Classic MELAS syndrome (Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), MIDD (maternally inherited diabetes mellitus and deafness) and Mixed Phenotypes all belong to a clinical spectrum of mitochondrial diseases most frequently caused by a mutation, the m.3243A>G mutation, in the MT-TL1 gene in the mitochondrial DNA (mtDNA). Most DNA, called nuclear DNA, is situated in chromosomes within the nucleus of a cell. Mitochondria however, which are found within all cells of the human body, except red blood cells, and are responsible for producing energy necessary for life, also contain small copies of their own DNA known as mitochondrial DNA. In this first of a series of forthcoming mitochondrial disease spotlights we focus on classic MELAS syndrome.
MELAS syndrome begins in childhood, usually between the ages of two and fifteen years, with approximately 75 percent of cases reporting an onset of the disorder before the age of 20 years. Although rare, it is one of the most common types of mitochondrial diseases caused by mutations in the mtDNA, with an estimated prevalence for MELAS spectrum disorders in adults and children of risk of 4.4 in 100,000 people. MELAS syndrome is a progressive and often early fatal disorder affecting organs and tissues with a high-energy demand, such as the brain and skeletal muscle.
Current existing therapies only manage the symptoms and don’t target the underlying cause of the disease.
Given MELAS is caused by mutations in the genes within mtDNA, it follows a maternal inheritance pattern meaning that it can only be inherited from the mother. Mitochondria cannot inherited from the father, as paternal mitochondria are found only in the tailpiece of sperm and are lost during fertilisation. In rare cases, however, the disorder can also result from a new, spontaneous mutation in a mitochondrial gene and are not inherited.
Signs and symptoms of MELAS often appear in childhood following a period of normal development and include seizures, recurrent headaches, recurrent vomiting and loss of appetite. Most affected individuals experience stroke-like episodes beginning before the age of 40 years. This can result in temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision and hearing loss, loss of motor skills and intellectual disability. Most people with MELAS have a build up of lactic acid in the blood above the normal upper limit, which can lead to vomiting, muscle weakness, abdominal pain, fatigue, and breathing difficulties.
Diagnosing a genetic or rare disease can often be challenging. Epidemiological studies show high though variable disease prevalence figures indicating a high number of undiagnosed carriers of the m.3243A>G mutation.