North American Mitochondrial Disease Consortium

Information for Patients and Families

In Detail: Mitochondrial Diseases

AID: Aminoglycoside-Induced Deafness

Hearing loss triggered by aminoglycoside drugs (e.g. gentamicin) in patients with the m.1555A>G mutation. Besides causing AID, this maternally inherited mitochondrial DNA mutation also causes spontaneous deafness called non-syndromic hearing loss (NSHL)

Alpers syndrome (Progressive Infantile Poliodystrophy)

Seizures, liver dysfunction, dementia, spasticity, blindness, and cerebral degeneration.

Barth Syndrome

Childhood X-linked disease characterized clinically by cardiomyopathy, mitochondrial myopathy, growth retardation, and leucopenia. Laboratory abnormalities include increased urinary excretion of 3-methylglutaconic acid and hypocholesterolemia. The mutated gene (G4.5 or TAZ) encodes proteins named "tafazzins," involved in the biosynthesis of cardiolipin, the most abundant phospholipid component of the inner mitochondrial membrane and directly involved in respiratory chain function.

CoQ Deficiency

Autosomal recessive conditions characterized by:

  1. Encephalomyopathy, mental retardation, exercise intolerance, ragged-red fibers, and recurrent myoglobinuria (dark brown urine).
  2. Isolated myopathy with ragged red fibers and excessive fat droplets.
  3. Infantile multisystem diseases often with brain and kidney involvement.
  4. Cerebellar ataxia (severe incoordination) and cerebellar atrophy.

CPEO (Chronic Progressive External Ophthalmoplegia)

Weakness of eye muscles causing droopy eyelids (ptosis) and inability to move the eyeballs.

Cause: Single or multiple mtDNA deletions; mtDNA point mutations (A3243G most common)

DAD: Diabetes and Deafness

Usually maternally inherited condition defined by diabetes mellitus and hearing loss.

Encephalopathy

Generic term to indicate brain dysfunction

Encephalomyopathy

A disorder affecting the brain and skeletal muscle (usually with weakness)

FBSN (Familial Bilateral Striatal Necrosis)

Inherited encephalopathy defined by symmetrical damage of deep brain structures (basal ganglia)

Hepatocerebral disease

A disease characterized by combined involvement of brain and liver (typical example is Alpers syndrome)

KSS (Kearns-Sayre Syndrome)

KSS is a progressive multi-system disease that often begins with CPEO (see above). Degeneration of the retina usually causes difficulty seeing in dark environments. Incoordination (ataxia) and abnormalities of cardiac electrical conduction are common.

Patients with KSS may also have other problems, such as deafness, dementia, kidney dysfunction, and muscle weakness. Endocrine abnormalities including growth retardation, short stature, diabetes, and deficiency of parathyroid hormone may also occur.

KSS is usually caused by a single large deletion (segmental loss) of mtDNA). These deletions, of which there are over 150 species, typically arise spontaneously. Rarely, the mutation is transmitted by the mother.

As with all mitochondrial diseases, there is no cure for KSS. Treatments are based on the types of symptoms and organs involved, and may include: CoQ10, insulin for diabetes, cardiac drugs, and a cardiac pacemaker, which may be life-saving. Surgical intervention for drooping eyelids may be considered but should be performed by specialists in ophthalmic surgical centers.

The prognosis varies depending on severity. Death is common in the third or fourth decade and may be due to organ system failures.

Leigh Syndrome

Symptoms: Psychomotor regression (loss of acquired skills), abnormal respiration, vomiting, seizures, hypotonia, nystagmus (oscillation of the eyeballs), poor reflexes, eating and swallowing difficulties, ataxia, dystonia (abnormal posturing of the limbs).

Leigh syndrome is a neurodegenerative disorder with onset usually in infancy or childhood, rarely in teens and adults. It is characterized on MRI by necrotizing (dead or dying tissue) lesions on the brain, particularly in the basal ganglia and brainstem.
There is more than one genetic defect that causes Leigh's Disease. According to Dr. David Thorburn, at least 26 defects have been identified. These include pyruvate dehydrogenase (PDHC) deficiency, and respiratory chain enzyme defects (complexes I, II, IV, and V). Depending on the defect, the mode of inheritance may be X-linked (defect on the X chromosome) usually affecting males only), autosomal recessive (one mutation from the mother and one from the father), and maternal (mtDNA mutation from mother only). There may also be spontaneous cases that are not inherited at all.

There is no cure for Leigh syndrome. Treatments generally involve cocktails of vitamins and supplements, which are only partially effective. Supplements include: thiamine, CoQ10, riboflavin, biotin, creatine, and idebenone. Experimental drugs such as dichloroacetate (DCA) are also being tried in some clinics.
The prognosis for Leigh syndrome is poor. Depending on the defect, individuals typically live a few years.

Leukoencephalopathy

Diseases associated with degeneration of the white matter of the brain (usually detected by MRI) causing cognitive impairment, increased muscle tone (spasticity) and hyperactive reflexes.

LHON: Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) presents as blindness and is often associated with a cardiac conduction abnormality known as pre-excitation syndrome or Wolff-Parkinson White syndrome. LHON is more common in men than than in women.

Cause: Mitochondrial DNA point mutations: G11778A, G3460A, and T14484C, and G14459A.

LHON-Plus: Leber Hereditary Optic Neuropathy Plus

Leber hereditary optic neuropathy Plus (LHON-Plus) presents as blindness, cardiac pre-excitation syndrome, plus additional clinical manifestations such as dystonia, ataxia, myoclonus, olivopontocerebellar degeneration, or multiple sclerosis-like syndrome due to a mitochondrial DNA mutation. Common symptoms: abnormal movements, incoordination, spasticity, and heart defects

Cause: Mitochondrial DNA point mutations: G11778A, G3460A, and T14484C, and G14459A.

MELAS (Mitochondrial Encephalopathy Lactic Acidosis with Stroke-like Episodes)

Symptoms: stroke-like episodes with focal neurological deficits, short stature, seizures, deafness, recurrent headaches, cognitive regression, diabetes, cardiopathy, gastrointestinal dysmotility, peripheral neuropathy.

Cause: Mitochondrial DNA point mutations: A3243G (most common).

MELAS is a progressive neurodegenerative disorder with typical onset between the ages of 2 and 15, although it may occur in infancy and adulthood. Initial symptoms may include stroke-like episodes, seizures, migraine headaches, and recurrent vomiting.

Stroke-like episodes, often accompanied by seizures, are the hallmark symptom of MELAS and cause partial paralysis, loss of vision, and focal neurological defects. The gradual cumulative effects of these episodes often result in variable combinations of loss of motor skills (speech, movement, and eating), impaired sensation (vision loss and loss of body sensations), and mental impairment (dementia). Lactic acid usually accumulates at high levels in the blood, cerebrospinal fluid, or both.

There is no cure or specific treatment for MELAS. Although no therapeutic trial has proven effective, general treatments may include supplements such as CoQ10, dichloroacetate (DCA), creatine, menadione, and phylloquinone. Seizure medications and insulin may be required for additional symptom management. Some patients with muscle dysfunction may benefit from moderate supervised exercise.

The prognosis for MELAS is poor. Typically, the age of death is between 10 to 35 years, although some patients may live longer. Death may come as a result of general body wasting or to complications from other affected organs, such as heart or kidneys.

MERRF (Myoclonus Epilepsy Ragged-red Fibers)

Myoclonus, epilepsy, progressive ataxia, muscle weakness, deafness, and dementia.

Cause: Mitochondrial DNA point mutations: A8344G, T8356C

MERRF is a progressive multi-system syndrome presenting in childhood or in adulthood. The rate of progression varies widely. Onset and extent of symptoms can differ among affected siblings.

The classic features of MERRF include:

MILS (Maternally Inherited Leigh Syndrome)

This is a form of Leigh syndrome due to mutations in mtDNA and therefore inherited maternally. Besides the common symptoms described above for Leigh syndrome, retinitis pigmentosa is often present and an important diagnostic clue.

MNGIE (Mitochondrial Neurogastrointestinal Encephalomyopathy)

CPEO, peripheral neuropathy, digestive tract dysfunction, leukoencephalopathy, cachexia (extreme wasting), lactic acidosis, ragged red fibers.

It is an autosomal recessive disease due to mutations in the TYMP gene encoding the enzyme thymidine phosphorylase.

Mitochondrial DNA Depletion Syndrome

These diverse genetic disorders cause two main syndromes:

  1. Myopathy, with onset usually in infancy (floppy baby syndrome) or childhood (muscular dystrophy-like presentation)

  2. Hepatocerebral syndrome, defined above as a combination of brain and liver dysfunctions.

These are autosomal recessive diseases due to mutations in genes that encode proteins providing the building blocks and the upkeep of mtDNA.

They are progressive disorders often fatal in childhood and for which no specific or effective therapy is available.

Multiple Deletions of Mitochondrial DNA

This alteration of mtDNA can be due to diverse genetic defects (at least 5 nuclear genes are known) but have similar clinical presentations, usually characterized by CPEO. Associated symptoms may include hearing loss, myopathy, ataxia, peripheral neuropathy, dysarthria, optic atrophy, dementia. parkinsonism, and psychiatric problems.

Muscle biopsy is required to detect the multiple mtDNA deletions and will also reveal ragged red fibers. Transmission is either autosomal dominant or autosomal recessive.

NARP (Neuropathy, Ataxia and Retinitis Pigmentosa Syndrome)

A neurodegenerative maternally inherited condition defined accurately by the acronym: neuropathy, ataxia, and retinitis pigmentosa. The same mutations when present in very high abundance cause MILS (see above), often within the same family. The T8993G mutation usually causes more severe symptoms than the T8993C mutation.

Pearson Syndrome

Symptoms: Bone marrow and pancreas dysfunction, causing severe anemia in infancy and digestive dysfunction due to pancreatic insufficiency. Even with blood cell transfusions, Pearson syndrome is usually lethal in infancy. Those who survive infancy usually develop Kearns-Sayre syndrome or CPEO.

Cause: Single mitochondrial DNA deletions. Cases are usually sporadic.

SANDO (Sensory Ataxia Neuropathy Dysarthria Ophthalmoplegia)

This autosomal recessive condition is one of the multiple mtDNA deletion syndromes (see above), due to mutations in the gene encoding the mtDNA polymerase (POLG). It is described by the acronym: patients develop CPEO, ataxia, peripheral neuropathy, and dysarthria (garbled speech).

Complex I Deficiency

The mitochondrion has two membranes. Embedded in the inner membrane are five protein complexes (complexes I through V), which carry electrons and produce energy in the form of ATP. This chain is known as the respiratory chain (RC).

Defects of complex I, the largest enzyme complex in the RC, are among the most common causes of mitochondrial diseases. Often presenting at birth or in early childhood, complex I deficiency usually causes progressive neuro-degenerative disorders, which are responsible for a variety of clinical symptoms, particularly in organs and tissues that require high energy levels, such as brain, heart, liver, and skeletal muscle. A number of specific mitochondrial disorders have been associated with Complex I deficiency including: Leber hereditary optic neuropathy (LHON), MELAS, and Leigh Syndrome (LS).

There are three major forms of Complex I deficiency:

  1. Fatal infantile multisystem disorder characterized by encephalopathy, poor muscle tone, developmental delay, heart disease, lactic acidosis, and respiratory failure.

  2. Myopathy (muscle disease) starting in childhood or adulthood, and characterized by weakness or exercise intolerance.

  3. Mitochondrial encephalomyopathy (brain and muscle disease) beginning in childhood or adulthood and involving variable symptom combinations which may include: eye muscle paralysis, pigmentary retinopathy (retinal color changes with loss of vision), hearing loss, neuropathy, seizures, dementia, ataxia, and involuntary movements. This form of Complex I deficiency may cause Leigh Syndrome and MELAS.

Most cases of Complex I deficiency result from autosomal recessive inheritance (one mutation from the mother and one from the father). Not infrequently, however, the disorder is maternally inherited. Sporadic and X-linked forms are very rare.
Treatment: As with all mitochondrial diseases, there is no cure for complex I deficiency. A variety of treatments, which may or may not be effective, include: riboflavin, thiamine, biotin, CoQ10, and carnitine. The clinical course and prognosis for Complex I patients is highly variable and may depend on the specific genetic defect, age of onset, organs involved, and other factors.

Complex II (SDH) Deficiency

Usually associated with Leigh syndrome (see above), including failure to thrive, developmental delay, hypotonia, lethargy, respiratory failure, ataxia, myoclonus. Lactic acidosis is common.

Transmission is autosomal recessive.

Complex III Deficiency

Four major forms of Symptoms:

  1. Fatal infantile encephalomyopathy, congenital lactic acidosis, hypotonia, dystonic posturing, seizures, and coma. Ragged-red fibers are common. Some infants present a characteristic set of symptoms and signs: growth retardation, aminoaciduria, cholestasis (block of the liver bile ducts), iron overload, lactic acidosis, and early death (GRACILE syndrome).
  2. Encephalomyopathies of later onset (childhood to adult life): various combinations of weakness, short stature, ataxia, dementia, hearing loss, sensory neuropathy, pigmentary retinopathy, and pyramidal signs. Ragged-red fibers common. Possible lactic acidosis.
  3. Myopathy, with exercise intolerance and sometimes recurrent myoglobinuria. Ragged-red fibers are usually present: notably, they stain positively for the COX reaction. Possible lactic acidosis.
  4. Infantile histiocytoid cardiomyopathy.

Transmission is generally autosomal recessive, but mutations in the cytochrome b gene are transmitted maternally or are sporadic.

Complex IV Deficiency

There are two major forms:

  1. Encephalomyopathy: These infants are typically normal for the first 6 to 12 months of life, then start showing features of Leigh syndrome, including developmental regression, ataxia, lactic acidosis, optic atrophy, ophthalmoplegia, nystagmus, dystonia, pyramidal signs, and respiratory problems.

  2. Myopathy: Two main variants:
    1. Fatal infantile myopathy: may begin soon after birth and is accompanied by hypotonia, weakness, lactic acidosis, ragged-red fibers, respiratory failure, and kidney problems.

    2. Reversible infantile myopathy: may begin soon after birth and is accompanied by hypotonia, weakness, lactic acidosis, ragged-red fibers, respiratory problems, but (if the child survives) is followed by spontaneous improvement and complete recovery.

Cause: The fatal infantile form is probably autosomal recessive. The reversible form is maternally inherited and due to a mutation in the tRNAGlu of mtDNA. The mutation is homoplasmic, i.e. it affects all copies of mtDNA.

Complex V Deficiency

Symptoms: NARP and MILS have been described above and are due to mutations in the ATPase 6 gene of mtDNA. Other mutations in ATPase 6 may cause familial bilateral striatal necrosis (FBSN, see above), which clinically manifests as a milder form of Leigh syndrome.

Mutations in nuclear genes encoding assembly factors for complex V cause severe infantile encephalomyopathies with lactic acidosis and early death.

Multiple Respiratory Chain Enzyme Deficiencies

This is not a disease, but a biochemical finding usually indicative of general mtDNA dysfunction that can be due to mtDNA depletion, multiple mtDNA deletions, or defective mtDNA translation. All these disorders are due to mutations in nuclear genes and are transmitted as autosomal recessive traits. However, multiple respiratory chain deficiencies may also accompany single mtDNA deletions (KSS, CPEO, Pearson syndrome) and mtDNA tRNA mutations (for example, MELAS, MERRF).

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