Novel mutation and prenatal sonographic findings of glutaric aciduria (type I) in two Taiwanese families

Abstract

Glutaric aciduria type I (GA I) is an autosomal recessively inherited inborn error with a defect of the enzyme glutaryl-CoA dehydrogenase (GCDH), which has never been diagnosed prenatally in Taiwanese patients. We present the prenatal sonographic findings and mutational analysis data of three children in two Taiwanese families. One patient from each family was diagnosed postnatally due to macrocephaly and neurological deterioration at 4 months and 10 months, respectively. The third child, sister of the first patient, was diagnosed prenatally at 11 weeks' gestation through chorionic villus sampling (CVS). Molecular analysis revealed that the fetus and child in Family 1 were homozygous for a common mutation, IVS10 -2A>C, which has not been reported in the Caucasian population. The patient in Family 2 was a compound heterozygote for IVS10 -2A>C and a novel mutation 749T>C (L238P). After genetic counseling, the couple decided to continue the second pregnancy. However, dilatation of quadrigeminal cistern (QC) and suspicious macrocephaly were noted at 30 weeks. Progressive dilatation of the QC associated with macrocephaly, fronto-temporal atrophy and wide space of perisylvian fissure were found in the follow-up scans. The affected girl was delivered at 37 weeks' gestation by cesarean section. Postnatal magnetic resonance imaging (MRI) studies confirmed the prenatal sonographic findings. With prenatal sonographic findings and mutational analysis presented in the present cases, the feasibility of prenatal diagnosis of GA I in high-risk pregnancy can not be overlooked.

Neurodevelopmental Profiles of Children with Glutaric Aciduria Type I Diagnosed by Newborn Screening: A Follow-Up Case Series

“…However, recent studies suggest that neurological damage can occur in the absence of an encephalopathic crisis due to neurotoxicity in utero or early life and that this may be associated with delayed myelination and brain maturation (Harting et al 2009). This theory is supported by findings of brain abnormalities and widening of the sylvian fissures and fronto-temporal atrophy in newborns and as early as 33 weeks gestation (Lin et al 2002;Mellerio et al 2008), which may resolve over time (Viau et al 2012).…”

“…The consistency of this finding at both time points indicates that this deficit is an on-going clinical feature of GA-I, likely to be due to an early impact of GA-I on brain development. Early effects of GA-I on the brain have been documented in newborns and as early as 33 weeks gestation (Lin et al 2002;Mellerio et al 2008). GA-I causes striatal and fronto-temporal pathology (Harting et al 2009), areas that are associated with motor skills and motor planning (Groenewegen et al 2003).…”

Diagnosis and management of glutaric aciduria type I – revised recommendations

“…MRI studies, in particular those using echo-planar imaging spin-echo or apparent diffusion coefficient maps, detect striatal lesions earlier and more reliably than CT scans (Brismar and Ozand 1995; Desai et al 2003; Elster 2004; Neumaier-Probst et al 2004; Oguz et al 2005; Strauss et al 2007; Twomey et al 2003). Some of these neuroradiological changes can also be detected by ultrasound (Forstner et al 1999), even already during the last trimester of pregnancy (Lin et al 2002; Mellerio et al 2008). The benefit of serial MRI investigations is unclear and is not considered essential for regular monitoring.…”

Striatal necrosis in type 1 glutaric aciduria: Different stages in two siblings

“…When there is a family history of GA-1, prenatal diagnosis at 11 week's gestation through chorionic villus sampling[8] can be done if the responsible mutation is known. Later in pregnancy, ultrasound[8] and MRI[9] can diagnose GA-1 in suspected cases.…”

“…Later in pregnancy, ultrasound[8] and MRI[9] can diagnose GA-1 in suspected cases. Progressive dilatation of the quadrigeminal cisterns associated with macrocephaly, fronto-temporal atrophy and wide space of perisylvian fissure were found in the follow-up scans when parents decided to continue pregnancy in affected cases.…”