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Disease Database



 

CPEO

 

MELAS


What’s in the name?


Dot MELAS – Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes is a rare inherited neurodegenerative disease


Dot Encephalo

Of, or relating to the brain/central nervous system (CNS)


DotMyo-pathy

myo- Pertaining to muscles
-pathy - a disease or disorder


 Dot Lactic Acidosis

The condition of having lactic acid (in excess) in body fluids such as blood and cerebrospinal fluid

Who is affected?


Dot MELAS generally affects children, usually before adolescence
Dot The prevalence is only about 1 in 10 000
Dot There is no ethnic or gender predisposition to the disease

Symptoms


Clinical features:
Dot Short stature
Dot External ophthalmoplegia (a rare symptom in MELAS)

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

External Ophthalmoplegia


Neurological:


Dot Seizures
Dot Recurrent severe headaches and migraines
Dot Altered states of consciousness
Dot Dementia (loss of intellectual ability)
Dot Ataxia

From the Greek word meaning “without coordination”
Patients can report clumsiness in the movement of their hands, arms, legs as well as their balance

Dot Temporary local paralysis

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


Musculoskeletal:
Dot Overall muscle weakness
Dot Exercise intolerance

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


Testing


Lab Testing:


Dot Body fluids:

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


DotMuscle Biopsy:

Dot Abnormal mitochondria from under the muscle tissue membrane appear as “ragged red fibres” under a microscope

 

Red Ragged FibresRagged Red Fibres

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


Dot Brain scans using MRI or CT reveal:

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

MRI NormalMRI abnormal basal ganglia

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


Dot Damage to certain brain areas following stroke

Normal MRIMRI Stroke

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

 

Dot Changes in the area of the brain known as white matter

White matter changes

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

 

Dot MRS testing reveals increase in lactate concentration in the brain

Increase in lactate

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

 

 

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

 

Respiratory chain complex I and IV

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


Dot 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


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


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


Dot tRNA molecules are responsible for bringing amino acids together to make proteins
Dot A genetic change in the tRNALeu gene affects the function of these molecules
Dot The cannot properly make proteins including those of the respiratory chain which creates dysfunctional mitochondria
Dot Vital organs like the brain and muscles become energy deprived
Dot Nerve and muscle cells are very energy demanding, and die if they are not provided with ATP
Dot This results in the many neuromuscular problems that MELAS patients suffer
Dot 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.

Mitochondrial Inheritance

 

Treatments


Dot Although prognosis may be poor, many treatment options are available to improve the daily lifestyle of MELAS patients.
Dot Medical care under the following specialists may be required: neurologist, medical geneticist, ophthalmologist and cardiologist
Dot Nutrition plays a vital role in the management of metabolic disorders and mitochondrial disorders.
Dot 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.
DotArginine (an amino acid) supplementation has been found to be helpful in acute stroke like episodes and also for chronic prevention of stroke like episodes
Dot Lactic acidosis is treated by sodium bicarbonate or sodium citrate
Dot Vitamins help reduce tissue damage caused by the faulty proteins of the mitochondria.
Dot Seizures can be treated for the most part with traditional anticonvulsant drugs
Dot Surgical measures may be required to treat hearing loss
Dot 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.

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MERRF


What’s in the name?


Dot MERRF – Myoclonic epilepsy with ragged red fibres
Dot Myoclonus

DotThe sudden contraction of muscles, causing brief jerking movements

Dot Epilepsy

DotThe condition of having severe, recurrent seizures

Dot 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


Dot Neurological:

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

Dot Ocular:

Dot Retinitis Pigmentosa – a group of diseases characterized by

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

Healthy optic disc

rimary optic atrophy

 

Dot External ophthalmoplegia/ophthalmoperesis

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

External ophthalmoplegia

Dot Physical appearance:

Dot Short stature( may be present)

Dot Other Symptoms:

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

Testing


Laboratory Test:


Dot Body fluids:

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

Dot Muscle biopsy:

Dot Mitochondria from muscle biopsy appear as ragged red fibres

Red Ragged FibresRagged Red Fibres

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

Dot Brain scans:

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

 

MRI NormalMRI abnormal basal ganglia


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

 

Dot ECG tests often show abnormalities in heart function
Dot Testing enzymes of the respiratory chain often reveal defects in particular proteins – complex I and IV are common in MERRF

 

Respiratory chain complex I and IV

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

 

Dot DNA studies:

Dot 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


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

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


Dot Molecules of tRNA are responsible for bringing amino acids together to make proteins
Dot A genetic change in the tRNALeu gene affects the function of these molecules
Dot The cannot properly make proteins including those of the respiratory chain which creates dysfunctional mitochondria
Dot Like most mitochondrial diseases, MERRF also disrupts the function of the respiratory chain proteins
Dot Vital organs like the brain and muscles become energy deprived
Dot Nerve and muscle cells are very energy demanding, and die if they are not provided with ATP
Dot This creates the many neuromuscular symptoms that MERRF patients suffer
Dot 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.

 

Mitochondrial Inheritance

 

Treatments


Dot Medical care under the following specialists may be required: neurologist, medical geneticist, ophthalmologist, cardiologist, and audiologist
Dot 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
Dot Lactic acidosis is treated by sodium bicarbonate or sodium citrate
Dot Traditional anticonvulsant drugs are used to treat the epilepsy
Dot Physical therapy is used to improve motor function
Dot 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.

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NARP


What’s in the name?


Dot NARP - Neuropathy, Ataxia, Retinitis Pigmentosa
Dot Neuropathy – disease of the peripheral nervous system
Dot Ataxia – without balance or coordination
Dot Retinitis Pigmentosa

Dot Retinitis – inflammation of the retina
Dot Pigmentosa – deposition of pigments on the retina
Dot 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:


Dot Developmental delay
Dot Seizures
Dot Ataxia –inability to maintain normal posture and smoothness of movement
 Dot Sensory neuropathy – pain, numbness, tingling sensation in the arms and legs


Muscular:


Dot General muscle weakness and fatigue
Dot Exercise intolerance


Retinitis Pigmentosa:


Dot Night blindness
Dot Tunnel vision
Dot Loss of central vision
Dot 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:


Dot Muscle biopsy:

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

Red Ragged FibresRagged Red Fibres

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

Dot Body fluids:

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


Dot Brain scans:

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

Increase in lactate

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

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

Dot 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


Dot Caused by a T-G or T-C mutation to the MT-ATP6 gene of the mitochondria
Dot MT-ATP6 codes part of ATP Synthase, the last component of the respiratory chainRespiratory chain

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

Mitochondrial Inheritance

Treatments


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

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

Dot Lactic acidosis is treated by sodium bicarbonate or sodium citrate
Dot To treat retinitis pigmentosa, Vitamin A and E are prescribed
Dot 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.

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LHON


What’s in the name?


Dot LHON – Leber’s Hereditary Optic Neuropathy
Dot Optic Neuropathy - a disease affecting the optic nerve
Dot 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


Dot Pain, discomfort, tingling sensation in and around both eyes
Dot Visual field defects, which decreases peripheral vision
Dot Decrease in sharpness in sight, called visual acuity
Dot Decrease in colour vision
Dot Progressive loss of central vision, eventually resulting in complete blindness


Other symptoms


Dot Developing neurological features similar to multiple sclerosis
Dot Movement disorders such as tremors, muscle contractions, and twisted repetitive movements known as dystonia
Dot Poor coordination
Dot Numbness in limbs
Dot Muscle weakness
Dot Cardiac conduction block - Abnormalities in the electrical impulses that control heartbeat


Testing


Lab testing:


Dot Geneticists can identify the exact change in DNA from the blood, and the diagnosis is almost 100% accurate, once blindness has already occurred
Dot Testing enzymes of the respiratory chain often reveal defects in complex I

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.

Mitochondrial Inheritance

Biological basis of the disease


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


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


Dot  These genetic changes may affect more than one protein of the respiratory chain thereby decreasing the effectiveness of the mitochondria to produce ATP
Dot Complex I is the protein commonly affected by this mutation

Complex I

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


Dot These mutations also increase the risk of making molecules known as reactive oxygen species (ROS) which damage mtDNA
Dot Optic nerve cells are unable to produce energy, and cannot function, resulting in cell death causing blindness


Treatments


Dot No current cure or effective treatments are available to reverse or improve vision loss from LHON
Dot Experimental trails with vitamin B12 and C supplementation and quinone are currently being tested, with limited success
Dot 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


DotThere 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.

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Leigh’s Disease


What’s in the name?


Dot Leigh’s Disease is named after the neurologist who first described it in 1951
Dot Also known as Subacute Necrotizing Encephalomyelopathy (SNEM)

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


Dot 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:
Dot Lack of motor control (cannot hold toys in hands etc)
Dot Dementia – loss of intellectual ability
Dot Seizures


Musculoskeletal:
Dot Generalized weakness
Dot Exercise intolerance
Dot Lack of muscle tone


Other:
Dot Loss of appetite
Dot Vomiting
Dot Overall irritability and continuous crying
Dot Kidney and respiratory failure


Testing


Lab Testing:
Dot Muscle biopsy:

DotMitochondria appear as ragged red fibres under a microscope

Red Ragged FibresRagged Red Fibres

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

 

Dot Body fluids:

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


Dot Brain scans:

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

MRI NormalMRI abnormal basal ganglia


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

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

Respiratory chain complex I and IV

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

Dot 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:


Dot A genetic change is carried on the X chromosome
Dot Most individuals with Leigh’s disease do not reproduce:

Dot 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

X linked recessive

Dot 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:


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

Autosomal recessive

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

Mitochondrial:


Dot 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

Mitochondrial 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


Dot Consultation with a metabolic geneticist, neurologist, and cardiologist may be required
Dot Most treatments target controlling the symptoms rather than the disease itself
Dot Lactic acidosis is treated by sodium bicarbonate or sodium citrate
Dot Traditional anticonvulsant drugs are used to treat seizures
Dot A “vitamin cocktail” consisting of riboflavin, thiamine, and coenzyme Q10, and vitamin B1 is used to improve mitochondrial function
Dot A high fat diet is often recommended due to the enzyme pyruvate dehydrogenase deficiency


Prognosis


Dot 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.

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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


Dot Ophthalmoplegia – the paralysis of ocular muscles
Dot Myopathy – a disease of muscle tissue
Dot 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


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


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

External ophthalmoplegia


Dot Retinitis pigmentosa – accumulation of coloured pigments on the retina, at the back of the eye, which can lead to blindness
Dot Inflammation of the nerves on the retina
Dot Degeneration of retinal tissue

Healthy optic disc

rimary optic atrophy

 

Other Symptoms


Dot Short, stooped stature
Dot Cardiac conduction block - problems in the electrical system of the heart
Ataxia – uncoordinated movements in the limbs as well as loss of balance
Dot Dementia – loss of intellectual ability

Dot Hearing loss
Dot Exercise intolerance
Dot Kidney dysfunction


Endocrine symptoms


Dot Diabetes mellitus
Dot Hypoparathyroidism
Dot Growth hormone deficiency


Testing


Lab Testing


Dot Body fluids:

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

Dot Muscle biopsy

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


Red Ragged FibresRagged Red Fibres

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

 

Dot Brain scans:

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

White matter changes

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

 

Dot Atrophy in various regions of the brain

Dot Cardiac:

Dot Electrocardiogram (ECG) is used to test heart function

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

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

Dot 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?


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

Mitochondrial Inheritance

Biological basis of the disease


Dot Large scale deletions of mitochondrial DNA, at varying areas of the genome
Dot A common deletion is of approximately 1/3 of the genome 
Dot In mtDNA deletions, many essential mitochondrial genes are lost, particularly those of the respiratory chain
Dot This affects mitochondrial function, and energy production
Dot Vital organs like the brain and muscles become energy deprived
Dot 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


Dot No cure is available to reverse or slow the progression of the disease, but treatments are available to control the symptoms
Dot Consultation with an ophthalmologist, neurologist, endocrinologist and cardiologist are usually required
Dot Cardiac pacemaker to treat heart conduction block
Dot Surgery may be necessary for severe drooping eyelids
Dot Lactic acidosis is treated by sodium bicarbonate or sodium citrate
Dot Administration of coenzyme Q10, L-carnitine and antioxidants to treat defective proteins of the respiratory chain
Dot Hormone replacement therapy for disorders of the endocrine system
Dot Physical therapy and occupational therapy to improve mobility
Dot 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.

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MNGIE


What’s in the name?


Dot MNGIE – Mitochondrial neurogastrointestinal encephalopathy

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

Dot Encephalo-pathy – disease of the nervous system

Dot Alternate names for MNGIE are

Dot Myoneurogastrointestinal encephalopathy syndrome
Dot 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:
DotDysmotility – Muscles of the gastrointestinal tract do not function effectively due to problems in the nerves controlling the muscles. This causes:

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

Neurological:
Dot Peripheral neuropathy – tingling, numbness and weakness in the limbs
Dot External ophthalmoplegia/ophthalmoperesis – paralysis of muscles in and around the eyes causing restricted eye movement and drooping eyelids

External ophthalmoplegia


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


Appearance:


Dot Significant weight loss
Dot Reduced muscle mass
Dot Short stature


Testing


Lab Testing


Dot Body fluids

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

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

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

Dot Muscle biopsy

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

Red Ragged FibresRagged Red Fibres

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

 

Dot Brain scans

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

White matter changes

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

Dot EMG tests for nerve conduction studies

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

Complex IV

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

 

Dot 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.

Autosomal recessive

Biological basis of the disease

Dot A mutation to a gene in the nucleus called TYMP has been associated with causing MNGIE
Dot The gene codes for a protein called thymidine phosphorylase, which is essential for regulating the level of the molecule thymidine
Dot When regulated, small amounts of thymidine are essential for normal mitochondrial function, but a drastic increase in thymidine causes problems to mitochondrial DNA
Dot 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
Dot Problems to mitochondrial DNA include:

Dot Deletions of parts of the DNA
Dot Duplications to parts of the DNA

Dot These deletions and duplications affect genes which code for proteins of the respiratory chain
Dot This creates mitochondria that don’t function properly and as a result muscle and nerve cells become energy deprived
Dot The exact causes of specific symptoms of MNGIE however are still unknown


Treatments


Dot Medical care under the following specialists may be required: neurologist, gastroenterologist, medical geneticist, psychiatrist, ophthalmologist
Dot There is no medication to slow the progression of the disease and treatments only target at controlling the symptoms
Dot Lactic acidosis is treated by sodium bicarbonate or sodium citrate
Dot Antiemetic drugs are used to treat nausea and vomiting
Dot Those with extreme dysphagia may require nutritional support using food tubes
Dot Dysmotility may cause intestinal bacterial growth, and antibiotics may be required
Dot Physical therapy and occupational therapy help increase mobility and comfort
Dot 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.

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PEARSON’S SYNDROME


What’s in the name?


Dot Pearson’s syndrome was named after the physician who first described it in 1979
Dot Alternate names for Pearson’s syndrome are Pearson’s marrow pancreas syndrome or Sideroblastic anemia with marrow cell vacuolization and exocrine pancreatic dysfunction

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

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

Dot Marrow cell vacuolization – the formation of vacuoles (membrane bound structures inside cells that store many chemicals) in bone marrow cells
Dot 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
Dot Tremor
Dot Lack of muscle tone
Dot Fatigue


Digestive
Dot Chronic diarrhoea
Dot Vomiting episodes
Dot Fatty stool
Dot Liver failure


Other symptoms (may be present)
Dot Pallor – pale skin which is generally caused by anemia
Dot Erythema – redness of the skin
Dot Sensitivity to light
Dot Short stature
Dot Weight loss


Testing


Lab Testing:


Dot Body fluids:

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

Dot Biopsy:

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

Dot Brain scans using MRI and MRS may be ordered for individuals with severe neurological symptoms
Dot Enzymology:

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

DotDNA testing on white blood cells reveals deletions of mitochondrial DNA


Biological basis of the disease


Dot Large scale deletions and duplications of mitochondrial DNA
Dot In mtDNA deletions, many essential mitochondrial genes are lost, particularly those of the respiratory chain proteins
Dot This affects mitochondrial function, and energy production in cells
Dot Cells of vital organs, especially of the digestive system become energy deprived and cannot function


How is it inherited?


Dot 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

Mitochondrial Inheritance

Treatments


Dot Generally, consultation with a metabolic geneticist and haematologist are required
Dot There are no treatments for the disease itself, but only to control the symptoms
Sodium bicarbonate is used to treat acidosis
Dot Red blood cell transfusions may be required for the various anemias that may occur as a result of Pearson’s
Dot Stem cell transplantation has been used effectively in one case of Pearson’s syndrome
Dot Physical therapy and occupational therapy may be used to improve mobility and comfort


Prognosis


Dot 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.

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CPEO


What’s in the name?


Dot CPEO- Chronic Progressive External Ophthalmoplegia
Dot Chronic – a medical condition that has developed over an extended period of time, or is long lasting
Dot Progressive – Symptoms worsen as time passes
Dot External Ophthalmoplegia – Paralysis of the muscles surrounding the eyes, restricting movement of the eyes and causing the appearance of drooping eyelids


Who is affected?


Dot 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


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


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

External ophthalmoplegia


Other Symptoms


Dot Short, stooped stature
Dot 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


Dot Body fluids:

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

Dot Muscle biopsy

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

 

Red Ragged FibresRagged Red Fibres

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

Dot Brain scans:

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

White matter changes

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

 

Dot Atrophy in various regions of the brain


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

Complex IV

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

 

Dot 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?


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

Mitochondrial Inheritance

Biological basis of the disease


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

Dot 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
Dot This affects mitochondrial function, and energy production
Dot Energy demanding parts of the body like the eyes and nerves are particularly affected


Treatments


Dot No cure is available to reverse or slow the progression of the disease, but treatments are available to control the symptoms
Dot Consultation with a neurologist, ophthalmologist and endocrinologist may be required
Dot Surgery may be necessary for severe drooping eyelids
Dot Lactic acidosis is treated by sodium bicarbonate or sodium citrate
Dot 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.

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ALPERS’ DISEASE


What’s in the name?


Dot Alpers’ disease was named after the physician who first described it in 1931
Dot Also termed Progressive Neuronal Degeneration of Childhood with Liver Disease and poliodystrophy

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


Who is affected?


Dot 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:


Dot Severe epilepsy which causes the seizures, and is generally the first symptom
Dot Dementia - a loss of intellectual ability
Dot A gradual loss of previously learnt skills
Dot nvoluntary movements of the limbs, face and head
Dot Spastic quadriplegia - inability to use and control movements of the arms and legs, in the later stages of the disease
Dot Optic atrophy – the degeneration of the optic nerve causing blindness

Healthy optic disc

rimary optic atrophy

 

 

Liver:


Dot Jaundice - a liver disease causing yellowish discolouration of the skin and eyes
Dot In rare cases, complete liver failure


Lab Testing:


Biopsy:


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

DotEEG tests reveal distinct brain wave patterns

DotConfirmed diagnosis of the disease is only available from autopsy of the brain after death
Dot 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?


Dot Alpers’ disease follows an autosomal recessive pattern of inheritance

 

Autosomal recessive

 

Biological basis of the disease


Dot A mutation to the gene known as polymerase gamma which makes a protein involved in replication and repair of DNA
Dot This gene is found in nuclear DNA
Dot 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
Dot This affects mitochondrial function, and therefore energy production
Dot 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


DotConsultation with a neurologist, metabolic geneticist and a hepatologist (liver specialist) may be required
Dot There is no current cure or treatment to slow the progression of the disease but drugs are prescribed to control the symptoms
Dot Anticonvulsant medication to treat seizures
Dot 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.

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MITOCHONDRIAL DNA DEPLETION SYNDROMES


What’s in the name?


Dot A single mitochondrion may contain multiple copies of its DNA
Dot 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:
Dot Psychomotor delay – a delayed development of intellect and motor ability
Dot Dystonia – uncontrollable muscle contractions causing repetitive twisting movements
Dot Epilepsy - The condition of having severe, recurrent seizures
Dot External ophthalmoplegia

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


Muscular:
Dot Muscle hypotonia – low muscle tone, and an overall reduced muscle mass

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

Physical Appearance:
Dot Kyphosis- the appearance of a hunchback
Dot Scoliosis – a spine that curves side to side in a person


Testing


Lab Testing:
Dot Body Fluids:

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

Dot Muscle Biopsy:
Dot Brain Scans:

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

 

MRI NormalMRI abnormal basal ganglia


(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

Autosomal recessive

 

Biological Basis of the Disease

Dot Most commonly, the cause is a mutation to SUCLA2 gene on chromosome 13
Dot SUCLA2 is responsible for making an enzyme that is involved in the initial breakdown of food molecules once they enter the mitochondria
Dot A mutation makes faulty enzymes that don’t allow proper energy production
Dot SUCLA2 is also responsible for regular maintenance and repair of mtDNA in the mitochondria
Dot 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.
Dot Physical therapy and occupational therapy to improve mobility and comfort
Dot Bracing or surgery for kyphosis and scoliosis
Dot 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.

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Last Updated October 22, 2010 | © 2007, LHSC, London Ontario Canada