3-methylcrotonyl-CoA carboxylase deficiency in a child with developmental regression and delay: call for early diagnosis and multidisciplinary approach

Summary

3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (3-MCC-D) is an autosomal recessive disorder with a variable phenotype. Reduced 3-MCC enzyme activity results in impaired leucine metabolism causing, for example, metabolic acidosis, ketotic hypoglycaemia and carnitine deficiency. The spectrum of clinical presentation is wide, ranging from severe early-onset presentations to incidental findings in asymptomatic individuals. This report describes the case of a young girl who underwent dramatic developmental regression at 11 months of age, following a respiratory tract infection. Metabolic investigations revealed high excretions of urinary 3-methylcrotonylglycine and 3-hydroxyisovaleric acid, consistent with 3-MCC-D. Treatment was commenced immediately, including carnitine, biotin and moderate dietetic modifications. Molecular genetic investigations confirmed compound heterozygosity for two pathogenic variants in the MCCC1 gene, Trp358Cysfs*13 and duplication of exons 2 and 3. Now in middle childhood, the girl is meeting all her developmental milestones and has had no metabolic decompensation in 6 years of follow-up.

Background

Isolated 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (3-MCC-D), or 3-methylcrotonylglycinuria, is a disorder of leucine metabolism caused by pathogenic variants in the MCCC1 or MCCC2 genes. These genes encode the alpha and beta subunits of methylcrotonyl-CoA carboxylase enzyme, respectively. 3-MCC is a mitochondrial enzyme which belongs to the group of biotin-dependent carboxylases and catalyses the fourth catabolic step in the leucine degradation pathway (figure 1). In the case of 3-MCC-D, intermediary metabolites accumulate in blood and urine, particularly 3-methylcrotonylglycine and 3-hydroxyisovaleric acid, which are then detectable on urine organic acid analysis. Affected individuals are predisposed to ketotic hypoglycaemia and metabolic acidosis or even ketoacidosis. The clinical course, however, is noted to be milder than other inborn metabolic defects in this pathway.^{1 2} The estimated incidence of 3-MCC-D ranges from 1:40 000 to 1:68 000 depending on the population examined.³ Many individuals remain asymptomatic, and so this number may be higher.

Figure 1. Schematics of the metabolic pathway and defect in 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency.

This report describes the case of a young girl who underwent dramatic developmental regression and delay at 11 months of age following an upper respiratory tract infection with ear infection. Metabolic testing demonstrated significantly elevated urinary 3-methylcrotonylglycine and 3-hydroxyisovaleric acid excretion on organic acid analysis, consistent with 3-MCC-D, which was subsequently genetically confirmed. The girl recovered well following the commencement of treatment, including also multidisciplinary management; she is now in middle childhood and developmentally appropriate.

Case presentation

The patient was born at term to non-consanguineous Irish parents. The perinatal course was unremarkable, and newborn bloodspot screening (NBS) performed as per Irish guidelines did not reveal any diagnostic findings. She was a healthy infant and received vaccinations according to schedule without any issues. She was formula-fed, and weaning was commenced at 6 months. Family history was unremarkable.

The girl was referred to the National Centre for Inherited Metabolic Disorders in Dublin for metabolic input with a history of developmental regression and global developmental delay with poor weight gain. Of note, she had met all developmental milestones for the first 10 months of life, for example, crawling at 6 months, pulling to stand at 8 months of age and cruising by the age of 10 months. Speech and language development was initially appropriate with babbling noted at 6 months. She had developed single words with meaning at 10 months, for example, ‘mama’, ‘dada’ and ‘yes’; however, she remained static for some time after that. She suffered from an intercurrent infection at around 11 months of age with an ear infection and was noted to be pale and lethargic around that time during a febrile episode. Her interest in food subsequently declined, and in hindsight, the parents noted an avoidance of protein-rich foods, such as dairy products or meat, with an interest in fruit and carbohydrates.

On examination, the girl was pink and non-dysmorphic. Anthropometric measurements were taken, with head circumference and weight on the 50th centile and height on the second centile for age. There were no neuro-cutaneous stigmata. Neurological examination appeared unrevealing, including normal deep tendon reflexes and normal funduscopy. There was no evident organomegaly or lymphadenopathy.

An Ages & Stages Questionnaires was performed when the patient was well demonstrated scoring as follows: communication=30, gross motor=30, fine motor=60, problem solving=55 and personal and social=50, thereby reflecting delayed gross motor milestones and mildly delayed speech and language acquisition. Dietetic, physiotherapy, speech and language therapy and audiology were consulted for further input, and she was referred to early intervention services.

Investigations

Baseline biochemical investigations performed, including blood gas analysis, renal, liver and bone profiles, glucose, lactate, plasma ammonia and bedside ketone testing, were essentially normal. Plasma amino acids demonstrated marginally elevated branched-chain amino acids with a leucine of 225 µmol/L (range 59–223 µmol/L), and alloisoleucine was not detected. However, on her urine organic acid profile, there was a marked increase in the excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, without an associated increase in lactate or propionate metabolites. This pattern is overall consistent with 3-MCC-D. A subsequent acylcarnitine profile on dried blood spots demonstrated an extremely low free carnitine at 2.3 µmol/L (reference range 15.5–46.7 µmol/L) with a high C5-OH-carnitine of 14.47 µmol/L (0.0–0.43 µmol/L); these findings are almost pathognomonic of 3-MCC-D.

Carnitine supplementation was commenced, initially at 100 mg/kg/day after which the patient’s free carnitine was normalised to 21.2 µmol/L. C5-OH-carnitine remained grossly elevated, however, at 14.88 µmol/L. Since she went on targeted treatment, including carnitine supplementation, her free carnitine in blood has remained normal or even high normal at subsequent clinical reviews. She was also started on biotin (5 mgs od), a cofactor of biotin-dependent carboxylases, including 3-MCC.

To confirm 3-MCC-D, genetic analysis was performed using leukocyte-derived DNA. The girl was found to be compound heterozygous for two different pathogenic variants, Trp358Cysfs*13 in the MCCC1 gene and also a duplication of exons 2 and 3 of the MCCC1 gene which were found to be segregating in this family. The mother is a carrier for the pathogenic variant c.1074delG (Trp358Cysfs*13). Her father is a carrier of a duplication of exons 2 and 3 of the MCCC1 gene. This was identified via multiplex ligation-dependent probe amplification. MCCC2 gene analysis was unrevealing.

Brain MRI was deferred in light of the girl’s immediate response to targeted treatment and her good clinical progress. Appropriate local ethics/research approval and written informed consent were obtained prior to publication.

Differential diagnosis

• Other inborn errors of intermediate metabolism, such as other organic acidurias and amino acidopathies or disorders of ketone body metabolism, including, for example,

  • Biotinidase deficiency.

  • Methylmalonic aciduria.

  • Propionic aciduria.

  • Maple syrup urine disease.

  • Holocarboxylase synthetase deficiency.

  • 3-hydroxy-3-methylglutaryl-coenzyme-A lyase deficiency.

  • β-ketothiolase deficiency.

• Primary mitochondrial disorders (eg, Leigh syndrome).

• Neurodegenerative diseases, including, for example,

  • Neuronal ceroid lipofuscinoses (Batten disease).

  • Krabbe disease (globoid cell leukodystrophy).

Treatment

• Correct hypoglycaemia and acidosis where present.

• Re-establish anabolism.

• Carnitine PO or intravenous (metabolic conjunction), 100 mg/kg/day in 2–3 divided doses, adjusted as needed in order to prevent deficiency.

• Biotin (cofactor), 5 mg OD PO.

• Dietetic modification (adequate caloric supply, avoid protein excess, restrict prolonged fasting, carbohydrate supplements if PO is reduced and in the setting of intercurrent illness).

• Multidisciplinary team input.

• Emergency treatment (particularly during illnesses with poor oral feeding; commence intravenous dextrose 10 (−12.5)% at 1–1.2 (1.5) times maintenance, add NaCl and KCl depending on plasma electrolyte levels, until PO intake is fully established).

• Biochemical monitoring, routinely and as clinically indicated.

Outcome and follow-up

The girl, now in middle childhood, continues to attend the National Centre for Inherited Metabolic Disorders, Dublin. She attends every 6 months and has achieved pleasing metabolic control. She remains under dietetic and pharmacological management, including carnitine and biotin.

In terms of her developmental progress, she is now age-appropriate and in mainstream school. Her parents had dietetic input in relation to dietetic requirements in symptomatic patients with 3-MCC-D, such as avoidance of protein excess and ‘sick day’ management with the addition of extra carbohydrates. They also had genetic input regarding the diagnosis. The girl initially attended early intervention services but has since been discharged and follows up regularly with her primary paediatrician and local GP. Since she was commenced on treatment, no further episodes of acute decompensation, regression or altered state of consciousness were noted, and she made a full recovery. We are pleased to observe that she is meeting all her developmental milestones, is in mainstream school and has had no further metabolic decompensation during 6 years of follow-up.

Discussion

3-MCC-D can present with a variety of symptoms, ranging from mild to severe, or may indeed remain asymptomatic. Biochemical features of 3-MCC-D are more pronounced during catabolic states, such as acute illnesses and prolonged fasting. While 3-MCC-D may remain asymptomatic in a number of affected individuals, early recognition of symptomatic patients with 3-MCC-D and commencement of treatment without any unnecessary delays is essential in order to prevent long-term sequelae in this subgroup of patients. A cohort of 53 patients with 3-MCC-D was identified by Grünert et al, among whom five were initially asymptomatic but developed metabolic decomposition later in life.¹ Due to the risk of acute metabolic decompensation with neurological sequelae, early diagnosis is essential for clinically affected individuals.² However, NBS by use of tandem mass spectrometry has disclosed a high incidence of 3-MCC-D with a significant number of asymptomatic cases, including mothers.^{3 4} This is a significant finding, as present data indicate that 3-MCC-D can indeed be both an inborn metabolic disorder with a severe clinical presentation and, in some cases, a biochemical phenotype or non-disease which may remain entirely asymptomatic or may only become evident after a triggering event.⁵,⁸ In the USA, an estimated incidence rate of 1:41 676–1:1:64 000 was noted,^{4 9 10} including mild phenotypes. Taken together, this condition can have a severe phenotype in some individuals, and therefore, early detection and appropriate management are essential in securing optimal outcomes for clinically affected patients. A timely intervention that allows achieving immediate response to treatment can lead to full recovery, as in the case presented here.

Patient’s perspective.

The parents are very pleased with their daughter’s overall progress. Her mother stated that since she went on targeted treatment, ‘she is like a different child’ and ‘she is keeping up with her peers’.

Learning points.

• Focused history taking and clinical examination remain gold standards for identifying developmental delay in a child. The use of a standardised developmental screener may be helpful for diagnosis as well as clinical follow-up.

• Paediatric patients presenting with global development delay, regardless of the underlying cause, should have prompt early intervention with a multidisciplinary team.

• Global developmental delay or developmental regression following an intercurrent illness should raise the suspicion of an underlying metabolic disorder, such as 3-methylcrotonyl-CoA carboxylase deficiency or other disorders of intermediary metabolism. Baseline metabolic investigations should be undertaken in parallel with other medical tests, as clinically indicated, in children with static development/regression or global developmental delay.

• Baseline metabolic workup and point-of-care testing for children may include, for example, blood glucose, lactate, blood gas analysis, ketone testing, ammonia, full blood count, renal, liver, bone profiles, uric acid, thyroid function test, creatine kinase, blood acylcarnitines and plasma amino acids together with urinary organic acids and glycosaminoglycans, with other tests as clinically indicated. Further investigations along with molecular genetic testing or other confirmatory tests may be required to confirm the diagnosis.

• An early diagnosis, timely intervention and specific treatments are crucial in many inborn metabolic disorders to prevent neurological sequelae.