Inborn errors of metabolism in a cohort of pregnancies with non-immune hydrops fetalis: a single center experience

Bruwer, Zandrè; Riyami, Nihal Al; Dughaishi, Tamima Al; Murshedi, Fathiya Al; Sayegh, Abeer Al; Kindy, Adila Al; Meftah, Douja; Kharusi, Khalsa Al; Foori, Amel Al; Yarubi, Naeema Al; Scott, Patrick; Al‐Thihli, Khalid

doi:10.1515/jpm-2017-0124

Cited by 8 publications

(11 citation statements)

References 27 publications

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“…Hydrops fetalis, the abnormal accumulation of fluid in at least two body areas, has been described in cases of GD2 and may present at birth or perinatally [8]. GD and other LSDs remain a small but significant cause of hydrops fetalis, with some variability in incidence based on population [9–12]. As such, GD is not usually considered until a couple experiences multiple spontaneous abortions or perinatal deaths.…”

Section: Pediatric Diagnosis At Different Agesmentioning

confidence: 99%

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Recent advances in the diagnosis and management of Gaucher disease

Gary

Ryan

Steward

et al. 2018

Expert Review of Endocrinology & Metabolism

102

107

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Gaucher disease, the autosomal recessive deficiency of the lysosomal enzyme glucocerebrosidase, is associated with wide phenotypic diversity including non-neuronopathic, acute neuronopathic, and chronic neuronopathic forms. Overlap between types can render definitive diagnoses difficult. However, differentiating between the different phenotypes is essential due to the vast differences in clinical outcomes and response to therapy. Genotypic information is helpful, but cannot always be used to make clinical predictions. Current treatments for Gaucher disease, including enzyme replacement therapy and substrate reduction therapy, can reverse many of the non-neurological manifestations, but these therapies must be administered continually and are extremely costly. Areas covered: We reviewed the literature concerning the varied clinical presentations of Gaucher disease throughout the lifetime, along with treatment options, management goals, and current and future research challenges. A PubMed literature search was performed for relevant publications between 1991 to January 2018. Expert commentary: Interest and research in the field of Gaucher disease is rapidly expanding. However, significant barriers remain in our ability to predict phenotype, assess disease progression using objective biomarkers, and determine optimal treatment strategy on an individual basis. As the field grows, we anticipate identification of genetic modifiers, new biomarkers, and small-molecule chaperone therapies, which may improve patient quality of life.

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Section: Pediatric Diagnosis At Different Agesmentioning

confidence: 99%

“…The etiology of approximately 20% of cases of hydrops fetalis remains unknown. Testing for GD and other LSDs may elucidate the underlying cause in some cases and inform prenatal counseling [9].…”

Section: Pediatric Diagnosis At Different Agesmentioning

confidence: 99%

Recent advances in the diagnosis and management of Gaucher disease

Gary

Ryan

Steward

et al. 2018

Expert Review of Endocrinology & Metabolism

102

107

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“…Although hypoplastic lungs were not reported in this individual, an ungenotyped sibling who previously died with lactic acidosis and coagulopathy was found on autopsy to have pulmonary hypoplasia without report of cardiomegaly. Finally, a novel AARS2 homozygous missense variant was detected in five fetuses with nonimmune hydrops from consanguineous Omani families (Bruwer et al 2017). Of these, one stillborn baby had normal echocardiography.…”

Section: Discussionmentioning

confidence: 98%

Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the AARS2 gene: further delineation of the phenotypic spectrum

Kiraly-Borri

Jevon

et al. 2019

Cold Spring Harb Mol Case Stud

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Variants in the mitochondrial alanyl-tRNA synthetase 2 gene AARS2 (OMIM 612035) are associated with infantile mitochondrial cardiomyopathy or later-onset leukoencephalopathy with premature ovarian insufficiency. Here, we report two newborn siblings who died soon after birth with primary pulmonary hypoplasia without evidence of cardiomyopathy. Whole-exome sequencing detected the same compound heterozygous AARS2 variants in both siblings (c.1774C>T, p.Arg592Trp and c.647dup, p.Cys218Leufs*6) that have previously been associated with infantile mitochondrial cardiomyopathy. Segregation analysis in the family confirmed carrier status of the parents and an unaffected sibling. To our knowledge, this is the first report of primary pulmonary hypoplasia in the absence of cardiomyopathy associated with recessive AARS2 variants and further defines the phenotypic spectrum associated with this gene.

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“…Autosomal recessive AARS2 variants were first described in patients with fatal infantile cardiomyopathy (19). Recently, the clinical spectrum has expanded to include childhood and adult-onset leukodystrophy (with POF in females) (9), retinopathy and optic atrophy (29) and fatal non-immune hydrops fetalis (30). However, cardiomyopathy is conspicuously absent in more recently described phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Recessively inherited variants in AARS2 (NM_020745.2), encoding mitochondrial alanyl-tRNA synthetase (mt-AlaRS), were first described in patients presenting with fatal infantile cardiomyopathy and multiple OXPHOS defects (19), with additional patients subsequently identified (20–24). However, the spectrum of AARS2 -related disease has expanded to include childhood to adulthood-onset leukoencephalopathy with premature ovarian failure (POF) in females (9,25–28), retinopathy and optic atrophy (29) and fatal non-immune hydrops fetalis (30); all with conspicuous absence of cardiac involvement. Currently, AARS2 -related fatal infantile cardiomyopathy is associated with a recurrent pathogenic c.1774C>T (p.Arg592Trp) founder mutation that is either homozygous or compound heterozygous in all described patients.…”

Section: Introductionmentioning

confidence: 99%

Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy

Sommerville

Zhou

Oláhová

et al. 2018

Human Molecular Genetics

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Recessively inherited variants in AARS2 (NM_020745.2) encoding mitochondrial alanyl-tRNA synthetase (mt-AlaRS) were first described in patients presenting with fatal infantile cardiomyopathy and multiple oxidative phosphorylation defects. To date, all described patients with AARS2-related fatal infantile cardiomyopathy are united by either a homozygous or compound heterozygous c.1774C>T (p.Arg592Trp) missense founder mutation that is absent in patients with other AARS2-related phenotypes. We describe the clinical, biochemical and molecular investigations of two unrelated boys presenting with fatal infantile cardiomyopathy, lactic acidosis and respiratory failure. Oxidative histochemistry showed cytochrome c oxidase-deficient fibres in skeletal and cardiac muscle. Biochemical studies showed markedly decreased activities of mitochondrial respiratory chain complexes I and IV with a mild decrease of complex III activity in skeletal and cardiac muscle. Using next-generation sequencing, we identified a c.1738C>T (p.Arg580Trp) AARS2 variant shared by both patients that was in trans with a loss-of-function heterozygous AARS2 variant; a c.1008dupT (p.Asp337*) nonsense variant or an intragenic deletion encompassing AARS2 exons 5–7. Interestingly, our patients did not harbour the p.Arg592Trp AARS2 founder mutation. In silico modelling of the p.Arg580Trp substitution suggested a deleterious impact on protein stability and folding. We confirmed markedly decreased mt-AlaRS protein levels in patient fibroblasts, skeletal and cardiac muscle, although mitochondrial protein synthesis defects were confined to skeletal and cardiac muscle. In vitro data showed that the p.Arg580Trp variant had a minimal effect on activation, aminoacylation or misaminoacylation activities relative to wild-type mt-AlaRS, demonstrating that instability of mt-AlaRS is the biological mechanism underlying the fatal cardiomyopathy phenotype in our patients.

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Inborn errors of metabolism in a cohort of pregnancies with non-immune hydrops fetalis: a single center experience

Abstract: IEM was a major cause of NIHF in this cohort. The AARS2 variant accounts for a significant number of cases with NIHF in this cohort of Omani patients.

Cited by 8 publications

References 27 publications

Recent advances in the diagnosis and management of Gaucher disease

Recent advances in the diagnosis and management of Gaucher disease

Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the AARS2 gene: further delineation of the phenotypic spectrum

Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy

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