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Alpers-Huttenlochen Syndrome (AHS, Alper Disease)

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Last Update: May 18, 2019.

Introduction

Alpers-Huttenlocher syndrome (AHS) is an autosomal recessive disease caused by a mutation in the POLG1 gene, which leads to the reduced functionality of polymerase gamma - a key component of mitochondrial DNA (mtDNA) replication and repair.  The brain and liver are the classic organs affected by this disease due to their high energy demand and proportional need for mitochondria. Decreased mitochondria in these organ systems lead to a variety of symptoms, with seizures and liver failure being the most common.  This pathology is a rapidly progressive disease that presents early in life and invariably ends in a fatality.[1]

Etiology

Alpers-Huttenlocher syndrome is a mitochondrial disorder caused by an autosomal recessive mutation in the POLG1 gene resulting in damage to polymerase gamma.[2] The inheritance of a heterozygous mutation in POLG1 leads to the classic presentation of the disease between 2 and 4 years of age.  The presence of a homozygous mutation in POLG1, however, is associated with a later and milder presentation; between 17 to 24 years of age.[3]

Epidemiology

Approximately 1 in 100000 children will develop Alpers-Huttenlocher syndrome, with males and females being affected equally. There appears to be a slightly higher carrier frequency in people of Northern European descent, although there are reports of the condition in many ethnic groups.[3]

Pathophysiology

An autosomal recessive mutation in POLG1 leads to decreased functionality of polymerase gamma, leading to a reduction of mitochondrial DNA.[4] Mitochondria are present in high numbers in tissue with high energy requirements - such as the central nervous system, liver, and skeletal muscle.  This reduction in mitochondrial support leads to the symptoms of AHS.[3]

Histopathology

The primary organs in Alpers-Huttenlocher syndrome demonstrating histologic changes are the liver and brain.  Neural tissue from the cerebral cortex shows spongiosis, neuronal loss, and astrocytosis.  These findings correlate with the progressive cognitive decline seen with the progression of the disease.  The hepatic findings are more specific to AHS. A minimum of three of the following eight criteria must be present, in the absence of Wilson disease: bridging fibrosis or cirrhosis, bile ductular proliferation, collapse of liver plate cells, hepatocyte dropout or focal necrosis with or without portal inflammation, microvesicular steatosis, oncocytic change, regenerative nodules, and  parenchymal disease or disorganization of the normal lobular architecture.[5]

History and Physical

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.

Evaluation

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 / Management

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]

Differential Diagnosis

Alpers-Huttenlocher syndrome requires differentiation from the other mitochondrial disorders associated with POLG gene mutations - most notably childhood myocerbro-hepatopathy. This disease has some overlapping features, 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 between 2 to 4 years old.[9] Other syndromes associated with the POLG gene mutation include ataxia-neuropathy syndrome, myoclonus epilepsy myopathy sensory ataxia, autosomal recessive progressive external ophthalmoplegia plus, and autosomal dominant progressive ophthalmoplegia plus.[10]

Toxicity and Side Effect Management

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 diagnosis AHS early to avoid this medication and the detrimental effects it may have on the patient's clinical course.[3]

Prognosis

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]

Complications

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]

Deterrence and Patient Education

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.

Enhancing Healthcare Team Outcomes

Patients with Alpers-Huttenlocher syndrome require a collaborative effort from many medical 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 patient make the decisions they feel will result in the best quality of life.[6]

Questions

To access free multiple choice questions on this topic, click here.

References

1.
Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Huttenlocher syndrome. Pediatr. Neurol. 2013 Mar;48(3):167-78. [PMC free article: PMC3578656] [PubMed: 23419467]
2.
Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D, Karpinski NC, Haas RH. Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome. Ann. Neurol. 1999 Jan;45(1):54-8. [PubMed: 9894877]
3.
Cohen BH, Chinnery PF, Copeland WC. POLG-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. University of Washington, Seattle; Seattle (WA): Mar 16, 2010. [PubMed: 20301791]
4.
Saneto RP. Alpers-Huttenlocher syndrome: the role of a multidisciplinary health care team. J Multidiscip Healthc. 2016;9:323-33. [PMC free article: PMC4968991] [PubMed: 27555780]
5.
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 Jun;50(6):1596-607. [PubMed: 19054397]
6.
Park S, Kang HC, Lee JS, Park YN, Kim S, Koh H. Alpers-Huttenlocher Syndrome First Presented with Hepatic Failure: Can Liver Transplantation Be Considered as Treatment Option? Pediatr Gastroenterol Hepatol Nutr. 2017 Dec;20(4):259-262. [PMC free article: PMC5750381] [PubMed: 29302508]
7.
Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, Milone M, Cohen BH, Wical B, Ganesh J, Basinger AA, Burton BK, Swoboda K, Gilbert DL, Vanderver A, Saneto RP, Maranda B, Arnold G, Abdenur JE, Waters PJ, Copeland WC. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum. Mutat. 2008 Sep;29(9):E150-72. [PMC free article: PMC2891192] [PubMed: 18546365]
8.
Qian Y, Ziehr JL, Johnson KA. Alpers disease mutations in human DNA polymerase gamma cause catalytic defects in mitochondrial DNA replication by distinct mechanisms. Front Genet. 2015;6:135. [PMC free article: PMC4391263] [PubMed: 25914719]
9.
Hikmat O, Eichele T, Tzoulis C, Bindoff LA. Understanding the Epilepsy in POLG Related Disease. Int J Mol Sci. 2017 Aug 24;18(9) [PMC free article: PMC5618494] [PubMed: 28837072]
10.
Copeland WC. Defects in mitochondrial DNA replication and human disease. Crit. Rev. Biochem. Mol. Biol. 2012 Jan-Feb;47(1):64-74. [PMC free article: PMC3244805] [PubMed: 22176657]
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Bookshelf ID: NBK540966PMID: 31082010

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