POLG-related disorders, or polymerase gamma-related disorders, describes a spectrum of genetic mitochondrial disorders with overlapping phenotypes.
POLG-related disorders are very rare, with the most common sub-type having an incidence of approximately one in 50,000 people 1.
The clinical presentation and onset of symptoms is very varied and largely depends on the phenotype that is expressed, which are summarised below. It should be noted that despite being divided into different phenotypes, there is a significant amount of overlap between them 2,3. A family history of mitochondrial disorders is often not noted 2,3.
Also known as Alpers-Huttenlocher syndrome (AHS) and previously as progressive cerebral poliodystrophy, this is the most well-studied POLG-related disorder 2-6. It describes a childhood-onset progressive and severe encephalopathy with patients presenting with the classic triad of 2-5:
- psychomotor regression 2-5
- intractable seizures: partial (including epilepsia partialis continua) or generalised (including both convulsive and non-convulsive status epilepticus), often myoclonus and visual phenomena are described 2-5
- liver failure: generally precedes neurological features 2-5
A childhood-onset form also exists, known as ‘childhood myocerebrohepatopathy spectrum (MCHS)’, which shares the same clinical presentation 2,3. In some patients Alpers syndrome may exist without liver failure, and the term ‘Alpers-like encephalopathy’ is used in these cases 2,3.
Ataxia neuropathy spectrum (ANS)
Characterised by sensory or cerebellar ataxia and peripheral sensory neuropathy, although approximately two-thirds also develop epilepsy, often myoclonic, and half also develop ophthalmoplegia 2,3,5.
Progressive external ophthalmoplegia (PEO)
PEO is characterised by progressive weakness of the extraocular muscles causing ophthalmoparesis and ptosis 2,3,5. It has autosomal dominant and autosomal recessive forms, each with distinct clinical presentations:
- autosomal dominant (adPEO): PEO with systemic involvement such as generalised myopathy, sensorineural hearing loss, Parkinsonism, ataxia, neuropathy, ovarian failure, and psychiatric symptoms 2,3,5
- autosomal recessive (arPEO): PEO generally without systemic involvement 2,3,5
Myoclonic epilepsy myopathy sensory ataxia (MEMSA)
As its name described, MEMSA is characterised by myoclonic epilepsy, myopathy, and ataxia. Of note, and unlike autosomal dominant PEO, these patients have no ophthalmoplegia 2,3,5.
Mitochondria contain their own DNA (mtDNA) and their replication and repair is mediated primarily by DNA polymerase γ 2,3,7. DNA polymerase γ replicates this mtDNA continuously and independent of cell division, but does need a catalytic accessory sub-unit in order to function properly 2,3,7.
The polymerase gamma (POLG) gene (POLG1) is located on the long arm of chromosome 15 and encodes for DNA polymerase γ, while the POLG2 gene, located on the long arm of chromosome 17, encodes for its catalytic accessory sub-unit 2,3,7. Damage to either of these genes result in uncontrolled mtDNA defects which result in a very varied clinical phenotype that changes across a patient’s lifespan 2,3,7.
Generally, mutations to POLG2 only result in autosomal dominant PEO, while mutations to POLG1 result in any other POLG-related disorder, all of which are inherited in an autosomal recessive pattern 2,3,7.
Radiographic features of POLG-related disorders are not well-described beyond case series-level evidence whereby neuroimaging features of POLG-related disorders featuring epilepsy, such as Alpers syndrome, are most commonly described 8-13.
Findings are often subtle and include low densities in the cortex and white matter, especially in the occipital lobes, and cerebral atrophy 11.
Features described include:
- regions of increased signal intensity on T2-weighted sequences and DWI, most often in the occipital lobes and thalami, involving both the cortex and deep gray matter 8,9,12
- these regions often correspond to areas of pathological electroencephalogram (EEG) activity and may even be absent if no recent seizure activity has occurred 8,9,12
- generalised cerebral atrophy, although may have an occipital preponderance 8-13
- prior to development of POLG-related neurological manifestations, features of chronic hepatic encephalopathy, such as increased signal intensity on T1-weighted sequences in the globi pallidi and subthalamic regions, or acute hepatic encephalopathy may be seen 10
- these features may be detected in prenatal MRI 9
MR spectroscopy may demonstrate an elevated lactate signal intensity and a reduced NAA signal intensity, in areas of high diffusion signal 10.
Treatment and prognosis
Treatment is complex and non-curative, with focuses on family education, genetic counselling, symptom management, and supportive care 4. Sodium valproate as an agent for epilepsy control is generally avoided due to its hepatotoxicity which may result in rapid decline in liver function in patients with a predisposition to liver failure, such as those with Alpers syndrome 8,11.
Prognosis depends on the specific POLG-related disorder present and the degree of epilepsy control and multi-organ dysfunction, but is generally poor 4,8.
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