The first step to diagnosing Alpers-Huttenlocher syndrome is recognizing the triad of refractory seizures, psychomotor regression, and hepatopathy.  Patients may experience blindless - first temporarily, but often permanently.  Other symptoms include migraines with possible hallucinations, ataxia, spastic paraparesis, cognitive impairment, anxiety, and depression.[6] A confirmation of the diagnosis is possible with polymerase gamma gene sequencing, liver biopsy, and ultimately autopsy.

Seizure activity is often an early feature of the disease and should undergo an evaluation with an electroencephalography (EEG).  EEG findings in the early stages of the disease have shown focal slowing of the frequency with epileptiform discharges from the occipital region.[3] One report showed that a characteristic EEG finding is unilateral occipital rhythmic high-amplitude delta with superimposed (poly)spikes (RHADS).[7]  Brain magnetic resonance imaging (MRI) may aid in supporting an overall diagnosis of Alpers-Huttenlocher syndrome by showing gray matter involvement in the posterior cortical structures and thalamus, in addition to the involvement of the occipital cortex - the portion of the brain with the highest metabolic activity.[8]

Treatment for Alpers-Huttenlocher syndrome is supportive and eventually palliative. Clinicians should weigh the benefits of seizure management against the risk of side effects.  If prescribing anticonvulsants, the newer generation (lamotrigine, topiramate, oxcarbazepine, primidone) is the recommendation due to a lower hepatic processing burden. Valproic acid and sodium divalproate should be avoided to prevent accelerated hepatic damage. Impaired gluconeogenesis may lead to nutritional deficiencies.  Small, frequent, low-protein meals are recommended. Eventually, as the patient's disease progresses, a gastrostomy feeding tube can be offered to supplement nutritional status. Long-term respiratory support is often needed, with the use of tracheostomy and mechanical ventilation. Pain medications and muscle relaxants should be available to keep the patient comfortable.[3]

Alpers-Huttenlocher syndrome requires differentiation from the other mitochondrial disorders associated with POLG gene mutations. These include:

• Childhood myocerbro-hepatopathy
  • This disease has some overlapping features with AHS, so it is important to recognize the unique features. Childhood myocerebro-hepatopathy syndrome leads to liver failure and encephalopathy. Helpful distinguishing symptoms for this entity include lactic acidosis, hearing loss, cyclic vomiting and lack of prominent seizure activity.  This disease usually presents by six months of age - earlier than the typical onset of AHS which is between 2 to 4 years old.[9] 
• Ataxia-neuropathy syndrome
• Myoclonus epilepsy myopathy sensory ataxia
• Autosomal recessive progressive external ophthalmoplegia plus
• Autosomal dominant progressive ophthalmoplegia plus.[10]

Valproic acid is appropriate in the management of seizures - a common feature in Alpers-Huttenlocher syndrome. Valproic acid, however, has been shown to cause a rapid progression of liver failure in patients with AHS. For this reason, it is critical to diagnose AHS early to avoid this medication and the detrimental effects it may have on the patient's clinical course.[3]

The prognosis for patients with Alpers-Huttenlocher syndrome is poor, with patients surviving less than 4 years after the initial presentation of symptoms. Common causes of death are fatal encephalopathy and liver failure.[1]

Patients with Alpers-Huttenlocher syndrome can expect to experience numerous complications with the progression of the disease.  Several features of end-stage AHS may find their explanation with the specific neural structures affected.  Blindness is attributable to damage to the occipital cortex.  Ataxia is traceable to the loss of Purkinje cells in the cerebellum.  Loss of central respiratory drive often leads to hypoxia and possibly placement of a tracheostomy tube. Spastic paraparesis results from damage to the cerebral cortex.  This spasticity may lead to difficulty walking, with the ultimate loss of the ability to walk.  Decreased bulbar reflexes, in addition to muscle weakness, may cause dysphagia- leading patients to aspirate or become malnourished. If the dysphagia is severe, families may consider the placement of a gastrostomy tube.[6]

Due to the progressive nature of Alpers-Huttenlocher syndrome, patients and families will need frequent counsel throughout the course of the disease.  Families should be educated about the general progression of the disease and be trained on specific skills as the needs arise.  Due to the loss of mobility and cognitive abilities, the burden of care is likely to grow in the later stages of the disease.  It is crucial to ensure the family has the resources they need at home to deliver the patient care and treatment required.  Genetic counseling may also be of value if future pregnancies are a consideration.

Patients with Alpers-Huttenlocher syndrome require a collaborative effort from multiple specialties and supportive/specialty-trained nursing services, working collaboratively as an interprofessional team.  There is no cure for Alpers-Huttenlocher syndrome at this time, so treatment should focus on symptom management.  As discussed previously, the primary systems involved by this disease are the hepatic and central nervous systems.  Seizures are often the presenting symptom and will need to be followed by neurology.   With the progression of the disease, motor skills, and muscle strength declines, necessitating the services of physical therapy and occupational therapy. Liver failure may cause coagulopathies and hypoglycemia, leading to the addition of gastrointestinal specialists, hematology, and nutritional support to the team.  Due to the relentless nature of this disease, chaplain and psychiatric care should be offered for the patients.  Ultimately, a palliative care team should discuss the treatment options and help the family and patients make the decisions they feel will result in the best quality of life.[6]

The nursing staff should assist with patient and family education, discussing the need to take seizure precautions. The nurses can also assist with the coordination of assistance with daily living activities. Often the nurse will identify the progression of the disease and need to report to the clinician the need for additional care. Home health nurses will often manage the care of the patient until a palliative care team assumes management. Nurses must work in conjunction with the clinicians to assure the patient's family is well educated about the clinical course and coordination of care is achieved.

Valproic acid is appropriate in the management of seizures but it has been shown to cause a rapid progression of liver failure in patients with AHS. For this reason, it is critical to avoid this medication and the detrimental effects it may have on the patient's clinical course as long as possible. Once initiated the pharmacist needs to assist the clinical team in monitoring for toxicity and advice the lowest dose possible.[3]

An interprofessional approach to the management of clinicians, pharmacists, and nurses will produce the best outcomes in the care of Alpers-Huttenlocher syndrome. [Level V]