Mitochondrial syndromes

Alpers’ Syndrome is part of a larger group of conditions known collectively as mitochondrial DNA depletion disorders and is most often caused by an error in the DNA of a gene called POLG. Whilst it usually affects children under the age of 3, Alpers’ Syndrome has also been reported in older children, adolescents and young adults.

The three major clinical features associated with Alpers’ Syndrome are severe epilepsy, loss of developmental skills and liver failure. There is no specific treatment and, like all mitochondrial diseases, there is currently no cure, but symptoms can be relieved to an extent with symptomatic treatment and support.

Mitochondrial DNA Depletion Syndromes are caused by problems with the maintenance of mitochondrial DNA (mtDNA), which can reduce the amount and quality of the mtDNA, leading to impaired energy production. These types of syndromes are extremely rare but can affect both children and adults. The early-onset form is most severe, affecting infants and young children. This form is often fatal in early life. The late-onset form affects adults and is less severe, with disease progression often slower.

The type and severity of symptoms depends on the particular gene affected. These symptoms typically affect the muscles, brain and liver, while there may also be problems with the kidney and gastrointestinal tract, and hearing loss is a feature in some gene mutations.

Leigh Syndrome, also known as Leigh’s disease, usually affects young children. It’s caused by a number of different genetic errors found in either the nuclear or mitochondrial DNA and so can be inherited in many different ways. It’s a severe neurological condition that typically affects the development of movement, posture and cognitive abilities, with children sometimes losing their skills after a period of what appears to be normal development.

Leigh Syndrome typically starts in the early years of life. Some people may not develop symptoms until early adult life, while others may have symptoms that develop more slowly in childhood. However these instances are rare. One of the hallmark features of this mitochondrial disease is loss of previously acquired intellectual or motor skills, typically if a child is unwell with a minor illness like a tummy bug, cough or cold.

Leber’s is one of the most common forms of mitochondrial disease, predominantly affecting young adult males. Most patients carry one of three specific gene errors in their mitochondrial DNA. Usually this is inherited from the mother but sometimes the error arises for the first time in the patient. Although both sexes can have the error, more men go on to have symptoms.

It primarily affects the optic nerve – that’s the large nerve that leaves the back of each eye to carry visual information to the brain. Patients usually first notice problems with their vision in their 20s or 30s, with initial symptoms being blurring of the central vision and loss of colour vision. This loss of vision often starts in just one eye but usually affects the other eye within six months. Although not usually painful, eventually vision may be limited to merely making out rough shapes or counting fingers.

This genetic error is one of the most common causes of mitochondrial disease. Patients with this mutation have a mixture of good and bad mitochondrial DNA, and that ratio of good to bad is one factor that influences the severity of symptoms. Someone with a lot of bad mitochondrial DNA may develop more symptoms and the disease might be more serious. However, there’s huge variation between individuals with the same levels of mutation, which can be seen even within families.

Some individuals carry the mutation but are asymptomatic, while others have mild symptoms perhaps with a predisposition to diabetes, poor bowel function often leading to irritable bowel disease or severe constipation, or very mild deafness requiring no treatment. Others require the use of hearing aids, or insulin to control their diabetes. Patients with more severe symptoms can suffer muscle weakness, heart disease and encephalopathy – an episode that disturbs brain function, usually manifesting as a stroke-like episode or seizure (MELAS).

With the m.8344A>G mutation there are individuals who are clinically unaffected as well as others who develop a severe mitochondrial disease associated with epilepsy, muscle weakness and unsteadiness. This difference is due to the fact that there’s a mixture of good and bad mitochondrial DNA (mtDNA) and those with high amounts of mutated or abnormal mtDNA are much more likely to develop symptoms compared to those with only a small amount of this mutation.

Symptoms often first present in late adolescence or early adulthood and are predominantly neurological, with patients often developing myoclonic epilepsy. Myoclonus is a brief jerk that often happens first thing in the morning, and can be a run of jerks, sudden in onset and not necessarily associated with loss of consciousness. Patients may also develop seizures, muscle weakness or unsteadiness which can be quite disabling, as well as symptoms associated with short-term memory loss, although this is only present in those affected severely. Finally, some patients develop a curious phenomenon which is associated with the development of fat deposits (lipoma) in and around the back of the neck.

MNGIE is a very rare condition which is due to an error in an enzyme called thymidine phosphorylase, rather than an error in the mitochondrial DNA. The syndrome is not inherited through the mitochondrial DNA, and only occurs if both parents carry the faulty gene. The disease presents in childhood, but often goes unnoticed for many years.

MNGIE presents predominantly either with disturbances of bowel function or with weakness due largely to a damaged nerve supply. It’s variable in its severity, with some patients developing quite severe disease early in life, and others not developing symptoms until much later in life. Other complications can develop, and approximately 10% of all those affected may develop cognitive problems.

The mutations responsible for NARP are maternally inherited and affect Complex V, responsible for the final step in the energy conversion process. It can begin during childhood or early adulthood and often proves difficult to identify.

This syndrome describes a group of patients who have a combination of symptoms including weakness of the muscles around large joints such as the hip or shoulder, unsteadiness of movement, impaired sensation and visual disturbance. Additional symptoms include developmental delay or dementia and children with very high levels of mutated mitochondrial DNA develop Leigh Syndrome.

CPEO describes patients who have progressive weakness of the eye muscles. This means that the eyes do not move normally and often have drooping eyelids, making it difficult to see. Many different genetic abnormalities can cause this syndrome – some patients have errors of mitochondrial DNA and others errors of nuclear DNA. It’s important to determine the cause of CPEO to see if other family members could become affected, and the likelihood that you will develop other symptoms, some of which can be treated.

This type of mitochondrial disease may begin at any age but typically manifests in the young adult years. Some patients do not develop other symptoms but others can have swallowing difficulties, heart problems, weakness and exercise intolerance. Additional problems include issues with balance and sometimes altered or no sensation in the hands and feet. Management of CPEO should include help from an ophthalmologist with experience of this condition.

Kearn’s-Sayre Syndrome is a single deletion syndrome, meaning a piece of DNA is missing from lots of copies of mitochondrial DNA (mtDNA) in each cell. This is usually not an inherited condition but one that occurs by chance. The amount of deleted mitochondrial DNA is very high in proportion to the amount of remaining normal mtDNA.

Typical onset for this type of mitochondrial disease is before the age of 20. Most often, patients experience difficulty with eye movement and develop droopy eyelids on one or both sides (CPEO). Patients also suffer swallowing problems and, as is seen with many other mitochondrial disorders, weakness, unsteadiness and fatigue. Heart problems are also common.

Pearson Syndrome is a single deletion syndrome where there is a very high proportion of deleted mitochondrial DNA (mtDNA) versus remaining normal mtDNA, and most reported cases happen for the first time in a family – it’s not passed down from either parent.

Symptoms of this very rare condition generally appear in infancy or early childhood and may include pale skin and fatigue due to anaemia, frequent infections due to underproduction of white blood cells and bleeding due to underproduction of platelets, as well as recurrent diarrhoea and stomach pain.