Lysosomal storage diseases in non-immune hydrops fetalis pregnancies

doi:10.1016/j.cca.2006.03.007

Clinica Chimica Acta

Volume 371, Issues 1–2, September 2006, Pages 176-182

https://doi.org/10.1016/j.cca.2006.03.007 Get rights and content

Abstract

Background

At least 20 inborn errors of metabolism may cause hydrops fetalis. Most of these are lysosomal storage diseases. The study proposes a diagnostic flowchart for prenatal diagnosis of non-immune hydrops fetalis.

Methods

This study contains a series of 75 non-immune hydrops fetalis pregnancies. Mucopolysaccharides, oligosaccharides, neuraminic acid and 21 lysosomal enzymes were measured in amniotic fluid and cultured amniotic cells.

Results

The study gives reference values for mucopolysaccharides and neuraminic acid at various stages of gestation. Four definite and two probable lysosomal diagnoses were found among the 75 investigated cases (= 5.3–8%). Fetal death was found to cause false positive values for mucopolysaccharides in amniotic fluid. In the galactosialidosis case, two novel mutations were found in the cathepsin A gene.

Conclusions

Reference values for mucopolysaccharides and neuraminic acid depend on gestational age. In a relatively high percentage of the hydrops foetalis pregnancies, a lysosomal aetiology is found. This study provides a strategy to diagnose lysosomal diseases in hydrops fetalis pregnancies. Awareness of lysosomal storage diseases causing hydrops fetalis is useful as it gives an opportunity for risk evaluation, genetic counseling to parents and targeted prenatal diagnostics for ensuing pregnancies.

Introduction

The diagnosis of hydrops fetalis (= HF), the presence of excessive fluid in more than one body cavity in the fetus, is being made increasingly and at an earlier stage during pregnancy owing to routine prenatal ultrasound screening. Estimates of the incidence of HF vary between one in 600 and 4000 pregnancies [1], [2], [3]. Estimates of mortality vary between 60% and 90% [3]. HF can have diverse and widely ranging causes due to disease processes in the cardiovascular or thoracic regions, fetal arrhythmia, monochorial twin pregnancies, fetal anaemia, chromosomal aberrations and genetic syndromes [4]. Traditionally, HF is subdivided in immunological and non-immunological HF (= NIHF). Inborn errors of metabolism are among the causes of NIHF and the group of lysosomal diseases is the most important subgroup. Prenatal diagnosis of a lysosomal disease in families at risk is well established in chorionic villi and in amniocytes. For the prenatal diagnosis of a lysosomal disease in NIHF cases, the accumulating substrate of the defective enzyme and/or the enzymatic activity can be determined [5], [6], [7], [8]. We have investigated a series of 75 pregnancies with NIHF at the metabolite level and at the enzyme level by measuring 21 lysosomal enzymes. Reference values for mucopolysaccharides (= MPS) and neuraminic acid are not available in literature. This paper gives gestational age-related reference ranges for MPS and neuraminic acid and gives examples of abnormal oligosaccharide profiles of amniotic fluid. Four definite and two probable cases of NIHF pregnancies due to lysosomal etiology are described.

Section snippets

Patients

We have investigated a series of 75 pregnancies with NIHF. In all pregnancies, routine maternal antibody screening had excluded irregular antibodies. The classification of NIHF is based on the maternal blood group and the absence of irregular antibodies to red cell antigens Rhesus, c, E and Kell. Chromosomal abnormalities had been excluded in all cases. Investigations were carried out at the metabolite level and at the enzyme level to diagnose lysosomal diseases. In amniotic fluid these

Reference ranges

No reference ranges are available for MPS and neuraminic acid in amniotic fluid. To establish these we have expressed both compounds per protein (MPS, Fig. 1A; neuraminic acid, Fig. 1B). Fig. 1 gives the individual values for the control samples and the NIHF cases. The figure shows a gradual increase in concentration of both parameters with gestational age. The increase is more pronounced for neuraminic acid.

Amniotic fluid

Out of 75 NIHF pregnancies and 40 control pregnancies, 71 were investigated at the

Discussion

Lysosomal storage diseases (LSD) are extremely rare. However, the estimated combined birth incidence for all lysosomal diseases is 14 per 100,000 live births [14]. Deficiency of a lysosomal enzyme (nearly always) results in accumulation of the substrate of the specific enzyme in the lysosomes and leads to cell and tissue damage, swelling and organomegaly. The liver, spleen and bone marrow are among the targets. Damage to these organs and bone marrow may result in decreased haematopoiesis,

Acknowledgements

We thank Dr. M. Verjaal, clinical geneticist and Dr. C.M. Bilardo, gynaecologist of Academic Medical Centre Amsterdam for their comments in 3 cases and Dr. W. Kleijer, clinical biochemical geneticist Erasmus MC Rotterdam for measuring cathepsin A. The authors thank Dr. W. Lissens (Brussels, Belgium), Dr. E. Paschke (Graz, Austria) and Prof. A. D'Azzo (Memphis, USA) for molecular genetic analysis of the cases with β-glucuronidase, β-d-galactosidase and cathepsin A deficiency respectively. We are

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Cited by (44)

β-Galactosidase deficiency: GM1 gangliosidosis, Morquio B disease, and galactosialidosis
2020, Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease: Volume 1
Whole exome sequencing is now being used to diagnose genetic diseases of the sort described here for thousands of patients in our hospitals and clinics all over the country at manageable cost (Medicare or Medicaid), in some disorders for the first time. Laboratories, academic or commercial, around the country do this in reasonable time frames, usually using small blood samples from the patient alone or from a few additional family members. New mutations are now found for previously known diseases of all sorts. Whole-genome sequencing is done where costs permit.
The Clinical and Molecular Spectrum of GM1 Gangliosidosis
2019, Journal of Pediatrics
To evaluate the clinical presentation of patients with GM1 gangliosidosis and to determine whether specific clinical or biochemical signs could lead to a prompt diagnosis.
We retrospectively analyzed clinical, biochemical, and genetic data of 22 patients with GM1 gangliosidosis from 5 metabolic centers in Germany and Austria.
Eight patients were classified as infantile, 11 as late-infantile, and 3 as juvenile form. Delay of diagnosis was 6 ± 2.6 months in the infantile, 2.6 ± 3.79 years in the late-infantile, and 14 ± 3.48 years in the juvenile form. Coarse facial features, cherry red spots, and visceromegaly occurred only in patients with the infantile form. Patients with the late-infantile and juvenile forms presented with variable neurologic symptoms. Seventeen patients presented with dystonia and 14 with dysphagia. Laboratory analysis revealed an increased ASAT concentration (13/20), chitotriosidase activity (12/15), and pathologic urinary oligosaccharides (10/19). Genotype analyses revealed 23 causative or likely causative mutations in 19 patients, 7 of them being novel variants. In the majority, a clear genotype–phenotype correlation was found.
Diagnosis of GM1 gangliosidosis often is delayed, especially in patients with milder forms of the disease. GM1 gangliosidosis should be considered in patients with progressive neurodegeneration and spastic-dystonic movement disorders, even in the absence of visceral symptoms or cherry red spots. ASAT serum concentrations and chitotriosidase activity may be of value in screening for GM1 gangliosidosis.
Nonimmune hydrops fetalis: identifying the underlying genetic etiology
2019, Genetics in Medicine
Citation Excerpt :
For example, 19% of all NIHF cases have been attributed to rare genetic syndromes and nearly one-third of idiopathic cases to lysosomal storage disorders (LSDs),7,13 which are not detected through karyotype or CMA. Because the majority of existing literature consists of case reports and small series focusing on specific genetic diseases,14-25 the true frequency of each underlying cause remains uncertain. Without a better understanding of the causes of NIHF, it is challenging to effectively manage these pregnancies, counsel about prognosis and recurrence risk, and anticipate neonatal care requirements.
Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes.
Retrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal–Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology.
Sixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach–Merritt syndrome.
In this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing.
No. 363-Investigation and Management of Non-immune Fetal Hydrops
2018, Journal of Obstetrics and Gynaecology Canada
Citation Excerpt :
Structural congenital anomalies should be evaluated as they represent a large group of disorders that can be identified through detailed fetal imaging and may be treatable. Primary chylothorax,2,33 congenital cystic adenomatoid malformation,34 various fetal tumours,35 and metabolic diseases have been also described as causal factors of hydrops.36,37 Known single-gene disorders affecting metabolic pathways, hematological conditions, skeletal dysplasia, neurologic disorders, cardiomyopathies, congenital nephrosis, congenital lymphedema, and mitochondrial mutations have been reported as causes of potentially recurring fetal hydrops.22
To describe the current investigation and management of non-immune fetal hydrops with a focus on treatable or recurring etiologies.
To provide better counselling and management in cases of prenatally diagnosed non-immune hydrops.
Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2017 using key words (non-immune hydrops fetalis, fetal hydrops, fetal therapy, fetal metabolism). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, observational studies, and significant case reports. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to September 2017. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinicalpractice guideline collections, clinical trial registries, and national and international medical specialty societies.
These guidelines educate readers about the causes of non-immune fetal hydrops and its prenatal counselling and management. It also provides a standardized approach to non-immune fetal hydrops, emphasizing the search for prenatally treatable conditions and recurrent genetic etiologies.
The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care.
- 1.
  All patients with fetal hydrops should be referred promptly to a tertiary care centre for evaluation. Some conditions amenable to prenatal treatment represent a therapeutic emergency after 18 weeks, allowing prolongation of pregnancy with improved fetal/neonatal outcomes (II-2A).
- 2.
  Fetal chromosome analysis through array comparative genomic hybridization (microarray) molecular testing should be offered where available in all cases of non-immune fetal hydrops (II-2A).
- 3.
  Imaging studies should include comprehensive obstetrical ultrasound (including arterial and venous fetal Doppler) and fetal echocardiography (II-2A).
- 4.
  Investigation for maternal–fetal infections and alpha-thalassemia in women at risk because of their ethnicity should be performed in all cases of unexplained fetal hydrops (II-2A).
- 5.
  To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. In case of suspected fetal anemia, fetal blood sampling and intrauterine transfusion should be offered rapidly (II-2A).
- 6.
  All cases of unexplained fetal hydrops should be referred to a medical genetics service where available. Detailed postnatal evaluation by a medical geneticist should be performed on all cases of newborns with unexplained non-immune hydrops (II-2A).
- 7.
  Autopsy is strongly recommended for all cases of fetal or neonatal death for which no diagnosis is reached prenatally (II-2A).
N° 363 - Évaluation et prise en charge de l'anasarque fœtoplacentaire non immune
2018, Journal of Obstetrics and Gynaecology Canada
Citation Excerpt :
L'anasarque fœtoplacentaire est relativement courante en cas de MPS de type VII40, de galactosialidose infantile41, de maladie de Gaucher de type 2 et de maladie de surcharge en acide sialique libre infantile. Au moins 15 autres erreurs innées du métabolisme peuvent provoquer une AFNI37,42 : gangliosidose à GM1, maladie de Niemann-Pick de type A, maladie de Niemann-Pick de type C, MPS de type I, MPS de type IV A, mucolipidose de type II, sialidose, déficit multiple en sulfatase, maladie de Farber, maladie de Wolman, maladie des cellules à inclusion, glycogénose de type IV39, déficit en transaldolase43, syndrome de Pearson (maladie mitochondriale) et troubles congénitaux de la glycosylation. Des tests d'activité enzymatique spécifiques sont disponibles pour dépister quelques-un sde ces troubles en se servant d'amniocytes cultivés ou en mesurant des métabolites particuliers dans le surnageant du liquide amniotique38,44–47.
Décrire les méthodes actuelles d’évaluation et de prise en charge de l'anasarque fœtoplacentaire non immune en mettant l'accent sur les étiologies traitables ou récurrentes.
Offrir de meilleurs services de conseil et de prise en charge en cas d'anasarque fœtoplacentaire non immune diagnostiquée en période prénatale.
La littérature publiée a été récupérée au moyen de recherches menées dans PubMed, MEDLINE, CINAHL, et la Bibliothèque Cochrane en 2017 à l'aide de mots-clés (« non-immune hydrops fetalis », « fetal hydrops », « fetal therapy », « fetal metabolism »). Les articles retenus portaient sur des revues systématiques, des essais cliniques contrôlés, randomisés ou non, des études observationnelles et des études de cas importantes. D'autres publications ont été repérées dans les bibliographies de ces articles. Aucune restriction de date ou de langue n'a été employée. Les recherches ont été mis à jour régulièrement, et les résultats ont été incorporés à la directive clinique jusqu'en septembre 2017. Nous avons également tenu compte de la littérature grise (non publiée) trouvée sur les sites Web d'organismes d’évaluation des technologies de la santé et d'autres organismes liés aux technologies de la santé, dans des collections de directives cliniques et des registres d'essais cliniques, et obtenue auprès d'associations nationales et internationales de médecins spécialistes.
La présente directive clinique renseigne les lecteurs sur les causes de l'anasarque fœtoplacentaire non immune ainsi que sur son évaluation et sa prise en charge. Elle propose également une approche standardisée d’évaluation et de prise en charge, et met l'accent sur la recherche des conditions traitables en période prénatale et des étiologies génétiques récurrentes.
La qualité des données probantes a été évaluée en fonction des critères décrits dans le rapport du Groupe d’étude canadien sur les soins de santé préventifs.
- 1.
  Toutes les patientes présentent une anasarque fœtoplacentaire devraient être rapidement dirigées vers un centre de soins tertiaires pour y subir une évaluation. Certains conditions traitables en période prénatale constituent une urgence thérapeutique après 18 semaines de grossesse; leur traitement peut permettre la poursuite de la grossesse et l'amélioration des issues fœtales et néonatales (II-2A).
- 2.
  L'analyse des chromosomes fœtaux par hybridation génomique comparative sur microréseaux d'ADN devrait être offerte, lorsque disponible, à toutes les femmes qui présentent une anasarque fœtoplacentaire non immune (II-2A).
- 3.
  Les examens d'imagerie devraient comprendre une échographie obstétricale exhaustive (y compris un Doppler fœtal artériel et veineux) ainsi qu'une échocardiographie fœtale (II-2A).
- 4.
  Le dépistage d'infections fœtomaternelles et de l'alpha-thalassémie devrait être effectué chez toutes les femmes qui présentent une anasarque fœtoplacentaire inexpliquée et qui sont à risque en raison de leur origine ethnique (II-2A).
- 5.
  Un Doppler visant à mesurer le pic de vitesse systolique dans l'artère cérébrale moyenne devrait être effectué après 16 semaines de grossesse chez tous les fœtus hydropiques afin d’évaluer le risque d'anémie fœtale. Si une anémie fœtale est soupçonnée, un prélèvement de sang fœtal et une transfusion intra-utérine devraient être offerts rapidement (II-2A).
- 6.
  Toutes les patientes qui présentent une anasarque fœtoplacentaire inexpliquée devraient être dirigées vers des services de génétique médicale lorsque cela est possible. Une évaluation postnatale exhaustive de tout nouveau-né atteint d'anasarque non immune inexpliquée devrait être réalisée par un médecin généticien (II-2A).
- 7.
  Une autopsie est fortement recommandé en tout cas de décès fœtal ou néonatal en l'absence d'un diagnositc prénatal (II-2A).
Metabolic causes of nonimmune hydrops fetalis: A next-generation sequencing panel as a first-line investigation
2018, Clinica Chimica Acta
Hydrops fetalis is a life-threatening fetal condition, and 85% of all cases are classified as nonimmune hydrops fetalis (NIHF). Up to 15% of NIHF cases may be due to inborn errors of metabolism (IEM), but a large proportion of cases linked to metabolic disorders remains undiagnosed. This lack of diagnosis may be related to the limitations of conventional biological procedures, which involve sequential investigations and require multiple samples and steps. In addition, this approach is time consuming. We have developed a next-generation sequencing (NGS) panel to investigate metabolic causes of NIHF, ascites, and polyhydramnios associated to another fetal abnormality.
The hydrops fetalis (HydFet) panel was designed to cover the coding regions and flanking intronic sequences of 41 genes. A retrospective study of amniotic fluid samples from 40 subjects was conducted. A prospective study was subsequently initiated, and six samples were analyzed using the NGS panel.
Five IEM diagnoses were made using the HydFet panel (Niemann-Pick type C (NPC), Barth syndrome, HNF1Β deficiency, GM1 gangliosidosis, and Gaucher disease). This analysis also allowed the identification of 8p sequence triplication in an additional case.
NGS combined with robust bioinformatics analyses is a useful tool for identifying the causative variants of NIHF. Subsequent functional characterization of the protein encoded by the altered gene and morphological studies may confirm the diagnosis. This paradigm shift allows a significant improvement of IEM diagnosis in NIHF.

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Lysosomal storage diseases in non-immune hydrops fetalis pregnancies

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Reference ranges

Amniotic fluid

Discussion

Acknowledgements

Adv Pediatr

Clin Chim Acta

Clin Chim Acta

Am J Hum Genet

Non-immune hydrops fetalis

Semin Perinatol

Non-immune hydrops fetalis (chapter 17)

Variable clinical presentation in lysosomal storage disorders

J Inherit Metab Dis

Diagnosis of lysosomal storage diseases with fetal presentation

Ann Pathol

Fetal ascites as a manifestation of infantile sialidosis. Significance of a study of oligosaccharides in amniotic fluid

J Genet Hum

Measuring urinary glycosaminoglycans in the presence of protein: an improved screening procedure for mucopolysaccharidoses based on dimethylmethylene blue

Clin Chem

Novel missense mutations in beta-glactosidase that result in GM1-gangliosidosis

Am J Hum Genet

Mutations in mucopolysacharidosis type VII and heterogeneity of the polyadenylation region

Hum Genet

Novel missense mutations in beta-glactosidase that result in GM₁-gangliosidosis