Temporary local paralysis
Loss of sensation and strength in selective areas, following stroke like episodes
Sensorineural hearing loss – damage to the nerve of the inner ear, resulting in deafness

Musculoskeletal:

Overall muscle weakness
Exercise intolerance

Other symptoms

Vomiting
Loss of bowel control
Kidney dysfunction
Hormonal problems causing diseases like diabetes mellitus
Cardiac conduction block – problems in the electrical system of the heart that controls heartbeat

Testing

Lab Testing:

Body fluids:
- A high lactic acid and pyruvic acid (acids found in the mitochondria) concentration in cerebrospinal fluid (CSF) and blood
- An increase in protein concentration in CSF

Muscle Biopsy:
- Abnormal mitochondria from under the muscle tissue membrane appear as “ragged red fibres” under a microscope

Chemical staining identifies diseased mitochondria, appearing as “ragged red fibres”. Left and right show lower and higher magnification, respectively.

Brain scans using MRI or CT reveal:

Abnormal signals from certain brain areas, often from the basal ganglia

(Left) MRI scan of a healthy brain. (Right) The basal ganglia region of the brain shows abnormal signals.

Damage to certain brain areas following stroke

(Left) MRI scan of a healthy brain. (Right) Damage to the brain, after a MELAS patient suffered a stroke.

Changes in the area of the brain known as white matter

The scan shows changes in white matter within the brain as well as symmetrical abnormalities in signals (white areas) in the area known as the putamen (bottom arrows), in both hemispheres

MRS testing reveals increase in lactate concentration in the brain

Two inverted peaks that resemble a “W” at around 1.2 on the horizontal axis indicate a high lactate concentration

• Electrocardiogram (ECG) tests may reveal problems with the cardiac muscle, or problems with the conduction system of the heart
• Testing enzymes of the respiratory chain often reveal defects in particular proteins – complex I and IV are common in MELAS

The protein complexes of the respiratory chain that are particularly affected by this disease

• DNA testing from blood reveals a mutation in mtDNA at base pair 3243 for the tRNALeu gene

Is there prenatal testing available?

Prenatal testing for most mitochondrial disorders is available. Molecular testing for prenatal diagnosis is available only when the familial mutation(s) have been found; however, the availability of testing also depends on the mode of inheritance of the condition.

When there is a known genetic diagnosis in the family, it is important for a couple to meet with a genetic counsellor prior to becoming pregnant. This enables the couple to plan in advance, as genetic testing can be a lengthy process.

It is important to note that mitochondrial conditions caused by mutations in mitochondrial DNA (mtDNA) have limited use in prenatal diagnosis, due to principles of heteroplasmy and threshold effect discussed in the inheritance section.

Questions regarding your specific genetic diagnosis and the availability of prenatal diagnosis should always be discussed with a genetic counsellor and/or your obstetrician.

Biological basis of the disease

• Genetic changes in the DNA of the mitochondria – most commonly a point mutation at base pair 3243, for the tRNALeu gene

• An A is replaced by a G, therefore an A-T pair becomes a G-C pair
• This changes the tRNA molecule slightly
• This video further explains the point mutation: http://www.youtube.com/watch?v=vNWwSL55gUM&feature=related

• tRNA molecules are responsible for bringing amino acids together to make proteins

• A genetic change in the tRNALeu gene affects the function of these molecules

• The cannot properly make proteins including those of the respiratory chain which creates dysfunctional mitochondria

• Vital organs like the brain and muscles become energy deprived

• Nerve and muscle cells are very energy demanding, and die if they are not provided with ATP

• This results in the many neuromuscular problems that MELAS patients suffer

• Improper functioning of the mitochondria also creates an excess of mitochondrial acids such as pyruvate and lactate to be in body fluids like the blood and CSF, and disrupt the chemical balance in the body

How is it inherited?

The mutation for MELAS occurs in mitochondrial DNA and therefore it follows the pattern of maternal or mitochondrial inheritance.

Treatments

• Although prognosis may be poor, many treatment options are available to improve the daily lifestyle of MELAS patients.

• Medical care under the following specialists may be required: neurologist, medical geneticist, ophthalmologist and cardiologist

• Nutrition plays a vital role in the management of metabolic disorders and mitochondrial disorders.

• Vitamin and mineral supplements are often prescribed with variable success from patient to patient. The important components of this prescribed “vitamin cocktail” include riboflavin, Coenzyme Q and vitamins E, and C.

• Arginine (an amino acid) supplementation has been found to be helpful in acute stroke like episodes and also for chronic prevention of stroke like episodes

• Lactic acidosis is treated by sodium bicarbonate or sodium citrate

• Vitamins help reduce tissue damage caused by the faulty proteins of the mitochondria.

• Seizures can be treated for the most part with traditional anticonvulsant drugs

•

Surgical measures may be required to treat hearing loss

• Physical therapy and occupational therapy can help improve mobility and comfort

Prognosis

Prognosis for the most part is poor, although it varies greatly from patient to patient. Severity of complications is what eventually determines the life expectancy.

Top of Page

MERRF

What’s in the name?

• MERRF – Myoclonic epilepsy with ragged red fibres

• Myoclonus

• The sudden contraction of muscles, causing brief jerking movements

• Epilepsy

• The condition of having severe, recurrent seizures

• Ragged red fibres Abnormal mitochondria accumulated under the muscle membrane, appear as red strands in muscles, when stained

Who is affected?

MERRF generally affects children and adolescents or even adults at times, and almost always occurs after normal development in infancy. MERRF is very rare with prevalence being less than 1 in 100 000. No ethnic or gender predisposition is found in MERRF.

Symptoms

• Neurological:

• Myoclonus – The sudden contraction of muscles, causing brief jerking movements is often the primary symptom
• Generalized Epilepsy – the condition of having frequent, unprovoked seizures
• Ataxia – Gross lack of coordination in muscle movements
• Dementia – a deficit in intellectual ability

• Ocular:

• Retinitis Pigmentosa – a group of diseases characterized by

• Swelling of cells in the retina
• Vision loss in the night
• Peripheral vision loss
• Central vision loss

• External ophthalmoplegia/ophthalmoperesis

• Paralysis/weakness of the muscles that open eyelids and move the eyes, resulting in restricted eye movement and droopy eyes

• Physical appearance:

• Short stature( may be present)

• Other Symptoms:

• Exercise intolerance
• Cardiomyopathy – disease affecting the heart muscle, which may lead to heart failure
• Lipomas – benign tumours found beneath the skin, that are composed of fatty tissue

Testing

Laboratory Test:

• Body fluids:

• A higher than normal lactic acid and pyruvic acid (acids found in the mitochondria) concentration in the cerebrospinal fluid (CSF) and blood
• An increase in protein concentration in CSF than normal

• Muscle biopsy:

• Mitochondria from muscle biopsy appear as ragged red fibres

Chemical staining identifies diseased mitochondria, appearing as “ragged red fibres”. Left and right show lower and higher magnification, respectively.

• Brain scans:

• Brain MRI shows basal ganglia calcification (hardening) and atrophy (decrease in size) of certain brain areas

(Left) MRI scan of a healthy brain. (Right) The basal ganglia region of the brain shows abnormal signals.

• ECG tests often show abnormalities in heart function

• Testing enzymes of the respiratory chain often reveal defects in particular proteins – complex I and IV are common in MERRF

The protein complexes of the respiratory chain that are particularly affected by this disease

• DNA studies:

• Abnormal mitochondrial mutation at base pair 8344, for tRNALys gene

Is there prenatal testing available?

Prenatal testing for most mitochondrial disorders is available. Molecular testing for prenatal diagnosis is available only when the familial mutation(s) have been found; however, the availability of testing also depends on the mode of inheritance of the condition.

When there is a known genetic diagnosis in the family, it is important for a couple to meet with a genetic counsellor prior to becoming pregnant. This enables the couple to plan in advance, as genetic testing can be a lengthy process.

It is important to note that mitochondrial conditions caused by mutations in mitochondrial DNA (mtDNA) have limited use in prenatal diagnosis, due to principles of heteroplasmy and threshold effect discussed in the inheritance section.

Questions regarding your specific genetic diagnosis and the availability of prenatal diagnosis should always be discussed with a genetic counsellor and/or your obstetrician.

Biological basis of the disease

• Mutations in the DNA of the mitochondria is the cause – most commonly a point mutation at base pair 8344, for the tRNALys gene

• An A is replaced by a G, therefore an A-T pair becomes a G-C pair
• This video link explains the point mutation further: http://www.youtube.com/watch?v=vNWwSL55gUM&feature=related

• Molecules of tRNA are responsible for bringing amino acids together to make proteins

• A genetic change in the tRNALeu gene affects the function of these molecules

• The cannot properly make proteins including those of the respiratory chain which creates dysfunctional mitochondria

• Like most mitochondrial diseases, MERRF also disrupts the function of the respiratory chain proteins

• Vital organs like the brain and muscles become energy deprived

• Nerve and muscle cells are very energy demanding, and die if they are not provided with ATP

• This creates the many neuromuscular symptoms that MERRF patients suffer

• Improper functioning of the mitochondria also creates an excess of mitochondrial acids such as pyruvate and lactate to be in body fluids like the blood and CSF, and disrupt the chemical balance in the body

How is it inherited?

The mutation for MERRF occurs in mitochondrial DNA and therefore it follows the pattern of maternal or mitochondrial inheritance.

Treatments

• Medical care under the following specialists may be required: neurologist, medical geneticist, ophthalmologist, cardiologist, and audiologist

• Coenzyme Q10 and L-carnitine are often used to help the dysfunctional proteins of the respiratory chain but most treatments target the manifestations of MERRF rather than the disease itself

• Lactic acidosis is treated by sodium bicarbonate or sodium citrate

• Traditional anticonvulsant drugs are used to treat the epilepsy

• Physical therapy is used to improve motor function

• Mild to moderate aerobic exercise, depending upon tolerance, is recommended for all mitochondrial disease patients

Prognosis

There is extreme variance in the prognosis of those with MERRF. Severity, rate of progression, age of onset, and many other factors determine this.

Top of Page

NARP

What’s in the name?

• NARP - Neuropathy, Ataxia, Retinitis Pigmentosa

• Neuropathy – disease of the peripheral nervous system

• Ataxia – without balance or coordination

• Retinitis Pigmentosa

• Retinitis – inflammation of the retina
• Pigmentosa – deposition of pigments on the retina
• This is a group of diseases which can lead to blindness

Who is affected?

Onset of the disease is generally in childhood or early adulthood. NARP is very rare, and its prevalence is actually unknown. There seems to be no ethnic or gender predisposition however.

Symptoms

Neurological Symptoms:

• Developmental delay

• Seizures

• Ataxia –inability to maintain normal posture and smoothness of movement

• Sensory neuropathy – pain, numbness, tingling sensation in the arms and legs

Muscular:

• General muscle weakness and fatigue

• Exercise intolerance

Retinitis Pigmentosa:

• Night blindness

•

Tunnel vision

• Loss of central vision

• Caused by damage to the light sensing photoreceptor cells of the retina known as rods and cones (usually damage to the rods)

Testing

Lab Testing:

• Muscle biopsy:

• Abnormal mitochondria from muscle tissue may appear as “ragged red fibres” under a microscope

Chemical staining identifies diseased mitochondria, appearing as “ragged red fibres”. Left and right show lower and higher magnification, respectively.

•

Body fluids:

• Elevated concentration of lactic acid in cerebrospinal fluid especially
• Blood plasma shows a higher than normal concentration of the amino acid alanine

• Brain scans:

• Magnetic resonance spectroscopy (MRS) can detect higher than normal lactic acid concentration in certain brain areas

Two inverted peaks that resemble a “W” at around 1.2 on the horizontal axis indicate a high lactate concentration

• Atrophy (a decrease in size) of the cerebrum and cerebellum is sometimes seen

• DNA testing in blood usually reveals a T-G or T-C point mutation to the MT-ATP6 gene of the mitochondria

Is there prenatal testing available?

Prenatal testing for most mitochondrial disorders is available. Molecular testing for prenatal diagnosis is available only when the familial mutation(s) have been found; however, the availability of testing also depends on the mode of inheritance of the condition.

When there is a known genetic diagnosis in the family, it is important for a couple to meet with a genetic counsellor prior to becoming pregnant. This enables the couple to plan in advance, as genetic testing can be a lengthy process.

It is important to note that mitochondrial conditions caused by mutations in mitochondrial DNA (mtDNA) have limited use in prenatal diagnosis, due to principles of heteroplasmy and threshold effect discussed in the inheritance section.

Questions regarding your specific genetic diagnosis and the availability of prenatal diagnosis should always be discussed with a genetic counsellor and/or your obstetrician.

Biological basis of the disease

• Caused by a T-G or T-C mutation to the MT-ATP6 gene of the mitochondria

• MT-ATP6 codes part of ATP Synthase, the last component of the respiratory chain

• The consequence is an altered ATP Synthase function, that doesn’t allow ATP production in all cells that contain this diseased mitochondria

• The effects are similar to most mitochondrial point mutation diseases which include neurological symptoms, muscle weakness, and diseases of the eye

How is it inherited?

The mutation for NARP occurs in mitochondrial DNA and therefore it follows the pattern of maternal or mitochondrial inheritance.

Treatments

• High doses of CoQ-10 are prescribed to treat ataxia

• Coenzyme Q-10 is an important component to help the faulty proteins of the respiratory chain function properly, especially complex II.

• Lactic acidosis is treated by sodium bicarbonate or sodium citrate

• To treat retinitis pigmentosa, Vitamin A and E are prescribed

• Antioxidant drugs are used to prevent damage to retinal cells by molecules known as reactive oxygen species (ROS)

Prognosis

There is extreme variance in the prognosis of those with NARP. Severity, rate of progression, age of onset, and many other factors determine this. The condition of patients can be stable for many years, but progression of the disease worsens the symptoms.

Top of Page

LHON

What’s in the name?

• LHON – Leber’s Hereditary Optic Neuropathy

• Optic Neuropathy - a disease affecting the optic nerve

• Named after German ophthalmologist Alfred Theodor Leber who first described it in the late 1800s

Who is affected?

The onset of LHON is usually when people are in their late teens or mid twenties. For an unknown reason, males are affected four times as frequently as females. The prevalence of LHON is about 1 in 40000 people. Majority of people (up to 85% in females and 50% in males) with the mutations for LHON, actually do not get LHON, suggesting strong environmental factors.

Symptoms

LHON can result in complete blindness in one or both eyes, within about 6 months of initial symptoms. Along with the common ophthalmological symptoms, other neurological symptoms that are characteristic of mitochondrial disorders are also present.

Ophthalmological Symptoms

• Pain, discomfort, tingling sensation in and around both eyes

• Visual field defects, which decreases peripheral vision

• Decrease in sharpness in sight, called visual acuity

• Decrease in colour vision

• Progressive loss of central vision, eventually resulting in complete blindness

Other symptoms

• Developing neurological features similar to multiple sclerosis

• Movement disorders such as tremors, muscle contractions, and twisted repetitive movements known as dystonia

• Poor coordination

• Numbness in limbs

• Muscle weakness

• Cardiac conduction block - Abnormalities in the electrical impulses that control heartbeat

Testing

Lab testing:

• Geneticists can identify the exact change in DNA from the blood, and the diagnosis is almost 100% accurate, once blindness has already occurred

• Testing enzymes of the respiratory chain often reveal defects in complex I

The protein complex of the respiratory chain that is particularly affected by this disease

Is there prenatal testing available?

Prenatal testing for most mitochondrial disorders is available. Molecular testing for prenatal diagnosis is available only when the familial mutation(s) have been found; however, the availability of testing also depends on the mode of inheritance of the condition.

When there is a known genetic diagnosis in the family, it is important for a couple to meet with a genetic counsellor prior to becoming pregnant. This enables the couple to plan in advance, as genetic testing can be a lengthy process.

It is important to note that mitochondrial conditions caused by mutations in mitochondrial DNA (mtDNA) have limited use in prenatal diagnosis, due to principles of heteroplasmy and threshold effect discussed in the inheritance section.

Questions regarding your specific genetic diagnosis and the availability of prenatal diagnosis should always be discussed with a genetic counsellor and/or your obstetrician.

How is it inherited?

The mutation for LHON occurs in mitochondrial DNA and therefore it follows the pattern of maternal or mitochondrial inheritance.

Biological basis of the disease

• Caused by one of the three following point mutations in the mitochondrial DNA:

• G-A at nucleotide 3460
• G-A at nucleotide 11778
• T-C at nucleotide 14484

• These genetic changes may affect more than one protein of the respiratory chain thereby decreasing the effectiveness of the mitochondria to produce ATP

• Complex I is the protein commonly affected by this mutation

The protein complex of the respiratory chain that is particularly affected by this disease

• These mutations also increase the risk of making molecules known as reactive oxygen species (ROS) which damage mtDNA

• Optic nerve cells are unable to produce energy, and cannot function, resulting in cell death causing blindness

Treatments

• No current cure or effective treatments are available to reverse or improve vision loss from LHON

• Experimental trails with vitamin B12 and C supplementation and quinone are currently being tested, with limited success

•

Those with LHON in their families, are of course at a higher risk for developing it themselves, and are advised to avoid smoking and heavy alcohol consumption which may act as environmental triggers

Prognosis

• There is extreme variance in the prognosis of those with LHON. Severity, rate of progression, age of onset, and type of mutation are just a few of the factors that determine this, however blindness is almost always certain. The mutation “T>C 14484” is generally associated with the best prognosis.

Top of Page

Leigh’s Disease

What’s in the name?

• Leigh’s Disease is named after the neurologist who first described it in 1951

• Also known as Subacute Necrotizing Encephalomyelopathy (SNEM)

• Subacute- a rather sudden onset of a disease
• Necrotizing - causing death to a certain area or tissue
• Encephalo – -pertaining to the brain and nervous system
• –myelopathy – disease of the spine, causing dysfunction

• Leigh’s disease therefore damages tissue of the nervous system causing neurological problems, particularly with motor control

Who is affected?

The onset of the disease is usually in the first year of life. Later onset (after infancy) generally means a slower progression of the disease. The prevalence of Leigh’s disease is about 1 in 35 000. There is no ethnic or gender predisposition to the disease.

Symptoms

The brain and muscles are most affected which is very typical of mitochondrial disease.

Neurological:

• Lack of motor control (cannot hold toys in hands etc)

• Dementia – loss of intellectual ability

• Seizures

Musculoskeletal:

• Generalized weakness

• Exercise intolerance

• Lack of muscle tone

Other:

• Loss of appetite

• Vomiting

• Overall irritability and continuous crying

• Kidney and respiratory failure

Testing

Lab Testing:

• Muscle biopsy:

• Mitochondria appear as ragged red fibres under a microscope

Chemical staining identifies diseased mitochondria, appearing as “ragged red fibres”. Left and right show lower and higher magnification, respectively.

• Body fluids:

• Elevated concentration of lactic acid in cerebrospinal fluid especially
• Blood plasma shows a higher than normal concentration of the amino acid alanine

• Brain scans:

• MRI scans may show calcification (hardening) of certain brain areas like the basal ganglia

(Left) MRI scan of a healthy brain. (Right) The basal ganglia region of the brain shows abnormal signals.

• Testing enzymes of the respiratory chain often reveal defects in particular proteins – complex I, IV are common

The protein complexes of the respiratory chain that are particularly affected by this disease

• DNA testing shows one of many possible mutations in mitochondrial DNA genes – a common mutation is T8993G or T8993C MT-ATP6

Is there prenatal testing available?

Prenatal testing for most mitochondrial disorders is available. Molecular testing for prenatal diagnosis is available only when the familial mutation(s) have been found; however, the availability of testing also depends on the mode of inheritance of the condition.

When there is a known genetic diagnosis in the family, it is important for a couple to meet with a genetic counsellor prior to becoming pregnant. This enables the couple to plan in advance, as genetic testing can be a lengthy process.

It is important to note that mitochondrial conditions caused by mutations in mitochondrial DNA (mtDNA) have limited use in prenatal diagnosis, due to principles of heteroplasmy and threshold effect discussed in the inheritance section.

Questions regarding your specific genetic diagnosis and the availability of prenatal diagnosis should always be discussed with a genetic counsellor and/or your obstetrician.

Biological basis of the disease and the mechanism of inheritance

There are many ways that Leigh’s disease can occur, each with a distinct genetic change.

X Linked:

• A genetic change is carried on the X chromosome

• Most individuals with Leigh’s disease do not reproduce:

• Therefore only carriers can pass down the mutation in Leigh’s disease and since only females can be carriers in X-linked diseases, only females can pass down the Leigh’s disease mutation

• This particular genetic change causes defect in the pyruvate dehydrogenase enzyme, which is required for food molecules (particularly glucose from carbohydrates) to enter the mitochondria

Autosomal Recessive:

•

Both parents must be carriers of the disease in order to pass it down to the next generation

• This mutation affects the gene for the protein called cytochrome-c-oxidase (COX), the fourth protein in the respiratory chain

Mitochondrial:

• The final method for inheritance of Leigh’s disease is maternally, due to one of many point mutations in mitochondrial DNA
This follows a maternal, or mitochondrial pattern of inheritance

All methods of inheritance of Leigh’s disease present the same end result (i.e. dysfunctional mitochondria, and decreased ATP production). This results in energy deficits under stressful conditions within neurons, in particular regions of the nervous system, and leads to the symptoms described above.

Treatments

• Consultation with a metabolic geneticist, neurologist, and cardiologist may be required

• Most treatments target controlling the symptoms rather than the disease itself

• Lactic acidosis is treated by sodium bicarbonate or sodium citrate

• Traditional anticonvulsant drugs are used to treat seizures

• A “vitamin cocktail” consisting of riboflavin, thiamine, and coenzyme Q10, and vitamin B1 is used to improve mitochondrial function

• A high fat diet is often recommended due to the enzyme pyruvate dehydrogenase deficiency

Prognosis

• Unfortunately, prognosis is generally poor although it largely depends on the type of mutation. Pyruvate dehydrogenase and complex IV deficiency is associated with the worst prognosis. Those with less severe forms of the disease may have a longer lifespan.

Top of Page

KEARNS-SAYRE

What’s in the name?

Kearns-Sayre syndrome is also referred to as Chronic Progressive External Ophthalmoplegia and Myopathy or Ophthalmoplegia, Pigmentary Degeneration of the Retina and Cadiomyopathy

• Ophthalmoplegia – the paralysis of ocular muscles

• Myopathy – a disease of muscle tissue

• Cardiomyopathy – a disease of the cardiac muscle

Hence, Kearns-Sayre syndrome affects various energy demanding muscles and nerves in the body. Heart muscle and the many muscles controlling eye movement are particularly affected.

Who is affected?

The disease usually occurs in early childhood, and almost always before 20 years of age. Kearns-Sayre disease is extremely rare with prevalence being about 1-3 in 100 000 individuals. No ethnic or gender predisposition exists for Kearns-Sayre disease

Symptoms

Kearns-Sayre syndrome has symptoms characteristic of most other mitochondrial disease however the eyes are especially affected.

Ocular

• Chronic progressive external ophthalmoplegia (CPEO) – progressive paralysis of muscles in and around the eyes causing:

• restricted movement of the eyes
• the appearance of drooping eyelids

• Retinitis pigmentosa – accumulation of coloured pigments on the retina, at the back of the eye, which can lead to blindness

• Inflammation of the nerves on the retina

• Degeneration of retinal tissue

Other Symptoms

• Short, stooped stature

• Cardiac conduction block - problems in the electrical system of the heart
Ataxia – uncoordinated movements in the limbs as well as loss of balance

• Dementia – loss of intellectual ability

• Hearing loss

• Exercise intolerance

• Kidney dysfunction

Endocrine symptoms

• Diabetes mellitus

• Hypoparathyroidism

• Growth hormone deficiency

Testing

Lab Testing

• Body fluids:

• Elevated levels of lactic acid and pyruvic acid (mitochondrial acids) in the blood and cerebrospinal fluid (CSF)

• Muscle biopsy

• Testing using electromyogram (EMG) indicate muscle disease
• Mitochondria from muscle tissue appear as “ragged red fibres” under a microscope

Chemical staining identifies diseased mitochondria, appearing as “ragged red fibres”. Left and right show lower and higher magnification, respectively.

• Brain scans:

• MRI scans may show destruction of an area of the brain called white matter, a condition called leukoencephalopathy

The scan shows changes in white matter within the brain as well as symmetrical abnormalities in signals (white areas) in the area known as the putamen (bottom arrows), in both hemispheres

• Atrophy in various regions of the brain

• Cardiac:

• Electrocardiogram (ECG) is used to test heart function

• Testing enzymes of the respiratory chain often reveal defects in particular proteins – complex IV is especially affected in Kearns-Sayre

The protein complex of the respiratory chain that is particularly affected by this disease

• DNA testing reveals mitochondria that have deletions in large amounts to their DNA

Is there prenatal testing available?

Prenatal testing for most mitochondrial disorders is available. Molecular testing for prenatal diagnosis is available only when the familial mutation(s) have been found; however, the availability of testing also depends on the mode of inheritance of the condition.

When there is a known genetic diagnosis in the family, it is important for a couple to meet with a genetic counsellor prior to becoming pregnant. This enables the couple to plan in advance, as genetic testing can be a lengthy process.

It is important to note that mitochondrial conditions caused by mutations in mitochondrial DNA (mtDNA) have limited use in prenatal diagnosis, due to principles of heteroplasmy and threshold effect discussed in the inheritance section.

Questions regarding your specific genetic diagnosis and the availability of prenatal diagnosis should always be discussed with a genetic counsellor and/or your obstetrician.

How is it inherited?

• Kearns-Sayre disease, when inherited, follows a maternal or mitochondrial pattern of inheritance

• Interestingly however, Kearns-Sayre disease unlike most other mitochondrial disorders is rarely inherited (1 in 24 chance a baby will be affected if the mother has the disease) – most often it occurs spontaneously in a sporadic mutation.

Biological basis of the disease

• Large scale deletions of mitochondrial DNA, at varying areas of the genome

• A common deletion is of approximately 1/3 of the genome

• In mtDNA deletions, many essential mitochondrial genes are lost, particularly those of the respiratory chain

• This affects mitochondrial function, and energy production

• Vital organs like the brain and muscles become energy deprived

• Nerve and muscle cells are very energy demanding, and die if they are not provided with ATP
This results in the many neuromuscular problems that Kearns-Sayre patients suffer

Treatments

• No cure is available to reverse or slow the progression of the disease, but treatments are available to control the symptoms

• Consultation with an ophthalmologist, neurologist, endocrinologist and cardiologist are usually required

• Cardiac pacemaker to treat heart conduction block

• Surgery may be necessary for severe drooping eyelids

• Lactic acidosis is treated by sodium bicarbonate or sodium citrate

• Administration of coenzyme Q10, L-carnitine and antioxidants to treat defective proteins of the respiratory chain

• Hormone replacement therapy for disorders of the endocrine system

• Physical therapy and occupational therapy to improve mobility

• Mild to moderate physical activity is also recommended for patients with muscle weakness

Prognosis

Prognosis varies widely from patient to patient due to severity, amount of damage to organs and other factors. Kearns-Sayre is a degenerative disease with slow progression. Unfortunately most patients have a life expectancy much shorter than average.

Top of Page

MNGIE

What’s in the name?

• MNGIE – Mitochondrial neurogastrointestinal encephalopathy

• Neurogastrointesintal – the brain and organs of the digestive system are affected

• Encephalo-pathy – disease of the nervous system

• Alternate names for MNGIE are

• Myoneurogastrointestinal encephalopathy syndrome
• Oculogastrointestinal muscular dystrophy

Who is affected?

MNGIE is extremely rare with only about 70 cases reported worldwide. It usually affects children and adolescents before the age of 20. There is no ethnic or gender predisposition for MNGIE.

Symptoms

MNGIE presents a wide spectrum of different symptoms of the nervous, gastrointestinal and muscular systems. The symptoms may begin presenting themselves at any age however children and adolescents under 20 are most commonly affected.

Gastrointestinal:

• Dysmotility – Muscles of the gastrointestinal tract do not function effectively due to problems in the nerves controlling the muscles. This causes:

• Feeling full after only eating small amounts
• Dysphagia – difficulty swallowing
• Nausea and vomiting
• Abdominal pain
• Diarrhea

Neurological:

• Peripheral neuropathy – tingling, numbness and weakness in the limbs

• External ophthalmoplegia/ophthalmoperesis – paralysis of muscles in and around the eyes causing restricted eye movement and drooping eyelids

• Leukoencephalopathy – a disease causing destruction of an area of the brain called white matter

Appearance:

• Significant weight loss

• Reduced muscle mass

• Short stature

Testing

Lab Testing

• Body fluids

• A change in particular enzyme concentration or activity in the blood:

• An increase in plasma thymidine concentration
• An increase in deoxyuridine concentration
• Decreased activity of thymidine phosphorylase

• Lactic Acidosis - an increased concentration of lactic acid in blood and cerebrospinal fluid
• The following link provides detailed information and videos on obtaining CSF via lumbar puncture: http://emedicine.medscape.com/article/80773-treatment

• Muscle biopsy

• After chemical staining, diseased mitochondria appear as ragged red fibres under a microscope

Chemical staining identifies diseased mitochondria, appearing as “ragged red fibres”. Left and right show lower and higher magnification, respectively.

• Brain scans

• MRI scans reveal a destruction in an area of the brain known as white matter, a condition called leukoencephalopathy

The scan shows changes in white matter within the brain as well as symmetrical abnormalities in signals (white areas) in the area known as the putamen (bottom arrows), in both hemispheres

• EMG tests for nerve conduction studies

• Testing enzymes of the respiratory chain often reveal defects in multiple proteins – complex IV is particularly affected

The protein complex of the respiratory chain that is particularly affected by this disease

• DNA testing in blood for TYMP gene, reveals a mutation in nearly 100% of those affected

Is there prenatal testing available?

Prenatal testing for most mitochondrial disorders is available. Molecular testing for prenatal diagnosis is available only when the familial mutation(s) have been found; however, the availability of testing also depends on the mode of inheritance of the condition.

When there is a known genetic diagnosis in the family, it is important for a couple to meet with a genetic counsellor prior to becoming pregnant. This enables the couple to plan in advance, as genetic testing can be a lengthy process.

Questions regarding your specific genetic diagnosis and the availability of prenatal diagnosis should always be discussed with a genetic counsellor and/or your obstetrician.

How is it inherited?

MNGIE follows the pattern of an autosomal recessive form of inheritance.

Biological basis of the disease

• A mutation to a gene in the nucleus called TYMP has been associated with causing MNGIE

• The gene codes for a protein called thymidine phosphorylase, which is essential for regulating the level of the molecule thymidine

• When regulated, small amounts of thymidine are essential for normal mitochondrial function, but a drastic increase in thymidine causes problems to mitochondrial DNA

• Lab tests for MNGIE patients show a decrease in thymidine phosphorylase protein and therefore an increase in thymidine since there is nothing to regulate its levels

• Problems to mitochondrial DNA include:

• Deletions of parts of the DNA
• Duplications to parts of the DNA

• These deletions and duplications affect genes which code for proteins of the respiratory chain

• This creates mitochondria that don’t function properly and as a result muscle and nerve cells become energy deprived

• The exact causes of specific symptoms of MNGIE however are still unknown

Treatments

• Medical care under the following specialists may be required: neurologist, gastroenterologist, medical geneticist, psychiatrist, ophthalmologist

• There is no medication to slow the progression of the disease and treatments only target at controlling the symptoms

• Lactic acidosis is treated by sodium bicarbonate or sodium citrate

• Antiemetic drugs are used to treat nausea and vomiting

• Those with extreme dysphagia may require nutritional support using food tubes

• Dysmotility may cause intestinal bacterial growth, and antibiotics may be required

• Physical therapy and occupational therapy help increase mobility and comfort

• To treat the excess thymidine levels, stem cell (bone marrow) transplants have been used

Prognosis

Prognosis is generally quite poor. As the disease progresses, symptoms gradually worsen. Unfortunately, MNGIE patients’ lifespan is much shorter than average.

Top of Page

PEARSON’S SYNDROME

What’s in the name?

• Pearson’s syndrome was named after the physician who first described it in 1979

• Alternate names for Pearson’s syndrome are Pearson’s marrow pancreas syndrome or Sideroblastic anemia with marrow cell vacuolization and exocrine pancreatic dysfunction

• Sideroblast- a nucleated red blood cell which contains excess iron, and is found in the bone marrow
• Anemia – a low count in haemoglobin protein, which is used to carry iron

• The body has plenty of iron available yet cannot use it due to haemoglobin deficiency

• Marrow cell vacuolization – the formation of vacuoles (membrane bound structures inside cells that store many chemicals) in bone marrow cells

• Exocrine pancreas – the component of the pancreas that releases enzymes via ducts in the intestines, during digestion

Who is affected?

The onset of Pearson’s is most common during infancy or early childhood. It is extremely rare with only about 80 cases reported worldwide. There is no ethnic or gender predisposition to the disease.

Symptoms

Neuromuscular

• Tremor

• Lack of muscle tone

• Fatigue

Digestive

• Chronic diarrhoea

• Vomiting episodes

• Fatty stool

• Liver failure

Other symptoms (may be present)

• Pallor – pale skin which is generally caused by anemia

•

Erythema – redness of the skin

• Sensitivity to light

• Short stature

• Weight loss

Testing

Lab Testing:

• Body fluids:

• Abnormally low count of reticulocytes (red blood cells which still have not fully developed), as well as white blood cells and platelets
• Lactic acidosis - Increase in lactic acid concentration (a mitochondrial acid) in the blood and CSF
• Increased glucose, amino acids and other chemicals in the urine which are normally filtered out by kidneys (therefore indicates a kidney problem)

• Biopsy:

• Bone marrow biopsy shows a change in the appearance of bone cells

• Brain scans using MRI and MRS may be ordered for individuals with severe neurological symptoms

• Enzymology:

• Tests on particular liver enzymes such as transaminase
• Pancreatic enzyme tests may be performed on isoamylase, trypsinogen, and lipase enzymes

• DNA testing on white blood cells reveals deletions of mitochondrial DNA

Biological basis of the disease

• Large scale deletions and duplications of mitochondrial DNA

• In mtDNA deletions, many essential mitochondrial genes are lost, particularly those of the respiratory chain proteins

• This affects mitochondrial function, and energy production in cells

• Cells of vital organs, especially of the digestive system become energy deprived and cannot function

How is it inherited?

• Pearson’s disease is caused by mtDNA mutations, which can only be inherited maternally. However, Pearson’s actually more commonly occurs spontaneously due to a sporadic mutation

Treatments

• Generally, consultation with a metabolic geneticist and haematologist are required

• There are no treatments for the disease itself, but only to control the symptoms
Sodium bicarbonate is used to treat acidosis

• Red blood cell transfusions may be required for the various anemias that may occur as a result of Pearson’s

• Stem cell transplantation has been used effectively in one case of Pearson’s syndrome

• Physical therapy and occupational therapy may be used to improve mobility and comfort

Prognosis

• Prognosis may be poor for patients but it actually depends on severity of complications arising from Pearson’s. Life expectancy may also be greatly reduced. Other complications such as symptoms of Kearns-Sayre syndrome are sometimes found in the later stages of Pearson’s.

Top of Page

CPEO

What’s in the name?

• CPEO- Chronic Progressive External Ophthalmoplegia

• Chronic – a medical condition that has developed over an extended period of time, or is long lasting

• Progressive – Symptoms worsen as time passes

• External Ophthalmoplegia – Paralysis of the muscles surrounding the eyes, restricting movement of the eyes and causing the appearance of drooping eyelids

Who is affected?

• The disease usually occurs in early childhood, and almost always before 20 years of age. CPEO is extremely rare with prevalence being about 1-3 in 100 000 individuals. No ethnic or gender predisposition exists for CPEO

Symptoms

Ocular

• External ophthalmoplegia–Paralysis of muscles in and around the eyes causing:

• restricted movement of the eyes
• the appearance of drooping eyelids

Other Symptoms

• Short, stooped stature
• Severe weakness in limbs

Often, other symptoms which are characteristic of Kearns-Sayre syndrome (KSS) are present but not enough to be clinically considered KSS. In these cases, CPEO is often referred to as “KSS minus”.

Testing

Lab Testing

• Body fluids:

• Elevated levels of lactic acid and pyruvic acid (mitochondrial acids) in the blood and cerebrospinal fluid (CSF)
• The following link provides detailed information and videos lumbar puncture, the procedure of obtaining cerebrospinal fluid http://emedicine.medscape.com/article/80773-treatment

• Muscle biopsy

• Testing using electromyogram (EMG) indicate muscle disease
• Mitochondria from muscle tissue appear as “ragged red fibres” under a microscope

Chemical staining identifies diseased mitochondria, appearing as “ragged red fibres”. Left and right show lower and higher magnification, respectively.

• Brain scans:

• MRI scans may show destruction of an area of the brain called white matter, a condition called leukoencephalopathy

The scan shows changes in white matter within the brain as well as symmetrical abnormalities in signals (white areas) in the area known as the putamen (bottom arrows), in both hemispheres

• Atrophy in various regions of the brain

• Testing enzymes of the respiratory chain often reveal defects in particular proteins – complex IV is especially affected in CPEO

The protein complex of the respiratory chain that is particularly affected by this disease

• DNA testing reveals mitochondria that have deletions in large amounts to their DNA

Is there prenatal testing available?

Prenatal testing for most mitochondrial disorders is available. Molecular testing for prenatal diagnosis is available only when the familial mutation(s) have been found; however, the availability of testing also depends on the mode of inheritance of the condition.

When there is a known genetic diagnosis in the family, it is important for a couple to meet with a genetic counsellor prior to becoming pregnant. This enables the couple to plan in advance, as genetic testing can be a lengthy process.

It is important to note that mitochondrial conditions caused by mutations in mitochondrial DNA (mtDNA) have limited use in prenatal diagnosis, due to principles of heteroplasmy and threshold effect discussed in the inheritance section.

Questions regarding your specific genetic diagnosis and the availability of prenatal diagnosis should always be discussed with a genetic counsellor and/or your obstetrician.

How is it inherited?

• Since mitochondrial DNA is affected in CPEO, it follows a mitochondrial or maternal pattern of inheritance

Biological basis of the disease

• Large scale deletions of mitochondrial DNA, at varying areas of the genome

• A common deletion is of approximately 1/3 of the genome
In mtDNA deletions, many essential mitochondrial genes are lost, particularly those of the respiratory chain

• This affects mitochondrial function, and energy production

• Energy demanding parts of the body like the eyes and nerves are particularly affected

Treatments

• No cure is available to reverse or slow the progression of the disease, but treatments are available to control the symptoms

• Consultation with a neurologist, ophthalmologist and endocrinologist may be required

• Surgery may be necessary for severe drooping eyelids

• Lactic acidosis is treated by sodium bicarbonate or sodium citrate

• Administration of coenzyme Q10, L-carnitine and antioxidants to treat defective proteins of the respiratory chain

Prognosis

Prognosis varies widely from patient to patient due to severity, amount of damage to organs and other factors. CPEO is a degenerative disease with slow progression. Unfortunately most patients have a life expectancy much shorter than average.

Top of Page

ALPERS’ DISEASE

What’s in the name?

• Alpers’ disease was named after the physician who first described it in 1931

• Also termed Progressive Neuronal Degeneration of Childhood with Liver Disease and poliodystrophy

• Poliodystrophy – disease of the nervous system caused by a decrease in the area the brain known as grey matter

Who is affected?

• Alpers’ disease generally affects young children before the age of five although there have been cases where symptoms begin in adolescence. This is termed as Juvenile Alpers’ disease. The prevalence of Alpers’ is only about 1 in every 200 000. There is no ethnic or gender predisposition to the disease.

Symptoms

Neurological:

• Severe epilepsy which causes the seizures, and is generally the first symptom

• Dementia - a loss of intellectual ability

• A gradual loss of previously learnt skills

• nvoluntary movements of the limbs, face and head

• Spastic quadriplegia - inability to use and control movements of the arms and legs, in the later stages of the disease

• Optic atrophy – the degeneration of the optic nerve causing blindness

Liver:

• Jaundice - a liver disease causing yellowish discolouration of the skin and eyes

• In rare cases, complete liver failure

Lab Testing:

Biopsy:

• Liver biopsy test may be helpful to diagnose in later stages of the disease

• EEG tests reveal distinct brain wave patterns

• Confirmed diagnosis of the disease is only available from autopsy of the brain after death

• Autopsy reveals degradation of the area of the brain known as grey matter

Is there prenatal testing available?

Prenatal testing for most mitochondrial disorders is available. Molecular testing for prenatal diagnosis is available only when the familial mutation(s) have been found; however, the availability of testing also depends on the mode of inheritance of the condition.

When there is a known genetic diagnosis in the family, it is important for a couple to meet with a genetic counsellor prior to becoming pregnant. This enables the couple to plan in advance, as genetic testing can be a lengthy process.

Questions regarding your specific genetic diagnosis and the availability of prenatal diagnosis should always be discussed with a genetic counsellor and/or your obstetrician.

How is it inherited?

• Alpers’ disease follows an autosomal recessive pattern of inheritance

Biological basis of the disease

• A mutation to the gene known as polymerase gamma which makes a protein involved in replication and repair of DNA

• This gene is found in nuclear DNA

• A mutation to this gene causes large scale deletions of mitochondrial DNA
In mtDNA deletions, many essential mitochondrial genes are lost, particularly those of the respiratory chain

• This affects mitochondrial function, and therefore energy production

• Energy demanding cells of the body such as those located in the brain or liver often suffer, causing the symptoms seen in Alpers’ disease

Treatments

• Consultation with a neurologist, metabolic geneticist and a hepatologist (liver specialist) may be required

• There is no current cure or treatment to slow the progression of the disease but drugs are prescribed to control the symptoms

• Anticonvulsant medication to treat seizures

• Physical therapy and occupational therapy is used to improve mobility and comfort

Prognosis

There is extreme variance in the prognosis of those with Alpers’ disease. Severity, rate of progression, age of onset, and many other factors determine this, although life expectancy is generally drastically reduced.

Top of Page

MITOCHONDRIAL DNA DEPLETION SYNDROMES

What’s in the name?

• A single mitochondrion may contain multiple copies of its DNA

• Like its name sake, DNA depletion syndromes causes a reduction in the number of copies of DNA within the mitochondrion

Who is affected?

The onset of the disease is early, with symptoms beginning in infancy (before about 5 months of age). The disease is extremely rare with only about 17 cases reported worldwide. Although various ethnic groups have been affected, a common mutation has been found in Faroese people (an ethnic group with a population of about 25 000 living Scandinavia)

Symptoms

Neurological:

• Psychomotor delay – a delayed development of intellect and motor ability

• Dystonia – uncontrollable muscle contractions causing repetitive twisting movements

• Epilepsy - The condition of having severe, recurrent seizures

• External ophthalmoplegia

• Paralysis of the muscles that open eyelids, and control eye movement
• Results in drooping of the eyelids

Muscular:

• Muscle hypotonia – low muscle tone, and an overall reduced muscle mass

• Results in a lack of control of head and neck movement

Physical Appearance:

• Kyphosis- the appearance of a hunchback

• Scoliosis – a spine that curves side to side in a person

Testing

Lab Testing:

• Body Fluids:

• Elevated levels of lactic acid found in the blood and cerebrospinal fluid

• Muscle Biopsy:

• Brain Scans:

• Atrophy of certain areas of the brain
• Abnormal signals from basal ganglia region of the brain on an MRI

(Left) MRI scan of a healthy brain. (Right) The basal ganglia region of the brain shows abnormal signals.

How is it inherited?

SUCLA2 related DNA depletion syndrome follows a pattern of autosomal recessive inheritance

Biological Basis of the Disease

• Most commonly, the cause is a mutation to SUCLA2 gene on chromosome 13

• SUCLA2 is responsible for making an enzyme that is involved in the initial breakdown of food molecules once they enter the mitochondria

• A mutation makes faulty enzymes that don’t allow proper energy production

• SUCLA2 is also responsible for regular maintenance and repair of mtDNA in the mitochondria

• With dysfunctional SUCLA2 product, regular maintenance of DNA is affected and mtDNA molecules begin disintegrating if they aren’t repaired

Treatments

Like most mitochondrial diseases, no cure exists for this disease and the primary goal is to control the symptoms as much as possible to improve the quality of life.

• Physical therapy and occupational therapy to improve mobility and comfort

• Bracing or surgery for kyphosis and scoliosis

• Anti-epileptic drugs to treat epileptic seizures

Prognosis

Prognosis for the most part is poor, although it varies greatly from patient to patient. Severity of complications is what eventually determines the life expectancy.

Top of Page