Abstract
Methylmalonic acidaemia (MMA) and ornithine transcarbamylase deficiency (OTCD) are both intoxication-type inborn errors of metabolism (IEM). Presently, genetic testing is the primary method for prenatally diagnosing these diseases. However, some reports have demonstrated that mass spectrometry approaches can prenatally diagnose some forms of inborn errors of metabolism using amniotic fluid. Therefore, in this study, genetic and mass spectrometry approaches were used for prenatally diagnosing MMA and OTCD. We collected amniotic fluid samples from 19 foetuses referred, 15 cases were referred for MMA and 4 for OTCD. Of the 15 MMA cases, seven were affected, as determined by genetic testing and the metabolite levels; the characteristic metabolites propionylcarnitine (C3), C3/acetylcarnitine (C2) ratio, methylmalonic acid and methylcitrate levels were significantly higher than the reference range. Eight foetuses were unaffected, and the C3, C3/C2 ratio, methylmalonic acid and methylcitrate levels were within the reference range. The C3, C3/C2, methylmalonic acid, and methylcitrate levels in the amniotic fluid significantly differed between the affected and unaffected foetuses (P = 0.0014, P = 0.0014, P = 0.0003, P = 0.0014, respectively). Moreover, the homocysteine level increased in the amniotic fluid of affected foetuses with MMACHC gene mutations. Of the four OTCD cases, genetic testing confirmed that two foetuses were affected and two were unaffected. However, the characteristic metabolite levels were within the reference range for all foetuses, including citrulline, orotic acid, and uracil. The genetic testing results were confirmed to be correct through the abortion tissue of the foetus and the postnatal follow-up. Our results suggest that mass spectrometry approaches are convenient method for improving the prenatal diagnosis of MMA. The characteristic metabolites C3, C3/C2, methylmalonic acid, and methylcitrate levels in amniotic fluid were reliable biochemical markers for the prenatal diagnosis of MMA.
Highlights
Methylmalonic acidaemia (MMA) and ornithine transcarbamylase deficiency (OTCD) are both common intoxication-type inborn errors of metabolism (IEM) in China [1, 2]
Since the MS/MS and gas chromatography-mass spectrometry (GC/MS) methodologies are mature for diagnosing IEMs, this study describes our experiences with prenatally diagnosing IEM by measuring metabolites in the supernatant of amniotic fluid together with direct mutation analysis in MMA and OTC high-risk pregnancies
The standard method for prenatally diagnosing IEM is the detection of genetic mutations in amniotic fluid cells or chorionic tissues, but the disease-causing genes and mutation sites of the proband must be confirmed to complete the prenatal diagnosis
Summary
Methylmalonic acidaemia (MMA) and ornithine transcarbamylase deficiency (OTCD) are both common intoxication-type inborn errors of metabolism (IEM) in China [1, 2]. The estimated incidence of MMA is 1.5–3 cases per 100 000 people, and the OTCD incidence is between 1 case per 77 000 people and 1 per 14,000 people [3, 4]. MMA is an autosomal recessive organic acidaemia associated with methylmalonyl-CoA mutase and cobalamin metabolic defects. OTCD is an X-linked inherited metabolic disease caused by pathogenic variants of the OTC gene, and is the most common type of congenital urea cycle disorder [5]. MMA and OTCD patients either die shortly after birth or present with acute deterioration, metabolic acidosis, or hyperammonaemia, and later in life, the presentations include intellectual disabilities or abnormal growth and development [1, 6, 7]. Diagnosis and treatment can prevent complications, and prenatal diagnosis is an important way for families with an IEM proband to prevent IEM recurrence
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