3-alpha-methylcrotonylglycinuria

Neurogenetic Disorders

Updated 09.28.2023
Released 09.19.2003
Expires For CME 09.28.2026

3-alpha-methylcrotonylglycinuria

Authors: Georg F Hoffmann MD, Friederike Hoerster MD

See Contributor Disclosures

Editor: Deepa S Rajan MD

3-alpha-methylcrotonylglycinuria

In This Article

Quick Link

Introduction

Overview

In this clinical article, the authors describe the different manifestations of this inborn error of leucine catabolism and explain pathophysiology, disease diagnosis, and treatment. 3-alpha-methylcrotonylglycinuria appears to be the most common as well as one of the most puzzling of the organoacidopathies. Clinical presentations range from severe neonatal metabolic decompensation and lethal outcome to mostly asymptomatic adults never diagnosed nor treated. This review explains the current knowledge and management of this disease, which can present to pediatricians, neurologists, and internists.

Historical note and terminology

3-alpha-methylcrotonylglycinuria is an inborn error of leucine catabolism due to a deficiency of 3-methylcrotonyl-CoA carboxylase. As the enzyme requires biotin as a cofactor, the isolated enzymatic defect must be differentiated from other forms of methylcrotonylglycinuria caused by deficiencies in the biotin pathway (biotinidase and holocarboxylase synthetase deficiencies). The disease has a wide range of manifestations. Very few affected infants develop severe metabolic crisis, ketoacidosis, and vomiting that may lead to coma and death without appropriate treatment. On the other hand, most individuals remain symptom-free for life. The key metabolites leading to diagnosis are 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in urine and 3-hydroxyisovalerylcarnitine in plasma.

The first case reports of 3-alpha-methylcrotonylglycinuria date from 1970, and it was postulated that 3-methylcrotonyl-CoA carboxylase was deficient (48). The enzyme 3-methylcrotonyl-CoA carboxylase is now recognized to be composed of two different subunits. The respective genes were identified in 2001: Gallardo and coworkers as well as Baumgartner and coworkers localized the gene for the alpha-subunit to 3q25-q27 and the gene for the beta-subunit to 5q12-q13 (04; 19). Several pathologic mutations in both genes have been described. Gallardo and colleagues also reported an unexpectedly high incidence of biochemical markers of this disorder detected in newborn screening programs (19).

Clinical manifestations

Presentation and course

Patients with isolated 3-methylcrotonyl-CoA carboxylase deficiency show at least a short period of normal development. Most remain symptom-free throughout their lives, and over time 3-methylcrotonyl-CoA carboxylase deficiency may eventually become classified as a nondisease (02; 21). Comparative analysis of case reports with newborn screening data suggests that without treatment less than 10% of affected individuals ever develop even minor symptoms and less than 1% to 2% have a more severe outcome (46). Reported clinical symptoms vary from mild nonspecific symptoms to a fulminant course with lethality in infancy. In some patients, symptoms have been reported to fit into the spectrum of metabolic diseases similar to other classical organic acidemias or to be rather nonspecific, such as isolated epilepsy or failure to thrive. A neonate who presented in the first day of life and progressed to necrotizing encephalopathy and death at 33 days of age has been described (06). Two patients who presented with metabolic stroke have been reported (37). Metabolic crises occur most frequently between the ages of 6 months to 3 years but have been described in neonates and older children (48). Crises may be triggered by minor infections. Patients present with vomiting, feeding difficulties, lethargy, and apnea with neurologic symptoms, such as muscular hypotonia, hyperreflexia, spasms, and seizures (focal or generalized). A few patients were found to have neutropenia, loss of scalp hair, and fatty changes of the liver reminiscent of Reye syndrome (48). Death is mainly due to cerebral edema (29) or cardiocirculatory arrest (48).

Laboratory tests may reveal a constellation of findings, including hypoglycemia, elevated liver enzymes, hyperammonemia, mild acidosis, moderate ketosis, and very low plasma carnitine (48). Additional patients with the following possibly related clinical presentations were identified: neonatal failure to thrive, isolated intellectual disability, mental retardation, recurrent attacks of status epilepticus, familial hypotonia or hypertonia, lethargy after head trauma, and severe multiple sclerosis (48; 11; 13).

Often, completely asymptomatic individuals were recognized when family members of patients were investigated (20), including women identified because of low acylcarnitine profiles on their children’s newborn screening. These women were asymptomatic or showed only minor symptoms, such as fatigue, weakness, and myopathy. However, some abnormal laboratory findings have been found, including elevated liver enzymes, elevated uric acid, and low free and total carnitine.

The reason for this broad spectrum of clinical manifestations from early death in metabolic crisis to a mostly asymptomatic and benign course remains as yet poorly understood. A study identified much higher consanguinity in symptomatic patients as compared to asymptomatic patients, and furthermore, it identified damaging mutations in other unrelated genes of these individuals. For example, in one case whole exome sequencing identified a homozygous deletion in IGHMBP2, known to cause spinal muscular atrophy, which was more likely to account for the phenotype of the patient (42). This study strengthens the possibility that 3-methylcrotonyl-CoA carboxylase deficiency may be a nondisease altogether.

Isolated 3-methylcrotonyl-CoA carboxylase deficiency has mostly been reported to be unresponsive to biotin. However, two patients were reportedly biotin-responsive (05). The first patient showed progressive psychomotor retardation and seizures, and biotin treatment resulted in a rapid and dramatic improvement of the clinical and biochemical phenotypes. However, psychomotor delay persisted, and the seizures reoccurred (18). The second patient was detected by newborn screening and remained clinically asymptomatic; the biochemical phenotype was also completely corrected by biotin. In both children, heterozygosity for the mutation MCCC1 p.-R385S was found; thus, this variant may have a dominant-negative effect that is responsive to pharmacological doses of biotin. This mutation has been expressed in Escherichia coli, and detailed kinetic studies have been performed (43), supporting the hypothesis of a dominant-negative effect. Other mutations causing 3-alpha-methylcrotonylglycinuria have also been expressed, and null or severely diminished 3-methylcrotonyl-CoA carboxylase (MCC) activity has been demonstrated, but there is no correlation with the clinical phenotype (12; 02).

Prognosis and complications

With the widely varying clinical spectrum of symptoms, it is difficult to make definite statements about the prognosis of 3-methylcrotonylglycinuria. In the first reports, 3-methylcrotonylglycinemia was associated with a poor prognosis as patients succumbed during acute decompensation or suffered severe sequelae (29). It is reasonable to assume that initiation of treatment before severe metabolic decompensation will significantly ameliorate the patient’s prognosis, including potentially normal psychomotor development. A report of a 19-month-old girl who suffered a severe metabolic crisis due to her parents’ nonadherence to medical advice highlights the importance of follow-up programs to improve parental compliance with treatment recommendations (14).

On the other hand, almost all patients identified by newborn screening appear never to develop symptoms, even without treatment. The lack of genetic or biochemical markers to differentiate these individuals from those who are at risk for decompensation has led to controversy about the benefit of newborn screening for 3-methylcrotonylglycinuria (22; 46; 02; 42; 16; 52).

Gruenert and coworkers reported comprehensive clinical, biochemical, enzymatic, and molecular data on 88 individuals, which is the largest cohort published to date (21). The study confirmed the genetic heterogeneity of 3-methylcrotonylglycinuria and underlined the difficulty in predicting the clinical phenotype because there is no genotype-phenotype correlation and also residual enzyme activity cannot predict the clinical course. Arnold and colleagues reported similar findings in a cohort of 35 children diagnosed by newborn screening; they found an inverse correlation between initial metabolite levels and residual enzyme activity but no relationship with clinical (especially neurologic) outcome (02). The study by Shepard and colleagues even suggests that other independent causative diseases are likely and should be looked for in children with 3-methylcrotonyl-CoA carboxylase deficiency who develop symptoms (42).

Clinical vignette

A 9-year-old boy first developed infantile spasms (Blitz-Nick-Salaam convulsions) at three weeks of the age. The diagnosis of 3-methylcrotonylglycinuria was unfortunately delayed until two years of age when urine analysis revealed massive 3-methylcrotonylglycinuria and 3-hydroxyisovaleric aciduria, suggesting MCC deficiency. Biochemical findings showed partial MCC deficiency in cultured fibroblasts. Molecular genetic studies revealed a heterozygote missense mutation, MCCC1 p.-R385S, converting arginine to serine in a highly conserved region of the MCCC1 gene.

Interestingly, biotin therapy in this patient led to a dramatic decrease in the frequency of seizures, disappearance of hypsarrhythmia, as well as near normalization of organic aciduria. Four months later, a protein-restricted diet was introduced, and the boy remained clinically and metabolically stable. However, severe psychomotor delay persisted, and the seizures partially reoccurred.

At nine years of age, the boy is severely intellectually disabled and exhibits a significant delay in gross motor performance. Generalized hypotonia with lack of head control and tetraparesis is observed. Deep tendon reflexes cannot be elicited. The boy does not sit independently and cannot get up on his own. He is able to sit and walk a few steps supported under both arms. The patient does smile responsively and recognizes his parents. He has no speech development, and anger or pain are expressed by crying. Developmental milestones at nine years of age are less than one year of life according to the Denver developmental assessment. EEG shows mild to moderate background abnormalities and recurrent focal abnormalities suspicious for epileptic abnormalities. Treatment with valproate and vigabatrine does control seizures most of the time; however, especially during the courses of an infection, frequent brief multifocal predominantly clonic seizures occur. MRI studies revealed a predominantly fronto-parietal atrophy of the brain.

This is the first patient with MCC deficiency due to a heterozygous mutation and who demonstrates a substantial and sustained clinical and biochemical response to therapeutical doses of biotin (18).

Biological basis

Etiology and pathogenesis

3-alpha-methylcrotonylglycinuria is an inborn error of leucine catabolism due to deficiency of 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) (OMIM 210200).

Metabolic pathways - catabolism of branched-chain amino acids (2)

MCC = 3-methylcrotonyl-CoA carboxylase is deficient in methylcrotonylglycinuria, resulting in increased concentrations of 3-methylcrotonylglycine and other metabolites; BCKDH = branched chain alpha-keto acid dehydrogenase, deficie...

The disease usually shows an autosomal-recessive pattern of inheritance. In two patients, however, clinical and biochemical relevant 3-methylcrotonyl-CoA carboxylase deficiency was caused by a heterozygote MCC p.R385S (05). This mutation appears to exert a dominant negative influence on the wild type allele and, thus, on 3-methylcrotonyl-CoA carboxylase activity corresponding to a potentially autosomal dominant pattern of inheritance.

3-methylcrotonyl-CoA carboxylase belongs to a group of enzymes called biotin-dependent carboxylases, which are widely distributed in nature. Beside 3-methylcrotonyl-CoA carboxylase, two other members of this family are involved in human diseases: propionyl-CoA carboxylase (EC 6.4.1.3 activity is impaired in patients affected by propionic aciduria). Defective pyruvate carboxylase (EC 6.4.1.1) results in private carboxylase deficiency. Studies in pseudomonas aeruginosa have unraveled the crystal structures of 3-methylcrotonyl-CoA carboxylase and revealed unanticipated features in the architecture of the holoenzymes, particularly important structural differences between 3-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase despite strong sequence homologies between these two enzymes (25; 50).

Biotin-dependent carboxylases have two distinct enzymatic activities and catalyze their reactions in two steps. In the first, a biotin carboxylase component catalyzes the MgATP-dependent carboxylation of the N10 atom of the biotin cofactor using bicarbonate as the CO₂ donor while biotin is covalently linked through an amide bond to a lysine side chain in the biotin carboxyl carrier protein component. In the second step of the reaction, a carboxyltransferase component catalyzes the CO₂ transfer from carboxybiotin to the acceptor of the carboxyl group (50).

The human 3-methylcrotonyl-CoA carboxylase protein has been described (08). It comprises a larger alpha subunit and a smaller beta subunit, which form alpha6beta6 dodecamers (04; 19; 24). The alpha subunit is encoded by the MCCC1 (formerly MCCA, 19 exons, 3q25-q27) gene and contains biotin carboxylase and biotin carboxylase carrier domains. The beta unit is coded by the MCCC2 gene (formerly MCCB, 17 exons, 5q12-q13) and contains the carboxyltransferase domain (04; 19; 24).

The enzyme is located in the inner membrane of mitochondria. It is also expressed in human fibroblasts and lymphocytes.

Major advances in the understanding of the molecular mechanism of this disease have been made. Baumgartner and coworkers were able to demonstrate the dominant negative effect of the mutated allele MCCC1 p.-R385S, ie, its ability to reduce the activity of the MCCA wild type in a compound heterozygous state (05; 03). Additionally, the cleavage sites and the targeting signals of methylcrotonyl-CoA carboxylase have been identified by site-directed mutagenesis, an important prerequisite to understand the functional relevance of mutations (45). Cryptic exon activation by disruption of an exon splice enhancer by a particular point mutation (c.1054G> A mutation in exon 11 of MCCB gene) has been described as another mechanism (47).

One mutation with a clinically completely asymptomatic phenotype has been identified in the Amish population in Lancaster County of Pennsylvania (USA) and could be traced back to their Swiss ancestors (04; 19). Two series of mutations in the MCCA and MCCC2 locus have been reported (10; 34).

In patients, the activity of 3-methylcrotonyl-CoA carboxylase measured in fibroblasts is severely reduced to 0% to 12% of normal without response to biotin (48). Due to the enzymatic block, 3-methylcrotonyl-CoA accumulates and is further hydrated to 3-hydroxyisovaleryl-CoA by crotonase and deacylated to 3-hydroxyisovaleric acid.

Metabolic pathways - catabolism of branched-chain amino acids (2)

The other important pathway is the conjugation with glycine by glycine-N-acylase to form 3-methylcrotonylglycine. Usually, the excretion via 3-hydroxyisovaleric acid is more prominent, but there are also patients with opposite proportions reflecting a different activity of glycine N-acylase (36). Secondary severe carnitine depletion, which is known to develop in many patients, is caused by urinary excretion of acylcarnitine metabolites. The most characteristic acylcarnitine is 3-hydroxyisovalerylcarnitine formed from the conversion of 3-methylcrotonyl-CoA to methylcrotonyl carnitine and then to 3-hydroxyisovalerylcarnitine (40).

A first MCCA-deficient skin fibroblast transcriptome was published pointing to mitochondrial dysfunction, decreased antioxidant response, and disruption of energy homeostasis as possible mechanisms of pathophysiology (54).

Differential diagnosis

Confusing conditions

The acute metabolic decompensation can be similar to that in other organoacidopathies, fatty acid oxidation disorders, or urea cycle disorders.

Persistently elevated 3-hydroxy-isovalerylcarnitine in newborns detected by newborn screening programs can also be caused by maternal 3-alpha-methylcrotonylglycinuria (20; 15). Additionally, carriers of one deleterious mutation, mostly in the MCCA gene, may show elevated metabolites suggestive for 3-methylcrotonyl-CoA carboxylase deficiency in newborn screening or specific metabolic investigations (33).

Associated or underlying disorders

The catabolic pathway of leucine comprises six enzymes, each of which can be affected by monogenic defects.

Metabolic pathways - catabolism of branched-chain amino acids (2)

MSUD and isovaleric acidemia (deficiency of isovaleryl-CoA dehydrogenase) are described in separate clinical summaries. Organoacidopathies can best be differentiated by their specific patterns in gas chromatography-mass spectrometry analysis of nonvolatile urinary organic acids and their associated abnormalities in an acylcarnitine profile.

As biotin is the cofactor of all carboxylases (propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, acetyl-CoA carboxylase, and pyruvate carboxylase), deficiencies in the biotin pathway result in multiple carboxylase deficiency (biotinidase and holocarboxylase synthetase deficiency). These can be distinguished from 3-methylcrotonylcarboxylase deficiency by the presence of additional pathological metabolites, such as 3-hydroxypropionic acid, methylcitric acid, and lactic acid. The definitive diagnosis is by enzyme assay or mutation analysis.

Diagnostic workup

3-methylcrotonylglycinuria should be considered not only in patients with typical concomitants of organic acidurias but also in patients presenting with Reye syndrome, hypoglycemia, and unexplained encephalopathies. As in other organic acidurias, the clinical presentation can be nonspecific, so differentiation by laboratory workup is essential. The best way to distinguish the organic acidurias is through analysis of urinary nonvolatile organic acids by gas chromatography-mass spectrometry and acylcarnitine profiles by tandem mass spectrometry (23; 55). Newborn screening of acylcarnitine profiles using tandem mass spectrometry leads to early diagnosis and initiation of therapy (41; 35; 28). Nevertheless, the inclusion of 3-methylcrotonylglycinuria into national newborn screening programs remains controversial, even though the condition is included in the recommended uniform screening panel core conditions in the United States and some European countries (27); more information can be accessed at the following site: www.hrsa.gov/advisory-committees/heritable-disorders/rusp). Other countries, such as Germany, have excluded it from the national screening panel because of the high percentage (> 90%) of individuals who will remain asymptomatic (46).

In 3-methylcrotonyl-CoA carboxylase deficiency, the urinary organic acid profile reveals high excretion of 3-hydroxyisovaleric acid (500 to 7000 mmol/mol creatinine, compared with 1 to 20 mmol/mol creatinine in healthy individuals and 50 to 200 mmol/mol creatinine in patients with severe ketosis from other causes) as well as 3-methylcrotonylglycine (50 to 4000 mmol/mol creatinine, normally not detectable) (48). Elevations of 3-hydroxybutyric, acetoacetic, and dicarboxylic acids may be present in ketotic patients, but there is no elevation of 3-hydroxypropionic, methylcitric, or lactic acids that is present in multiple carboxylase deficiency. Examination of the carnitine status may reveal a low total carnitine level, an elevated ratio of esterified to free carnitine, and a high elevation of 3-hydroxyisovalerylcarnitine in plasma or dried blood spots. 3-hydroxyisovalerylcarnitine can be readily detected in newborn screening. 3-methylcrotonylcarnitine is sometimes but not always present. Two cases have been reported of patients with 3-alpha-methylcrotonylglycinuria deficiency in fibroblasts and homozygous mutations in the MCCB gene who did not have elevated 3-methylcrotonylglycine levels and had only moderate elevations of 3-hydroxyisovaleric acid (53).

The definitive diagnosis is made by identification of pathogenic mutations and/or assay of enzyme activity in fibroblasts or leukocytes with significant reduction of enzyme activity of 0% to 12% of control activity and, except in rare instances (05), no response to biotin (07). It is important to exclude multiple carboxylase deficiency up to demonstrating normal enzyme activities of propionyl-CoA carboxylase, pyruvate carboxylase, and biotinidase. An example of a work-up in an asymptomatic girl has been published (09).

Prenatal diagnosis is possible by stable isotope dilution analysis of amniotic fluid, which shows elevated 3-hydroxyisovaleric acid by enzyme activity assay in cultivated amniocytes or chorionic villi material (26). With the description of the gene locus, molecular prenatal diagnosis has also become possible in families with known mutations. In view of the likely nature as a benign variant, it is, however, difficult to envision indications for prenatal diagnosis for 3-methylcrotonyl-CoA carboxylase deficiency.

A diagnostic algorithm for elevation of C5OH acylcarnitine in newborn screening has been published by the American College of Medical Genetics (available at www.acmg.net), as well as a Delphi-based clinical practice protocol for the diagnosis and management of 3-alpha-methylcrotonylglycinuria (01).

Because data regarding the correlation between the degree of metabolite elevation and definite diagnosis and metabolic risk are sparse, the evaluation of the significance of persistently elevated metabolites and the decision about possible metabolic treatment has to be done in the clinical context of the individual patient and the pattern of abnormal metabolites in close discussion between clinicians and the diagnostic laboratory. Mutation analysis is now the most practical approach in most cases to confirm the diagnosis, and enzyme studies may only be necessary in selected cases.

Management

As discussed, there has been considerable and even increasing uncertainty about the clinical relevance of 3-methylcrotonyl-CoA carboxylase deficiency (42; 52). The main objective for patients is to prevent metabolic decompensation and crisis. During intercurrent illnesses up to acute decompensation, 3-methylcrotonylglycinemia is treated like other organic acidemias. Measures include increasing the provision of energy by 20% to 100% above the recommended daily requirements using carbohydrate (dextrose 20%) and fat (intralipid 20%) via oral, nasogastric, or intravenous routes. Insulin can be administered to avoid hyperglycemia and to support intracellular glucose uptake. The intake of natural protein is stopped for 24 to 48 hours and then is reintroduced gradually as tolerated (23). As mentioned below, augmented doses of glycine and L-carnitine are recommended (48). The New England Consortium of Metabolic Programs has created a list of emergency recommendations of the management of the acute illness in 3-alpha-methylcrotonylglycinuria patients, which can be found at: http://newenglandconsortium.org.

Patients with significant metabolic symptoms should be supplied with an emergency card, letter, or bracelet containing instructions for emergency measures and phone numbers. Logistics of emergency therapeutic measures should be regularly reviewed with the family and the primary care physicians.

As leucine is an essential amino acid, the catabolic pathway is challenged by increased protein intake or increased endogenous protein degradation (48). No randomized controlled studies of leucine-restricted diets have been published, thus, the efficacy of such diets to prevent or ameliorate symptoms remains doubtful. Therefore, decisions regarding diets in symptomatic children or mothers have to be individualized based on severity of symptoms, response to a diet trial, or other factors (01).

Carnitine depletion has been described in 3-methylcrotonyl-CoA carboxylase deficiency; therefore, L-carnitine levels should be monitored in plasma, aiming at normal levels of free carnitine (49). Supplemental carnitine should be initiated if free carnitine is very low. In previously symptomatic patients L-carnitine in a dosage of 40 to 100 mg/kg per day is used to prevent carnitine depletion during intercurrent illness (01).

In addition, detoxification is possible with glycine via 3-methylcrotonylglycine, which has been shown to be effective in well-documented cases. It seems to be especially effective during a crisis, but chronic prophylaxis is also a possibility (39). Therapeutic guidelines recommend a dosage of 150 mg/kg per day of glycine while the patient is stable. The dosage can be augmented up to 600 mg/kg per day during metabolic crisis. However, no randomized clinical trials have been published and a panel of metabolic specialists from Canada and the United States did not recommend the use of glycine (01).

The widely used anticonvulsant drug valproate has been shown to inhibit 3-methylcrotonyl-CoA carboxylase and should not be considered in patients with inborn errors of leucine degradation (32).

Outcomes

On the other hand, almost all “patients” identified by newborn screening never develop symptoms, even without treatment. The lack of genetic or biochemical markers to differentiate these individuals from those who are at risk for decompensation has led to controversy about the benefit of newborn screening for 3-methylcrotonylglycinuria (22; 46; 02; 42; 16; 52).

References

01: Arnold GL, Koeberl DD, Matern D, et al. A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency. Mol Genet Metab 2008;93(4):363-70.** PMID 18155630
02: Arnold GL, Salazar D, Neidich JA, et al. Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening. Mol Genet Metab 2012;106:439-41. PMID 22658692
03: Baumgartner MR. Molecular mechanism of dominant expression in 3-methylcrotonyl-coA carboxylase deficiency. J Inherit Metab Dis 2005;28:301-3. PMID 15868465
04: Baumgartner MR, Almashanu S, Suormala T, et al. The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. J Clin Invest 2001;107:495-504. PMID 11181649
05: Baumgartner MR, Dantas MF, Suormala T, et al. Isolated 3-methylcrotonyl-coA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy. Am J Hum Genet 2004;75(5):790-800. PMID 15359379
06: Baykal T, Gokcay GH, Ince Z, et al. Consanguineous 3-methylcrotonyl-coA carboxylase deficiency: early onset necrotizing encephalopathy with lethal outcome. J Inherit Metab Dis 2005;28: 229-33. PMID 15877210
07: Blau N, Duran M, Gibson, KM, Dionisi-Vici C, editors. Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases. Heidelberg: Springer, 2014.
08: Chu CH, Cheng D. Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC). Protein Expr Purif 2007;53(2):421-7. PMID 17360195
09: Cozzolino C, Villani GR, Frisso G, et al. Biochemical and molecular characterization of 3-methylcrotonylglycinuria in an Italian asymptomatic girl. Genet Mol Biol 2018;41(2):379-85. PMID 29767664
10: Dantas MF, Suormala T, Randolph A, et al. 3-methylcrotonyl-coA carboxylase deficiency mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening. Hum Mutat 2005;26(2):164. PMID 16010683
11: Darin N, Andersen O, Wiklund LM, Holmgren D, Holme E. 3-methylcrotonyl-coA carboxylase deficiency and severe multiple sclerosis. Pediatr Neurol 2007;132-4. PMID 17275669
12: Desviat LR, Perez-Cerda C, Perez B, et al. Functional analysis of MCCA and MCCB mutations causing methylcrotonylglycinuria. Mol Genet Metab 2003;80(3):315-20. PMID 14680978
13: Dirik E, Yis U, Pasaoglu G, Chambaz C, Baumgartner MR. Recurrent attacks of status epilepticus as predominant symptom in 3-methylcrotonyl-CoA carboxylase deficiency. Brain Dev 2008;30(3):218-20. PMID 17869468
14: Ficicioglu C, Payan I. 3-methylcrotonyl-coA carboxylase deficiency metabolic decompensation in a noncompliant child detected through newborn screening. Pediatrics 2006;118:2555-6. PMID 17142544
15: Fingerhut R, Röschinger W, Roscher AA, Olgemöller B. Influence of acylcarnitine concentrations in breast milk of mothers with 3- methylcrotonyl-coA Carboxylase deficiency on blood concentrations of breastfed babies. J Inherit Metab Dis 2003;26(Suppl 2):53.
16: Forsyth R, Vockley CW, Edick MJ, et al. Outcomes of cases with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency - report from the Inborn Errors of Metabolism Information System. Mol Genet Metab 2016;118(1):15-20. PMID 27033733
17: Frazier DM, Millington DS, McCandless SE, et al. The tandem mass spectrometry newborn screening experience in North Carolina: 1997-2005. J Inherit Metab Dis 2006;29:76-85. PMID 16601872
18: Friebel D, von der Hagen M, Baumgartner ER, et al. The first case of 3-methylcrotonyl-coA carboxylase (MCC) deficiency responsive to biotin. Neuropediatrics 2006;37:72-8. PMID 16773504
19: Gallardo ME, Desviat LR, Rodriguez JM, et al. The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism. Am J Hum Genet 2001;68:334-46. PMID 11170888
20: Gibson KM, Bennett MJ, Naylor EW, Morton DH. 3-methylcrotonyl-coA carboxylase deficiency in Amish/Mennonite adults identified by detection of increased acylcarnitines in blood spots of their children. J Pediatr 1998;132:519-23. PMID 9544913
21: Gruenert SC, Stucki M, Morscher RJ, et al. 3-methylcrotonyl-CoA carboxylase deficiency: Clinical, biochemical, enzymatic and molecular studies in 88 individuals. Orphanet J Rare Dis 2012;7:31.** PMID 22642865
22: Hess R. Beschluss über eine Änderung der Richtlinien des Bundesausschusses der Ärzte und Krankenkassen über die Früherkennung von Krankheiten bei Kindern bis zur Vollendung des 6. Lebensjahres (Kinder-Richtlinien) zur Einführung des erweiterten Neugeborenen-Screenings. Dtsch Aerztebl 2005;102(16):B970-5.
23: Hoffmann GF, Zschocke J, Nyhan WL. Inherited Metabolic Diseases: A clinical approach. Heidelberg: Springer, 2017.
24: Holzinger A, Roschinger W, Lagler F, et al. Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA carboxylase deficiency. Hum Mol Genet 2001;10:1299-306. PMID 11406611
25: Huang CS, Peng G, Hong Zhou Z, Tong L. An unanticipated architecture of the 750 kD holoenzyme of 3-methylcrotonyl-CoA carboxylase. Nature 2011;481(7380):219-23.** PMID 22158123
26: Jakobs C, Sweetman L, Nyhan WL, Packman S. Stable isotope dilution analysis of 3-hydroxyisovalericvaleric acidemia in amniotic fluid: contribution to the prenatal diagnosis of inherited disorders of leucine catabolism. J Inherit Metab Dis 1984;7:15-20. PMID 6429435
27: Jones SA, Cheillan D, Chakrapani A, et al. Application of a novel algorithm for expanding newborn screening for inherited metabolic disorders across Europe. Int J Neonatal Screen 2022;8(1):20. PMID 35323199
28: Jung CW, Lee BH, Kim JH, et al. Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations. J Hum Genet 2012;57(1):62-4. PMID 22030835
29: Kobori JA, Johnston K, Sweetman L. Isolated 3-methylcrotonyl-coA carboxylase deficiency presenting as Reye-like syndrome. Pediatr Res 1989;25:142A.
30: Lam C, Carter JM, Cederbaum SD, et al. Analysis of cases of 3-methylcrotonyl CoA carboxylase deficiency (3-MCCD) in the California newborn screening program reported in the state database. Mol Genet Metab 2013;110(4):477-83.** PMID 24103308
31: Landau YE, Waisbren SE, Chan LM, Levy HL. Long-term outcome of expanded newborn screening at Boston children's hospital: benefits and challenges in defining true disease. J Inherit Metab Dis 2017;40(2):209-18. PMID 28054209
32: Luis PB, Ruiter JP, Iljst L, et al. Inhibition of 3-methylcrotonyl-CoA carboxylase explains the increased excretion of 3-hydroxyisovaleric acid in valproate-treated patients. J Inherit Metab Dis 2012:35:443-9. PMID 22189597
33: Morscher RJ, Grünert SC, Bürer C, et al. A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency. Mol Genet Metab 2012;105(4):602-6. PMID 22264772
34: Nguyen KV, Naviaux RK, Patra S, Barshop BA, Nyhan WL. Novel mutations in the human MCCA and MCCB gene causing methylcrotonylglycinuria. Mol Genet Metab 2011;102(2):218-21. PMID 21071250
35: Niu DM, Chien YH, Chiang CC, et al. Nationwide survey of extended newborn screening by tandem mass spectrometry in Taiwan. J Inherit Metab Dis 2010;33(Suppl 2):S295-305. PMID 20567911
36: Nyhan WL, Barshop BA, Al-Aheed AI. 3-methylcrotonyl coA carboxylase deficiency/3-methylcrotonyl glycinuria. In: Atlas of Metabolic Disease. 3rd ed. London: Hodder Arnold, 2012:74-8.
37: Pinto L, Zen P, Rosa R, et al. Isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency in a child with metabolic stroke. J Inherit Metab Dis 2006;29:205-6. PMID 16601894
38: Rips J, Almashanu S, Mandel H, et al. Primary and maternal 3-methylcrotonyl-CoA carboxylase deficiency: insights from the Israel newborn screening program. J Inherit Metab Dis 2016;39(2):211-7. PMID 26566957
39: Rolland MO, Divry P, Zabot MT, et al. Isolated 3-methylcrotonyl-coA carboxylase deficiency in a 16-month-old child. J Inherit Metab Dis 1991;14:838-9. PMID 1779635
40: Roschinger W, Millington DS, Gage DA, et al. 3-hydroxyisovalerylcarnitine in patients with deficiency of 3-methylcrotonyl coA carboxylase. Clin Chim Acta 1995;240:35-51. PMID 8582058
41: Schulze A, Lindner M, Kohlmueller D, Olgemoeller K, Mayatepek E, Hoffmann GF. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics 2003;111:1399-406. PMID 12777559
42: Shepard PJ, Barshop BA, Baumgartner MR, et al. Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD. Genet Med 2015;17(8):660-7.** PMID 25356967
43: Sloane V, Waldrop GL. Kinetic characterization of mutations found in propionic acidemia and methylcrotonylglycinuria: evidence for cooperativity in biotin carboxylase. J Biol Chem 2004;279(16):15772-8. PMID 14960587
44: Smon A, Repic Lampret B, Groselj U, et al. Next generation sequencing as a follow-up test in an expanded newborn screening programme. Clin Biochem 2017;52:48-55. PMID 29111448
45: Stadler SC, Ploanetz R, Meier S, et al. Mitochondrial targeting signals and mature peptides of 3-methylcrotonyl-coA carboxylase. Biochem Biophys Res Commun 2005;334:939-96. PMID 16023992
46: Stadler SC, Polanetz R, Maier EM, et al. Newborn screening for 3-methylcrotonyl-coA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment. Hum Mutat 2006;27:748-59. PMID 16835865
47: Stucki M, Suormala T, Fowler B, Valle D, Baumgartner MR. Cryptic exon activation by disruption of exon splice enhancer: novel mechanism causing 3-methylcrotonyl-CoA carboxylase deficiency. J Biol Chem 2009;284(42):28953-7. PMID 19706617
48: Sweetman L, Williams J. Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw Hill, 2001:2125-63.
49: Thomsen JA, Lund AM, Olesen JH, Mohr M, Rasmussen J. Is L-Carnitine supplementation beneficial in 3-methylcrotonyl-CoA carboxylase deficiency? JIMD Rep 2015;21:79-88. PMID 25732994
50: Tong L. Structure and function of biotin-dependent carboxylases. Cell Mol Life Sci 2013;70:863-91. PMID 22869039
51: Wang T, Ma J, Zhang Q, et al. Expanded newborn screening for inborn errors of metabolism by tandem mass spectrometry in Suzhou, China: disease spectrum, prevalence, genetic characteristics in a Chinese population. Front Genet 2019;10:1052. PMID 31737040
52: Wilcken B. 3-Methylcrotonyl-CoA carboxylase deficiency: to screen or not to screen? J Inherit Metab Dis 2016;39(2):171-2. PMID 26660660
53: Wolfe LA, Finegold DN, Vockley J, et al. Potential misdiagnosis of 3-methylcrotonyl coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine. Pediatrics 2007;120(5):e1335-40. PMID 17908719
54: Zandberg L, van Dyk HC, van der Westhuizen FH, van Dijk AA. A 3-methylcrotonyl-CoA carboxylase deficient human skin fibroblast transcriptome reveals underlying mitochondrial dysfunction and oxidative stress. Int J Biochem Cell Biol 2016;78:116-29. PMID 27417235
55: Zschocke J, Hoffmann GF. Vademecum metabolicum. Manual of metabolic paediatrics. 5th edition. Stuttgart: Georg Thieme Verlag, 2020.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Georg F Hoffmann MD

Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.
See Profile
Friederike Hoerster MD

Dr. Hoerster of University Children's Hospital in Heidelberg, Germany, has no relevant financial relationships to disclose.
See Profile

Editor

Deepa S Rajan MD

Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
See Profile

Former Authors

Tyler Reimschisel MD
Jennifer Friedman MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor

autosomal recessive
Population groups selectively affected: Amish community, but occurs world-wide
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Disturbances of branched-chain amino-acid metabolism: 270.3
ICD-10: Disorders of branched-chain amino-acid metabolism, unspecified: E71.2
OMIM: 3-alpha-methylcrotonylglycinuria I: #210200

3-alpha-methylcrotonylglycinuria II: #210210

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

3-alpha-methylcrotonylglycinuria

Associated Disorders

Hyperreflexia
Infantile spasms
Mental retardation
Muscular hypotonia
Neutrophilia
- Reye syndrome
- Seizures

Differential Diagnosis

other organoacidopathies
urea cycle disorders
isovaleric acidemia
biotinidase deficiency
holocarboxylase synthetase deficiency

3-alpha-methylcrotonylglycinuria

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

This is an article preview.
Start a Free Account
to access the full version.