No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Abstract
Congenital sialidosis is a rare disease resulting from the absence of neurominidase and presenting with hydrops fetalis, hepatosplenomegaly, dysmorphic features, vacuolated lymphocytes and extensive vacuolation of the connective tissue. Elevated levels of sialooligosaccharides in the urine is characteristic. We describe a newborn baby with congenital sialidosis and discuss the difficulties in reaching the diagnosis.
... 8 Nephrosialidosis was already recognized as a part of the phenotypic spectrum of sialidosis II in 1978; however, only 16 cases have been described in the literature to date. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Here, we describe the implementation of parental WES to define the underlying molecular cause of nephrotic syndrome in a deceased child. Unexpectedly, this led to a sialidosis type II diagnosis. ...
Background:
Monogenetic renal diseases, including recessively inherited nephrotic syndromes, represent a significant health burden despite being rare conditions. Precise diagnostic including identification of the underlying molecular cause is especially difficult in low-income countries and/or if affected individuals are unavailable for biochemical testing. Whole exome sequencing (WES) has opened up novel diagnostic perspectives here. However, sometimes DNA of affected individuals is not suitable for WES due to low amounts or degradation.
Methods and results:
Here we report on the use of parental WES with implementation of specific stepwise variant filtering to identify the underlying molecular cause of childhood onset nephrotic syndrome as nephrosialidosis resulting from a mutation in NEU1. To date, only 16 other cases of nephrosialidosis have been reported in the literature with only one genetically confirmed case. Reviewing the clinical information of all reported cases, we find that the vast majority of patients presented with proteinuria starting mainly between 2 to 3 years of age. Renal pathology showed mainly FSGS with vacuolated cells and steroid treatment was always unsuccessful. Hepatomegaly was present in nearly all cases while corneal clouding and cherry-red spot of the macula was only observed in about 50%. 14/16 previously reported cases were no longer alive at the time of reporting.
Conclusion:
Our findings demonstrate the power of parental WES to diagnose rare genetic diseases such as childhood onset nephrotic syndrome. We further provide a comprehensive overview of the clinical course of Nephrosialidosis and raise awareness for this ultra-rare condition as an underlying cause of FSGS
... Başlıca belirtileri kaba yüz, dizostoz mültipleks (yetersiz kemikleşme), karaciğer ve dalak büyüklüğü, gelişme geriliği ve zeka geriliğidir. Doğuştan şekli anne karnında ölüme veya hidrops fetalise neden olur (6,7). ...
Sialidosis is a rare congenital lysosomal storage disease with autosomal recessive transmission caused by a deficiency of alpha-N-acetyl-neuraminidase (sialidase). The findings begin in the intrauterine period in congenital type of sialidosis and the cases die in the postnatal period due to hydrops fetalis with multiorgan failure. Here, a case of premature baby born to a consanguineous parents and diagnosed as sialidosis with hydrops fetalis is presented. It was learned that the first pregnancy of the mother ended in spontaneous abortion and the second pregnancy was ended up with intrauterine exitus due to hydrops fetalis in the 28th gestational age. On the first physical examination, generalized edema, abdominal distantion due to hepatomegaly and generalized ascites was observed. Direct hyperbilirubinemia and cytoplasmic vacuoli in the lymphomonocyte series in both the bone marrow and peripheral blood smear were detected. The same vacuoli were also observed in hepatocytes in the hystopathological sections of the liver biopsy. Sialidosis was diagnosed by showing that there was no activity of sialidase enzyme in the fibroblast culture. The case died due to cardiorespiratory insufficiency on the 53rd day of admission. In cases with hydrops fetalis which can have various etiologies, careful examination of the peripheral smear is very important in the differential diagnosis in addition to detailed familial history and physical examination. (Turk Arch Ped 2012; 47:290-3)
... Recurrent non-immune hydrops fetalis is an uncommon but important presentation of LSD. Several LSD are known to present in this way, including Farber's disease (Kattner et al, 1997), GMI gangliosidosis (Denis et al, 1996), galactosialidosis (Haverkamp et al, 1996), Niemann–Pick disease type C (Meizner et al, 1990), infantile free sialic acid storage disease, mucolipidosis II (I-cell disease) (Appelman et al, 1988), type 2 Gaucher's disease (Reissner et al, 1998), MPS IVA (Applegarth et al, 1987) and VII (Van Dorpe et al, 1996) and sialidosis (Ovali et al, 1998). Investigation of recurrent non-immune hydrops should include screening for LSD (Piraud et al, 1996). ...
Although the first description of a lysosomal storage disorder was that of Tay-Sachs disease in 1881, the lysosome was not discovered until 1955, by Christian De Duve. The first demonstration by Hers in 1963 of a link between an enzyme deficiency and a storage disorder (Pompe's disease) paved the way for a series of seminal discoveries about the intracellular biology of these enzymes and their substrates, culminating in the successful treatment of Gaucher's disease with beta-glucosidase in the early 1990s. It is now recognized that these disorders are not simply a consequence of pure storage, but result from perturbation of complex cell signalling mechanisms. These in turn give rise to secondary structural and biochemical changes, which have important implications for therapy. Significant challenges remain, particularly the treatment of central nervous system disease. It is hoped that recent advances in our understanding of lysosomal biology will enable successful therapies to be developed.
... Recurrent non-immune hydrops fetalis is an uncommon but important presentation of LSD. Several LSD are known to present in this way, including Farber's disease (Kattner et al, 1997), GMI gangliosidosis (Denis et al, 1996), galactosialidosis (Haverkamp et al, 1996), Niemann–Pick disease type C (Meizner et al, 1990), infantile free sialic acid storage disease, mucolipidosis II (I-cell disease) (Appelman et al, 1988), type 2 Gaucher's disease (Reissner et al, 1998), MPS IVA (Applegarth et al, 1987) and VII (Van Dorpe et al, 1996) and sialidosis (Ovali et al, 1998). Investigation of recurrent non-immune hydrops should include screening for LSD (Piraud et al, 1996). ...
Lysosomal storage disorders (LSDs) are genetic defects caused by lysosomal hydrolase deficiencies. These deficiencies lead to substrate accumulation affecting cells, tissues and organs. Detecting abnormal compound excretion and deficient enzymes assist diagnosis of these disorders for treatment and prevention. This mini review summarizes clinical presentations and diagnostic workup of LSDs and updates the new development in the area.
Sialidosis (MIM 256550) is a rare, autosomal recessive inherited disorder, caused by α-N-acetyl neuraminidase deficiency resulting from a mutation in the neuraminidase gene (NEU1), located on 6p21.33. This genetic alteration leads to abnormal intracellular accumulation as well as urinary excretion of sialyloligosaccharides. A definitive diagnosis is made after the identification of a mutation in the NEU1 gene. So far, 40 mutations of NEU1 have been reported. An association exists between the impact of the individual mutations and the severity of clinical presentation of sialidosis. According to the clinical symptoms, sialidosis has been divided into two subtypes with different ages of onset and severity, including sialidosis type I (normomorphic or mild form) and sialidosis type II (dysmorphic or severe form). Sialidosis II is further subdivided into (i) congenital; (ii) infantile; and (iii) juvenile. Despite being uncommon, sialidosis has enormous clinical relevance due to its debilitating character. A complete understanding of the underlying pathology remains a challenge, which in turn limits the development of effective therapeutic strategies. Furthermore, in the last few years, some atypical cases of sialidosis have been reported as well. We herein attempt to combine and discuss the underlying molecular biology, the clinical features, and the morphological patterns of sialidosis type I and II.
Lysosomal diseases are a significant and underrated cause of hydrops fetalis. In particular, the congenital hydropic form of type II sialidosis has been previously described in only a few patients. We provide detailed information about this rare form of sialidosis hoping to improve current understanding of this disorder and facilitate its diagnosis. We present the clinical history, with molecular analysis, of the first Italian case and a clinical review of previously described patients. Our patient represents the case with the longest survival so far reported; the clinical presentation includes cardiomyopathy, dysostosis multiplex and, from the age of 5 months, hydrocephalus - which has not been so far observed in congenital sialidosis. At a subsequent pregrancy, a prenatal diagnosis was made with biochemical and molecular examinations. Based on our review of the literature and on the clinical course of our patient, we identified distinctive and atypical features of hydropic sialidosis. The difficulties encountered in managing this patient demonstrate the severe damage that may occur during cerebrospinal fluid re-absorption. In addition, we recognized characteristics common to sialidosis, early infantile galactosidosis and infantile GM1 gangliosidosis, as well as to sialidosis and mucopolysaccharidosis. We would like to underline the importance of a correct diagnosis of lysosomal storage diseases for successful genetic counselling and, when available, enzymatic treatment.
Sialidosis is a lysosomal storage disease caused by the deficiency of alpha-N-acetyl neuraminidase-1 (NEU1). Sialidosis is classified into two main clinical variants: Type I, the milder form of the disease,
and Type II, which can in turn be subdivided into three forms: congenital, infantile and juvenile. We report herein the clinical,
biochemical and molecular characterisation of two patients with Type II sialidosis exhibiting the congenital (P1) and infantile
forms (P2). We also review clinical data on the rare Type II forms of sialidosis in the hope of improving understanding of
the disorder and facilitating its diagnosis. The genetic characterization of the two patients showed one known [c. 679G>A
(p.G227R)] NEU1 missense mutation (detected in P2), and the new c.807+1G>A splicing defect (detected in P1), a genetic lesion that is
extremely rare in this disease. Interestingly, P2 presented an extremely elevated level of chitotriosidase in plasma. This
is the first pathological detection of chitotriosidase in sialidosis patients.
Lysosomal storage disorders are rare inborn errors of metabolism, with a combined incidence of 1 in 1500 to 7000 live births. These relatively rare disorders are seldom considered when evaluating a sick newborn. A significant number of the >50 different lysosomal storage disorders, however, do manifest in the neonatal period and should be part of the differential diagnosis of several perinatal phenotypes. We review the earliest clinical features, diagnostic tests, and treatment options for lysosomal storage disorders that can present in the newborn. Although many of the lysosomal storage disorders are characterized by a range in phenotypes, the focus of this review is on the specific symptoms and clinical findings that present in the perinatal period, including neurologic, respiratory, endocrine, and cardiovascular manifestations, dysmorphic features, hepatosplenomegaly, skin or ocular involvement, and hydrops fetalis/congenital ascites. A greater awareness of these features may help to reduce misdiagnosis and promote the early detection of lysosomal storage disorders. Implementing therapy at the earliest stage possible is crucial for several of the lysosomal storage disorders; hence, an early appreciation of these disorders by physicians who treat newborns is essential.
Increased activity of several lysosomal hydrolases was demonstrated in amniotic fluid from a fifteenth week pregnancy in which the fetus had I-cell disease. Cultured cells from amniotic fluid had a decreased activity of the same enzymes. The diagnosis of I-cell disease was later confirmed by enzyme assays in cell cultures of fetal skin and by morphologic studies of several tissues from the aborted fetus. Electron microscopic studies of the fetal tissues and cultured fibroblasts had large numbers of typical inclusions of I-cell disease, thus substantiating the diagnosis and intrauterine manifestation of the disease. The results indicate that prenatal diagnosis of I-cell disease is possible with enzyme assays of amniotic fluid and in cultures of fetal cells from the fluid. Enzyme studies of amniotic fluid can provide a preliminary diagnosis within a few hours, but it is suggested that the definitive diagnosis should be based on assays in cultured cells from amniotic fluid.
Two patients are described in whom the diagnosis of I-cell disease was established in early infancy. These patients lacked many of the clinical and radiographic features described in other children with this disorder. Differences between the neonatal and early childhood presentation of ICD are discussed.
The authors report the sequence of the clinical symptoms in type I sialidosis or cherry-red spot myoclonus syndrome, derived from the cases personally observed and from the literature. They also report neuropathological and neurochemical data. A serial EEG study in a case shows the tendency to a progressive deregulation of cerebral electric activity. Therapeutic attempts to reduce myoclonus, which is one of the more disabling symptoms in this syndrome, are described.
An infant boy is described whose clinical findings include congenital ascites, hepatosplenomegaly, postnatal growth failure, dysostosis multiplex, delayed development, pericardial effusion, and the nephrotic syndrome. Death occurred before he reached 2 years of age. Evidence indicates that these abnormalities resulted from an autosomal recessive inherited deficiency of neuraminidase.
Sasagasako N, Miyahara S, Saito N, Shinnoh N, Kobayashi T, Goto I. Prenatal diagnosis of congenital sialidosis.
Clin Genet 1993: 44: 8–11. © Munksgaard, 1993
A case of prenatally diagnosed congenital sialidosis is described in a 21-week-old male fetus, which was the fifth product of non-consanguineous parents. The proband, the second product, was diagnosed as having sialidosis by the enzyme assay in peripheral leukocytes after birth. At the 17th week of pregnancy, the fetus at risk was proven to have isolated sialidase deficiency after analyzing a sample of the cultured amniotic fluid cells. There were many cytoplasmic vacuoles and increased amounts of sialyloligosaccharides in the tissue of the aborted fetus, while the amount and the pattern of gangliosides in the central nervous system were normal.