Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0026827 (
hypotonia
)
5,860
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Objectives Transcobalamin II (TC) is an essential plasma protein for the absorption, transportation, and cellular uptake of cobalamin. TC deficiency presents in the first year of life with failure to thrive,
hypotonia
, lethargy, diarrhea, pallor, mucosal ulceration, anemia, pancytopenia, and agammaglobulinemia. Herein, we present TC deficiency diagnosed in two cases (twin siblings) with a novel variant in the TCN2 gene. Case presentation 4-month-old twins were admitted with fever, respiratory distress, vomiting, diarrhea, and failure to thrive. Physical examination findings revealed developmental delay and
hypotonia
with no head control, and laboratory findings were severe anemia, neutropenia, and hypogammaglobulinemia. Despite normal vitamin B12 and folate levels, homocysteine and urine methylmalonic acid levels were elevated in both patients. Bone marrow examinations revealed hypocellular bone marrow in both cases. The patients had novel pathogenic homozygous c.241C>T (p.Gln81Ter) variant in the TCN2 gene. In both cases, with intramuscular hydroxycobalamin therapy, laboratory parameters improved, and a successful clinical response was achieved. Conclusions In infants with pancytopenia, growth retardation, gastrointestinal manifestations, and
immunodeficiency
, the inborn error of cobalamin metabolism should be kept in mind. Early diagnosis and treatment are crucial for better clinical outcomes. What is new? In literature, to date, less than 50 cases with TC deficiency were identified. In this report, we presented twins with TCN2 gene mutation. Both patients emphasized that early and aggressive treatment is crucial for achieving optimal outcomes. In this report, we identified a novel variation in TCN2 gene.
...
PMID:Transcobalamin II deficiency in twins with a novel variant in the TCN2 gene: case report and review of literature. 3284 Nov 61
Store-operated Ca
2+
entry (SOCE) is a ubiquitous and essential mechanism regulating Ca
2+
homeostasis in all tissues, and controls a wide range of cellular functions including keratinocyte differentiation, osteoblastogenesis and osteoclastogenesis, T cell proliferation, platelet activation, and muscle contraction. The main SOCE actors are STIM1 and ORAI1. Depletion of the reticular Ca
2+
stores induces oligomerization of the luminal Ca
2+
sensor STIM1, and the oligomers activate the plasma membrane Ca
2+
channel ORAI1 to trigger extracellular Ca
2+
entry. Mutations in
STIM1
and
ORAI1
result in abnormal SOCE and lead to multi-systemic disorders. Recessive loss-of-function mutations are associated with CRAC (Ca
2+
release-activated Ca
2+
) channelopathy, involving
immunodeficiency
and autoimmunity, muscular
hypotonia
, ectodermal dysplasia, and mydriasis. In contrast, dominant
STIM1
and
ORAI1
gain-of-function mutations give rise to tubular aggregate myopathy and Stormorken syndrome (TAM/STRMK), forming a clinical spectrum encompassing muscle weakness, thrombocytopenia, ichthyosis, hyposplenism, short stature, and miosis. Functional studies on patient-derived cells revealed that CRAC channelopathy mutations impair SOCE and extracellular Ca
2+
influx, while TAM/STRMK mutations induce excessive Ca
2+
entry through SOCE over-activation. In accordance with the opposite pathomechanisms underlying both disorders, CRAC channelopathy and TAM/STRMK patients show mirror phenotypes at the clinical and molecular levels, and the respective animal models recapitulate the skin, bones, immune system, platelet, and muscle anomalies. Here we review and compare the clinical presentations of CRAC channelopathy and TAM/STRMK patients and the histological and molecular findings obtained on human samples and murine models to highlight the mirror phenotypes in different tissues, and to point out potentially undiagnosed anomalies in patients, which may be relevant for disease management and prospective therapeutic approaches.
...
PMID:
STIM1
/
ORAI1
Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases. 3325 Jul 86
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