practice due to lack of evidence of benefits.

Complications — Long-term complications include growth delay, intellectual disability, metabolic stroke with basal ganglia injury leading to a movement disorder, pancreatitis, chronic kidney disease (CKD), cytopenias with impaired immune system, and optic nerve atrophy [6]. Complication rates appear to be higher in patients who are Cbl nonresponsive [88].

Kidney insufficiency and CKD are consequences of MMA [89]. CKD was found most frequently in mut⁰ (61 percent) and CblB (66 percent) patients in one series and was predicted by increased urinary excretion of methylmalonic acid [90]. Compared with age-matched controls, kidneys are also smaller in patients with isolated MMA. This finding correlates with methylmalonic acid and cystatin C levels [91].

One study of patients with isolated MMA showed that patients with early-onset mut disease had the most severe cognitive impairment [92]. Hyperammonemia and seizures were associated with lower full-scale intelligence quotient (FSIQ) scores (mean ± standard deviation):

●Early-onset mut (n = 21) – 71.1±14.75

●Late-onset mut (n = 6) – 88.5±27.62

●CblA (n = 7) – 100.7±10.95

●CblB (n = 6) – 96.6±10.92

●Mut patients diagnosed prenatally or by newborn screen (n = 3) – 106.7±6.66

Metabolic stroke, or, more specifically, globus pallidus infarcts (image 1), may also occur in isolated MMA and may lead to extrapyramidal symptoms, including dystonia and choreoathetosis [93,94]. In one study of 40 patients with isolated MMA and neurologic symptoms, almost one-half had evidence of bilateral globus pallidus infarcts on brain magnetic resonance imaging (MRI) [95]. The prevalence based upon the type of the mutation in the study was 5 of 7 (71 percent) for CblA, 3 of 7 (43 percent) for CblB, 10 of 22 (45 percent) for mut⁰, and 1 of 4 (25 percent) for mut^-.

Osteopenia and osteoporosis are seen in patients with MMA, and CKD-associated renal osteodystrophy may contribute [6].

Hepatoblastoma and hepatocellular carcinoma have been rarely reported [78,96,97].

Prognosis — One study examined long-term outcomes (median follow-up period, 18 years) in 83 patients with isolated MMA due to mut⁰ (42 patients), mut^- (10 patients), CblA (20 patients), and CblB (11 patients) born between 1971 and 1997 [90]. Thirty-seven percent of patients died, 31 percent of patients survived with a severe or moderate neurologic handicap, and 32 percent were neurologically uncompromised. Patients with mut⁰ and CblB defects had an earlier onset of symptoms and a higher frequency of complications and deaths than those with mut^- and CblA defects. In addition, long-term outcome was better in those born in later decades and in those who were cobalamin (Cbl) responsive. Another study of 273 patients found that poorer long-term outcome was associated with nonresponsiveness to Cbl, neonatal-onset disease, and birth in the 1970s and 1980s (compared with later decades) [98]. Patients with mut^- disease had the best outcomes of all the subtypes. Prevention of neonatal crises in patients diagnosed by newborn screening before onset of symptoms was associated with a lesser degree of handicap. In a subsequent smaller study of 23 patients with CblA, more than half were living independently [99].

METHYLMALONIC ACIDURIA WITH HOMOCYSTINURIA

Overview — Combined elevation of methylmalonic acid and homocysteine is seen in autosomal recessive cobalamin C (CblC; MMACHC), CblD-combined type (MMADHC-frameshift pathogenic variants in exon 5, exon 8, and intron 7 [100]), CblF (LMBRD1 [101,102]), and CblJ (ABCD4 [103,104]). Methionine may also be low.

Epi-CblC may also be caused by a heterozygous pathogenic variant in MMACHC and a heterozygous peroxiredoxin 1 (PRDX1) pathogenic variant that results in an epimutation (hypermethylation of a CpG island that includes the promoter and first exon of MMACHC that produces silencing of MMACHC) [105,106]. Epi-CblC may also be caused by biallelic variants in PRDX1 leading to an epimutation [106].

CblX disease is an X-linked recessive disorder caused by pathogenic variants in HCFC1, a transcriptional regulator of methylmalonic aciduria and homocystinuria type C (MMACHC) [107,108]. Patients have elevated methylmalonic acid and increased propionylcarnitine (C3), but not all patients have elevated plasma total homocysteine [107]. One patient with a homozygous missense variant in RONIN (THAP11) had a similar phenotype to CblX [108]. It is likely that more patients will be identified [109].

CblC is the most common of the cobalaminopathies and is reviewed in detail here. Patients with CblD combined type, CblF, CblJ, and CblX disease have similar phenotypes to CblC and are treated similarly [107].

Epidemiology — The incidence of CblC was estimated at 1 in 3920 live births in the Shandong province in China [110], whereas it was estimated at 1 in 67,000 in California (1 in 46,000 in Hispanic Americans) and 1 in 100,000 births in New York State based upon newborn screening [111,112].

Genotype-phenotype correlation — The genotype-phenotype correlation may be related to the level of the MMACHC messenger ribonucleic acid (mRNA) [113]. Plasma methionine and homocysteine levels at the time of diagnosis correlate with language outcomes [114]. In addition, general cognitive abilities can be predicted by the pathogenic variants present. Homozygotes or compound heterozygotes with the c.271dupA (p.R91KfsX14) or c.331C>T (p. R111X) pathogenic variants are associated with early-onset, severe, multisystem disease, and the 394C>T (p.R132X) pathogenic variant is associated with late-onset disease characterized by acute neurologic deterioration without systemic symptoms [113,115-119]. Conversely, milder, late-onset CblC disease is associated with missense alleles (c.394C>T, c.347T>C, c.440G>C, c.482G>A), c.271dupA, and c.445_446delTG [119-122]. Patients with the c.482G>A (p.A161G) pathogenic variant have a milder biochemical phenotype that leads to an increase in missed diagnosis on newborn screen but later onset of symptoms and easier metabolic control [123]. There is extensive characterization of MMACHC genotypes from multiple centers in China [46].

Epi-CblC may lead to a different transcriptional program, but further research is needed to understand how epi-CblC differs from CblC [124].

Clinical manifestations — Patients with CblC are usually classified into early- and late-onset disease. Plasma total homocysteine is higher and methionine lower in neonatal and early-onset CblC compared with late-onset disease [117].

●Early-onset disease:

•Growth restriction, microcephaly, and dilated cardiomyopathy may be noted in utero [125].

•In the neonatal period, patients may present with a positive newborn screen, poor feeding, recurrent emesis, dehydration, lethargy, failure to thrive, or hypotonia. In infancy or early childhood, other presentations include developmental delay, encephalopathy, seizures, microcephaly, cytopenias with megaloblastosis, nystagmus, poor tracking, maculopathy, pigmentary retinopathy, optic atrophy, hemolytic uremic syndrome (HUS), hydrocephalus [126,127], or cor pulmonale due to pulmonary hypertension [128]. CblC may also mimic diabetic ketoacidosis [129] or present with an erosive, desquamating dermatitis with histopathologic characteristics resembling acrodermatitis enteropathica [130]. Patients with CblC can also have structural heart defects such as left ventricular (LV) noncompaction, secundum atrial septal defect, muscular ventricular septal defect, dysplastic pulmonary valve without pulmonary stenosis, and mitral valve prolapse with mild mitral regurgitation [131].

•During childhood, patients may also have developmental regression, progressive encephalopathy, chronic thrombotic microangiopathy, microscopic hematuria and/or proteinuria, decreased creatinine clearance, or hypertensive encephalopathy. Early-onset patients have also presented with sensorimotor peripheral demyelinating neuropathy [132].

●Late-onset disease:

•Patients with late-onset disease may present in adolescence and adulthood with executive dysfunction, decline on school or work performance, social withdrawal, personality changes, neuropsychiatric disturbances, dementia, or acute mental confusion due to progressive encephalopathy with or without leukoencephalopathy [9,117].

•Adolescent and adult patients may also have subacute combined degeneration of the lateral and dorsal spinal cord, usually due to vitamin B12 deficiency. This may present as numbness of extremities, incontinence, progressive gait disorder, or lower-extremity weakness that may progress to upper extremities and respiratory muscles.

•Patients with late-onset disease may have thromboembolic events such as recurrent venous thrombosis, pulmonary embolism, or cerebrovascular events [133]. As an example, CblC was diagnosed in an adult in the setting of thrombotic microangiopathy [134].

•Other symptoms of late-onset disease include cardiovascular disease, such as cardiomyopathy, arrhythmia, kidney insufficiency, and anemia [135].

Management

Acute management — Patients with CblC and other forms of MMA with homocystinuria generally do not have metabolic decompensation [7]. However, if suspected, management is similar to the recommendations above for isolated methylmalonic aciduria. (See 'Significant catabolic event/metabolic decompensation' above.)

Consultation with other subspecialties may be needed for optimal care. Severe failure to thrive or recurrent emesis, especially with dehydration, may require hospital admission with gastrointestinal consultation. A peripheral smear to evaluate for schistocytes and renal consultation may be helpful in evaluating for HUS. Cardiology consultation is helpful for dilated cardiomyopathy. Neurology consultation is helpful for seizures. Hematology evaluation is suggested for persistent cytopenias.

Long-term management for MMA with homocystinuria — Long-term management includes medications such as hydroxycobalamin and betaine, medical and biochemical assessments to maintain good metabolic control, and surveillance for possible complications. Guidelines published in 2017 are primarily based upon case reports, case series, and expert opinion due to the small number of patients with these disorders [136]. Our approach is consistent with these guidelines.

Monitoring — Routine evaluation of the stable patient is reviewed above. (See 'Routine monitoring' above.)

Diet and supplements — Unlike the approach for isolated MMA, protein restriction is not recommended in patients with MMA with homocystinuria, due to limited benefits and potential adverse outcomes [136]. Treatment with parenteral hydroxocobalamin, betaine, folate/folinic acid, and carnitine can result in improvement of biochemical abnormalities, non-neurologic signs, and mortality in deficient patients, but the effect on the long-term neurologic and ophthalmologic outcomes is variable [7,117,137].

●Diet – Intake of medical foods, such as specially formulated foods and amino acid-modified formulas that are free of methionine and valine, led to better metabolic control of plasma MMA levels in one study of 12 patients, but there was no relationship between diet and cognitive outcomes [7]. In another study, higher intake of medical foods was correlated with lower Z-scores for head circumference [7]. Similarly, lower Z-scores for both head circumference and height were seen on protein-restricted diets [138]. Medical foods and protein-restricted diets may also lead to iatrogenic amino acid abnormalities [7,138].

●Hydroxocobalamin – Administration of hydroxocobalamin (vitamin B12) was deemed more efficacious than cyanocobalamin in two patients with CblC since it led to normalization of plasma homocysteine, undetectable amounts of methylmalonic acid, and improvement of growth [139]. However, no biochemical benefit of oral hydroxocobalamin was found in another study in two patients [140]. Hydroxocobalamin is usually administered at 1 mg intramuscular (IM) daily, but practices may vary from one center to another with regard to dosing. The dose is adjusted based upon the biochemical response [136].

●Betaine – Methylcobalamin normally acts as a methyl donor for the reaction of homocysteine to methionine. However, in cobalaminopathies, there may be a lack of methylcobalamin. Betaine acts as a methyl donor and facilitates conversion of homocysteine to methionine through betaine homocysteine methyltransferase [136,141,142]. The dose is usually 100 to 300 mg/kg/day and is given twice a day. There is no established maximum dose. Some clinicians prescribe as high as 20 grams/day for adult patients.

There have been case reports of cerebral edema with betaine administration in classical homocystinuria [141,142], possibly due to elevated methionine to levels greater than 1000 micromol/L [143,144]. Thus, methionine and homocysteine levels must be monitored while on treatment.

●Folic or folinic acid – Supplementation should only be given if folic acid levels are low. One study of two patients demonstrated no biochemical benefit of folinic acid supplementation [140], and overall there is no evidence that treatment is beneficial or detrimental in the absence of a deficiency [136].

●Methionine – It is essential to monitor plasma methionine levels and supplement methionine (10 to 20 mg/kg/day) as needed to keep methionine levels within normal range.

●Levocarnitine – Management is the same as for isolated MMA. (See 'Vitamin B12-responsive disease' above.)

Complications — The most commonly seen complications in patients with MMA with homocystinuria are neurologic, ocular, renal, and vascular.

●Neurologic complications – One study of neurodevelopmental outcomes in patients with early-onset CblC showed that all patients had developmental delay, 25 percent had clinical seizures, and 17 percent had microcephaly [145]. Children diagnosed by newborn screening had higher scores on neurodevelopmental testing [146]. Brain magnetic resonance imaging (MRI) may show callosal thinning, craniocaudally short pons, and increased T2 fluid-attenuated inversion recovery (FLAIR) signal in periventricular and periatrial white matter [145]. The abnormal MRI findings may lead to misdiagnosis as multiple sclerosis or metachromatic leukodystrophy [147,148]. Hydrocephalus may occur [126,127]; patients should be referred for neurosurgical consultation if suspected since more than half of patients with hydrocephalus in one retrospective study required ventriculoperitoneal shunt placement [149].

●Ocular complications – Patients with CblC disease have early-onset maculopathy [150]. Ocular manifestations of CblC disease include optic nerve pallor, peripheral pigmentary retinal changes, and central macular atrophy with bull's eye lesions. Retinal thinning in the area of the bull's eye lesions may be seen on optical coherence tomography. Electroretinography may be normal or show decreased scotopic and photopic responses [151]. There may also be associated photoreceptor degeneration [152]. One study of 14 patients homozygous for the c.271dupA (p.R91KfsX14) reported nystagmus (64 percent), strabismus (52 percent), macular degeneration (72 percent), optic nerve pallor (68 percent), and vascular changes (64 percent) [153-156]. Ophthalmology consultation is essential.

●Kidney complications – Kidney complications include thrombotic microangiopathy, nephrotic syndrome, HUS [157-160], and chronic kidney disease (CKD). One study of 36 patients with CblC and kidney disease demonstrated that all had intravascular hemolysis, hematuria, and proteinuria, with nephrotic-range proteinuria observed in three [161]. Intermittent dialysis was required in 22 percent of patients, although, dialysis was no longer required in three patients after they started hydroxocobalamin administration. Two-thirds of patients had atypical (diarrhea-negative) HUS. Thrombotic microangiopathy was seen in 44 percent of patients.

●Cardiovascular complications – Pulmonary hypertension has been reported alone [161-164] and with thrombotic microangiopathy [165-167]. Cardiology consultation is important for monitoring the progression of disease due to congenital structural malformations, as well as screening for the development of cardiomyopathy.

●Dermatologic complications – Dermatology evaluation may be helpful for treatment of erosive, desquamating dermatitis [130].

Prognosis — Long-term outcomes, particularly for neurocognitive complications, more closely correlate with the initial metabolic abnormalities than with long-term metabolic control in patients with CblC [7]. Thus, patients diagnosed via newborn screening and treated early usually have better outcomes.

In one study of 36 patients with CblC-associated renal thrombotic microangiopathy, mortality was 100 percent in untreated patients, 79 percent in patients with cardiopulmonary involvement, and 56 percent in patients with neurologic involvement [161]. Long-term outcomes in CblF range from developmental delay to asymptomatic long-term survival [168].

SUMMARY AND RECOMMENDATIONS

●Differential diagnosis – Elevation of methylmalonic acid in the blood is seen in a spectrum of disorders, including isolated methylmalonic aciduria, combined malonic and methylmalonic aciduria, methylmalonic aciduria with homocystinuria, and other cobalaminopathies. (See 'Introduction' above and 'Differential diagnosis' above.)

●Presenting features – Initial presentation may range from an infant that appears to be septic without infection to developmental delay and neurologic disability without metabolic decompensation in older children, adolescents, or adults. (See 'Clinical presentation' above and 'Clinical and laboratory features' above and 'Clinical manifestations' above.)

●Initial evaluation and diagnosis – Initial evaluation includes blood glucose, electrolytes, blood gas with lactate and ammonia, complete blood count (CBC) with differential, urine ketones, and liver function tests. Urine organic acids, plasma acylcarnitines, and plasma total homocysteine and methionine should be obtained for biochemical evaluation. Urine orotic should be included with hyperammonemia. Confirmatory genetic testing is necessary. (See 'Initial evaluation and diagnosis' above.)

●Emergency management – Emergency management is aimed at treating the underlying cause, stopping catabolism, and stabilizing the patient. Patients should be provided with an emergency management letter that contains their diagnosis, a list of common acute complications, initial management recommendations, laboratory evaluation, contraindication of systemic glucocorticoids, and the contact information for the managing clinician. (See 'Significant catabolic event/metabolic decompensation' above and 'Emergency management letter' above.)

●Long-term management – Long-term management is aimed at improving biochemical abnormalities. Management in isolated methylmalonic aciduria may include a diet limited in propiogenic precursors, L-carnitine supplementation, and hydroxocobalamin (vitamin B12) supplementation. In methylmalonic aciduria with homocystinuria, there are no diet limitations, and medications include hydroxocobalamin and betaine to decrease homocysteine. (See 'Long-term management for isolated MMA' above and 'Long-term management for MMA with homocystinuria' above.)