mtDNA

Pearson Marrow-Pancreas Syndrome

Clinical Characteristics
Ocular Features: 

Although systemic disease is usually evident during infancy, ocular symptoms such as ptosis and ophthalmoplegia may not be apparent until adulthood in those that survive.  The ocular myopathy in adults can resemble Kearns-Sayre syndrome (530000) as the result of a phenotypic shift from a predominantly hematopoietic disorder to a mitochondrial myopathy.  Bilateral zonular cataracts and strabismus have been reported in a 3 year old male.  A midperiphery pigmentary retinopathy has been observed.  Endothelial cell failure leads to corneal edema. 

Systemic Features: 

Low birth weight, failure to thrive, hypoplastic anemia and exocrine pancreatic dysfunction are often seen in infancy.  Precursor cells in the marrow show typical vacuolization. Malabsorption and insulin-dependent diabetes often develop.  The pancreas and bone marrow may become fibrotic.  Patients with the classic syndrome as a child can develop features of the Kearns-Sayre syndrome if they survive childhood.  Progressive muscle weakness in pharyngeal, facial, neck, and limb muscles is sometimes seen in older individuals and muscle biopsy reveals ragged-red fibers characteristic of mitochondrial disease.  Some patients have an organic aciduria and others develop hepatic failure with elevated transaminase, bilirubin and lipid levels.  Kidney damage results in Fanconi syndrome.  Young children may recover from the refractory anemia eventually but metabolic acidosis with life-threatening lactic acidosis is a constant threat and responsible for many childhood deaths.

Genetics

Deletions in mtDNA involving numerous genes are responsible for this condition.  As a result, it is maternally transmitted but somewhat inconsistently due to mitochondrial heteroplasmy.  Both sexes are affected.  The irregular size of the mtDNA deletions and the tissue distribution of affected mitochondria results in considerable variation in clinical expression.  Defective oxidative phosphorylation seems to be the underlying cause of many of the signs and symptoms.

Treatment
Treatment Options: 

This multisystem disease requires careful monitoring throughout life.  Blood transfusions may be required and careful attention needs to be given to nutrition and metabolic dysfunction.  A few patients have required insulin.  In spite of vigorous treatment of electrolyte imbalances, correction of acidosis, and hormonal supplements, many patients do not survive beyond childhood.  Organ failure requires individualized treatment.

References
Article Title: 

Pearson Syndrome

Farruggia P, Di Marco F, Dufour C. Pearson Syndrome. Expert Rev Hematol. 2018 Jan 16. doi: 10.1080/17474086.2018.1426454. [Epub ahead of print].

PubMed ID: 
29337599

Leber Optic Atrophy

Clinical Characteristics
Ocular Features: 

The hereditary optic atrophy of Leber usually begins during early midlife (approximately 30 years of age) and affects 4 times as many males as females.  The first symptom is usually a sudden onset of unilateral painless blurry vision, followed within two months by the same symptoms in the other eye.  In a minority of patients, vision deteriorates more slowly over several years.  Vision loss can be severe, often in the count fingers range, sometimes to no light perception.  However, not all patients have such extreme vision loss.  It is not uncommon, moreover, for some recovery of vision to occur, even months to years later. Visual field testing reveals a central or cecocentral scotoma and color vision defects.  In the acute phase the disc can be swollen and hyperemic.  The peripapillary nerve fiber layer becomes edematous while vessels on the nerve head and nearby retina appear tortuous and increased in number.  Shortly thereafter the optic disc becomes pale and visual evoked potentials confirm dysfunction of the optic nerve.

A small number of patients have an onset in childhood.

Systemic Features: 

A large number of associated neurologic abnormalities have been reported including ataxia, hyperreflexia, nonspecific myopathy, tremors, movement disorders, dystonia, and a peripheral neuropathy.  Cardiac conduction defects are present in some patients.  Some females have a multiple sclerosis-like neurologic illness.

Genetics

This disorder results from mutations in mitochondrial genes.  Mitochondrial DNA has 16,500 basepairs and codes for 37 genes, many of which are involved in oxidative phosphorylation.  For example, mutations in those that encode subunits of NADH dehydrogenase, MT-ND1, MT-ND2, MT-ND4, MT-ND5, and MT-ND6, are known to be responsible for LHON but at least 18 allelic variants are suspected to be causative. 

Changes in basepairs located at base pairs 3460, 11778, and 14484 account for more than 90% of cases.  In general, there is little clinical difference in the disease resulting from these mutations.  The vision loss seems to be least among patients with mutations at bp 14484 and over 50% of patients recover some vision up to a year later.  Those with mutations m.3460G>A and m.14484T>C are more likely to have some vision recovery.  Mutations at bp 11778 tends to cause the most severe loss, especially in females.

The disorder is always inherited from the maternal side (males do not contribute mitochondria via their sperm).  Many cases seem to arise de novo but in a majority of families there is a history of a similar disease among maternal relatives.

Treatment
Treatment Options: 

No effective therapy is available at this time.

References
Article Title: 

Hereditary optic neuropathies share a common mitochondrial coupling defect

Chevrollier A, Guillet V, Loiseau D, Gueguen N, de Crescenzo MA, Verny C, Ferre M, Dollfus H, Odent S, Milea D, Goizet C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P. Hereditary optic neuropathies share a common mitochondrial coupling defect. Ann Neurol. 2008 Jun;63(6):794-8.

PubMed ID: 
18496845

External Ophthalmoplegia, POLG and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Progressive external ophthalmoplegia of these types is often associated with widespread neurological and muscle manifestations.  The ophthalmoplegia is adult in onset and frequently combined with exercise intolerance.  Significant lens opacities may be seen in early childhood but may not cause vision problems until early adulthood. Progressive ptosis is often an early and disabling sign.

Systemic Features: 

Facial muscles can be weak, generally in older individuals.  Some patients complain of dysphagia.  Sensoirneural hearing loss, dysarthria, and dysphonia are often associated.  Neurological symptoms include ataxia, sensory neuropathy, tremors, depression and symptoms of parkinsonism but these are variable.   Some patients experience rhabdomyolysis following alcohol consumption.  Dilated cardiomyopathy can be a part of the autosomal recessive form of this disease.

A possible subcategory of this disease is associated with hypogonadism evidenced by delayed sexual maturation, primary amenorrhea, early menopause and testicular atrophy.  Other features as described above may be associated.  Muscle biopsy shows ragged-red fibers with multiple mitochondrial deletions.

Genetics

Progressive external ophthalmoplegia of the type described here is the result of mutations in the autosomal gene POLG combined with deletions in mitochondrial DNA.  POLG mutations account for 13-45% of patients with progressive external ophthalmoplegia who also have mitochondrial deletions.  The inheritance pattern in some families resembles the classical autosomal dominant pattern (PEOA1, 157640) whereas in others the pattern suggests autosomal recessive transmission (PEOB, 258450).  The autosomal defect is in the POLG gene at locus 15q25 which codes for the nuclear-encoded DNA polymerase-gamma gene.  The phenotype in the recessive disease tends to be more severe than in autosomal dominant cases. 

Other autosomal mutations with a less complex clinical picture associated with ophthalmoplegia are located in genes ANT1 (SLC25A4) (609283) at 4q35, and C10ORF2 (606075) at 10q24.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for the general disorder but consideration should be given to ptosis repair.

References
Article Title: 
Subscribe to RSS - mtDNA