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Methylmalonic Acidemia

Methylmalonic Aciduria

Methylmalonic acidemia (MMA) is a rare metabolic disorder that results as a consequence of the accumulation of toxic levels of methylmalonic acid. This rare condition is associated with serious sequelae such as neurological manifestations and/or even organ failure.

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Presentation

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]
  • Mutations in the X-linked gene CDKL5 cause early-onset epileptic encephalopathy and severe developmental delay. Because this disorder predominantly affects females, the full clinical spectrum of male patients remains elusive.[ncbi.nlm.nih.gov]
  • The clinical presentation is relatively nonspecific, such as feeding difficulty, recurrent vomiting, hypotonia, lethargy, seizures, progressive developmental delay, and mental retardation, together with anemia and metabolic acidosis.[ncbi.nlm.nih.gov]
  • All patients showed evidence of developmental delay with the exception of one patient with a genotype predictive of attenuated disease and near-normal biochemical parameters.[ncbi.nlm.nih.gov]
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]
  • History A history of poor feeding, vomiting, progressive lethargy, floppiness, and muscular hypotonia in a newborn who has been healthy for the first 1-2 weeks of life is typical for methylmalonic acidemia (MMA) mut0 or MMA mut-.[emedicine.medscape.com]
  • The clinical presentation of the majority of affected neonates and children manifests during an episode of metabolic decompensation, which is characterized by emesis, dehydration, hypotonia, lethargy, respiratory distress, poor feeding, failure to thrive[symptoma.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]
Recurrent Infection
  • 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]
  • Other complications that may occur include renal disease which may result in chronic renal failure ; pancreatitis ; cardiomyopathy ; recurrent infections; and hypoglycemia. [4] Survival in individuals with MMA has improved over time.[rarediseases.info.nih.gov]
  • 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.medscape.com]
Fatigue
  • Patients with methylmalonic acidemia with homocystinuria of all types can present with developmental delay, signs of megaloblastic anemia (pallor, fatigue, and anorexia), lethargy and seizures.[orpha.net]
  • 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]
  • [14] In one study, approximately 10% of patients with MMA had tubulointerstitial nephritis and was an important cause of renal failure in these patients. [15] When discovered, these patients may give a history of polydypsia, nocturia, weight loss or fatigue[sjkdt.org]
Hypoxemia
  • These lesions constitute a "metabolic stroke," probably because of the accumulation of toxic organic acid metabolites, because they cannot be accounted for by hypoxemia or vascular insufficiency.[ncbi.nlm.nih.gov]
Respiratory Distress
  • Affected infants often have recurrence of acute illness with metabolic acidosis, vomiting, failure to thrive, lethargy, hypotonia, hepatomegaly, seizures and respiratory distress.[genedx.com]
  • The clinical presentation of the majority of affected neonates and children manifests during an episode of metabolic decompensation, which is characterized by emesis, dehydration, hypotonia, lethargy, respiratory distress, poor feeding, failure to thrive[symptoma.com]
  • Symptoms may include lethargy, failure to thrive, recurrent vomiting, acidosis, dehydration, respiratory distress, diminished muscle tone, developmental retardation, seizures and/or an enlarged liver.[rarediseases.org]
  • 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]
  • distress [7] Cause [ edit ] Genetic [ edit ] Methylmalonic acidemia has an autosomal recessive pattern of inheritance.[en.wikipedia.org]
Sighing
  • 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]
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]
  • The clinical signs are recurrent episodes of ketoacidosis and bouts of vomiting, dehydration and mental retardation. These symptoms do not respond to the administration of vitamin B12.[ncbi.nlm.nih.gov]
  • Although propionic acidemia and methylmalonic acidemia, two disorders of branched-chain amino acid metabolism often complicated by chronic anorexia and vomiting, are not usually treated with parenteral nutrition for fear of amino acid overload and exacerbation[ncbi.nlm.nih.gov]
  • Affected infants can have vomiting, dehydration, hypotonia, developmental delay and failure to thrive.[ncbi.nlm.nih.gov]
  • 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]
Failure to Thrive
  • 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]
  • Methylmalonic acidemia (MMA) is an inborn error of organic acid metabolism that occurs in infancy with hypotonia, vomiting, dehydration, lethargy and failure to thrive and is biochemically characterized by metabolic ketoacidosis, hyperammonemia and sometimes[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]
Dysphagia
  • […] 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]
  • 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]
  • In patients with methylmalonic acidemia, acute onset of choreoathetosis, dystonia, dysphagia, or dysarthria should alert the physician to the possibility of stroke.[emedicine.medscape.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]
  • Affected infants can experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delay, excessive tiredness (lethargy), an enlarged liver (hepatomegaly), and failure to gain weight and grow at the expected rate (failure to thrive).[ghr.nlm.nih.gov]
  • They include vomiting, dehydration, hypotonia, developmental delays, hepatomegaly, lethargy, intellectual disabilities, and chronic kidney disease.[icd10data.com]
  • Acute Presentation Lethargy, altered mental status Nausea, vomiting Hepatomegaly Laboratory Findings Hypoglycemia Metabolic acidosis with anion gap Hyperammonemia There are two types of presentation, depending on the severity of the metabolic defect.[newenglandconsortium.org]
Muscle Hypotonia
  • 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]
  • 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]
Floppy Muscle
  • Symptoms of MMA may include vomiting, “floppymuscles, 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]
Skeletal Dysplasia
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]
  • "Even with careful management, children with MMA often experience severe chronic symptoms including cognitive disability, growth problems, seizures, kidney failure, and acute life-threatening metabolic attacks triggered by common infections."[ir.ptcbio.com]
Cesarean Section
  • Complications observed in pregnancies of women with MMA can include acute decompensation or hyperammonemia, deterioration of renal function, and obstetric complications including preeclampsia, preterm delivery, and cesarean section [ Raval et al 2015[ncbi.nlm.nih.gov]
Renal Injury
  • We speculate that prevention of renal injury may require lower tissue levels of MMA and its precursors than those required for prevention of ketoacidosis.[ncbi.nlm.nih.gov]
Lethargy
  • 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]
  • 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]
  • Methylmalonic acidemia (MMA) is an inborn error of organic acid metabolism that occurs in infancy with hypotonia, vomiting, dehydration, lethargy and failure to thrive and is biochemically characterized by metabolic ketoacidosis, hyperammonemia and sometimes[ncbi.nlm.nih.gov]
  • In the preoperative period, all patients showed lethargy and cognitive deficit, both of which were eradicated after LDLT in all surviving patients.[ncbi.nlm.nih.gov]
  • […] of propionyl-CoA carboxylase PCC, the enzyme that converts propionate to methylmalonate and with biotin as a cofactor; caused by a mutation in the gene PCCA encoding propionyl-CoA on 13q or PCCB on 3q; the clinical features are episodic vomiting and lethargy[medical-dictionary.thefreedictionary.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]
  • At 9 months of age, he developed brief tonic seizures, which showed polyspike bursts under EEG. His psychomotor development continued to deteriorate.[ncbi.nlm.nih.gov]
  • The disease can cause seizures and stroke.[nlm.nih.gov]
  • Hyperammonemia at diagnosis and the presence of a seizure disorder were associated with a lower FSIQ (P .001 and P .041, respectively), but other clinical variables, including basal ganglia injury and mutation status, did not.[ncbi.nlm.nih.gov]
  • Recognition of poor feeding, vomiting, dehydration, hypotonia, respiratory distress, and seizure may help in identifying ongoing metabolic decompensation.[emedicine.medscape.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]
  • Mutations in the X-linked gene CDKL5 cause early-onset epileptic encephalopathy and severe developmental delay. Because this disorder predominantly affects females, the full clinical spectrum of male patients remains elusive.[ncbi.nlm.nih.gov]
  • BACKGROUND: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are rare hereditary disorders of protein metabolism, manifesting early in life with ketoacidosis and encephalopathy and often resulting in chronic complications.[ncbi.nlm.nih.gov]
  • 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]
  • Most presented with neurological symptoms including cognitive decline, hypertensive encephalopathy, unsteady gait, myelopathy, and behavioral abnormalities.[emedicine.medscape.com]
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]
  • 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]
  • 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]
  • 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]
  • 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.medscape.com]
  • […] 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, and dysarthria[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]

Workup

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.

Focal Epileptiform Discharges
  • Serial electroencephalograms detected recurrent focal epileptiform discharges from age 4 months, which evolved to hypsarrhythmia later in infancy.[ncbi.nlm.nih.gov]
Ketonuria
  • Laboratory analysis showed hyperglycemia with acidosis and ketonuria. She was treated with parenteral fluid, electrolyte, and insulin infusion.[ncbi.nlm.nih.gov]
  • 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]
  • All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy.[ncbi.nlm.nih.gov]
  • 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]
  • […] seizures, and hypertonia; the intermediate and intermittent forms present in childhood or later with acute episodes of ataxia and vomiting Applies To Disturbances of metabolism of leucine, isoleucine, and valine Hypervalinemia Intermittent branched-chain ketonuria[icd9data.com]
Liver Biopsy
  • KEYWORDS: Methylmalonic acidemia; electron microscopy; liver biopsy; mitochondria[ncbi.nlm.nih.gov]

Treatment

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.

Prognosis

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].

Etiology

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].

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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.

Summary

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.

Patient Information

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:

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.

References

Article

  1. Manoli I, Sloan JL, Venditti CP. Methylmalonic Acidemia. Gene Reviews®. Seattle, Washington: University of Washington, Seattle; 2005 [updated 2016 Jan 7].
  2. Melo DR, Kowaltowski AJ, Wajner M, et al. Mitochondrial energy metabolism in neurodegeneration associated with methylmalonic acidemia. Journal of Bioenergetics and Biomembranes. 2011;43(1):39–46.
  3. Imataka G, Sakamoto O, Yamanouchi H, et al. Novel c.2216t> c (p.i739t) mutation in exon 13 and c.1481t > a (p.l494x) mutation in exon 8 of mut gene in a female with methylmalonic acidemia. Cell Biochemistry and Biophysics. 2013;67(1):185–87.
  4. Coelho D, Suormala T, Stucki M, et al. Gene identification for the cblD defect of vitamin B12 metabolism. New England Journal of Medicine. 2008;358(14):1454-64.
  5. Carrillo-Carrasco N, Venditti C. Propionic Acidemia. Seattle,WA: University of Washington;2012.
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Last updated: 2019-07-11 20:49