Alpers Disease: Symptoms, Types, Causes and Treatment

Alpers disease, also known as Alpers-Huttenlocher syndrome, is a rare but devastating neurodegenerative disorder. It typically affects infants and young children, though cases in older children and young adults have been reported. Characterized by progressive neurological decline, refractory seizures, and liver dysfunction, Alpers disease presents significant challenges in diagnosis and management. In this article, we explore the symptoms, types, underlying causes, and current treatment approaches for Alpers disease, synthesizing the latest research to provide a comprehensive understanding of this complex disorder.

Symptoms of Alpers Disease

Alpers disease is notorious for its diverse and rapidly progressing symptoms, which often leave families and healthcare providers racing against time. Understanding the earliest signs, as well as how the disease unfolds, is crucial for timely diagnosis and management. Children may appear healthy initially, but the onset can be sudden, with symptoms escalating swiftly.

Symptom	Description	Frequency/Age	Source
Seizures	Refractory, myoclonic, status epilepticus	Early, common	1 3 4 5 8
Developmental Regression	Loss of skills, psychomotor decline	Early, rapid	3 4 5 8
Liver Dysfunction	Hepatic failure, abnormal enzymes	Late/Variable	2 3 4 5
Visual Disturbance	Cortical blindness, visual symptoms	~25%	3 4 5 14
Ataxia	Uncoordinated movements	Common	3 4 7
Hypotonia	Reduced muscle tone	Early	2 4 5
GI Dysfunction	Vomiting, feeding difficulties	Early/Variable	2 5
Cardiac Issues	Cardiomyopathy (rare)	Rare	5

Table 1: Key Symptoms

Progression and Patterns of Symptoms

Alpers disease typically begins with non-specific symptoms such as vomiting, failure to thrive, and developmental delay. Seizures—often difficult to control—usually follow, and may manifest as myoclonic jerks, focal motor seizures, or even status epilepticus, a life-threatening condition of continuous seizures 1 3 4 5 8.

Developmental regression is a hallmark, with children losing previously acquired skills rapidly. The disease also affects muscle tone (hypotonia), movement coordination (ataxia), and, in some cases, vision due to cortical blindness 3 4 5. Gastrointestinal symptoms and, less frequently, cardiac involvement may also occur 2 5.

Neurological and Hepatic Manifestations

Neurological:

• Seizures are often refractory to standard treatment and can be the first or most prominent symptom.
• Progressive cognitive and motor decline is typical, and dementia is often episodic, sometimes triggered by infections 5.
• Status epilepticus is particularly dangerous and often requires intensive care 1.
• EEG studies reveal characteristic patterns such as rhythmic high-amplitude delta with superimposed spikes (RHADS) 8.
• Neuroimaging may show cortical and subcortical abnormalities, particularly in the occipital and parietal regions 3.

Hepatic:

• Liver involvement usually appears later in the disease, but in rare cases can be an initial sign 2 16.
• Manifestations include hepatomegaly, abnormal liver function tests, and progression to liver failure 2 3 4.
• Rapid hepatic failure is a leading cause of death, especially when valproic acid, a common anti-seizure medication, is used (which is contraindicated in Alpers disease) 1 2 4.

Other Notable Features

• Visual disturbances, notably cortical blindness, occur in about 25% of cases 5 14.
• Gastrointestinal symptoms include vomiting and feeding difficulties, sometimes leading to hypoglycemia 2 5.
• Cardiomyopathy and other organ involvement are rare but possible 5.
• Increased CSF protein and inflammatory markers may be detected 5 13.

Types of Alpers Disease

While Alpers disease is classically described as a childhood-onset condition, recent genetic discoveries have revealed a broader spectrum of disease types. Understanding these distinctions is essential for prognosis and management.

Type	Main Features	Genetic Basis	Source
Classic (Early-Onset)	Onset <2 years, rapid decline	POLG mutations	3 5 7 9 10
Juvenile-Onset	Onset 2–25 years, slower course	POLG mutations	5 14
Alpers-like (No Liver)	Encephalopathy, no liver disease	Non-POLG mutations, variable	5 7 8 12
Non-POLG Variants	Similar symptoms, other genes	FARS2, PARS2, CARS2, etc.	8 12

Table 2: Types of Alpers Disease

Classic Alpers Disease

Classic Alpers disease presents in infancy or early childhood, with most children developing symptoms before age two. The triad of intractable seizures, developmental regression, and liver failure is typical 3 5 7 9 10. The disease is rapidly progressive and usually fatal within a few years of onset.

Juvenile-Onset Alpers Disease

Juvenile-onset Alpers disease emerges later, sometimes in adolescence or young adulthood, and may progress more slowly 5 14. However, it retains the core features—seizures, neurodegeneration, and hepatic dysfunction. Status epilepticus can be particularly severe in this group, often necessitating ICU care 14.

Alpers-like Disorders

Alpers-like disorders mimic the neurological features of classic Alpers but lack significant liver involvement. These cases are often genetically distinct and may not involve POLG mutations at all 5 7 8. Patients may have mutations in other mitochondrial or nuclear genes.

Non-POLG Genetic Variants

Recent research has identified several non-POLG genetic causes of Alpers-like phenotypes, including mutations in the FARS2, PARS2, CARS2, NARS2, and GABRB2 genes 8 12. While clinical features often overlap—such as seizures and developmental regression—the presence and severity of liver involvement may differ. These discoveries underscore the importance of genetic testing in atypical cases.

Causes of Alpers Disease

Alpers disease is fundamentally a genetic disorder caused by mutations that disrupt mitochondrial function in the brain and liver. Understanding these genetic and molecular underpinnings is key to diagnosis, counseling, and research into future therapies.

Cause	Mechanism	Prevalence/Features	Source
POLG Mutations	mtDNA depletion, polymerase defect	Most common; autosomal recessive	3 5 6 9 10 11
Other Mitochondrial Genes	Deficient tRNA synthetase, etc.	Rare, variable symptoms	8 12
Inheritance	Autosomal recessive	Both sexes, variable onset	5 6 11
Environmental/Medications	Valproic acid triggers liver failure	Not causative, but significant	1 2 4

Table 3: Causes of Alpers Disease

POLG Mutations: The Central Culprit

The vast majority of Alpers disease cases are caused by mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. This enzyme is essential for the replication and repair of mitochondrial DNA (mtDNA). Mutations lead to mtDNA depletion, crippling energy production in neurons and hepatocytes 3 5 6 9 10 11.

• Common mutations: A467T and W748S are the most frequent, particularly in populations of European descent 9 10 11.
• Inheritance: The disorder is autosomal recessive, meaning both parents must carry a defective gene copy 5 6 11.
• Genetic testing: Screening for these mutations is now the standard for rapid diagnosis 9.

Other Genetic Causes

A minority of patients have Alpers-like syndromes due to mutations in other mitochondrial or nuclear genes, including FARS2, PARS2, CARS2, NARS2, and GABRB2 8 12. These genes are involved in mitochondrial translation or maintenance. Their disruption can produce overlapping neurological and hepatic symptoms, sometimes without liver involvement 8 12.

Environmental Triggers and Medication Sensitivity

While not causal, certain medications can precipitate catastrophic deterioration in Alpers disease. Most notably, valproic acid, a common anticonvulsant, can trigger rapid, fatal hepatic failure and is contraindicated in these patients 1 2 4. Infections and metabolic stress may also exacerbate symptoms or provoke acute encephalopathy 5.

Pathophysiology

• Mitochondrial dysfunction leads to impaired energy metabolism in the brain and liver 4 5.
• Secondary complications include lactic acidosis, cerebral folate deficiency, and increased inflammatory markers in the cerebrospinal fluid 13.

Treatment of Alpers Disease

There is no cure for Alpers disease, and treatment is primarily supportive. However, advances in genetic testing and symptom management have improved the outlook for some patients. Here, we summarize the main approaches and emerging therapies.

Treatment	Purpose/Effect	Special Considerations	Source
Seizure Management	Control epilepsy, status epilepticus	Avoid valproic acid; magnesium, surgery	1 4 8 14 15
Supportive Care	Multidisciplinary, palliative	Gastroenterology, neurology	4 5 15
Experimental	Folinic acid (cerebral folate), gene therapy	Limited evidence, case reports	13 16
Liver Transplant	Replace failing liver	Controversial; rarely helps CNS	16

Table 4: Alpers Disease Treatments

Seizure Management

• Traditional anticonvulsants are often ineffective; seizures can be relentless and difficult to control 1 3 4 8.
• Valproic acid is strictly contraindicated due to risk of fatal liver failure 1 2 4.
• Magnesium infusion has shown promise in controlling refractory status epilepticus in some juvenile-onset cases 14.
• Palliative epilepsy surgery (such as hemispherectomy) may improve quality of life in select cases, though it does not alter the course of the disease 15.

Supportive and Multidisciplinary Care

• Nutritional support, physical therapy, and palliative care are critical for maintaining comfort and dignity 4 5 15.
• Monitoring for liver dysfunction and managing complications such as infections and metabolic imbalances are key 2 4 5.
• Family counseling is essential, as the disease is progressive and ultimately fatal.

Experimental and Adjunctive Therapies

• Folinic acid (Leucovorin) therapy: In rare cases, treatment of secondary cerebral folate deficiency has led to improved communication and reduced seizures, but does not halt progression 13.
• Liver transplantation: Traditionally contraindicated due to poor neurological prognosis. However, there are rare reports of improved outcomes in select cases, particularly when CNS involvement is less severe or after "cocktail therapy" 16.

Diagnostic Advances

• Genetic testing for POLG mutations allows for early and accurate diagnosis, which is essential for avoiding harmful medications and providing appropriate counseling 9.
• EEG and MRI can help identify characteristic patterns that support the diagnosis and guide management 1 3 8.

Conclusion

Alpers disease is a complex and tragic disorder that demands coordinated care, expert diagnostic work-up, and sensitivity to family needs. Understanding its clinical features, genetic underpinnings, and management options is key to improving outcomes for affected children and their families.

Key Points:

• Alpers disease presents with a triad of seizures, developmental regression, and liver failure, but symptoms and onset can vary.
• Most cases are caused by autosomal recessive mutations in the POLG gene, with other rare genetic causes now recognized.
• Seizures are often difficult to control and liver involvement can be rapidly fatal, especially if valproic acid is used.
• Diagnosis relies on clinical suspicion, EEG/MRI findings, and especially genetic testing for POLG and related genes.
• There is no cure; treatment is supportive, with an emphasis on seizure control (excluding valproic acid), palliative interventions, and multidisciplinary care.
• Experimental therapies and rare cases of liver transplantation have been reported, but prognosis remains poor.
• Ongoing research into the genetic and molecular basis of Alpers disease offers hope for future targeted therapies.

Understanding and recognizing Alpers disease early is crucial for optimizing care, supporting families, and advancing research toward better treatments.