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Mol Genet Metab Rep
Mol Genet Metab Rep
Molecular Genetics and Metabolism Reports
2214-4269
Elsevier

S2214-4269(24)00091-0
10.1016/j.ymgmr.2024.101138
101138
Case Report
An acute life-threatening episode of rhabdomyolysis, renal failure, altered mental status and hyperammonemia in an adult with 3-methylcrotonyl-CoA carboxylase deficiency
McGowan Rachel
Yano Shoji syano@usc.edu
⁎
Genetics Division, Pediatrics, Los Angeles General Hospital, University of Southern California, Los Angeles, CA, USA
⁎ Corresponding author. syano@usc.edu
31 8 2024
12 2024
31 8 2024
41 10113813 3 2024
27 8 2024
27 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency is an autosomal recessive disorder of leucine metabolism. Since 3-MCC deficiency is thought to be a benign condition, a few newborn screening programs discontinued to screen this condition. We report a case of a 24-year-old previously healthy male patient who developed generalized rhabdomyolysis, weakness, respiratory and renal failure, acute pancreatitis, hyperammonemia, and altered consciousness after strenuous exercise. Diagnosis of 3-MCC was made based on increased plasma C5OH carnitine, urine 3-methylcrotonylglycine, and 3-hydroxyisovalerate, and later whole genome sequencing study confirmed the diagnosis. Low plasma carnitine and high creatine kinase (CK) levels were again noted after two months of poor compliance with carnitine therapy. Since 3-MCC deficiency is often incidentally diagnosed in asymptomatic mothers through positive newborn screening in the newborns and most positive newborn screening cases have benign clinical outcomes, 3-MCC deficiency has been considered a benign condition. Observation of a life-threatening episode triggered by strenuous exercise and recurrent occurrence of low carnitine and high CK without carnitine supplementation may support 3-MCC deficiency to be the condition covered by the newborn screen since carnitine supplementation likely prevents an episode that can be life-threatening. Asymptomatic adults with 3-MCC deficiency may benefit from periodic evaluation of plasma carnitine levels.

Keywords

Hypocarnitinemia
Rhabdomyolysis
Hyperammonemia
Pancreatitis
Newborn screen
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pmc1 Introduction

3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency is an autosomal recessive disorder of leucine metabolism. The incidence is approximately 1:40,000 per California Newborn Screening (NBS) office (personal communication, 2022). This alteration in leucine catabolism leads to an increase in plasma concentration of 3-hydroxyisovalerylcarnitine and urinary excretions of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid [1,2]. This disorder is one of the most common organic acidemias diagnosed by NBS [2]. Screening for many organic acidurias including 3-MCC deficiency started in 2005 in California when the tandem mass spectrometry analysis using dried blood spot samples was introduced. Adults born before the introduction of the expanded NBS were not tested for 3-MCC deficiency and many of them are unaware of their condition even though they may have 3-MCC deficiency. 3-MCC deficiency is thought to be a benign condition since most cases are asymptomatic although metabolic decompensation, including hypoglycemia and hyperammonemia associated with hypocarnitinemia, is reported in rare cases [3]. Some of the NBS programs decided to discontinue to screen 3-MCC deficiency in NBS and some of the individuals who were diagnosed with 3-MCC deficiency may be no longer followed. We report on a 24-year-old male who developed a life-threatening episode of metabolic decompensation triggered by strenuous exercise and was later diagnosed with 3MCC deficiency.

2 Case report

A 24-year-old, previously healthy male patient, was hospitalized following a 13-mile hiking trip in harsh conditions. The patient was hospitalized due to dehydration, acute onset of emesis, weakness, altered consciousness, and acute renal injury. Upon admission, the patient was noted to have hyperammonemia (217 uM) and developed respiratory failure requiring assisted ventilation. Fig. 1A shows hyperammonemia levels throughout admission. He also had rhabdomyolysis with a creatine kinase (CK) level of 4465 units/L associated with renal failure requiring dialysis. After obtaining specimens for laboratory blood and urine studies, the patient was placed on carnitine supplementation (50 mg/kg/d) and intravenous hydration with D10. High amylase and lipase levels were noted on admission, peaked on day 7 (amylase 411, lipase 1120; u/L), and normalized in 2 weeks. On day 3 of admission, ammonia levels peaked at 321 uM and started to normalize around day 4 of admission. The patient was extubated on day 6. CK levels normalized on day 6 before briefly elevating again. Fig. 1B shows plasma CK levels throughout the diagnostic process. Throughout his clinical course, analyses of plasma carnitine, acylcarnitines, and urine organic acids collected on the day of admission showed results consistent with 3-MCC deficiency: decreased levels of plasma carnitines and C2 carnitine, increased levels of plasma C5OH carnitine, urine 3-methylcrotonylglycine, and 3-hydroxyisovalerate being measured. Low levels of plasma citrulline were also detected.Fig. 1 (A) The patient's ammonia levels throughout hospitalization. Normal range defined as 16–60 uM. Continuous Venovenous hemodiafiltration (CVVHDF) (day 4–6). (B) The patient's CK levels throughout hospitalization and afterwards. Normal range defined as 39–308 U/L, as shown in shaded area. *Post-admission values. (C) Patient was on carnitine supplementation for 1 month prior to levels taken on day 36. Patient discontinued carnitine supplementation 26 days prior to levels taken on day 93.

Fig. 1

The patient was discharged on carnitine supplementation on the 19th day of admission after being fully recovered. The patient discontinued carnitine supplementation 2 months after discharge due to not obtaining a refill of his medication. Twenty-four days after discontinuing carnitine supplementation, the patient participated in minor physical activity. Laboratory studies obtained 2 days after the exercise, the patient had significantly elevated blood CK (8887 units/L) and low carnitine levels (Total/Esterified/Free carnitine: 7/4/3 uM). The patient presented to the clinic 5 days following lab work and reported feeling in good health despite elevated CK levels. Carnitine supplementation was restarted since this follow up clinic evaluation. Fig. 1C shows carnitine levels post-admission.

Plasma carnitine levels were again decreased after about 1 month of poor compliance with carnitine supplementation. The whole genome sequencing study performed at the first follow-up clinic visit showed a homozygous pathogenic mutation (c.994C > T) in the MCCC2 gene.

3 Discussion

3-MCC deficiency is one of the most common organic acid metabolism disorders diagnosed by NBS [2]. While this disease is generally thought to be benign, it can develop severe symptoms in rare cases [[2], [3], [4]]. 3-MCC deficiency is not included in some NBS programs and many patients with 3-MCC deficiency may be discharged from the clinics after a positive NBS. Patients who are unaware of their metabolic disorder may develop severe symptoms later in life, as seen in our case.

The patient we reported on showed symptoms after strenuous exercise, heat exposure, and dehydration. Chronic consumption of carnitine due to accumulation of C5OH carnitine leads to hypocarnitinemia and likely secondary systemic carnitine deficiency. Systemic carnitine deficiency likely contributed to cause rhabdomyolysis triggered by strenuous exercise through fatty acid oxidation defects. The patient also developed hyperammonemia which may be due to an acetyl-CoA depletion, leading to an N-acetylglutamate reduction. This caused an inhibition of carbamoyl phosphate synthetase, which resulted in high ammonia levels. This hypothesis might be supported by an observation of low plasma free carnitine, C2 carnitine, and citrulline levels at the time of hyperammonemia.

Pancreatitis is well known to be associated with other organic acidemias, particularly branched chain amino acid metabolism defects including methylmalonic acidemia and propionic acidemia [5]. There are also case reports of patients with pancreatitis in other disorders of leucine metabolism, such as MSUD and isovaleric acidemia [6,7]. However, pancreatitis has not been reported in patients with 3-MCC deficiency to the best of our knowledge.

Since tandem mass spectrometry (MS-MS) was introduced around 2005, individuals born before 2005 were never tested for 3-MCC deficiency. Healthy females can be diagnosed with 3-MCC deficiency by NBS through positive NBS in their babies. Males who were born before 2005 likely do not have a chance to be tested for 3-MCC deficiency. Considering metabolic decompensation, which could be life-threatening and triggered by strenuous exercise, adult males with previously undiagnosed 3-MCC may have a chance to develop metabolic decompensation. Although 3-MCC itself may not disrupt energy synthesis or urea cycle disruption, it may cause disruptions in the metabolism through secondary carnitine deficiency.

No clear correlation was identified between NBS C5OH level and the presence of metabolic, newborn, later-life, or developmental abnormalities in patients with 3-MCC deficiency [2,4]. No clear correlation between genotype and phenotype has been established either [4,8]. Dantas et al. reported a single case of 3-MCC deficiency due to the compound heterozygous mutations in the MCCC2: c.517dupT/c.994C > T (frameshift/nonsense) who presented with mild clinical symptoms (late onset, good recovery after acute attack, no or mild developmental delay) [8]. No case of 3-MCC deficiency carrying the homozygous mutation of c.994C > T has been reported to the best of our knowledge. Factors other than the genotype, such as environmental factors and modifying genes appear to have a major influence on the phenotype of 3-MCC deficiency [8].

Since 3-MCC is a high incidence condition, can present with life-threatening symptoms, and its preventive intervention is straightforward, i.e., carnitine supplementation, we believe that NBS should include 3-MCC deficiency and positive cases should be followed periodically to prevent the individuals from developing hypocarnitinemia and systemic carnitine deficiency.

4 Synopsis

Although 3-MCC deficiency is often considered a benign condition, those not treated with carnitine or not yet diagnosed adults may have more significant health risks than previously thought. Long term follow-up with evaluation of plasma carnitine levels may be suggested for individuals with positive NBS for 3MCC deficiency and healthy adults with 3MCC deficiency.

CRediT authorship contribution statement

Rachel McGowan: Writing – review & editing, Writing – original draft, Visualization, Conceptualization. Shoji Yano: Writing – review & editing, Writing – original draft, Visualization, Supervision, Conceptualization.

Declaration of competing interest

None.

Data availability

No data was used for the research described in the article.
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