Orthopnea or orthopnoea is shortness of breath (dyspnea) that occurs when lying flat, causing the person to have to sleep propped up in bed or sitting in a chair. It is commonly seen as a late manifestation of heart failure, resulting from fluid redistribution into the central circulation, causing an increase in pulmonary capillary pressure and causing difficulty in breathing. It is also seen in cases of abdominal obesity or pulmonary disease. Orthopnea is the opposite of platypnea, shortness of breath that worsens when sitting or standing upright. Causes
Orthopnea is often a symptom of left ventricular heart failure and/or cardiogenic pulmonary edema. It can also occur in those with asthma and chronic bronchitis, as well as those with sleep apnea or panic disorder. It is also as associated with polycystic liver disease. From a neuromuscular perspective, orthopnea is potentially a sign of severe diaphragmatic weakness. Under such circumstances, patients may describe shortness of breath when they bend over (e.g. when tying shoelaces), called bendopnea. Mechanism
Orthopnea is due to increased distribution of blood to the pulmonary circulation when a person lies flat or closer to a horizontal position. Lying flat decreases the inhibitory effect that the gravity usually has on the blood when coming back to the heart from the lower extremities of the body. This increases the right sided venous return.
These reactions take place primarily in the kidney and pancreas. The clinical manifestations of AGAT deficiency are caused by the decreased amounts of creatine produced. Diagnosis
AGAT deficiency can be suspected from clinical findings, although there is significant phenotypic overlap with the most common presenting symptoms of intellectual disability and muscle weakness. Laboratory testing of plasma and urine will show decreased levels of creatine and guanidinoacetate. Non-specific elevations of metabolites on urine testing that are normalized to creatinine may appear falsely elevated. Magnetic resonance spectroscopy (MRS) of the brain will also show an absence of creatine, which is normally present. This finding is not specific to AGAT deficiency, it can be observed in all three cerebral creatine deficiencies. The combination of biochemical testing and MRS findings can be strongly suggestive of AGAT deficiency. Confirmation would most often be done with molecular testing of GATM. Identification of biallelic pathogenic variants in GATM would be confirmation of a diagnosis of AGAT deficiency. Uncertain findings on molecular testing may be able to be confirmed by enzyme assays, or by measuring creatine uptake in fibroblasts. Prenatal testing for AGAT deficiency can be performed on chorionic villi samples if the causative pathogenic variants in the family are known. Treatment
The main focus of treatment for AGAT deficiency is supplementation of creatine, with the goal of replenishing cerebral creatine to normal levels. This is done with oral creatine supplementation. Treatment is most effective if it is started early in life, before symptoms are apparent.