mitochondria

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

External Ophthalmoplegia, C10ORF2 and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Ptosis and external ophthalmoplegia are found in almost all patients.  These have a variable onset with some patients not symptomatic until midlife or later.  External ophthalmoplegia may be the only symptom.  Onset in late adolescence has also been reported.  Cataracts often occur.

Systemic Features: 

About half (52%) of patients have fatigue and weakness.  Ataxia and peripheral neuropathy with paresthesias are sometimes present. Some patients report bulbar symptoms of dysphagia, dysarthria and dysphonia.  Skeletal muscle biopsies show typical ragged red fibers and evidence of mitochondrial dysfunction with cytochrome c oxidase (COX) deficiency.  Late onset of typical features of parkinsonism including a resting tremor, rigidity, and bradykinesia is seen in some patients.  Several individuals have reported major depression and/or bipolar disorder. Myopathy (33%) with muscle wasting and respiratory difficulties can occur.   As many as 24% of patients have cardiac abnormalities consisting primarily of conduction defects.

Genetics

This an autosomal dominant disorder secondary to mutations in the C10ORF2 (Twinkle) gene (10q24) in association with mitochondrial DNA depletion.  It accounts for approximately 35% of autosomal dominant cases of external ophthalmoplegia.

At least two additional mutations cause similar external ophthalmoplegia syndromes: PEOA1 (157640, 258450), and PEOA2 (609283).

The same gene may have mutations that are responsible for spinocerebellar ataxia, infantile-onset (271245), a more generalized and progressive neurodegenerative disease transmitted in an autosomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

The clinical, histochemical, and molecular spectrum of PEO1(Twinkle)-linked adPEO

Fratter C, Gorman GS, Stewart JD, Buddles M, Smith C, Evans J, Seller A, Poulton J, Roberts M, Hanna MG, Rahman S, Omer SE, Klopstock T, Schoser B, Kornblum C, Czermin B, Lecky B, Blakely EL, Craig K, Chinnery PF, Turnbull DM, Horvath R, Taylor RW. The clinical, histochemical, and molecular spectrum of PEO1(Twinkle)-linked adPEO. Neurology. 2010 May 18;74(20):1619-26.

PubMed ID: 
20479361

External Ophthalmoplegia, ANT1 and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Ptosis and progressive external ophthalmoplegia are the outstanding features of this form of external ophthalmoplegia.  These symptoms may appear in early adulthood.  A few patients have had thyroid disease as well.  Muscle biopsies from limb muscles show the characteristic ragged red appearance of myopathy in a minority of fibers.  Multiple deletions occur in the mitochondria of skeletal muscles.  EMG studies show myopathy while nerve conduction studies are normal.  Respiratory chain analysis often shows evidence of mitochondrial dysfunction.

Systemic Features: 

Adult patients with SLC25A4 (4q35.1) and mtDNA (ANT1) mutations have exercise intolerance and sometimes skeletal muscle weakness.  They are less likely to have symptoms of parkinsonism or peripheral neuropathy than those with mutations in POLG.  Hearing loss is minimal.

Genetics

This autosomal dominant disorder results from the combination of a mutation in the ANT1 (SLC25A4) gene (4q35) (encoding the adenine nucleotide translocator-1) and mitochondrial DNA deletions.  About 11% of autosomal dominant cases with progressive external ophthalmoplegia have mutations in this gene.  Most reported families have been from Italy.

External ophthalmoplegia may also result from mutations in POLG (most common), and in C10ORF2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

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: 
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