Friedreich’s ataxia is a severely debilitating neuromuscular disease that causes severe morbidity and mortality in affected patients. The condition is characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, decreased vibration sense, muscular weakness in the legs, and vision loss. There are also non-neurological signs, including hypertrophic cardiomyopathy and diabetes mellitus. Nearly all patients become paraplegic and eventually require wheelchairs.
The prevalence of Friedreich’s ataxia is highest in Western Europe, with more than one case per 30,000 individuals. In the United States the prevalence is about one case per 50,000 individuals. Typical disease onset occurs during puberty; however, both early-onset and late-onset variants exist. Median age of death is 35. More than 95 percent of patients are homozygous for a large expansion (60 - 2,000) of a guanine-adenine-adenine (GAA) trinucleotide-repeat sequence located within the first intron of the gene for frataxin on chromosome 9q13. The mutation causes a defect in transcription of the frataxin protein, a 210-aminio acid protein found in the mitochondria.
There are no approved therapies for Friedreich’s ataxia.
Leigh syndrome is a fatal early-onset progressive neurodegenerative disorder exhibiting considerable variability in clinical signs, symptoms, onset time, and disease course. Dr. Denis Leigh first described Leigh syndrome in 1951, as “subacute necrotizing encephalomyopathy.”
The disease occurs in ~1:30,000 live births in the US and Europe. Characteristic neuropathologic features of Leigh syndrome consist of spongiform necrosis, myelin degeneration, vascular proliferation, and gliosis in one or more areas of the central nervous system, including thalamus, basal ganglia, brainstem, and spinal cord. The clinical features include psychomotor retardation, lactic acidemia, abnormal respiration, nystagmus, ophthalmoparesis, ataxia, dystonia, and optic atrophy.
The typical disease progression of Leigh syndrome results in patient death by respiratory failure by age five. Leigh syndrome is a mitochondrial disease that can be maternally inherited due to mutations in the mitochondrial DNA (mtDNA) genes; sex-linked due to pyruvate dehydrogenase deficiency; or autosomal recessive due to mutations in nuclear encoded respiratory chain complex subunits or complex assembly genes.
There are currently no approved therapies for Leigh syndrome and treatment is supportive.
Rett syndrome is a severe neurodevelopmental disorder affecting mainly females that results in slowing of brain growth, seizures, loss of motor function, loss of speech, impaired respiratory function, as well as a characteristic hand wringing. Rett syndrome is an autism spectrum disorder and children with Rett syndrome demonstrate a number of autistic-like features including diminished eye contact. Recent studies have demonstrated that Rett syndrome is characterized by high levels of systemic oxidative stress and alterations in mitochondrial morphology.
Rett syndrome affects one in every 10,000 to 15,000 live female births. The majority of cases result from a mutation in the MeCP2 gene that is carried on the X chromosome. Rett syndrome is most commonly diagnosed between six months and 18 months of age. Children typically progress through the four stages of Rett syndrome, which are characterized by worsening neurological status and seizures. Death typically occurs prior to age 40.
There is no cure for Rett syndrome. Therapy is directed at management of disease symptoms.
Cobalamin C (Cbl-C) defect belongs to the family of diseases known as methylmalonic acidemiasand is the most common inborn error of vitamin B12 metabolism. Cbl-C defect is a syndrome that results in multi-organ system disease most significantly impacting the central nervous system. While the clinical presentation can be heterogeneous, the onset of symptoms typically arises within the first year of life and includes seizures, hypotonia, hydrocephalus, developmental delay and failure to thrive. Visual impairment results from retinal atrophy and oculomotor defects. Cardiovascular disease, hemolytic uremic syndrome and gastrointestinal involvement may also occur. A smaller subset of patients may present later in childhood or early adulthood and typically have a milder phentotype with neurological and vascular manifestations. Cbl-C defect is an autosomal recessive disorder with an estimated incidence of 1:60,000 to 1:100,000. The gene responsible for the Cbl-C defect is known as MMACHC and is located on chromosome 1p.
On a biochemical level, the Cbl-C defect prevents the conversion of vitamin B12 into its most important metabolically active forms—methylcobalamin and adenosylcobalamin. This in turn leads to the accumulation of methylmalonic acid and homocysteine as well as to the reduced synthesis of methionine. It is believed that the accumulation of methylmalonic acid and homocysteine, along with reduced synthesis of methionine, results in increased cellular oxidative stress. It also leads to perturbation in glutathione metabolism, a critical and native cellular antioxidant. In addition, the accumulation of homocysteine can lead to cardiovascular disease.
Despite existing vitamin replacement therapies, biochemical abnormalities never fully normalize and there is an unsatisfactory impact on the neurologic outcome.
Individuals with extremely rare or undiagnosed diseases often find it difficult to receive appropriate diagnoses and treatments. A subset of patients with undiagnosed diseases has clinical findings that suggest defective energy utilization or an abnormal reduction/oxidation (redox) state within cells. These abnormalities are generally attributable to mitochondrial disorders, but they could also involve cytoplasmic defects. The diseases themselves are sometimes fatal in the first decade of life.
Patients often present with significant neurological and/or muscular findings that can include growth failure, short stature, psychomotor retardation, abnormal respiration, nystagmus, ophthalmoparesis, ataxia, dystonia, optic atrophy, retinitis pigmentosa, hypotonia, myopathy, seizures, or Parkinsonism. Laboratory findings can include elevated lactate and pyruvate levels in plasma and/or cerebrospinal fluid, abnormal mitochondrial morphology on muscle, nerve, or liver biopsy, and the presence of mutations on sequencing of mitochondrial genes or nuclear genes encoding mitochondrial proteins. In addition, muscle biopsy can reveal abnormal electron transport chain enzymology, changes in mtDNA copy number, or muscle-specific coenzyme Q deficiency.
To address the problem of diagnosing extremely rare and enigmatic diseases, the National Institutes of Health Undiagnosed Diseases Program (UDP) was established in 2008. Details of the program and its accomplishments were recently reported in Genetics in Medicine (The National Institutes of Health Undiagnosed Disease Program: Insights into rare disease, 2012;13:51-59). The UDP multidisciplinary team combines sophisticated cutting-edge basic science and molecular diagnostic techniques with high-level clinical care to provide diagnoses and therapies for patients with previously undiagnosed diseases.
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a mitochondrial disorder that affects many of the body’s organ symptoms but principally affects the brain, peripheral nervous system, and muscles. The disease typically appears in childhood following a period of normal development. Initial symptoms include muscle weakness, seizures, headaches, and vision loss as well as repeated stroke-like episodes that result in progressive neurologic deterioration. MELAS may also lead to cardiac disorders including cardiomyopathy and conduction abnormalities.
MELAS is typically diagnosed between the ages of two and 10 following a seizure or stroke-like episode. MELAS is caused by mutations in mitochondrial DNA and is transmitted by maternal inheritance. The majority of patients have a defect in the tRNA-Leu(UUR)gene at base pair 3243. The reported prevalence of disease varies widely though it is thought to affect about one in 6,000 people.
There is currently no treatment for MELAS and the disease is uniformly progressive and fatal.
Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease principally affecting the retinal ganglion cells, which results in persistent bilateral blindness. LHON is the most common mitochondrial optic neuropathy with a prevalence of one in 50,000. The peak age of onset in LHON is between the ages of 15– 30 years. 95% of carriers who will experience visual failure will do so before the age of 50 years.
Typically LHON presents with sudden unilateral, followed by bilateral, blindness. With the exception of rare cases of spontaneous partial and late recovery, the resulting visual impairment is permanent. LHON results from one of three pathogenic mitochondrial DNA mutations occurring at positions 11778/ND4, 3450/ND1 or 14486/ND6 of the NADH dehydrogenase gene leading to dysfunction of complex 1 of the mitochondrial respiratory chain.
There are currently no approved therapies for LHON.
Parkinson’s disease (PD) is an adult neurodegenerative disease, which results in loss of neuromuscular coordination, cognitive function, visual impairment, alterations in behavior and mood, and other systemic manifestations. The majority of patients are diagnosed between the ages of 50 and 60. The rate of disease progression varies from patient to patient. The main pathologic characteristic of PD is cell death in the substantia nigra of the basal ganglia and the primary motor symptoms of disease reflect this pathological defect. Owing to its variable clinical manifestations and disease course, Parkinson’s disease is often referred to as Parkinson’s syndrome. A number of different genetic defects have been associated with Parkinson’s disease, though the majority of patients do not have an identifiable genetic defect.
Over 50,000 people are diagnosed with Parkinson’s disease in the United States each year, and it is estimated that over 6,000,000 people worldwide suffer from Parkinson’s disease. Parkinson’s disease is highly morbid and often fatal. According to the Centers for Disease Control it is the 14th leading cause of death in the United States.
There is no treatment for Parkinson’s disease. Current therapies are directed at specific symptoms associated with the disease.