Clinical, molecular and glycophenotype insights in SLC39A8-CDG

Orphanet Journal of Rare Diseases

Luisa Sturiale¹  Rita Barone²  Rosa Pasquariello³  Maria Grazia Alessandrì³  Giovanni Cioni⁴  Roberta Battini⁴  Eleonora Bonaventura⁴  Anna Maria Pinto⁵  Alessandra Renieri⁶  Barbara Garavaglia⁷  Celeste Panteghini⁷ 

[1] CNR, Institute for Polymers, Composites and Biomaterials, IPCB, Catania, Italy;Department of Clinical and Experimental Medicine-Child Neuropsychiatry Section, University of Catania, Catania, Italy;CNR, Institute for Polymers, Composites and Biomaterials, IPCB, Catania, Italy;Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Viale del Tirreno 331, Calambrone, 56128, Pisa, Italy;Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Viale del Tirreno 331, Calambrone, 56128, Pisa, Italy;Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy;Department of Medical Genetics, University of Siena, Siena, Italy;Department of Medical Genetics, University of Siena, Siena, Italy;Department of Medical Biotechnologies, Med Biotech Hub and Competence Center, University of Siena, Siena, Italy;Department of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy;

关键词: SLC39A8;    Congenital disorder of glycosylation (CDG);    Movement disorder;    Leigh syndrome-like;    MALDI-MS;    Serum N-glycomics;   

DOI  :  10.1186/s13023-021-01941-y

来源: Springer

【 摘 要 】

BackgroundSLC39A8, 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.ResultsHere, 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.ConclusionsClinical, 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.

【 授权许可】

CC BY