Alpers Syndrome

Alpers syndrome, also known as mitochondrial DNA depletion syndrome-4A, is an autosomal recessive disorder characterized by a triad of psychomotor retardation, intractable epilepsy, and liver failure.

The disease is related to the following processes:  hereditary and has an incidence of about  5 / 100.000.

Presentation

Most children with Alpers syndrome appear healthy at birth and develop symptoms usually in the first few months of life. Most patients show symptoms in the first 2 years of life but some show symptoms as late as the second decade of life.

Children present with seizures in half of the cases. Seizures may be focal, generalized or myoclonic. Epilepsia partialis continua (EPC) is a specific type of motor seizures in which myoclonic jerks of a one part of a body occur for hours or even days [5]. Some children may present with status epilepticus [6].

Headaches associated with visual auras and stroke like syndromes may occur. Myoclonus and choreoathetosis may also be seen in children with Alpers syndrome. Cortical dysfunction and neuropathy leads to hypotonia and areflexia respectively. Later progressive cortical dysfunction leads to spasticity of all limbs. Developmental delays and cognitive dysfunction is present which manifests in the form of increased sleepiness, dementia and loss of concentration.

Cortical blindness (25% patients) and retinitis pigmentosa are present in Alpers syndrome. Hearing impairment is also present in some children.

Cardiomyopathy and gastrointestinal dysmotility can occur.
Liver disease may manifest initially as hypoglycemic episodes. Liver involvement progresses to end stage liver disease characterized by hypoalbuminemia, coagulopathy and hyperammonemia. Acute liver failure can be precipitated in these patients with the use of valproate [7]. Longer survival in Alpers syndrome is associated with more cases of late onset hepatic impairment.

The disease progression is variable. Neurodegeneration leads to dementia, encephalopathy, spastic quadreparesis, visual loss and death.

Workup

Imaging: CT scan and MRI brain may be normal in the early cases. In advanced neuroimaging shows atrophy and gliosis of the affected parts of the brain. FLAIR and T2 weighted images show hyperintense lesions in the cerebral cortex, basal ganglia and brainstem. Hyperintensities in the inferior olivary nuclei are associated with palatal myoclonus [8].

MR spectroscopy shows focal lactate peaks and decreased N-acetyl aspartate.

EEG may help in diagnosis if Alpers syndrome is clinically suspected. The patterns of EEG seen in are highly variable and may include high amplitude slow activity or intermittent continuous spike-wave activity. In cases of Epilepsia partialis continua (EPC), EEG may be normal or show background slow waves.

CSF proteins are raised in patients with Alpers syndrome.
POLG gene testing is nowadays used to confirm the diagnosis [9].

Formal assessment of vision, hearing and developmental milestones should be done

Liver function tests: bilirubin, alanine aminotransferase, coagulation studies, glucose and ammonia levels, ultrasound of liver to assess degree of hepatic damage.

ECG and echocardiogram to rule out cardiomyopathy should be considered.

Audiogram and brainstem auditory evoked responses to assess hearing impairment are done in selected cases.

Treatment

There is no cure for this disease and treatment is supportive. Counselling and education of the family is of paramount importance. Treatment issues should be discussed with the family to decide the quality of life and intensity of treatment factors.

Options of a gastrostomy feeding tube, noninvasive and invasive ventilation techniques are considered. Occupational, physical and speech therapy is offered to minimize neurologic disability. Gastric feeding tube can help in nutrition and prevention of aspiration.

Anticonvulsants are required for the control of seizures. Although it is preferable to use one drug to control epilepsy in such patients, it is seldom possible due to the relentless nature of seizures. Multiple anticonvulsants have the disadvantage of increased sedation and risk of aspiration pneumonia. Newer generation antiepileptics like levetiracetam, topiramate and felbamate may not be more effective than the traditional antiepileptics (valproate, phenytoin and carbamazepine) but certainly are less sedating.

Valproate should be avoided because there is a possible risk of acute liver failure with its use. Liver function tests should be monitored regularly [10].

In these patients there is a need to strike a balance between minimizing the disability caused by intractable seizures and adverse effects of anticonvulsants.

Liver failure is treated with the use of osmotic laxatives, frequent meals to prevent hypoglycemia and restriction of protein intake. Levocarnitine may be of some benefit in such patients.

Frequent consultations and reviews by neurologists, gastroenterologists, pulmonologists, psychiatrist and occupational therapists are required for these patients.

Infections, fever, hypoglycemia and dehydration can lead to rapid clinical deterioration in such patients and must be avoided and treated aggressively.

Prognosis

The life expectancy ranges from 3 months to about 10 years.
Liver transplantation in such patients does not prevent progressive neurodegeneration and death.

In a few individuals with stable disease and acceptable quality of life with hepatic cirrhosis, hepatic transplantation may be of some benefit.

Etiology

Alpers syndrome is a mitochondrial disorder caused by mutations in the POLG gene [2]. It is an autosomal recessive disorder.

Epidemiology

Alpers syndrome is a rare disease which occurs in about 1:100,000 to 1:250,000 individuals. Alpers syndrome occurs in both sexes.

Sex distribution
Age distribution

Pathophysiology

POLG is the gene that encodes the catalytic subunit of mitochondrial DNA polymerase. Mitochondrial DNA polymerase is essential for mitochondrial DNA replication and repair. Defective POLG leads to depletion of mitochondrial DNA and mitochondrial oxidative-phosphorylation defect [3]. This results in neurodegeneration, encephalopathy and liver failure.

Pathologically, brain shows atrophy and gliosis in the regions of cerebral hemispheres, cerebellum, basal ganglia and brainstem. Spongiform and microcystic degeneration occurs [4].
Microscopically, spongiosis, astrocytosis and gliosis of the affected brain tissue are visible.

Histopathology of the liver in Alpers syndrome shows steatosis and disruption of the lobular architecture, centrilobular necrosis and ultimately fibrosis and regenerative nodules in later stages.

Prevention

There are no guidelines for prevention of Alpers syndrome.

Summary

Alpers syndrome is a rare neurodevelopmental mitochondrial DNA depletion syndrome which is characterized by seizures, progressive encephalopathy and liver disease.

Alpers syndrome is also known as Alpers disease, Alpers-Huttelocher syndrome (AHS), progressive sclerosing poliodystrophy, progressive cerebral poliodystrophy, progressive infantile poliodystrophy and diffuse cerebral degeneration in infancy.

It is a progressive neurodegenerative disease that occurs in infants and children. It is an autosomal recessive disorder caused by genetic mutations in the mitochondrial DNA polymerase gene (POLG gene) [1].

Affected individuals present usually in the first year of life with intractable seizures and developmental delay. Other clinical features include hypotonias, spasticity, myoclonus, optic atrophy and deafness. The disease is diagnosed on clinical grounds and by identification of POLG mutations.

Alpers syndrome is progressive and there is no cure. Treatment is symptomatic and consists of anticonvulsants. The prognosis is poor and most children die in the first decade of life mainly due to intractable epilepsy.

Patient Information

Alpers syndrome is an uncommon disease of infants and children. It affects the brain and liver of the children. It is caused by a genetic abnormality.

Babies are healthy at birth but within a few months develop seizures (fits) and failure to achieve normal developmental milestones. Children may also develop muscle stiffness and muscle jerks. Blindness and deafness can also occur. When liver function is affected these children develop swelling of body, low blood sugar and loss of consciousness.

The disease is diagnosed by clinical features. Certain tests like MRI brain, EEG and blood tests are required for assessment of severity of disease.

There is no cure of this disease. Medicines to control seizures are used. Children with Alpers syndrome are vulnerable to develop infections and low blood glucose which is treated accordingly.

Many children with this disease survive only up to 10 years or more.

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References

  1. Naviaux RK, Nguyen KV. POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Ann Neurol 2004; 55:706–712.
  2. Davidzon G, Mancuso M, Ferraris S, Quinzii C, Hirano M, Peters HL, Kirby D, Thorburn DR, DiMauro S. POLG mutations and Alpers syndrome. Ann Neurol. 2005;57:921–3.
  3. Gauthier-Villars M, Landrieu P, Cormier-Daire V, Jacquemin E, Chretien D, Rotig A, Rustin P, Munnich A, de Lonlay P. Respiratory chain deficiency in Alpers syndrome. Neuropediatrics.2001;32:150–2.
  4. Harding BN. Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review. J Child Neurol 1990;5:273–287.
  5. Worle H, Kohler B, Schlote W, Winkler P, Bastanier CK. Progressive cerebral degeneration of childhood with liver disease (Alpers-Huttenlocher disease) with cytochrome oxidase deficiency presenting with epilepsia partialis continua as the first clinical manifestation. Clin Neuropathol. 1998;17:63–8
  6. Wolf NI, Rahman S, Schmitt B, Taanman JW, Duncan AJ, Harting I, Wohlrab G, Ebinger F, Rating D, Bast T. Status epilepticus in children with Alpers' disease caused by POLG1 mutations: EEG and MRI features. Epilepsia. 2009;50:1596–1607
  7. Stewart JD, Horvath R, Baruffini E, Ferrero I, Bulst S, Watkins PB, Fontana RJ, Day CP, Chinnery PF. Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010;52:1791–6.
  8. Smith JK, Mah JK, Castillo M. Brain MR imaging findings in two patients with Alpers' syndrome. Clin Imaging.1996;20:235–7.
  9. Cohen BH, Naviaux RK. The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders.Methods. 2010;51:364–73.
  10. Saneto RP, Lee IC, Koenig MK, Bao X, Weng SW, Naviaux RK, Wong LJ. POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders. Seizure. 2010; 19:140–146.

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