Although some affected individuals present with a classic syndrome, many have some, but not all, of the features of one or more of the recognized phenotypes. POLG-related disorders can therefore be considered as an overlapping spectrum of disease presenting from early childhood to late adulthood. The age of onset broadly correlates with the clinical phenotype.
Alpers-Huttenlocher Syndrome (AHS)
AHS, one of the most severe phenotypic manifestations in the spectrum of POLG-related disorders, is characterized by a progressive and ultimately severe encephalopathy with intractable epilepsy, neuropathy, and hepatic failure. While AHS is usually fatal, the age of onset, rate of neurologic degeneration, presence of hepatic failure, and age of death vary [Davidzon et al 2006, Nguyen et al 2006, Wong et al 2008, Cohen & Naviaux 2010, Saneto et al 2013].
Children with AHS appear healthy at birth and may develop normally over the first few weeks to years of life. Some have variable degrees of developmental delay prior to the initial recognition of neurodegeneration. Onset is usually between ages two and four years, but ranges from one month to 36 years.
Seizures are the first sign of AHS in about 50% of affected children. Seizures may be simple focal, primary generalized, or myoclonic. The most common early seizure types are partial seizures and secondary generalized tonic-clonic seizures. In some children the first seizure presents with status epilepticus. EEG findings include high-amplitude slow activity with smaller polyspikes or intermittent continuous spike-wave activity [Wörle et al 1998].
In some instances the first seizure type is epilepsia partialis continua (EPC), a classic seizure type in which the motor seizure involves only one portion of the body (e.g., a limb) with a constant and repetitive myoclonic jerking, continuing for hours or days with or without dramatic effects on consciousness. EPC is not always apparent as an abnormality on EEG and can be mistaken for a conversion reaction. EEG may be normal or show only focal slowing of the background rhythm.
Over time the seizures can evolve into a complex epileptic disorder such as focal status epilepticus, epilepsia partialis continua, or multifocal myoclonic epilepsy [Horvath et al 2006, Tzoulis et al 2006].
In some children the seizures are initially controllable with usual dosages of anticonvulsants; in others the seizures, such as EPC, are refractory from the onset. Over time the seizures become increasingly resistant to anticonvulsant therapy. See Treatment of Manifestations for further information about management of seizures. Of note, valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) can precipitate the liver dysfunction in AHS and should be avoided [Saneto et al 2010].
Headaches, another common first presenting symptom, are typically associated with visual sensations or visual auras that reflect early occipital lobe dysfunction [Hakonen et al 2005, Tzoulis et al 2006]. Stroke and stroke-like episodes may occur in this disorder as well [Horvath et al 2006].
Movement disorders, primarily myoclonus and choreoathetosis, are common [Horvath et al 2006]. Myoclonus can be difficult to distinguish from myoclonic seizures and EPC. Palatal myoclonus resulting from involvement of the inferior olivary nuclei can be seen as well. Some develop parkinsonism, which may temporarily respond to levodopa [Luoma et al 2004, Mancuso et al 2004].
Neuropathy and ataxia develop in all persons with AHS unless the disease process is so rapid that it results in early death. All neurologic signs and symptoms, including ataxia and nystagmus, may worsen during infections or with other physiologic stressors.
Areflexia (resulting from neuropathy) and hypotonia (possibly the result of generalized weakness as part of systemic illness or pyramidal or extrapyramidal dysfunction) are often both present early in the disease course.
Episodic psychomotor regression is variably present at the time of initial consideration of the diagnosis. The major motor manifestation is a progressive spastic paraparesis resulting from progressive loss of cortical neuronal function. Progressive spasticity occurs universally; has variable onset, and evolves over months to years.
Loss of cognitive function occurs throughout the course of the disease, but the time of onset and rate of progression are variable. Significant sudden or rapid regression is often seen during infectious illnesses. The clinical manifestations may include somnolence, loss of concentration, loss of language skills (both receptive and expressive), irritability with loss of normal emotional responses, and memory deficits. In addition to the dementia caused by loss of brain tissue and the refractory seizures, the high dosages of medication used to treat those seizures can lead to significant cognitive impairment. The degree of dementia is often difficult to assess because of the frequent seizures and high therapeutic doses of anticonvulsants, which can cloud the sensorium.
Cortical visual loss leading to blindness may appear months to years after the onset of other neurologic manifestations. Retinopathy (retinitis pigmentosa) may also play a less important role in vision loss [Hakonen et al 2005]. Hearing loss is variable [Hakonen et al 2005, Horvath et al 2006].
Liver involvement can progress rapidly to end-stage liver failure within a few months, although this is highly variable. End-stage liver disease is often heralded by hypoalbuminemia and prolonged coagulation time, followed shortly thereafter by fasting hypoglycemia and hyperammonemia. Rapid onset of liver failure is described when valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) have been used to treat seizures, although the introduction of other anticonvulsants, including phenytoin, may also play a role in onset of hepatic failure. Longer survival in AHS through improved care for those with profound dementia and motor dysfunction results in the occurrence of late-onset hepatic involvement in a higher percentage of children with AHS now than previously noted.
Disease progression is variable in timing and rapidity. Loss of neurologic function culminates in dementia, spastic quadriparesis from corticospinal tract involvement, visual loss, and death. The rate of neurodegeneration varies and is marked by periods of stability. The typical life expectancy from onset of first symptoms ranges from three months to 12 years.
Neuroimaging. CT or MRI of the brain may be normal early in the course of AHS. As the illness evolves neuroimaging shows gliosis (initially more pronounced in the occipital lobe regions) and generalized brain atrophy.
FLAIR and T2-weighted sequence images demonstrate high signal intensity in deep gray matter nuclei, especially in the thalamus and cerebellum [Smith et al 1996]. Lesions described in the inferior olivary nuclei may also be a part of AHS and are associated with palatal myoclonus.
Pathophysiology. Depletion of mtDNA develops in clinically affected tissues causing a mitochondrial oxidative-phosphorylation defect resulting in the clinical findings of AHS.
Brain. The gross appearance of the brain varies from normal to severe atrophy, depending on the state of disease progression. The central nervous system regions affected in AHS are the same as those affected by Leigh syndrome but typically evolve in the reverse order. For example, in AHS the gliosis is most severe and occurs earliest in the cerebral cortex, followed by the cerebellum, basal ganglia, and brain stem. Involved regions demonstrate neuronal degeneration, characteristic spongiform or microcystic degeneration, and – as seen in Leigh syndrome – gliosis, necrosis, and capillary proliferation. The cortical ribbon shows patchy lesions, but the calcarine cortex, which is characteristically involved early in the course of the disease, is usually narrowed, granular, and discolored.
Microscopic abnormalities, present throughout the cerebral cortex, evolve as the disease progresses. Early in the course of the disease spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later the deeper laminae are affected. In the most advanced stage the entire cortex becomes a thin dense gliotic scar. Usually the striate cortex is the most affected part of the brain followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure.
Liver. Liver histology may demonstrate macro- and microvesicular steatosis, centrilobular necrosis, disorganization of the normal lobular architecture, hepatocyte loss with or without bridging fibrosis or cirrhosis, regenerative nodules, bile duct proliferation, or mitochondrial proliferation with a vivid eosinophilic cytoplasm (oncocytic change). Florid cirrhosis occurs late in the disease. This pathology differs from that seen in chemically induced or toxic hepatopathies.