The age of onset and clinical picture are correlated to the phenotype of the disease, which may occur in ages ranging from neonatal period through adulthood [1]. The neonatal form can be fatal within the first month of life. Those with the infantile, or the B12 unresponsive, phenotype are normal at birth but soon develop symptoms with the first few weeks or early infancy. The intermediate B12 responsiveness form appears in infancy or early childhood. There is also an atypical phenotype that occurs in adults but is usually benign and is characterized by increased methylmalonic acid in the urine [1].

The clinical presentation of the majority of affected neonates and children manifests during an episode of metabolic decompensation [1] [11], which is characterized by emesis, dehydration, hypotonia, lethargy, respiratory distress, poor feeding, failure to thrive, and seizures. Patients with MMA may develop recurrent infections, which often precipitates the decompensation [1]. Moreover, renal failure and end-stage liver failure are common in certain phenotypes.

During these acute episodes, neurological features such as seizures and progressive hyperammonemic encephalopathy may occur. Additionally, the metabolic crisis may result in strokes in the brainstem which are typified by dysarthria, dysphagia, dystonia, and choreoathetosis.

They may also exhibit developmental delay and intellectual deficit.

Physical exam

Remarkable findings on the physical exam may include hepatomegaly, lethargy, floppiness, dehydration, and failure to thrive. Additionally, they may display neurological signs and deficits suggestive of stroke.

• Developmental Delay

  See a provider if your child has signs of failure-to-thrive or developmental delays. A low-protein diet can help reduce the number of acidemia attacks. [nlm.nih.gov]

  Affected infants can have vomiting, dehydration, hypotonia, developmental delay and failure to thrive. [ncbi.nlm.nih.gov]

  Common initial findings include vomiting, dehydration, lethargy, developmental delay, hypotonia, failure to thrive, and hepatomegaly. [visualdx.com]

• Poor Feeding

  Clinical considerations: Poor feeding, vomiting, lethargy, tachypnea Dehydration Metabolic ketoacidosis Hyperammonemia Hypoglycemia Referral: If signs are present or infant is ill, check urine ketones and initiate emergency treatment with start IV glucose [archildrens.org]

  Symptoms of a metabolic crisis include: poor feeding vomiting low muscle tone excessive sleepiness irritability rapid breathing muscle spasms If a metabolic crisis is not treated, seizures, stroke, coma, brain damage and sometimes death can occur. [newbornscreening.on.ca]

  The most common signs and symptoms at onset after a period of normal feeding are lethargy or coma, poor feeding with failure to thrive, recurrent vomiting with dehydration, hepatosplenomegaly, respiratory distress, and muscular hypotonia. [accessanesthesiology.mhmedical.com]

  Diagnosis In newborns, a history of poor feeding, increasing lethargy, and vomiting are typical symptoms of MMA. In older infants, an episode of lethargy, often accompanied by seizures, is symptomatic. [encyclopedia.com]

  This leads to a build-up of toxic substances and bouts of serious illness called decompensation events or metabolic crises.[1] Symptoms of a decompensation event include poor feeding, vomiting, trouble breathing, and lack of energy (lethargy). [rarediseases.info.nih.gov]

• Fever

  A 3-month-old male infant had two episodes of fever, projectile vomiting, dehydration, generalized fine tremors and gross metabloic ketoacidosis. [ncbi.nlm.nih.gov]

  Infection, fever, prolonged fasting, or any kind of stress can precipitate and cause acute metabolic decompensation, especially in the first years of life. [pediatrics.or.kr]

  For babies, signs of Cbl A, B can include Sleeping longer or more often Vomiting Weak muscle tone (also called hypotonia) Fever Breathing trouble Increased number of illnesses and infections Increased bleeding and bruising Many of these signs may occur [babysfirsttest.org]

• Pain

  Complete metabolic destructive liquefaction of the pallidi, that is, autopallidotomy, necessitated an alternative, bilateral subthalamic nucleus (STN) target for deep brain stimulation (DBS) with a marked improvement in dystonia and reduction in pain. [ncbi.nlm.nih.gov]

  Wrapping the baby tightly in a blanket, or offering a pacifier dipped in sugar water, may also help ease pain and calm the baby. The hearing test and the CCHD screen should not cause the baby to feel pain, cry, or respond. [nlm.nih.gov]

  Glycogen storage diseases: Problems with sugar storage lead to low blood sugar levels, muscle pain, and weakness. Mitochondrial disorders: Problems inside mitochondria, the powerhouses of cells, lead to muscle damage. [webmd.com]

  These include vomiting, abdominal pain, and feeding intolerance. [newenglandconsortium.org]

  Postoperatively, the patient did not experience pain at rest; however, she experienced mild pain during movement. The patient did not use any rescue analgesic agents in the postoperative period. [jaclinicalreports.springeropen.com]

• Recurrent Infection

  Complications may include: Coma Death Kidney failure Pancreatitis Cardiomyopathy Recurrent infections Hypoglycemia Seek medical help right away if your child is having a seizure for the first time. [medlineplus.gov]

  These may include: decreased muscle tone (hypotonia), failure to thrive, anorexia, delayed development, and recurrent infections with Candida sp. If not treated, catastrophic acidosis, seizures, coma and death can follow. [mmaresearch.com]

  So most do not, beware indicator disturbances in children, among others: * Malas eating and drinking * Food or beverages that are often entry dimuntahkan * Muscle weakness * The growth and development of the subject * Mushroom recurrent infection * Front [infant-health-care.blogspot.com]

  Patients with MMA may develop recurrent infections, which often precipitates the decompensation. Moreover, renal failure and end-stage liver failure are common in certain phenotypes. [symptoma.com]

  Symptoms In most children, the disease is diagnosed in the middle of an episode of metabolic decompensation. [18] Vomiting, dehydration, lethargy, seizures, recurrent infections, and progressive encephalopathy are some features of methylmalonic acidemia [emedicine.com]

• Respiratory Distress

  On admission, she had SBP 130mmHg (above 99th), DBP 75mmHg (above 99th), periorbital and legs pitting edema and respiratory distress. [revistanefrologia.com]

  Clinical description Clinical signs include lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and muscle hypotonia, as well as developmental delay, intellectual deficit, hepatomegaly and coma. [orpha.net]

  The most common signs and symptoms at onset after a period of normal feeding are lethargy or coma, poor feeding with failure to thrive, recurrent vomiting with dehydration, hepatosplenomegaly, respiratory distress, and muscular hypotonia. [accessanesthesiology.mhmedical.com]

• Aspiration

  Given the long duration and unusual severity of the cytopenias, evolving aplastic anemia was considered, and a bone marrow aspirate and biopsy were performed. [bloodjournal.org]

  Bone marrow aspiration (BMA) was performed because of pancytopenia which was normal. Patient's hypertension did not respond to Losartan, Hydralazine, Captopril and Amlodipine. [revistanefrologia.com]

  On biochemical analysis, the yellow fluid within the cyst resembles cerebrospinal fluid [3],[6] Aspiration of cyst is the simplest mode of management but the cyst usually recurs. [ijo.in]

  Where there exists a high risk for aspiration or a contraindication to enteral feeding, consideration should be given to providing a specialized parenteral amino acid solution available through specific TPN pharmacies. 3. [newenglandconsortium.org]

• Vomiting

  She had clinical signs of diabetic ketoacidosis such as dehydration, deep sighing respiration, smell of ketones, lethargy, and vomiting. Laboratory analysis showed hyperglycemia with acidosis and ketonuria. [ncbi.nlm.nih.gov]

• Failure to Thrive

  Complications may include: Coma Death Kidney failure Seek medical help right away if your child is having a seizure for the first time. See a provider if your child has signs of failure-to-thrive or developmental delays. [nlm.nih.gov]

  Affected infants can have vomiting, dehydration, hypotonia, developmental delay and failure to thrive. [ncbi.nlm.nih.gov]

  Typical episodic features include vomiting, dehydration, lethargy, failure to thrive, hypotonia, seizures, and even coma. Long-term complications such a metabolic stroke and renal failure may occur. [symptoma.com]

  Complications Coma Death Kidney failure Calling your health care provider Seek immediate medical help if a child is having a seizure for the first time. See a pediatrician if your child has signs of failure-to-thrive or developmental delays. [nicklauschildrens.org]

• Dysphagia

  Uncoordinated muscle movements (choreoathetosis), disordered muscle tone ( dystonia ), slurred speech (dysarthria), and difficulty swallowing (dysphagia), when observed in individuals affected with MMA may be signs of an acidemia-induced stroke. [encyclopedia.com]

  […] hypotonia, floppiness Developmental delay Facial dysmorphism (eg, high forehead, broad nasal bridge, epicanthal folds, long smooth philtrum, triangular mouth) Skin lesions (eg, moniliasis) Occasional hepatomegaly Acute onset of choreoathetosis, dystonia, dysphagia [emedicine.medscape.com]

  Additionally, the metabolic crisis may result in strokes in the brainstem which are typified by dysarthria, dysphagia, dystonia, and choreoathetosis. They may also exhibit developmental delay and intellectual deficit. [symptoma.com]

  In patients with methylmalonic acidemia, acute onset of choreoathetosis, dystonia, dysphagia, or dysarthria should alert the physician to the possibility of stroke. [emedicine.com]

• Abdominal Pain

  Some symptoms of inherited metabolic disorders include: Lethargy Poor appetite Abdominal pain Vomiting Weight loss Jaundice Failure to gain weight or grow Developmental delay Seizures Coma Abnormal odor of urine, breath, sweat, or saliva The symptoms [webmd.com]

  These include vomiting, abdominal pain, and feeding intolerance. [newenglandconsortium.org]

  Written informed consent was obtained prior to the report. 2 Case report The patient was admitted to our emergency department because of intermittent cramping abdominal pain, nausea, vomiting, and progressive exertional dyspnea. [journals.lww.com]

  Abdominal pain (97%) was a major symptom, and weight loss (88%), diarrhea (85%), and arthralgia (12%) followed it. However, other extraintestinal manfestations were very rare. [kiss.kstudy.com]

• Diarrhea

  Zinc dependency as a cause of chronic diarrhea in variant acrodermatitis enteropathica. Pediatrics. 1982;69(6):773-7. 22. Koch SE, Packman S, Koch TK, Williams ML. Dermatitis in treated maple syrup urine disease. [ijp.mums.ac.ir]

  Clinical manifestations were various and mainly related to neurologic, respiratory and gastrointestinal symptoms such as poor response, coma, drowsiness, abnormal muscle tone, convulsions, polypnea, dyspnea, milk refusal, diarrhea and jaundice. [flipper.diff.org]

  HUS is defined as a triad of azotemia, thrombocytopenia, and microangiopathic hemolytic anemia, often preceded by a prodrome of hematic diarrhea (15). [ajnr.org]

  The chronic SBBO was diagnosed based on recurring symptoms of gaseous abdominal discomfort and diarrhea confirmed by abnormal hydrogen breath test. He responded to periodic antibiotics (metronidazole) and decreasing consumption of simple sugars. [journals.lww.com]

  To prevent serious health problems, call your doctor right away when your child has any of the following: loss of appetite vomiting diarrhea infection or illness fever When ill, your child needs extra fluids and carbohydrates in order to prevent a metabolic [newbornscreening.info]

• Hypotension

  Impairment of autonomic function does not appear specifically related to dialysis-induced hypotension or hypotension in chronic dialysis. [kiss.kstudy.com]

• Hepatomegaly

  Two days after her discharge, after having a meal rich in protein, she was brought unconscious with hepatomegaly, severe acidosis, ketonuria, and mild hyperammonemia. [ncbi.nlm.nih.gov]

  Common initial findings include vomiting, dehydration, lethargy, developmental delay, hypotonia, failure to thrive, and hepatomegaly. [visualdx.com]

  Clinical description Clinical signs include lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and muscle hypotonia, as well as developmental delay, intellectual deficit, hepatomegaly and coma. [orpha.net]

• Muscle Hypotonia

  Clinical description Clinical signs include lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and muscle hypotonia, as well as developmental delay, intellectual deficit, hepatomegaly and coma. [orpha.net]

  These 27 patients were also accompanied with other neurological manifestations including mental retardation or regression (n=22), lethargy (n=10), increased muscle tone (n=8), muscle hypotonia (n=8), recurrent vomiting (n=4), tremor (n=2), ataxia (n=2 [ncbi.nlm.nih.gov]

• Floppy Muscle

  Symptoms of MMA may include vomiting, “floppy” muscles, and excessive fatigue. Children with MMA do not gain weight and grow as they would be expected to. Jerry Vockley, MD, PhD Chief of Medical Genetics Dr. [chp.edu]

  Some of the first symptoms of a metabolic crisis are: poor appetite vomiting extreme sleepiness or lack of energy low muscle tone (floppy muscles and joints) Common blood and urine findings are: ketones in the urine high levels of acidic substances in [newbornscreening.info]

• Kidney Failure

  He died 20 days after admission with severe kidney failure (creatinine 1.3mg/dl, urea 193mg/dl, potassium 6.6mEq/l). [revistanefrologia.com]

  Complications may include: Coma Death Kidney failure Seek medical help right away if your child is having a seizure for the first time. See a provider if your child has signs of failure-to-thrive or developmental delays. [nlm.nih.gov]

  Complications Coma Death Kidney failure Calling your health care provider Seek immediate medical help if a child is having a seizure for the first time. See a pediatrician if your child has signs of failure-to-thrive or developmental delays. [nicklauschildrens.org]

• Lethargy

  Diagnosis In newborns, a history of poor feeding, increasing lethargy, and vomiting are typical symptoms of MMA. In older infants, an episode of lethargy, often accompanied by seizures, is symptomatic. [encyclopedia.com]

  A 14 month-old boy presented with an acute generalized dystonia and lethargy preceded by fever, vomiting and lethargy at the age of 13 months. Biological investigations showed a hyperglycemia, a lactic acidosis and a hyperammonemia. [ncbi.nlm.nih.gov]

  Typical episodic features include vomiting, dehydration, lethargy, failure to thrive, hypotonia, seizures, and even coma. Long-term complications such a metabolic stroke and renal failure may occur. [symptoma.com]

  Older infants or children with one of the other forms of MMA or mild mut- may present for the first time during an episode of decompensation with lethargy, seizures, and hypoglycemia. [emedicine.medscape.com]

• Seizure

  The seizure types included partial seizure (n=21), generalized tonic-clonic seizure (n=5), tonic seizure (n=3), myoclonic seizure (n=3), and epileptic spasms (n=2). Five patients had two or three seizure types. [ncbi.nlm.nih.gov]

  The disease can cause seizures and stroke. [nlm.nih.gov]

  During these acute episodes, neurological features such as seizures and progressive hyperammonemic encephalopathy may occur. [symptoma.com]

• Encephalopathy

  A child was seen because of encephalopathy and metabolic ketoacidosis at 19 months. She was found to have a cobalamin-responsive form of methylmalonic acidemia of the cbl A complementation group. [ncbi.nlm.nih.gov]

  Most presented with neurological symptoms including cognitive decline, hypertensive encephalopathy, unsteady gait, myelopathy, and behavioral abnormalities. [emedicine.com]

  Symptoms include: Brain disease that gets worse (progressive encephalopathy) Dehydration Developmental delays Failure to thrive Lethargy Repeated yeast infections Seizures Vomiting Treatment consists of cobalamin and carnitine supplements and a low-protein [nlm.nih.gov]

• Dystonia

  This case of total body dystonia due to MMA in a 4-year-old boy had been medically refractory for 15 months. [ncbi.nlm.nih.gov]

  Severe generalized dystonia induced by metoclopramide in a girl with methylmalonic acidemia. Brain Dev. 2003 Mar. 25(2):144-5. [Medline]. Dobson CM, Wai T, Leclerc D, et al. [emedicine.medscape.com]

  Gene MUT (AR) Diagnostic Test Urine Organic Acids, Acylcarnitine Profile Neurological Encephalopathic crisis, psychosis/depression, stroke, dystonia, Basal ganglia lesions (MRIscan) Non-Neurological Renal insufficiency, alopecia, pancytopenia, (pseudo [treatable-id.org]

  She had microcephaly, generalized hypotonia, brisk stretch reflexes, extensor plantar response, choreiform movements, and dystonia of hands and feet. Evaluation showed metabolic acidosis and hyperammonemia. [neurology.org]

• Dysarthria

  In patients with methylmalonic acidemia, acute onset of choreoathetosis, dystonia, dysphagia, or dysarthria should alert the physician to the possibility of stroke. [emedicine.com]

  Uncoordinated muscle movements (choreoathetosis), disordered muscle tone ( dystonia ), slurred speech (dysarthria), and difficulty swallowing (dysphagia), when observed in individuals affected with MMA may be signs of an acidemia-induced stroke. [encyclopedia.com]

Neonates and children presenting with clinical features suspicious for MMA should be evaluated thoroughly through a personal and family history. The clinician should ascertain specifics in the family history such as neonatal deaths, neurological disorders, consanguinity, and evidence of similar symptoms in siblings. Additionally, the clinician should perform a full physical exam and obtain the pertinent studies.

Laboratory tests

The investigation is typically comprehensive with a myriad of findings. In addition to a clinical picture suggestive of MMA and positive results for methylmalonic acid on urine organic acid screen, further testing will support the diagnosis. For example, the baseline studies in these patients will reveal anemia, neutropenia as well as thrombocytopenia on complete blood count (CBC), high anion gap metabolic acidosis on arterial blood gas, lactic acidosis, hyperammonemia, and ketonuria. Additionally, plasma glucose, electrolytes, renal functional tests, and amylase and lipase are also ordered.

Note that while levels of methylmalonic acid in the plasma and urine are elevated, B12, homocysteine, and methionine are normal. These combined findings will exclude differential diagnoses. Hence, all of these must be performed in all individuals suspected to have MMA.

In another context, asymptomatic neonates may have positive newborn screening for propionylcarnitine (C3). When this occurs, gas chromatography-mass spectrometry (GC-MS) will confirm the high levels of methylmalonic acid if they truly have the disease. There are also other biochemicals that may be positive.

Vitamin B12 response

Testing is also done through observation of the patient's response to administered vitamin B12. This is monitored by measurements of plasma methylmalonic acid, C3, and homocysteine and/or urine organic acid analyses. A successful response is indicated by a greater than 50% decrease in plasma concentration [12] [13].

Biochemical and genetic studies

The gold standard study in characterizing the subtype of MMA involves biochemical testing on skin fibroblasts using vitamin B12 in vitro. The responsiveness will allow for the distinction of which subtype is the culprit.

Genetic analysis can establish the diagnosis of MMA through detection of the specific phenotype. In vitamin B12 unresponsive patients, the clinician should assess for mutations in MUT and MMAB genes while vitamin B12 responsive individuals will be evaluated for defects in the MMAA gene. If these genes are not involved, then there is further testing other genes.

Newborn screening

Many states and countries across the globe have implemented mass spectrometry in newborn screening, which has resulted in the detection of C3 and the diagnosis of MMA [14]. Although the C3 marker lacks specificity, it may help identify affected newborns early [14].

Imaging

Computed tomography (CT) and/or magnetic resonance imaging (MRI) of the brain will be performed if a stroke is suspected.

• Ketonuria

  Laboratory analysis showed hyperglycemia with acidosis and ketonuria. She was treated with parenteral fluid, electrolyte, and insulin infusion. [ncbi.nlm.nih.gov]

  An inborn error leading to metabolic acidosis, long-chain ketonuria and intermittent hyperglycinemia. [^] 8. Rosenberg LE et al. (1968) Methylmalonic aciduria: metabolic block localization and vitamin B 12 dependency. [^] 9. [moldiag.com]

  For example, the baseline studies in these patients will reveal anemia, neutropenia as well as thrombocytopenia on complete blood count (CBC), high anion gap metabolic acidosis on arterial blood gas, lactic acidosis, hyperammonemia, and ketonuria. [symptoma.com]

• Methylmalonic Acid Increased

  […] acidemia is a progressive condition; the symptoms of this disorder are compounded as the concentration of methylmalonic acid increases. [en.wikipedia.org]

• Hypoglycemia

  Hence, the constellation of laboratory findings in MMA is the following: Metabolic acidosis with anion gap Ketonuria Hypoglycemia Hyperammonemia Hyperglycinemia The ketoacidosis, hyperammonemia and hypoglycemia can explain the lethargy and obtundation [newenglandconsortium.org]

  Methylmalonic acidemia, an inherited metabolic disease affecting the catabolism of propionic acid, is manifested by persistent metabolic acidosis, urinary excretion of large amounts of methylmalonic acid, and occasionally by hypoglycemia. [ncbi.nlm.nih.gov]

  […] branched-chain amino acids; metabolites accumulate in body fluids and render a "maple syrup" odor; divided into classic, intermediate, intermittent, and thiamine responsive subtypes; classic form presents in the first week of life with ketoacidosis, hypoglycemia [icd9data.com]

• Neutropenia

  We report an infant with methylmalonic acidemia who presented severe neutropenia. [ncbi.nlm.nih.gov]

  2004 47 Growth hormone deficiency associated with methylmalonic acidemia. 61 24 Al-Owain M...Thomas J 15055362 2004 48 Living-related liver transplantation for methylmalonic acidemia: report of one case. 61 24 Hsui JY...Hwu WL 14521026 2003 49 Severe neutropenia [malacards.org]

  For example, the baseline studies in these patients will reveal anemia, neutropenia as well as thrombocytopenia on complete blood count (CBC), high anion gap metabolic acidosis on arterial blood gas, lactic acidosis, hyperammonemia, and ketonuria. [symptoma.com]

  These patients can also have hypotonia, hepatomegaly, liver dysfunction, and neutropenia, thrombocytopenia, or pancytopenia due to secondary bone-marrow suppression. Others can present with Reye-like syndrome. [invitae.com]

  Prolonged metabolic decompensation can lead to bone marrow suppression with resulting neutropenia. [newenglandconsortium.org]

• Leukopenia

  Biochemically, the disorder is typically characterized by: metabolic acidosis, ketonemia or ketonuria, hyperammonemia, leukopenia, thrombocytopenia and anemia. Hypoglycemia is a frequent manifestation of MMA. [ncbi.nlm.nih.gov]

  Metabolic disorders are well known to initiate this response by altering normal cell functions. [6] During acidotic crises methylmalonic acid suppresses bone marrow resulting in anemia, leukopenia and thrombocytopenia. [sjkdt.org]

Since the patients are at risk for severe complications such as stroke and coma, the treatment must be initiated early and promptly while the workup is being performed. They should be stabilized, protein intake should be terminated, and intravenous glucose must be administered along with volume and electrolyte replacement.

As part of the crucial inpatient management, these individuals are placed on a protein-restricted diet with nutritional supplementation of 1) L-carnitine, which metabolizes long-chain fatty acids and helps promote the excretion of acyl-CoA metabolites that result from low protein diets and 2) vitamin B12 (cobalamin) which is a cofactor in the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA.

As dietary modifications are being implemented, the patient is assessed clinically and quantitatively through measurement of methylmalonic acid in the urine. Typically, vitamin B12 responsive patients will experience better outcomes in comparison to those who are vitamin B12 unresponsive [15] [16].

The overall nutrition needs to be carefully managed. Moreover, ill infants may require total parenteral nutrition (TPN). Additionally, plasma amino acids, electrolytes, and urine output should be monitored frequently.

Other

Infections and other coexisting complications will be treated appropriately.

Liver and kidney transplantation are considered in children with certain phenotypes and clinical manifestations.

Prevention of recurrent episodes

Patients should adhere to a diet low in protein in order to prevent further episodes of metabolic crises and to avoid the development of organ damage [1]. The clinical team will provide the parents and/or caretakers with education on the correct diet for the child. Additionally, nutritionists and other specialists are available to help guide families through this process.

The outcomes associated with MMA have improved with better management in neonatal and long-term contexts when comparing pre and post- 1990. In recent decades, less than 20% died in infancy or prior to the age of 10 [10], although the surviving patients exhibited poor nutrition as well as growth retardation. Furthermore, approximately 40% demonstrated neurological deficits. However, 40% showed a developmental improvement [10]. The same study also observed a better quality of life in the few that have received organ transplantation (liver and/or kidney). Overall, the investigation suggested that long-term metabolic and nutritional strategies are paramount in children with MMA [10].

Another study reported that patients with the mut0 subtype had a 100% mortality rate (at a median age of 1.6 years) in the 1970s. However, in the 1990s, this rate was 20% and the related median age was 2.2 years [11]. The report also noted that mortality was greatest in the mut0 subtype (50% at the median age of 2), followed by cblB (50% at the median age of 2.9), mut– (40% at the median age of 4.5), and cblA enzymatic subtype (rare) [11].

There are two types of this autosomal recessive disorder. The vitamin B12 responsive form occurs secondary to impaired synthesis of AdoCbl, which is a cofactor for the conversion of methylmalonyl-CoA to succinyl-CoA. Mutations occur in one of three proteins that is involved in the production of AdoCbl: MMAA, MMAB and MMADHC. These are associated with distinct subtypes: MMA cblA, MMA cblB, and MMA cblD [1] [2] [3] [4].

The vitamin B12 unresponsive type results from a genetic mutation in the mitochondrial enzyme methylmalonyl-CoA mutase (MUT) itself. The deficiency of the activity of MUT can be complete (mut0) or partial (mut-) [1] [2] [3] [4]. Moreover, the mut0 apoenzyme has no activity while the mut- subtype exhibits low to moderate activity [1] [2] [3] [4].

In North America, the prevalence of MMA is 1 in 48,000 to 1 in 61,000 live births [1]. It is more common in China with a prevalence of 1 in 26,000 [1]. The prevalence of isolated cases of MMA overall is thought to be 1 in 50,000 newborns [5].

There is no gender preference. Additionally, the disease may occur more frequently in populations with increased consanguinity.

MMA is caused by an insufficiency of L- methylmalonyl-CoA mutase activity or an abnormality in the synthesis of AdoCbl. Specifically, methylmalonyl-CoA mutase plays a role in the catabolism of isoleucine, valine, methionine, threonine, thymine, as well as cholesterol, and certain fatty acids [6]. Therefore, low activity of this enzyme will result in the build up of methylmalonic acid in tissues such as the brain, which produces neurological complications and damage to the globus pallidus [6].

Researchers investigating the neurological symptoms found in MMA patients have reported that this metabolite inhibits key enzymes such as pyruvate carboxylase, which is required for energy metabolism pathways in the brain [7]. Other studies found that methylmalonic acid impairs the mitochondrial utilization of ketone bodies in the brain [8]. Further in vivo studies have demonstrated antagonistic effects of methylmalonic acid on the respiratory chain complex mechanisms, which ultimately leads to a deficiency in energy for the brain [9]. These conclusions, as well as plenty of others, may explain the neurological outcomes that occur in individuals with this metabolic disorder.

Genetic counseling and testing are available for family members who are at risk of being carriers. Additionally, prenatal testing for high-risk patients may be offered if the pathogenic variants in the family have been identified. Prenatal diagnosis may be obtained by using cultured fetal cells retrieved through chorionic villus sampling or amniocentesis. Enzymatic and metabolite analysis of the sample will determine the diagnosis of the fetus.

Methylmalonic acidemia (MMA) is a rare autosomal recessive disorder that develops from an inborn error in the metabolism of vitamin B12. This type of organic acidemia emerges from either genetic mutations that cause a deficiency in the activity of mitochondrial enzyme methylmalonyl-CoA mutase or an impairment in the synthesis of adenosylcobalamin (AdoCbl). As a result, there are two forms of MMA which are classified as vitamin B12 unresponsive or vitamin B12 responsive.

The clinical presentation typically manifests during the neonatal period or early childhood. Typical episodic features include vomiting, dehydration, lethargy, failure to thrive, hypotonia, seizures, and even coma. Long-term complications such a metabolic stroke and renal failure may occur.

The assessment of neonates and children suspected to have MMA and newborns with positive screening includes a detailed personal and family history. Additionally affected individuals warrant a physical exam and a thorough workup that includes the demonstration of elevated plasma and urine levels of methylmalonic acid and hallmark findings such as high anion gap metabolic acidosis, increased lactate, hyperammonemia, and ketonuria. Further studies include the patient's response to vitamin B12 treatment, as well as biochemical and genetic testing.

The treatment requires stabilization, infusion of glucose, withdrawal of protein intake, and the initiation of a low protein diet with vitamin B12 and carnitine supplementation. In certain cases, liver and/or kidney transplantation may be attempted to relieve or prevent the disease from developing.

Overall, the therapeutic principles consist of improving the child's nutritional status and tailoring the diet according to the disease, which have resulted in better outcomes over the past decades. Hence, the long-term management should include goals that focus on implementing a diet that maintains a metabolic balance.

What is Methylmalonic Acidemia (MMA)?

MMA is composed of a group of genetic disorders that affect the breakdown of certain proteins and fats. Therefore, methylmalonic acid builds up in the blood and tissues such as the brain. This occurs due to errors in the metabolism.

What are the causes of MMA?

This disorder is caused by inherited genetic mutations. Specifically, it is inherited in an autosomal recessive pattern. This means that the affected individual inherits a bad copy of the gene from each parent. In other words, the patient must receive two bad copies in order to develop MMA.

What are the signs and symptoms of MMA?

The signs and symptoms usually develop in patients while they are young infants or children. These features include:

• Vomiting
• Dehydration
• Lethargy
• Seizures
• Poor muscle tone
• Stroke
• Trouble with breathing
• Repeated episodes of yeast infections
• Coma
• Developmental delay
• Intellectual deficit

These symptoms can worsen if the child gets an infection, starves, or eats too much protein.

How is it diagnosed?

Infants and children with the above signs and symptoms or with specific findings on newborn screening biochemical tests will raise suspicion for this disorder. The clinician will obtain a thorough history of the patient and the family. Additionally, s/he will perform a physical exam and order very important blood tests such as:

• Methylmalonic acid levels (high in the blood and urine)
• Amino acid levels (high)
• Complete blood count
• Electrolytes
• Ammonia (high)
• Arterial blood gas
• Genetic and biochemistry tests

How is it treated?

Since patients usually present in a state of critical illness, they are immediately hospitalized and stabilized. They are treated with:

• Intravenous glucose and fluids
• Placed on a diet low in protein
• Given nutritional supplementation with vitamin B12 and carnitine

There is no cure but the symptoms can be controlled by adhering to a strict diet. In fact, long-term management of diet and nutrition is necessary in order to prevent further episodes from recurring.

Can it be prevented?

Since this disease is inherited, it cannot be prevented.

Genetic counseling and testing are offered to family members at risk for being a carrier of the disease. Prenatal testing may be offered in high-risk pregnancies.

What is the prognosis?

The prognosis has improved over the past few decades. This is due to the implementation of a diet that is low in protein as well as other specific modifications tailored to the child's disease.

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