Progressive neuronal degeneration of childhood with liver disease (Alpers' disease) presenting in young adults.

Abstract

Two unrelated and previously healthy girls, aged 17 and 18, presented with a subacute encephalopathy, visual and sensory symptoms and signs, and prominent seizures that were difficult to control. Brain MRI showed lesions (high signal on T2 weighted images) in the occipital lobes and thalamus; EEG showed slow wave activity with superimposed polyspikes. Inexorable downhill progression led to death in hepatic failure within eight months of onset. Histopathological findings in both patients ((a) chronic hepatitis with prominent bile duct proliferation, fatty change, and fibrosis; (b) This young woman, who was entirely normal until 18 years of age, suddenly saw flashing lights and had impaired vision in both upper visual fields. The teichopsia resolved after three days but blurred vision persisted and she complained of headache. Next day she had a generalised seizure: examination showed pendular nystagmus and left homonymous hemianopia, but no other abnormal findings. Routine haematological and biochemical investigations including liver function tests, brain CT, carotid angiography and CSF examination were normal. An EEG showed almost continuous polymorphic slow waves (2/s) and polyspikes over the posterior part of the hemisphere (fig 1). She was treated with carbamazepine; her alanine aminotransferase was marginally increased on this, but bilirubin and alkaline phosphatase were normal. She then started to have frequent focal seizures, with clonic jerking of the left arm and deviation of the eyes to the left. Positive visual symptoms recurred. The EEG had deteriorated with polyspike and slow wave activity now over the left hemisphere, although the right sided predominance of the abnormality persisted. Repeat CT showed an ill defined low density lesion in the right occipital lobe, mainly involving white matter. Brain MRI showed increased signal in the medial temporal and occipital lobes on the right on T2 weighted images. She then developed multifocal myoclonus and a left lateral gaze palsy. Three weeks after admission she had five generalised seizures, and one week later continuous left sided jerking with confusion and drowsiness. There was cervical lymphadenopathy. She developed a left hemiparesis; plantar responses were extensor. A further CT was normal, but MRI showed bilateral areas of high signal in the occipital lobes and thalamus (fig 2). Pattern visual evoked potentials were of normal latency, but asymmetric, with smaller responses over the right hemisphere. Sensory nerve action potentials were reduced in amplitude. She was treated with intravenous acyclovir. Routine blood investigations and repeat CSF examination remained normal; blood and CSF viral titres were normal. Her seizures did not respond to intravenous phenytoin or chlormethiazole, but were partly suppressed by phenobarbitone and carbamazepine.She made a partial recovery, with resolution of her field defect to a left lower 320 on 11 May 2018 by guest. Protected by copyright.

Cerebral folate deficiency and CNS inflammatory markers in Alpers disease

“…Epileptic status is often the terminating event. The use of valproic acid as an anticonvulsant drug has repeatedly led to a terminal hepatic failure and should be avoided [13].…”

POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion

“…The mitochondrial respiratory chain abnormalities in the liver of patients with Alpers' syndrome were confirmed in 2001. 7 Children with Alpers' syndrome are normal at birth and develop normally over the first few weeks to years of life but develop the signs and symptoms of the disease incrementally between the ages of 1 month and 25 years 8,9 of age and then die with a degenerative, episodic course of stasis, or brief periods of improvement, punctuated by progression over 3 months to 12 years. The clinical tetrad that is often diagnostic is (1) refractory seizures, (2) episodic psychomotor regression, (3) cortical blindness, and (4) liver disease with micronodular cirrhosis.…”

Disease Mutations in the Human Mitochondrial DNA Polymerase Thumb Subdomain Impart Severe Defects in Mitochondrial DNA Replication

“…These diseases generally manifest during the first few weeks to years of life, and symptoms gradually develop in a stepwise manner eventually leading to death. Alpers syndrome is characterized by refractory seizures, psychomotor regression, and hepatic failure (11,12). Mutation of POLG was first linked to Alpers syndrome in 2004 (13), and to date 45 different point mutations in POLG (18 localized to the polymerase domain) are associated with Alpers syndrome (9,14,15).…”