Alternative titles; symbols
ORPHA: 168577;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.2 | Stomatin-deficient cryohydrocytosis with neurologic defects | 608885 | Autosomal dominant | 3 | SLC2A1 | 138140 |
A number sign (#) is used with this entry because of evidence that stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN) is caused by heterozygous mutation in the SLC2A1 gene (138140) on chromosome 1p34.
Stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN) is an autosomal dominant disorder characterized by delayed psychomotor development, seizures, cataracts, and pseudohyperkalemia resulting from defects in the red blood cell membrane. The disorder combines the neurologic features of Glut1 deficiency syndrome-1 (GLUT1DS1; 606777), resulting from impaired glucose transport at the blood-brain barrier, and hemolytic anemia/pseudohyperkalemia with stomatocytosis, resulting from a cation leak in erythrocytes (summary by Bawazir et al., 2012).
For a discussion of clinical and genetic heterogeneity of red cell stomatocyte disorders, see 194380.
Fricke et al. (2004) described 2 cases of cryohydrocytosis, one of which had previously been reported by Lande et al. (1982). In both cases, Fricke et al. (2004) confirmed that some stomatin (STOM; 133090) was present when peripheral blood was examined by immunocytochemistry using an antistomatin antibody. Both of the stomatin-deficient patients showed a neurologic syndrome of seizures, mental retardation, and cataracts associated with hepatosplenomegaly, a combination that had not previously been described. They noted that no other leaky cell disorder had shown evidence of neurologic dysfunction. Consanguinity was not present in either patient's family. One of the patients (D-II-2) was a 40-year-old French man who had been followed since his first year of life for neurologic problems, including seizures, cerebellar ataxia, and communicant tetraventricular hydrocephalus, and had been treated with a series of anticonvulsant medications. At the age of 6 years, he underwent ventriculoperitoneal shunting. He showed macrocephaly (3 SD above the mean), large ears (greater than the 97th percentile), short and wide neck and chest, and brachydactyly. A congenital zonular cataract and slight mental retardation were present. Massive hepatosplenomegaly associated with chronic jaundice without hemoglobinuria was regularly noted. He had 3 severe hemolytic crises, 1 of which occurred after surgery for ventricular hydrocephalus. His parents and a brother and sister were clinically asymptomatic and had normal blood counts with no biochemical signs of hemolysis. The other patient (E-II-1) was a 32-year-old Irish woman who had previously been found to be deficient in stomatin by Lande et al. (1982). Like patient D-II-2, she presented with a predominantly neurologic syndrome of seizures, spastic paraplegia, mental retardation, and cataracts associated with massive hepatosplenomegaly and 'blueberry muffin' spots on the skin. Short stature (below the 3rd centile for age) was noted. Lifelong hemolysis was present with interspersed hemolytic crises, usually associated with infection. She had a cholecystectomy at the age of 9 years. Sequencing of the stomatin gene in these patients showed no abnormality, and Fricke et al. (2004) concluded that lack of stomatin was unlikely to be the cause of the leak of sodium and potassium.
Bawazir et al. (2012) reported a neonate who presented with severe conjugated hyperbilirubinemia and variable hyperkalemia at age 22 hours. She later showed delayed psychomotor development, hypertonia, seizures, splenomegaly, microcephaly, nystagmus, and cataracts. Brain imaging showed periventricular calcifications, thalamic atrophy, global loss of white matter volume, and delayed myelination. Peripheral blood smear showed some echinocytes and stomatocytes, and there was in vitro pseudohyperkalemia resulting from leakage of potassium from red cells, with a more severe effect at low temperatures, consistent with cryohydrocytosis. Erythrocytes had high intracellular sodium and low potassium, indicating that the cells were leaky to these cations. There was also decreased membrane levels of the stomatin protein. Lumbar puncture showed severely decreased glucose, indicating hypoglycorrhachia and consistent with deficient transport of glucose across the blood-brain barrier. Treatment with a ketogenic diet resulted in some clinical improvement.
The heterozygous mutations in the SLC2A1 gene that were identified in patients with SDCHCN by Flatt et al. (2011) and Bawazir et al. (2012) occurred de novo.
In 2 unrelated patients with stomatin-deficient cryohydrocytosis with neurologic defects reported by Fricke et al. (2004), Flatt et al. (2011) identified 2 different heterozygous mutations in the SLC2A1 gene (138140.0023 and 138140.0024). In one family the parents did not carry the mutation, and in the other family the mutation was presumed to have occurred de novo. In vitro functional expression assays in Xenopus oocytes showed that the mutant proteins did not transport glucose and leaked cations.
In an infant with SDCHCN, Bawazir et al. (2012) identified a de novo heterozygous mutation in the SLC2A1 gene (138140.0024). Western blot analysis showed that GLUT1 was expressed normally at the red cell membrane. The same mutation was identified in 1 of the patients with a similar phenotype reported by Flatt et al. (2011).
Bawazir, W. M., Gevers, E. F., Flatt, J. F., Ang, A. L., Jacobs, B., Oren, C., Grunewald, S., Dattani, M., Bruce, L. J., Stewart, G. W. An infant with pseudohyperkalemia, hemolysis, and seizures: cation-leaky GLUT1-deficiency syndrome due to a SLC2A1 mutation. J. Clin. Endocr. Metab. 97: E987-E993, 2012. Note: Electronic Article. [PubMed: 22492876] [Full Text: https://doi.org/10.1210/jc.2012-1399]
Flatt, J. F., Guizouarn, H., Burton, N. M., Borgese, F., Tomlinson, R. J., Forsyth, R. J., Baldwin, S. A., Levinson, B. E., Quittet, P., Aguilar-Martinez, P., Delaunay, J., Stewart, G. W., Bruce, L. J. Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome. Blood 118: 5267-5277, 2011. [PubMed: 21791420] [Full Text: https://doi.org/10.1182/blood-2010-12-326645]
Fricke, B., Jarvis, H. G., Reid, C. D. L., Aguilar-Martinez, P., Robert, A., Quittet, P., Chetty, M., Pizzey, A., Cynober, T., Lande, W. F., Mentzer, W. C., von During, M., Winter, S., Delaunay, J., Stewart, G. W. Four new cases of stomatin-deficient hereditary stomatocytosis syndrome: association of the stomatin-deficient cryohydrocytosis variant with neurological dysfunction. Brit. J. Haemat. 125: 796-803, 2004. [PubMed: 15180870] [Full Text: https://doi.org/10.1111/j.1365-2141.2004.04965.x]
Lande, W. M., Thiemann, P. V. W., Mentzer, W. C., Jr. Missing band 7 membrane protein in two patients with high Na, low K erythrocytes. J. Clin. Invest. 70: 1273-1280, 1982. [PubMed: 7174793] [Full Text: https://doi.org/10.1172/jci110726]