Akademik Veri Yönetim Sistemi
INTERNATIONAL INBORN ERRORS OF METABOLISM AND NUTRITION CONGRESS, İstanbul, Türkiye, 10 - 14 Nisan 2019, ss.1-547
INTRODUCTION: 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency
(OMIM#210200, #210210) is an autosomal recessive organic aciduria in the catabolic
pathway of leucine due to deficiency of a biotin-dependent mitochondrial enzyme.
Methylcrotonylglycinuria was identified by Eldjarn et al. in 1970 (1). It is one of the most
common inborn errors of metabolic diseases diagnosed by newborn screening with a
prevalence ranging from 1:2400 to 1:68.000 depending on the population (2). The clinical
picture of MCC deficiency is heterogeneous and often highly variable even within the same
family. The clinical phenotype ranges from neonatal onset with severe neurological
involvement to asymptomatic adults. Symptomatic patients may present with failure to
thrive, vomiting, developmental delay, involuntary movements, hypotonia, seizures or
metabolic disturbances such as hypoglycemia, hyperammonemia, ketoacidosis or Reye
syndrome. Acute metabolic crisis may be triggered by infections or transition to a proteinrich
diet in early childhood. There are also asymptomatic or mildly symptomatic mothers
diagnosed as a result of neonatal screening of their children. We have observed muscular
symptoms and easy fatigue in these mothers as reported in the literature (3). 3-MCC
deficiency, due to mutations on MCCC1 and MCCC2 genes, leads to accumulation C5-OH
carnitine in plasma and 3-hydroxyisovaleric acid (3-HIVA) and 3-methylcrotonyl-glycine
(3-MCG) in urine. Secondary carnitine deficiency may develop in these patients. We report
the clinical and biochemical characterization of the patients with 3-MCC deficiency to
defined clinical phenotypes.
RESULTS: The patients with the diagnosis of 3-MCC deficiency were studied
retrospectively and the information in their patient records were evaluated. Twenty-eight
patients were included in the study. Eleven (39.3%) of them were males and seventeen
(60.7%) were females. The median age was 15.1 years (range:0.4-45.6). Sixteen patients(57.2%) were products of consanguineous marriages and one was preterm. The median birth
weight (n=16) was 2988g (range:1940-3590). Family history was negative for a similar
disease in nineteen patients (67.9%). Five patients (17.9%) were diagnosed by newborn
screening and ten (35.7%) were by family screening. Patients diagnosed by family screening
(n=5) had complaints such as fatigue and headache. Thirteen patients (46.4%) were latediagnosed.
Eight (27.5%) were mothers diagnosed after evaluation of their children. Median
age of diagnosis was 4.54 years (range:0-41). Physical examination was unremarkable in
twenty-two (78.6%) patients. Reported symptoms were fatigue (n= 5), seizures (n=4),
developmental delay (n=3), respiratuar distress (n=2), confusion (n=2), speech disorder
(n=1), lack of attention (n=1), headache (n=1), febrile seizures (n=1) and vomiting (n=1).
Symptomatic patients had hypoglycemia, hyperammonemia and metabolic acidosis. The
median C0 and C5-OH carnitine by tandem MSMS were 13.8 μmol/L (N:8.6-90) (range:2-
49.9) and 14.7μmol/L (N:0-0.8) (range: 1.05 - 65.2) respectively. 3-HIVA and 3-MCG were
elevated in urine. There was no 3-MCG excretion in seven patients. Twenty-four patients
received medical treatment. The initial and final treatment modalities are given in Table1.
The median follow-up period was 3.8 years (range:1-35). Physical examination was normal
in twenty-three patients, five patients had neuromotor retardation and two had tremors. The
final median C0 and C5-OH carnitine by tandem MSMS were 27.03 μmol/L (N:8.6-90)
(range: 8.85-54) and 22.5 μmol/L (N:0-0.8) (range: 0.41 – 77.4) respectively. Ten of the
patients underwent molecular analysis. MCCC1 gene mutation was detected in four and
MCCC2 gene in six patients. In the family screening of a symptomatic patient with
p.V694(c.2079delta) homozygous mutation in the MCCC1 gene, a heterozygous mutation
was found in the same gene in both two siblings. They had C5-OH elevation in tandem
MSMS and 3-HIVA and 3-MCG excretion in urine. One of them had neuromotor retardation
and seizures. The results of molecular analysis of patients are given in Table 2.
CONCLUSION: 3-MCC deficiency is a common inborn error of metabolism diagnosed by
newborn screening. The clinical picture of MCC deficiency is heterogeneous. There was no
clear relationship between symptoms and residual enzyme activities. The disease spectrum
is variable, leading to discussions about to treat or not to treat. The majority of children
diagnosed by newborn screening have been reported to have remained asymptomatic so far.
But some patients may be symptomatic in adulthood. A few cases muscular symptoms in
affected mothers have been reported in literature. In our study, eighteen (%64.3) had
complaints at diagnosis and eight (27.5%) were mothers diagnosed after evaluation of their
children. Five of the mothers had fatigue and headache before diagnosis.
In our study, the reason why asymptomatic patients are less is probably due to the fact that this disease is not in the neonatal screening program in our country. Screening of the mothers
of newborns with elevated C5-OH carnitine is should be recommended.