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Disease characteristics

Excerpted from the GeneReview: POLG-Related Disorders
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. These phenotypes exemplify the diversity that can result from mutations in a given gene. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from early childhood to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life up to about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, Parkinsonism, hypogonadism, and cataracts (in what has been called “chronic progressive external ophthalmoplegia plus,” or “CPEO+”).

Associated genes

    Summary: polymerase (DNA directed), gamma

Clinical features

  • Hypertonia
  • Abnormality of vision evoked potentials
  • Paralysis
  • Increased CSF protein
  • Increased serum lactate
  • Microcephaly
  • Neuronal loss in central nervous system
  • Cognitive impairment
  • Cerebral cortical neurodegeneration
  • Incoordination
  • Ethylmalonic aciduria
  • Seizure
  • Failure to thrive
  • Vomiting
  • Abnormality of the eye
  • Visual loss
  • Dementia
  • Ataxia
  • Muscular hypotonia
  • Global developmental delay
  • Cerebellar atrophy
  • Myoclonus
  • Hepatic failure
  • Bile duct proliferation
  • Micronodular cirrhosis
  • Microvesicular hepatic steatosis
  • Gliosis
  • Hepatomegaly
  • Developmental regression
  • Astrocytosis
  • Elevated hepatic transaminases
  • 3-Methylglutaconic aciduria
  • Hemiplegia/hemiparesis
  • Abnormality of movement
  • Cortical visual impairment
  • Epilepsia partialis continua
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