Table 4.

Disorders with Progressive External Ophthalmoplegia to Consider in the Differential Diagnosis of KSS and CPEO

GeneDisorderMOIFeatures of This Disorder Not Typically Associated with KSS or CPEO
~35 genes incl:
CHAT
CHRNE
COLQ
DOK7
RAPSN		Congenital myasthenic syndromes (See also Myasthenia Gravis after this table.)AR
AD 1
  • Primary muscle disorders
  • Do not involve cardiac muscle
  • Not multisystemic in nature
DMPK Myotonic dystrophy type 1 ADMyotonia
DNA2 DNA2-related mitochondrial DNA maintenance defectsAD
  • PEO w/variable, slowly progressive features; onset: childhood to adulthood
  • Slender build
  • Facial muscle weakness; exertional dyspnea; obstructive sleep apnea; myopathy w/weakness, atrophy, exercise intolerance, myalgia, & cramps; gait disturbance
  • ↑ CK
LRP12 Oculopharyngodistal myopathy (OMIM 164310)AD
  • Onset in early adulthood
  • Distal limb weakness
  • Frequent respiratory muscle weakness
MT-TL1 MT-TL1-related PEO; selected example: m.3243A>GMat
  • Stroke-like episodes
  • Typically large maternal family history of multiple persons w/deafness & diabetes
MYH2 MYH2-related myopathy (OMIM 605637)AR
AD
  • Childhood-onset myopathy
  • Generalized & extraocular muscle weakness
  • Minor progression (i.e., slowly progressive or nonprogressive)
  • Not multisystemic
OPA1 Optic atrophy type 1 (OMIM 165500)ADOptic atrophy w/variable other neurologic signs
PABPN1 Oculopharyngeal muscular dystrophy (OPMD)AD
  • Late onset
  • Ptosis w/mild ophthalmoparesis
  • Severe dysphagia
  • Abnormal EMG/NCV
POLG POLG-related PEO (See POLG-Related Disorders.)AD
AR
  • Highly variable phenotypes
  • adPEO presentation: generalized myopathy, sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, cataracts, premature ovarian/testicular failure
  • arPEO presentation: PEO may be initial feature; however, additional manifestations may appear years later (as for adPEO)
  • Mitochondrial DNA depletion
  • Typically adult onset
RRM2B RRM2B-related PEO (See RRM2B Mitochondrial DNA Maintenance Defects.)AD
AR
  • AR form may be multisystemic severe disorder w/marked progressive weakness due to skeletal myopathy.
  • AD form incl CPEO & variable manifestations: hearing loss, dysphagia, dysmotility, myopathy (exercise intolerance, fatigue, weakness), COX-deficient fibers & RRF on muscle biopsy, dysarthria, ataxic gait, peripheral neuropathy, & mood disorders.
SLC25A4 SLC25A4-related PEO (See Mitochondrial DNA Maintenance Defects Overview.)ADChildhood- or adult-onset PEO w/variable myopathy, cardiomyopathy, & encephalopathy
TWNK TWNK-related PEOAD
  • Adult onset (age 20-40 yrs)
  • Progressive hearing loss, cataracts, cardiomyopathy, dysphagia
  • Skeletal myopathy w/exercise intolerance, fatigue, progressive muscle weakness, myopathic EMG, & RRF & ↓ COX levels on muscle biopsy
  • DD, parkinsonism, gait difficulties, sensory ataxia
  • Cognitive decline, cerebral atrophy, peripheral neuropathy
  • Endocrinopathies (diabetes, infertility)
  • Mood disorders
TYMP Mitochondrial neurogastrointestinal encephalopathy disease AR
  • Peripheral neuropathy & GI dysmotility
  • ↓ thymidine phosphorylase & ↑ thymidine in blood

AD = autosomal dominant; AR = autosomal recessive; adPEO = autosomal dominant PEO; arPEO = autosomal recessive PEO; CPEO = chronic progressive external ophthalmoplegia; DD = developmental delay; CK = creatine kinase; COX = cytochrome-c oxidase; EMG = electromyography; GI = gastrointestinal; KSS = Kearns-Sayre syndrome; Mat = maternal; MOI = mode of inheritance; NCV = nerve conduction velocity; PEO = progressive external ophthalmoplegia; RRF = ragged red fibers

1.

Congenital myasthenic syndrome (CMS) is typically inherited in an autosomal recessive manner. Less commonly, CMS is inherited in an autosomal dominant manner.

From: Single Large-Scale Mitochondrial DNA Deletion Syndromes

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