Malonyl-CoA decarboxylase deficiency
CMAMMA due to malonyl-CoA decarboxylase is also inherited in an autosomal recessive manner. The MLYCD gene is located on chromosome 16 locus q23.3. Pathophysiology
ACSF3
ACSF3 encodes an acyl-CoA synthetase, which is localized in the mitochondria and has a high specificity for malonic acid and methylmalonic acid. Thus, the synthetase catalyzes the synthesis of malonyl-CoA as well as methylmalonyl-CoA. Malonic acid
The conversion of malonic acid to malonyl-CoA by acyl-CoA synthetase represents the first step in the mitochondrial fatty acid synthesis (mtFASII) pathway, which plays an important role in the regulation of energy metabolism and which should not be confused with the more familiar fatty acid synthesis that occurs in the cytoplasm. The dysfunctional mtFASII pathway leads to an accumulation of malonic acid, which has a competitive inhibitory effect on complex II, and also leads to a deficiency of malonyl-CoA. These deficiencies can be continued to the end-product of the mtFASII pathway, octanoyl-ACP. The consequences of this are diminished oxidative phosphorylation and major alterations in complex lipids, such as increased levels of sphingomyelins and cardiolipins and lower levels of phosphatidylcholines, phosphatidylglycerol and ceramides. Since octanoyl-ACP is the direct precursor in lipoic acid synthesis, this results in diminished lipoylation, since lipoic acid acts as an essential cofactor for several mitochondrial multienzyme complexes, such as pyruvate dehydrogenase complex (PDHC) and α-ketoglutarate dehydrogenase complex (α-KGDHC), among others. This diminished lipoylation also leads to a reduced glycolytic flux.
Chronic mountain sickness (CMS) is a disease in which the proportion of blood volume that is occupied by red blood cells increases (polycythaemia) and there is an abnormally low level of oxygen in the blood (hypoxemia). CMS typically develops after extended time living at high altitude (over 2,500 metres (8,200 ft)). It is most common amongst native populations of high altitude nations. The most frequent symptoms of CMS are headache, dizziness, tinnitus, breathlessness, palpitations, sleep disturbance, fatigue, loss of appetite, confusion, cyanosis, and dilation of veins.CMS was first described in 1925 by Carlos Monge Medrano, a Peruvian doctor who specialised in diseases of high altitude. While acute mountain sickness is experienced shortly after ascent to high altitude, chronic mountain sickness may develop only after many years of living at high altitude. In medicine, high altitude is defined as over 2,500 metres (8,200 ft), but most cases of CMS occur at over 3,000 metres (9,800 ft). It has recently been correlated with increased expression of the genes ANP32D and SENP1. Diagnosis
CMS is characterised by polycythaemia (with subsequent increased haematocrit) and hypoxaemia; raised blood pressure in the lungs (pulmonary hypertension) can develop over time and in some cases progress to heart failure (cor pulmonale). CMS is believed to arise because of an excessive production of red blood cells (erythrocytes) due to the low oxygen levels at altitude, which increases the oxygen carrying capacity of the blood[1]. The increased levels of erythrocytes causes increased blood viscosity and uneven blood flow through the lungs (V/Q mismatch).