Alternative titles; symbols
SNOMEDCT: 723624008; ORPHA: 238459; DO: 0070258;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q15 | Congenital disorder of glycosylation, type IIf | 603585 | Autosomal recessive | 3 | SLC35A1 | 605634 |
A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type IIf (CDG2F) is caused by compound heterozygous or homozygous mutation in the gene encoding the CMP-sialic acid transporter (SLC35A1; 605634) on chromosome 6q15.
For an overview of congenital disorders of glycosylation (CDG), see CDG1A (212065) and CDG2A (212066).
Willig et al. (2001) reported a 4-month-old boy who presented with a spontaneous massive bleed in the posterior chamber of the right eye along with cutaneous hemorrhages. Laboratory studies showed marked thrombocytopenia and neutropenia. The patient experienced multiple episodes of bleeding over the next 30 months, including severe pulmonary hemorrhage. He also had multiple recurrent bacterial infections. Bone marrow transplantation was performed at age 34 months, but the patient died of complications at age 37 months.
Mohamed et al. (2013) reported a 22-year-old woman, born of consanguineous Turkish parents, with CDG2F. She apparently had normal early development until age 7 years, when she developed psychomotor delay and generalized tonic-clonic seizures. Behavioral abnormalities manifested at puberty. At age 20, she presented with microcephaly, mild ataxia, hypotonia and hyporeflexia of the lower extremities, intellectual disability, and a systolic cardiac murmur due to aortic insufficiency. Dysmorphic features included flat occiput, hypotelorism, deep-set eyes, short philtrum, webbed neck, clinodactyly, bilateral hallux valgus, and joint hyperlaxity. Brain imaging showed no structural abnormalities. Laboratory studies showed macrothrombocytopenia, proteinuria, aminoaciduria, and transiently reduced levels of coagulation factors. She died at age 22 years from surgical complications, including renal failure due to tubular necrosis. Isoelectric focusing of patient serum transferrin showed hypoglycosylation in a pattern consistent with type II CDG. Further protein analysis showed reduced sialylation and a combined defect in N- and mucin-type O-glycosylation.
Ng et al. (2017) reported a 12-year-old girl (patient CDG-374) of German ancestry with CDG2F manifest as severe encephalopathy. She presented with hypotonia and developed seizures with orofacial tics at age 4 months. The seizures were only partially controlled. EEG was normal at onset, but later showed slowing and generalized and focal spikes and polyspikes. She had severely delayed psychomotor development with intellectual disability (IQ less than 55), poor speech, and mild ataxic-dyskinetic movements. Additional features included nystagmus, autistic features, and dysarthria. She did not have coagulation defects or macrothrombocytopenia. Laboratory studies showed a serum transferrin CDG type II pattern and a combined defect in N- and O-glycosylation.
Kauskot et al. (2018) reported 2 sibs, born of consanguineous parents, with CDG2F confirmed by genetic analysis. The patients showed global developmental delay from birth, microcephaly, epilepsy, choreiform movements, and macrothrombocytopenia, resulting in easy bruising in both and menorrhagia in the female. Peripheral blood smear and bone marrow examination showed giant platelets and increased levels of immature megakaryocytes, respectively, which the authors suggested resulted from a compensatory mechanism for the peripheral thrombocytopenia. Analysis of patient serum transferrin showed elevated levels of hyposialylated glycoforms, consistent with a CDG.
By detailed laboratory analysis of a patient with thrombocytopenia and recurrent infections, Willig et al. (2001) found markedly decreased amounts of platelet membrane GP Ib (see GP1BA, 606672) and undetectable sialyl-Lewis-X on the surface of neutrophils, suggesting a defect in the posttranslational modification of glycoproteins. Martinez-Duncker et al. (2005) noted that the plasma of the patient reported by Willig et al. (2001) showed a normal sialylation pattern of transferrin (TF; 190000) and other major serum glycoproteins. The phenotype was due to the lack of sialyl-Lewis-X, which has considerable roles in cell-to-cell interactions, such as infections and megakaryocytic immaturity, that were defective in this patient.
Riemersma et al. (2015) found that transfection of the SLC35A1 Q101H mutation (605634.0003) into SLC35A1-deficient cells partially restored sialylation, but failed to restore deficient O-mannosylation, particularly on alpha-dystroglycan (DAG; 128239). In addition, laminin binding to DAG could not be restored, suggesting that abnormal glycosylation of DAG is another biochemical defect in patients with CDG2F. These findings indicated that the disorder represents a combined CDG and muscular dystrophy-dystroglycanopathy (see, e.g., MDDGA1, 236670). The patient who carried this mutation (Mohamed et al., 2013) showed reduced sialylation and a combined defect in N- and mucin-type O-glycosylation.
The transmission pattern of CDG2F in the family reported by Mohamed et al. (2013) was consistent with autosomal recessive inheritance.
In a patient originally described by Willig et al. (2001), Martinez-Duncker et al. (2005) identified compound heterozygosity for 2 mutations in the SLC35A1 gene (605634.0001; 605634.0002). Martinez-Duncker et al. (2005) referred to this disorder as CDG type IIf.
In a 22-year-old woman, born of consanguineous Turkish parents, with CDG2F, Mohamed et al. (2013) identified a homozygous missense mutation in the SLC35A1 gene (Q101H; 605634.0003). The mutation, which was found by homozygosity mapping and candidate gene sequencing, was found in heterozygous state in her unaffected parents. In vitro functional expression studies in yeast showed that the Q101H variant resulted in 50% decreased CMP-Sia transport activity compared to controls. SLC35A1-deficient mammalian cells transfected with the Q101H mutation showed significantly reduced (about 15%) restoration of polysialic acid expression compared to wildtype.
In a 12-year-old German girl (patient CDG-374) with CDG2F, Ng et al. (2017) identified compound heterozygous missense mutations in the SLC35A1 gene (T156R, 605634.0004 and E196K, 605634.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient cells showed decreased amounts of N- and O-glycans terminating in sialic acid as well as a severe loss of SLC35A1 transport function.
In 2 sibs, born of consanguineous parents, with CDG2F, Kauskot et al. (2018) identified a homozygous missense mutation in the SLC35A1 gene (S147P; 605634.0006). The mutation, which was found by a combination of whole-exome sequencing and genetic mapping of disease loci and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 150), 1000 Genomes Project, or ExAC databases. Serum transferrin analysis of 1 of the patients showed elevated levels of hyposialylated glycoforms. Platelets derived from 1 of the patients showed a sialylation defect, and injection of patient platelets into mice showed that they had a very short life span, suggesting increased clearance. Platelet formation did not appear to be affected. The patients had global developmental delay, seizures, and macrothrombocytopenia.
Kauskot, A., Pascreau, T., Adam, F., Bruneel, A., Reperant, C., Lourenco-Rodrigues, M.-D., Rosa, J.-P., Petermann, R., Maurey, H., Auditeau, C., Lasne, D., Denis, C. V., Bryckaert, M., de Lonlay, P., Lavenu-Bombled, C., Melki, J., Borgel, D. A mutation in the gene coding for the sialic acid transporter SLC35A1 is required for platelet life span but not proplatelet formation. Haematologica 103: e613-e617, 2018. [PubMed: 30115659] [Full Text: https://doi.org/10.3324/haematol.2018.198028]
Martinez-Duncker, I., Dupre, T., Piller, V., Piller, F., Candelier, J.-J., Trichet, C., Tchernia, G., Oriol, R., Mollicone, R. Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter. Blood 105: 2671-2676, 2005. [PubMed: 15576474] [Full Text: https://doi.org/10.1182/blood-2004-09-3509]
Mohamed, M., Ashikov, A., Guillard, M., Robben, J. H., Schmidt, S., van den Heuvel, B., de Brouwer, A. P. M., Gerardy-Schahn, R., Deen, P. M. T., Wevers, R. A., Lefeber, D. J., Morava, E. Intellectual disability and bleeding diathesis due to deficient CMP-sialic acid transport. Neurology 81: 681-687, 2013. [PubMed: 23873973] [Full Text: https://doi.org/10.1212/WNL.0b013e3182a08f53]
Ng, B. G., Asteggiano, C. G., Kircher, M., Buckingham, K. J., Raymond, K., Nickerson, D. A., Shendure, J., Bamshad, M. J., niversity of Washington Center for Mendelian Genomics, Ensslen, M., Freeze, H. H. Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1. Am. J. Med. Genet. 173A: 2906-2911, 2017. [PubMed: 28856833] [Full Text: https://doi.org/10.1002/ajmg.a.38412]
Riemersma, M., Sandrock, J., Boltje, T. J., Bull, C., Heise, T., Ashikov, A., Adema, G. J., van Bokhoven, H., Lefeber, D. J. Disease mutations in CMP-sialic acid transporter SLC35A1 result in abnormal alpha-dystroglycan O-mannosylation, independent from sialic acid. Hum. Molec. Genet. 24: 2241-2246, 2015. [PubMed: 25552652] [Full Text: https://doi.org/10.1093/hmg/ddu742]
Willig, T.-N., Breton-Gorius, J., Elbim, C., Mignotte, V., Kaplan, C., Mollicone, R., Pasquier, C., Filipe, A., Mielot, F., Cartron, J.-P., Gougerot-Pocidalo, M.-A., Debili, N., Guichard, J., Dommergues, J.-P., Mohandas, N., Tchernia, G. Macrothrombocytopenia with abnormal demarcation membranes in megakaryocytes and neutropenia with a complete lack of sialyl-Lewis-X antigen in leukocytes--a new syndrome? Blood 97: 826-828, 2001. [PubMed: 11157507] [Full Text: https://doi.org/10.1182/blood.v97.3.826]