Alpers' disease

Alpers’ disease is an autosomal recessive genetic syndrome characterized by seizures, hepatopathy, and progressive cognitive impairment. It is caused by mutation in the POLG gene resulting in mitochondrial DNA depletion.

• Alpers disease was first described by a North-American neurologist named, Bernard Jacob Alpers in 1931.^[1]
• In 1970, Peter Richard Huttenlocher a pediatric neurologist and neuroscientist described more phenotypic features associated with the disease. ^[2]
• Alpers disease is also refered as Alpers–Huttenlocher syndrome.

• There is no established system for the classification of Alpers disease.

• Alpers disease is inherited in an autosomal recessive pattern.
• Mutation in POLG1 gene reduces polymerase gamma functionality resulting in defective mitochondrial DNA replication and causing depletion of mitochondrial DNA. ^[3]
• Heterozygous mutation of POLG1 gene causes classic and severe presentation of the disease at an early age of onset.
• Homozygous mutation results in the milder form with onset of symptoms in adolescence.^[4]
• Brain, liver and skeletal muscles are most involved due to high number of mitochondria.^[5]

• Alpers disease is a mitochondrial disorder caused by a mutation in the POLG1 gene.^[6]

• Alpers disease must be differentiated from other mitochondrial diseases caused POLG gene mutation:
  • Childhood Myocerbrohepatopathy Spectrum Disorder^[7]
  • Myoclonus epilepsy myopathy sensory ataxia (MEMSA)
  • Progressive external ophthalmoplegia^[8]

• The prevalence of Alpers disease is approximately 1 per 100,000 individuals worldwide.
• Alpers disease affects men and women equally.
• Higher carrier frequency is seen in the Northern European population.^[5] Although, it is seen in other ethnic groups as well.

• There are no established risk factors for Alpers disease.

• There is insufficient evidence to recommend routine screening for Alpers disease.

• Common complications of Alpers disease include seizures, liver failure poor growth, infection-associated encephalopathy, increased muscle tone, gastrointesinal dysfunction, dilated cardiomyopathy, dementia, cortical blindness, spasticity, jaundice and/or ascites.^[9]
• The prognosis is generally poor, death usually occurs within ten years after diagnosis due to life threatening complications of the disease.

Diagnostic Study of Choice

• There are no established criteria for the diagnosis of Alpers disease. However, it usually manifests with a triad consist of refractory seizures, hepatopathy, and psychomotor regression.
• The diagnosis is established by testing for the POLG gene.^[4]

History and Symptoms

• Alpers disease has a bimodal age of onset. The majority cases present in first two years of life and the rest present between the ages of 2 and 25.^[10]
• Alpers disease is characterized by presence of refractory seizures, psychomotor regression and liver failure.
• Other symptoms may include hypoglycemia secondary to underlying liver disease, vision changes, migraines, hallucinations, cognitive impairment, depression, anxiety and/or ataxia.^[9]

Physical Examination

• Common physical examination findings of Alpers disease include spasticity, ataxia, altered muscle tone.
• Other physical findings include poor growth, developmental delay, failure to thrive, and/or vision changes.

Laboratory Findings

• There are no diagnostic laboratory findings associated with Alpers disease.
• However CSF lactate may be elevated in some cases due to respiratory chain disorder.^[11]

Electrocardiogram

• There are no ECG findings associated with Alpers disease. However, cardiomyopathy may be one of the possible complications of Alpers disease.^[12]

X-ray

• There are no x-ray findings associated with Alpers disease.

Echocardiography or Ultrasound

• There are no diagnostic echocardiography/ultrasound findings associated with Alpers disease.

CT scan

• CT may demonstrate areas of low density in occipital region and may show cerebral atrophy.^[13]

MRI

• MRI demonstrates gray matter involvement in regions with the highest metabolic activity.^[14]
• In most patients MRI demonstrated T2/FLAIR hyperintensities within the occipital region, basal ganglia, deep cerebellar nuclei, and thalamus.^[15]

Other Imaging Findings

• In areas of high diffusion signal, MR spectroscopy may show increased lactate signal intensity and decreased NAA signal intensity.^[16]

Other Diagnostic Studies

• Rhythmic high-amplitude delta with superimposed (poly)spikes(RHADS) on EEG are reported to be highly specific of Alpers disease.^[17]
• Other EEG finding includes abnormal, often assymetrical flash visual evoked potential (VEP).

Medical Therapy

• There is no treatment for Alpers disease and no way to slow its progression; the mainstay of therapy is supportive and palliative care, achieved by a multidisciplinary care team.
• Seizure management should be achieved by with drugs with newer generation drugs(lamotrigine, primidone, topiramate, oxcarbazepine) with low hepatic impact.
• Valproic acid should be avoided for seizure management as it can worsen liver disease.^[18]
• Physical therapy may help relieve spasticity.
• Occupational/speech therapies may also help with neurological deficits.
• Tracheostomy, gastric feeding tube, and/or artificial ventilation may be helpful once the disease progresses.^[19]

Surgery

• Surgical intervention is not recommended for the management of Alpers disease.

Primary Prevention

• There are no established measures for the primary prevention of Alpers disease.

Secondary Prevention

• There are no established measures for the secondary prevention of Alpers disease.

Template:Diseases of the nervous system

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