The following are diseases requiring MRT
Alpers Disease
Long name: Progressive Infantile Poliodystrophy.
Symptoms: seizures, dementia, spasticity, blindness, liver dysfunction, and
cerebral degeneration.
Links: OMIM
Source: Dr. Rolf Luft; The development of mitochondrial medicine. [Review] ; Proceedings
of the National Academy of Sciences of the United States of America ; 1994
; 91(19) ; 8731-8
Barth
Syndrome / LIC (Lethal Infantile Cardiomyopathy)
Symptoms: skeletal myopathy, cardiomyopathy, short
stature, and neutropenia.
Cause: X-linked recessive.
Links: Barth Syndrome Family Network
Source: Dr. J. Christodoulou; Barth syndrome: clinical observations and genetic
linkage studies.; American Journal of Medical Genetics; 1994 ; 50(3) ;
255-64
Carnitine-Acyl-Carnitine Deficiency
Symptoms: Seizures, apnea, bradycardia, vomiting,
lethargy, coma, enlarged liver, limb weakness, myoglobin in the urine,
Reye-like symptoms triggered by fasting.
Cause: Autosomal recessive.
Symptoms: Cardiomyopathy, failure to thrive, and
altered consciousness or coma, sometimes hypotonia.
Cause: Autosomal recessive.
Treatment: Diet supplementation with L-Carnitine.
Links: OMIM
eMedicine
Creatine
Deficiency Syndromes
Additional names: Cerebral Creatine Deficiency
Syndromes (CCDS) Includes: Guanidinoaceteate Methyltransferase Deficiency (GAMT
Deficiency), L-Arginine:Glycine Amidinotransferase Deficiency (AGAT
Deficiency), and SLC6A8-Related Creatine Transporter Deficiency (SLC6A8
Deficiency).
Symptoms: general: mental retardation, seizures, speech delay. Additional
possible symptoms: GAMT - behavioral disorder - including autistic behaviors;
movement disorders SLC6A8 – growth retardation; (males) mild to severe mental
retardation; (females) learning and behavior problems
Cause: GAMT & AGAT - autosomal recessive; SLC6A8 - X-linked.
Links: GENEReviews
Symptoms: Encephalomyopathy, mental retardation,
exercise intolerance, ragged-red fibers, and recurrent myoglobin in the urine.
Cause: Probably autosomal recessive.
Treatment: Administration of Co-enzyme Q10
Long Name: NADH dehydrogenase (NADH-CoQ reductase)
deficiency.
Inside the mitochondrion is a group of proteins that carry electrons along four
chain reactions (Complexes I-IV), resulting in energy production. This chain is
known as the Electron Transport Chain. A fifth group (Complex V) churns out the
ATP. Together, the electron transport chain and the ATP synthase form the
respiratory chain and the whole process is known as oxidative phosphorylation
or OXPHOS.
Complex I, the first step in this chain, is the most
common site for mitochondrial abnormalities, representing as much as one third
of the respiratory chain deficiencies. Often presenting at birth or in early
childhood, Complex I deficiency is usually a progressive neuro-degenerative
disorder and is responsible for a variety of clinical symptoms, particularly in
organs and tissues that require high energy levels, such as brain, heart,
liver, and skeletal muscles. A number of specific mitochondrial disorders have
been associated with Complex I deficiency including: Leber’s hereditary optic
neuropathy (LHON), MELAS, MERRF, and Leigh Syndrome (LS).
There are three major forms of Complex I deficiency:
1. Myopathy (muscle disease) – starting in childhood
or adulthood, and characterized by weakness or exercise intolerance.
2. 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, sensory neuropathy
(nerve damage involving the sense organs), seizures, dementia, ataxia (abnormal
muscle coordination), and involuntary movements. This form of Complex I
deficiency may cause Leigh Syndrome and MELAS.
3.Fatal infantile multisystem disorder – characterized by poor muscle tone,
developmental delay, heart disease, lactic acidosis, and respiratory failure.
Most cases of Complex I deficiency result from
autosomal recessive inheritance (combination of defective nuclear genes from
both the mother and the father). Less frequently, the disorder is maternally
inherited or sporadic and the genetic defect is in the mitochondrial DNA.
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, can include such metabolic therapies as: riboflavin,
thiamine, biotin, co-enzyme Q10, carnitine, and the ketogenic diet. Therapies
for the infantile multisystem form have been unsuccessful.
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.
Cause: Autosomal.
Long Name: Succinate dehydrogenase deficiency.
Symptoms: Encephalomyopathy and various manifestations, including failure to
thrive, developmental delay, hyoptonia, lethargy, respiratory failure, ataxia,
myoclonus. Lactic acidosis common. May cause Leigh Syndrome.
Cause: Probably autosomal recessive.
Links: OMIM
Long Name: Ubiquinone-cytochrome c oxidoreductase
deficiency.
Symptoms: Four major forms:
1.
Fatal infantile
encephalomyopathy, congenital lactic acidosis, hypotonia, dystrophic posturing,
seizures, and coma. Ragged-red fibers common.
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 evolving into fixed weakness. Ragged-red fibers common. Possible
lactic acidosis.
4.
Infantile histiocytoid
cardiomyopathy.
Cause: Probably autosomal recessive.
Links: OMIM
Complex
IV Deficiency / COX Deficiency
Long Name: Cytochrome c oxidase deficiency is caused
by a defect in Complex IV of the respiratory chain.
Symptoms: Two major forms:
1.
Encephalomyopathy:
Typically normal for the first 6 to 12 months of life and then show
developmental regression, ataxia, lactic acidosis, optic atrophy,
ophthalmoplegia, nystagmus, dystonia, pyramidal signs, and respiratory
problems. Frequent seizures. May cause Leigh Syndrome
2.
Myopathy: Two main
variants:
1.
Fatal infantile
myopathy: may begin soon after birth and accompanied by hypotonia, weakness,
lactic acidosis, ragged-red fibers, respiratory failure, and kidney problems.
2.
Benign infantile
myopathy: may begin soon after birth and accompanied by hypotonia, weakness,
lactic acidosis, ragged-red fibers, respiratory problems, but (if the child
survives) followed by spontaneous improvement.
Cause: Probably autosomal recessive.
Links: OMIM
Long Name: ATP synthase deficiency
Symptoms: Slow, progressive myopathy.
Links: OMIM
Long Name: Chronic Progressive External
Ophthalmoplegia Syndrome.
Symptoms: Similar to those of KSS plus: visual myopathy, retinitis pigmentosa,
dysfunction of the central nervous system.
Cause: Single mitochondrial DNA deletions. Mitochondrial DNA point mutations:
A3243G (most common)
Source: Dr. Rolf Luft; The development of mitochondrial medicine. [Review] ; Proceedings
of the National Academy of Sciences of the United States of America ; 1994
; 91(19) ; 8731-8
Links: OMIM
Symptoms: Enlarged liver and recurrent Reye-like
episodes triggered by fasting or illnesses.
Causes: Autosomal recessive.
Treatment: Medium-chain triglycerides.
Symptoms - Myopathic: Exercise intolerance, fasting
intolerance, muscle pain, muscle stiffness, and myoglobin in the urine.
Symptoms - Infantile: Reye-like syndrome, enlarged liver, hypoglycemia,
enlarged heart, and cardiac arrhythmia.
Causes: Autosomal recessive.
Treatment - Non-Infantile: High carbohydrate, low-fat diet.
Links: CPT II deficiency newsletter
OMIM
Long name: Kearns-Sayre Syndrome.
KSS is a slowly progressive multi-system
mitochondrial disease that often begins with drooping of the eyelids (ptosis).
Other eye muscles eventually become involved, resulting in paralysis of eye
movement. Degeneration of the retina usually causes difficulty seeing in dimly
lit environments.
KSS is characterized by three main features:
·
typical onset before age
20 although may occur in infancy or adulthood
·
paralysis of specific
eye muscles (called chronic progressive external ophthalmoplegia – CPEO)
·
degeneration of the
retina causing abnormal accumulation of pigmented (colored)material (pigmentary
retinopathy).
In addition, one or more of the following conditions
is present:
·
block of electrical signals
in the heart (cardiac conduction defects)
·
elevated cerebrospinal
fluid protein
·
incoordination of
movements (ataxia).
Patients with KSS may also have such problems as
deafness, dementia, kidney dysfunction, and muscle weakness. Endocrine
abnormalities including growth retardation, short stature, or diabetes may also
be evident.
KSS is a rare disorder. It is usually caused by a
single large deletion (loss) of genetic material within the DNA of the
mitochondria (mtDNA), rather than in the DNA of the cell nucleus. These
deletions, of which there are over 150 species, typically arise spontaneously.
Less frequently, 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: Coenzyme Q10, 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 undertaken by specialists in ophthalmic
surgical centers.
Cause: The accumulation of lactic acid due to its
production exceeding its use. Chronic lactic acidosis is a common symptom of
mitochondrial disease.
Leukoencephalopathy with brain stem and spinal cord
involvement and lactate elevation (LBSL) is a result of a DARS2 gene mutation
and is characterized by slowly progressive cerebellar ataxia and spasticity
with dorsal column dysfunction (decreased position and vibration sense). The
neurologic dysfunction involves the legs more than the arms. The tendon
reflexes are retained. Deterioration of motor skills usually starts in
childhood or adolescence, but occasionally not until adulthood. Dysarthria
develops over time. Occasional findings include epilepsy; learning problems;
cognitive decline; and reduced consciousness, neurologic deterioration, and
fever following minor head trauma. Many affected individuals become wheelchair
dependent in their teens or twenties. LBSL is inherited in an autosomal
recessive manner. At conception, each sib of an affected individual has a 25%
chance of being affected, a 50% chance of being an asymptomatic carrier, and a
25% chance of being unaffected and not a carrier. Carrier testing for at-risk
family members and prenatal testing for pregnancies at increased risk are
possible if the disease-causing mutations have been identified in the family.
Long Name: Long-Chain Acyl-CoA Dehydrongenase
Deficiency.
Symptoms: Usually causes a fatal syndrome, in infants, typified by failure to
thrive, enlarged liver, enlarged heart, metabolic encephalopathy, and
hypotonia.
Cause: Autosomal recessive.
Treatment: See Beta-oxidation Defects.
Links: OMIM
Symptoms: Encephalopathy, liver dysfunction,
cardiomyopathy, and myopathy. Also pigmentary retinopathy and peripheral
neuropathy.
Cause: Autosomal recessive.
Treatment: See Beta-oxidation Defects.
Leigh
Disease or Syndrome
Long Name: Subacute Necrotizing Encephalomyelopathy.
Symptoms: Seizures, hypotonia, fatigue, nystagmus, poor reflexes, eating &
swallowing difficulties, breathing problems, poor motor function, ataxia.
Causes: Pyruvate Dehydrogenase Deficiency, Complex I Deficiency, Complex II Deficiency, Complex IV/COX Deficiency, NARP.
Leigh’s Disease is a progressive neurometabolic
disorder with a general onset in infancy or childhood, often after a viral
infection, but can also occur in teens and adults. It is characterized on MRI
by visible necrotizing (dead or dying tissue) lesions on the brain,
particularly in the midbrain and brainstem.
The child often appears normal at birth but
typically begins displaying symptoms within a few months to two years of age,
although the timing may be much earlier or later. Initial symptoms can include
the loss of basic skills such as sucking, head control, walking and talking.
These may be accompanied by other problems such as irritability, loss of
appetite, vomiting and seizures. There may be periods of sharp decline or
temporary restoration of some functions. Eventually, the child may also have
heart, kidney, vision, and breathing complications.
There is more than one defect that causes Leigh’s
Disease. According to Dr. David Thorburn, at least 26 defects have been
identified. These include a 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 dominant (defect on the X
chromosome and disease usually occurs in males only), autosomal recessive
(inherited from genes from both mother and father), and maternal (from mother only).
There may also be spontaneous cases which are not inherited at all.
One estimate of the incidence of Leigh’s disease (Leigh
Syndrome: Clinical Features and Biochemical and DNA Abnormalities by Dr.
David Thorburn, PhD of Melbourne, Australia) is one in 77,000 births or one per
40,000 births for Leigh and Leigh-like disease (a milder version of the
syndrome, often not proven by imaging or autopsy). However, this may be an
underestimate since mitochondrial diseases tend to be under-diagnosed and misdiagnosed.
There is no cure for Leigh’s Disease. Treatments
generally involve variations of vitamin and supplement therapies, often in a
“cocktail” combination, and are only partially effective. Various resource
sites include the possible usage of: thiamine, coenzyme Q10, riboflavin,
biotin, creatine, succinate, and idebenone. Experimental drugs, such as
dichloroacetate (DCA) are also being tried in some clinics. In some cases, a
special diet may be ordered and must be monitored by a dietitian knowledgeable
in metabolic disorders.
The prognosis for Leigh’s Disease is poor. Depending
on the defect, individuals typically live anywhere from a few years to the
mid-teens. Those diagnosed with Leigh-like syndrome or who did not display
symptoms until adulthood tend to live longer.
Symptoms: Hypermetabolism, with fever, heat
intolerance, profuse perspiration, polyphagia, polydipsia, ragged-red fibers,
and resting tachycardia. Exercise intolerance with mild weakness.
Cause: Unknown inheritance.MAD
/ Glutaric Aciduria Type II
Long Name: Medium-Chain Acyl-CoA Dehydrongenase
Deficiency.
Symptoms: Afflicts infants or young children with episodes of encephalopathy,
enlarged and fatty degeneration of the liver, and low carnitine in the blood.
Cause: Autosomal recessive.
Treatment: See Beta-oxidation Defects.
Links: OMIM
Long Name: Mitochondrial Encephalomyopathy Lactic
Acidosis and Strokelike Episodes.
Symptoms: Short statue, seizures, stroke-like episodes with focused
neurological deficits, recurrent headaches, cognitive regression, disease
progression, ragged-red fibers.
CauMELAS - Mitochondrial Myopathy (muscle
weakness), Encephalopathy (brain and central nervous system disease), Lactic
Acidosis (buildup of a cell waste product), and Stroke-like
Episodes (partial paralysis, partial vision loss, or other neurological
abnormalities)
MELAS is a progressive neurodegenerative disorder with typical onset between
the ages of 2 and 15, although it may occur in infancy or as late as adulthood.
Initial symptoms may include stroke-like episodes, seizures, migraine
headaches, and recurrent vomiting.
Usually, the patient appears normal during infancy, although short stature is
common. Less common are early infancy symptoms that may include developmental
delay, learning disabilities or attention-deficit disorder. Exercise
intolerance, limb weakness, hearing loss, and diabetes may also precede the
occurrence of the stroke-like episodes.
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). MELAS patients may also suffer additional symptoms
including: muscle weakness, peripheral nerve dysfunction, diabetes, hearing
loss, cardiac and kidney problems, and digestive abnormalities. Lactic acid
usually accumulates at high levels in the blood, cerebrospinal fluid, or both.
MELAS is maternally inherited due to a defect in the DNA within mitochondria.
There are at least 17 different mutations that can cause MELAS. By far the most
prevalent is the A3243G mutation, which is responsible for about 80% of the
cases. The incidence is unknown, although the epidemiological studies of the
MELAS-3243 mtDNA mutation have estimated the prevalence to be 1-16/100,000 in
the adult population.
There is no cure or specific treatment for MELAS. Although clinical trials have
not proven their efficacy, general treatments may include such metabolic
therapies as: CoQ10, creatine, phylloquinone, and other vitamins and
supplements. Drugs such as seizure medications and insulin may be required for
additional symptom management. Some patients with muscle dysfunction may
benefit from moderate supervised exercise. In select cases, other therapies
that may be prescribed include dichloroacetate (DCA) and menadione, though
these are not routinely used due to their potential for having harmful side
effects.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 due to progressive dementia
and muscle weakness, or complications from other affected organs such as heart
or kidneys.
Source: Betty Koo, et. al.; Mitochondrial encephalomyopathy, lactic acidosis,
stroke-like episodes (MELAS): clinical, radiological, pathological, and genetic
observations. ; Annals of Neurology ; 1993 ; 34(1) ; 25-32
Links: GeneClinics Publication on MELAS
eMedicine
OMIM
a3243g
mtDNA mutation specific
Click Here to download this mito profile (PDF)
Long Name: Myoclonic Epilepsy and Ragged-Red Fiber
Disease.
Symptoms: Myoclonus, epilepsy, progressive ataxia, muscle weakness and
degeneration, deafness, and dementia.
Cause: Mitochondrial DNA point mutations: A8344G, T8356C
MERRF is a progressive multi-system syndrome usually beginning in childhood,
but onset may occur in adulthood. The rate of progression varies widely. Onset
and extent of symptoms can differ among affected siblings.
The classic features of MERRF include:
·
Myoclonus (brief,
sudden, twitching muscle spasms) – the most characteristic symptom
Epileptic seizures
·
Ataxia (impaired
coordination)
·
Ragged-red fibers (a
characteristic microscopic abnormality observed in muscle biopsy of patients
with MERRF and other mitochondrial disorders) Additional symptoms may include:
hearing loss, lactic acidosis (elevated lactic acid level in the blood), short
stature, exercise intolerance, dementia, cardiac defects, eye abnormalities,
and speech impairment.
Although a few cases of MERRF are sporadic, most
cases are maternally inherited due to a mutation within the mitochondria. The
most common MERRF mutation is A8344G, which accounted for over 80% of the cases
(GeneReview article). Four other mitochondrial DNA mutations have been reported
to cause MERRF. While a mother will transmit her MERRF mutation to all of her
offspring, some may never display symptoms.
As with all mitochondrial disorders, there is no cure for MERRF. Therapies may
include coenzyme Q10, L-carnitine, and various vitamins, often in a “cocktail”
combination. Management of seizures usually requires anticonvulsant drugs.
Medications for control of other symptoms may also be necessary.
The prognosis for MERRF varies widely depending on age of onset, type and
severity of symptoms, organs involved, and other factors.
Sources: Dr. Rolf Luft; The development of mitochondrial medicine. [Review] ; Proceedings
of the National Academy of Sciences of the United States of America ; 1994
; 91(19) ; 8731-8 & DiMauro
Links: OMIM
Long Name: Mitochondrial Recessive Ataxia Syndrome
Symptoms: encephalopathy, balance problems, ataxia, epilepsy, cognitive
impairment, psychiatric symptoms, eye movement disorders, involuntary
movements, peripheral neuropathy.
Cause: POLG mutation, Recessive inheritance: Many sporadic cases.
Links: Neuromuscular
PubMed Central
Mitochondrial DNA Depletion
Symptoms: Three forms:
1.
Congenital myopathy:
Neonatal weakness, hypotonia requiring assisted ventilation, possible renal
dysfunction. Severe lactic acidosis. Prominent ragged-red fibers. Death due to
respiratory failure usually occurs prior to one year of age.
2.
Infantile myopathy:
Following normal early development until one year old, weakness appears and
worsens rapidly, causing respiratory failure and death typically within a few
years.
3.
Hepatopathy: Enlarged
liver and intractable liver failure, myopathy. Severe lactic acidosis. Death is
typical within the first year.
Cause: Probably autosomal recessive.
Links: OMIM
Mitochondrial Encephalopathy
Includes: Encephalomyopathy, Encephalomyelopathy
See Co-Enzyme Q10 Deficiency, Complex I, Complex II, Complex III, Complex IV/COX, Leigh Syndrome, LCAD, LCHAD, MCAD, MELAS, MNGIE, NARP, SCHAD, VLCAD
Long Name: Myoneurogastointestinal Disorder and
Encephalopathy.
Symptoms: Progressive external ophthalmoplegia, limb weakness, peripheral
neuropathy, digestive tract disorders, leukodystrophy, lactic acidosis, ragged
red fibers.
Links: OMIM
Long Name: Neuropathy, Ataxia, and Retinitis
Pigmentosa
Cause: Mitochondrial DNA point mutations in genes associated with Complex V:
T8993G, (also T8993C by some researchers). Leigh Syndrome may result if the percentage of
mutation is high enough.
Links: OMIM
Symptoms: Bone marrow and pancreas dysfunction.
Cause: Single mitochondrial DNA deletions. Inheritance is usually sporadic.
Those who survive infancy usually develop Kearns-Sayre Syndrome.
Links: OMIM
Pyruvate
Carboxylase Deficiency
Symptoms: Lactic acidosis, hypoglycemia, severe
retardation, failure to thrive.
Common symptoms: seizures and spasticity.
Cause: Autosomal recessive.
Links: OMIM
Pyruvate
Dehydrogenase Deficiency
Symptoms: Lactic acidosis, ataxia, pyruvic acidosis,
spinal and cerebellar degeneration.
Less common: Agenesis of the corpus callosum and lesions in the basal ganglia,
cerebelum, and brain stem.
Also: growth delay, hypotonia, seizures, and polyneuropathy. Sometimes found to
be the cause of Leigh Syndrome.
Cause: Varies.
Links: OMIM
eMedicine
