dysphonia

External Ophthalmoplegia, Progressive, with mtDNA Deletions, AR 4

Clinical Characteristics
Ocular Features: 

Patients have adult onset (6th to 7th decade of life) and progressive ptosis and external ophthalmoplegia of variable severity.

Systemic Features: 

There is a great deal of clinical heterogeneity in this condition.  Some patients have adult onset proximal and limb girdle progressive muscle weakness.  Other individuals complain of exercise-induced muscle pain and increased weakness.  Dysphagia and dysphagia may be present.  More widespread signs such as peripheral neuropathy, hearing impairment, cortical atrophy, and liver disease are variably present.  

Genetics

Compound heterozygous mutations in the DGUOK (deoxyguanosine kinase) gene (2p13) have been identified in this disorder.  Multiple deletions in the mitochondrial DNA of skeletal muscle have been found as well.    

Biallelic mutations in the DGUOK gene also cause more widespread disease as evidenced in the mitochondrial DNA depletion syndrome MTDPS3 (251880). 

A similar condition, External Ophthalmoplegia, Progressive, with mtDNA Deletions, AR 3, (617069) is caused by mutations in the TK2 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Ptosis surgery may be of benefit.

References
Article Title: 

Oculopharyngeal Muscular Dystrophy

Clinical Characteristics
Ocular Features: 

Progressive ptosis is the cardinal ocular feature of this syndrome (present in at least 88% of patients).  External ophthalmoparesis of some degree is often present with weakness of upgaze most common.

Systemic Features: 

This is a late onset form of progressive muscular dystrophy with onset of symptoms during midlife (mean age of onset ~48 years).  Evidence of pharyngeal muscle weakness often occurs concomitantly with the ocular signs (43%).  Ptosis occurs first in 43% and dysphagia first in 14%.    Dysarthria and dysphagia are often associated with facial muscle weakness.  Swallowing times for ice cold water and dry food is usually prolonged.  Evidence of weakness and wasting of neck and limb muscles is usually noted later.  Life expectancy is normal in contrast to some other forms of muscular dystrophy.  Some patients have significant gait problems and generalized disability as a result of muscle weakness.

Microscopic studies of muscle biopsies usually show evidence of myopathy with abnormal fibers and accumulations of sarcoplasmic matter.  Intranuclear inclusions consisting of tubular filaments and mitochondrial abnormalities have also been described.  Serum CK can be significantly elevated in severe cases.  

Genetics

This is an autosomal dominant disorder resulting from mutations in the PABPN1 gene located at 14q11.2-q13. Several patients with homozygous and compound heterozygous mutations have also been reported.  The PABPN1 gene product is normally a facilitator of polyadenylation of mRNA molecules and may also be active in regulating mRNA production.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Blepharoplasty may be helpful in cases with severe ptosis.  Cricopharyngeal myotomy for dysphagia and recurrent pneumonia can alleviate symptoms in severe cases although recurrence has been noted after many years.

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: 
Subscribe to RSS - dysphonia