Abstract:Congenital disorders of glycosylation (CDG) are a growing group of inborn metabolic disorders with multiorgan presentation. SLC39A8-CDG is a severe subtype caused by biallelic mutations in the manganese transporter SLC39A8, reducing levels of this essential cofactor for many enzymes including glycosyltransferases. The current diagnostic standard for disorders of Nglycosylation is the analysis of serum transferrin. Exome and Sanger sequencing were performed in two patients with severe neurodevelopmental phenoty… Show more
“…Common clinical features of SLC39A8-CDG patients are hypotonia, poor postural control, increased peripheral tone, global developmental delay, intellectual disability, and failure to thrive. Strabismus is a recurring feature [ 2 – 5 ], also in this study (Patient-2). Hearing impairment was described in only one patient [ 2 ].…”
Section: Discussionmentioning
confidence: 61%
“…3 a). This glycoform, corresponding to the biantennary truncated N-glycan NeuAc 1 Gal 1 Man 3 GlcNAc 4 lacking one terminal NeuAc-Gal epitope, has been explicitly addressed to a distinctive serum N-glycome signature for B4GALT deficiency in SLC39A8-CDG patients [ 5 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Here, we report the identification of novel SCL39A8 variants and homozygosity for a common missense variant associated with clinical, neuroradiological and glycosylation findings consistent with SLC39A8-CDG. So far, a paucity of SLC39A8-CDG studies have been reported, including 14 patients with different clinical and neuroradiological characteristics and variable transferrin glycosylation changes [ 2 – 5 ] (Table 1 ). Common clinical features of SLC39A8-CDG patients are hypotonia, poor postural control, increased peripheral tone, global developmental delay, intellectual disability, and failure to thrive.…”
Section: Discussionmentioning
confidence: 99%
“…These blood measurements enable to distinguish between CDG-I (cytosol and endoplasmic reticulum defects of N-glycan assembly) and CDG-II (Golgi processing defects). So far fourteen subjects with SLC39A8-CDG have been reported [ 2 – 5 ]. Most patients exhibited a serum Tf IEF type 2 pattern and/or low to undetectable blood Mn levels and elevated Mn urine levels, consistent with renal wasting [ 3 , 6 ].…”
Section: Introductionmentioning
confidence: 99%
“…SLC39A8-CDG presents with developmental delay, severe intellectual disability, seizures, and cerebral and/or cerebellar atrophy [ 6 ]. Dystonia and basal ganglia T2-hyperintensities on magnetic resonance imaging (MRI) are also part of the neurological spectrum [ 4 , 5 ]. SLC39A8-CDG features have been related to both Mn deficiency and hypoglycosylation [ 2 ].…”
Background
SLC39A8, a gene located on chromosome 4q24, encodes for the manganese (Mn) transporter ZIP8 and its detrimental variants cause a type 2 congenital disorder of glycosylation (CDG). The common SLC39A8 missense variant A391T is associated with increased risk for multiple neurological and systemic disorders and with decreased serum Mn. Patients with SLC39A8-CDG present with different clinical and neuroradiological features linked to variable transferrin glycosylation profile. Galactose and Mn supplementation therapy results in the biochemical and clinical amelioration of treated patients.
Results
Here, we report clinical manifestations, neuroradiological features and glycophenotypes associated with novel SLC39A8 variants (c.1048G > A; p.Gly350Arg and c.131C > G; p.Ser44Trp) in two siblings of the same Italian family. Furthermore, we describe a third patient with overlapping clinical features harbouring the homozygous missense variant A391T. The clinical phenotype of the three patients was characterized by severe developmental disability, dystonic postural pattern and dyskinesia with a more severe progression of the disease in the two affected siblings. Neuroimaging showed a Leigh syndrome-like pattern involving the basal ganglia, thalami and white matter. In the two siblings, atrophic cerebral and cerebellum changes consistent with SLC39A8-CDG were detected as well. Serum transferrin isoelectric focusing (IEF) yielded variable results with slight increase of trisialotransferrin isoforms or even normal pattern. MALDI-MS showed the presence of hypogalactosylated transferrin N-glycans, spontaneously decreasing during the disease course, only in one affected sibling. Total serum N-glycome depicted a distinct pattern for the three patients, with increased levels of undergalactosylated and undersialylated precursors of fully sialylated biantennary glycans, including the monosialo-monogalacto-biantennary species A2G1S1.
Conclusions
Clinical, MRI and glycosylation features of patients are consistent with SLC39A8-CDG. We document two novel variants associated with Leigh syndrome-like disease presentation of SLC39A8-CDG. We show, for the first time, a severe neurological phenotype overlapping with that described for SLC39A8-CDG in association with the homozygous A391T missense variant. We observed a spontaneous amelioration of transferrin N-glycome, highlighting the efficacy of MS-based serum glycomics as auxiliary tool for the diagnosis and clinical management of therapy response in patients with SLC39A8-CDG. Further studies are needed to analyse more in depth the influence of SLC39A8 variants, including the common missense variant, on the expression and function of ZIP8 protein, and their impact on clinical, biochemical and neuroradiological features.
“…Common clinical features of SLC39A8-CDG patients are hypotonia, poor postural control, increased peripheral tone, global developmental delay, intellectual disability, and failure to thrive. Strabismus is a recurring feature [ 2 – 5 ], also in this study (Patient-2). Hearing impairment was described in only one patient [ 2 ].…”
Section: Discussionmentioning
confidence: 61%
“…3 a). This glycoform, corresponding to the biantennary truncated N-glycan NeuAc 1 Gal 1 Man 3 GlcNAc 4 lacking one terminal NeuAc-Gal epitope, has been explicitly addressed to a distinctive serum N-glycome signature for B4GALT deficiency in SLC39A8-CDG patients [ 5 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Here, we report the identification of novel SCL39A8 variants and homozygosity for a common missense variant associated with clinical, neuroradiological and glycosylation findings consistent with SLC39A8-CDG. So far, a paucity of SLC39A8-CDG studies have been reported, including 14 patients with different clinical and neuroradiological characteristics and variable transferrin glycosylation changes [ 2 – 5 ] (Table 1 ). Common clinical features of SLC39A8-CDG patients are hypotonia, poor postural control, increased peripheral tone, global developmental delay, intellectual disability, and failure to thrive.…”
Section: Discussionmentioning
confidence: 99%
“…These blood measurements enable to distinguish between CDG-I (cytosol and endoplasmic reticulum defects of N-glycan assembly) and CDG-II (Golgi processing defects). So far fourteen subjects with SLC39A8-CDG have been reported [ 2 – 5 ]. Most patients exhibited a serum Tf IEF type 2 pattern and/or low to undetectable blood Mn levels and elevated Mn urine levels, consistent with renal wasting [ 3 , 6 ].…”
Section: Introductionmentioning
confidence: 99%
“…SLC39A8-CDG presents with developmental delay, severe intellectual disability, seizures, and cerebral and/or cerebellar atrophy [ 6 ]. Dystonia and basal ganglia T2-hyperintensities on magnetic resonance imaging (MRI) are also part of the neurological spectrum [ 4 , 5 ]. SLC39A8-CDG features have been related to both Mn deficiency and hypoglycosylation [ 2 ].…”
Background
SLC39A8, a gene located on chromosome 4q24, encodes for the manganese (Mn) transporter ZIP8 and its detrimental variants cause a type 2 congenital disorder of glycosylation (CDG). The common SLC39A8 missense variant A391T is associated with increased risk for multiple neurological and systemic disorders and with decreased serum Mn. Patients with SLC39A8-CDG present with different clinical and neuroradiological features linked to variable transferrin glycosylation profile. Galactose and Mn supplementation therapy results in the biochemical and clinical amelioration of treated patients.
Results
Here, we report clinical manifestations, neuroradiological features and glycophenotypes associated with novel SLC39A8 variants (c.1048G > A; p.Gly350Arg and c.131C > G; p.Ser44Trp) in two siblings of the same Italian family. Furthermore, we describe a third patient with overlapping clinical features harbouring the homozygous missense variant A391T. The clinical phenotype of the three patients was characterized by severe developmental disability, dystonic postural pattern and dyskinesia with a more severe progression of the disease in the two affected siblings. Neuroimaging showed a Leigh syndrome-like pattern involving the basal ganglia, thalami and white matter. In the two siblings, atrophic cerebral and cerebellum changes consistent with SLC39A8-CDG were detected as well. Serum transferrin isoelectric focusing (IEF) yielded variable results with slight increase of trisialotransferrin isoforms or even normal pattern. MALDI-MS showed the presence of hypogalactosylated transferrin N-glycans, spontaneously decreasing during the disease course, only in one affected sibling. Total serum N-glycome depicted a distinct pattern for the three patients, with increased levels of undergalactosylated and undersialylated precursors of fully sialylated biantennary glycans, including the monosialo-monogalacto-biantennary species A2G1S1.
Conclusions
Clinical, MRI and glycosylation features of patients are consistent with SLC39A8-CDG. We document two novel variants associated with Leigh syndrome-like disease presentation of SLC39A8-CDG. We show, for the first time, a severe neurological phenotype overlapping with that described for SLC39A8-CDG in association with the homozygous A391T missense variant. We observed a spontaneous amelioration of transferrin N-glycome, highlighting the efficacy of MS-based serum glycomics as auxiliary tool for the diagnosis and clinical management of therapy response in patients with SLC39A8-CDG. Further studies are needed to analyse more in depth the influence of SLC39A8 variants, including the common missense variant, on the expression and function of ZIP8 protein, and their impact on clinical, biochemical and neuroradiological features.
This review is the tenth update of the original article published in 1999 on the application of matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2020. Also included are papers that describe methods appropriate to analysis by MALDI, such as sample preparation techniques, even though the ionization method is not MALDI. The review is basically divided into three sections: (1) general aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, fragmentation, quantification and the use of arrays. (2) Applications to various structural types such as oligo‐ and polysaccharides, glycoproteins, glycolipids, glycosides and biopharmaceuticals, and (3) other areas such as medicine, industrial processes and glycan synthesis where MALDI is extensively used. Much of the material relating to applications is presented in tabular form. The reported work shows increasing use of incorporation of new techniques such as ion mobility and the enormous impact that MALDI imaging is having. MALDI, although invented nearly 40 years ago is still an ideal technique for carbohydrate analysis and advancements in the technique and range of applications show little sign of diminishing.
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