Neurological Manifestations Of Batten Disease

Batten disease, a severe neurological disorder, presents with a series of symptoms that get progressively worse over time. This article allows you to explore the critical aspects of Batten disease to understand its impact on the nervous system.

Batten disease manifests itself neurologically through a series of progressively worsening symptoms. As the disease progresses, patients may also experience various dysfunctions, which can be fatal. Read the article and access the bibliographic sources to learn more. 

For a deeper understanding of Batten disease and its impact on the nervous system, as well as current treatment options and ongoing research, read on. Discover more about how this disorder progresses and what advances are made to combat its devastating effects.

Introduction

Origins

Neuronal Ceroid Lipofuscinoses (NCLs), commonly referred to as Batten Disease, comprise a group of fatal genetic disorders. The term "Batten disease" is specifically used to describe the 13 identified forms of NCLs. These disorders are inherited metabolic conditions caused by genetic mutations.¹

Classification

The term "Batten disease" specifically encompasses the 13 acknowledged types of NCLs. Each type is classified under "Ceroid Lipofuscinosis, neuronal" (CLN) and distinguished by a unique number denoting its subtype (e.g., CLN1, CLN2, etc.). These Batten disease variants (NCLs) exhibit varying degrees of severity, onset ages, and rates of progression, frequently influenced by the particular gene variant involved.¹

Symptoms

Batten disease is often diagnosed when parents or doctors notice a child experiencing progressive vision loss or developing seizures that were previously absent. Initial symptoms can be subtle and diverse, ranging from clumsiness to changes in behaviour. As the disease progresses, children often become blind, paralysed, and lose the ability to communicate. Life expectancy varies depending on the age at which symptoms appear, but very few children with Batten disease survive beyond their late teens.

Individuals with NCL might encounter the following symptoms:¹

• Gradual vision loss culminating in blindness
• Seizures
• Deterioration in cognitive abilities and the onset of dementia
• Movement difficulties
• Alterations in personality and behaviour
• Reduced life expectancy

In some cases, children with infantile Batten disease may also experience microcephaly. Vision loss typically presents as the initial symptom and can deteriorate rapidly. Parents may observe clumsiness and stumbling in older children due to impaired motor coordination. Eventually, affected children progress to blindness, loss of mobility and communication abilities, and reliance on a wheelchair or bed.

Causes 

Batten disease is caused by a defective gene, leading to the accumulation of fatty substances in the brain, which kills brain cells and affects other parts of the central nervous system. A child must inherit the defective gene from both carrier parents to develop the disease, resulting in a 25% chance of having Batten disease and a 50% chance of being a carrier.³

Batten disease results from genetic mutations, with at least 13 associated genes. Each form of the disease is named after the affected gene, such as CLN1 for the CLN1 gene mutation. The disease is usually inherited in an autosomal recessive manner, requiring two mutated gene copies - one from each parent, who are typically unaffected carriers. However, CLN4 is inherited in an autosomal dominant way, meaning only one mutated gene copy is needed to cause the disease.⁴

Diagnostic

Due to the rarity of Batten disease, accurate diagnosis can be challenging, often requiring genetic testing. Brineura® (cerliponase alfa) is approved to slow symptom progression in children with CLN2. For other NCL forms, no treatments can reverse or stop progression. Seizures may be managed with anticonvulsants, and symptoms are treated as they appear. Physical and occupational therapy can help maintain function.¹

Neurophysiological investigations assist in distinguishing between Neuronal Ceroid Lipofuscinoses (NCLs) and other Developmental and Epileptic Encephalopathies (DEEs). Late Infantile NCLs (LINCLs) are differentiated from DEEs with myoclonic seizures onset by Electroencephalography (EEG) patterns, with NCLs showing a progressive slowing of background activity and distinct muscle involvement in myoclonus. Lennox-Gastaut Syndrome (LGS) exhibits specific EEG abnormalities, while Photoparoxysmal Response (PPR) is rare in both Epilepsy with Myoclonic-Atonic Seizures (EMA) and LGS. Dravet Syndrome (DS), characterized by early onset seizures, may display PPR. Despite genetic advancements, phenotyping and neurophysiological assessments remain crucial for accurate diagnosis and management.²

Batten disease is often diagnosed when a parent or doctor observes a child's progressive vision loss or the onset of seizures. Early symptoms can be subtle and vary, including clumsiness and behavioural changes. As the disease advances, affected children typically become blind, paralysed, and unable to communicate. Life expectancy varies with the age of onset, but most children with Batten disease do not survive beyond their late teens.³

Risks

Epilepsy and vision-related complications are prevalent features of NCLs, exhibiting variability in onset and intensity based on the distinct NCL subtype. Vision-related impairments frequently precede other clinical signs, stemming from the accumulation of storage substances within the retinal tissue. Alterations in visual evoked potentials, notably the emergence of oversized responses, signify heightened cortical excitability and could potentially function as diagnostic indicators of disease advancement in individuals with NCLs.²

Future outcomes

A study led by researchers from the University of Rochester Medical Center, aimed to understand changes in brain function among individuals with CLN3 disease, also known as juvenile-onset Batten disease. Using EEG, they measured brain activity in participants with and without Batten disease while they listened to auditory stimuli. The results showed a decline in the functioning of the auditory sensory memory system as the disease progressed in patients with Batten disease. This finding suggests that this brain process could serve as a potential biomarker in evaluating treatment outcomes in clinical trials. The University of Rochester Batten Center, designated a Center of Excellence by the Batten Disease Support and Research Association, continues to lead research and treatment efforts for Batten disease. With ongoing research, including leveraging mouse models to test pharmaceutical interventions, the aim is to identify effective treatments and biomarkers to assess their impact.⁵

Summary

Introduction and Classification

Batten disease, or Neuronal Ceroid Lipofuscinoses (NCLs), consists of 13 fatal genetic disorders caused by metabolic genetic mutations. Each type is classified under "ceroid lipofuscinosis, neuronal" (CLN) with a specific number (e.g., CLN1, CLN2).

Symptoms

•   Gradual vision loss leading to blindness
•   Seizures
•   Cognitive decline and dementia
•   Motor difficulties
•   Behavioral changes
•   Reduced life expectancy

Causes

Caused by defective genes that lead to the accumulation of fatty substances in the brain. It is typically inherited in an autosomal recessive manner, with two mutated gene copies required, one from each parent. CLN4 is an exception, being inherited autosomal dominantly.

Diagnosis and Treatment

Diagnosis is challenging and often requires genetic testing. Brineura® (cerliponase alfa) is approved for slowing symptom progression in CLN2. Seizures are managed with anticonvulsants, and symptoms are treated as they appear. Physical and occupational therapy can help maintain function.

Neurophysiological Investigations

EEG and other neurophysiological assessments are essential for distinguishing NCLs from other epileptic encephalopathies, showing specific patterns of activity and muscle involvement.

Risks and Early Symptoms

Epilepsy and vision issues are common, with vision impairments often preceding other symptoms. Early signs include vision loss, seizures, clumsiness, and behavioural changes. Life expectancy generally does not extend beyond the late teens.

Future Outcomes and Research

Research at the University of Rochester Medical Center found a decline in auditory sensory memory function in CLN3 disease, suggesting it as a potential biomarker for treatment evaluation. The University of Rochester Batten Center leads ongoing research, including using mouse models to test pharmaceutical interventions and identify effective treatments and biomarkers. By understanding the classification, symptoms, causes, diagnostic methods, and ongoing research into Batten disease, we can better appreciate the complexities of this devastating condition and the efforts being made to find effective treatments.

FAQs

Is Batten disease a neurological disorder?

Yes, Batten disease is a neurological disorder. It is an inherited condition that progressively worsens and ultimately leads to terminal outcomes.

What are the first signs of Batten's disease?

The initial signs of Batten disease, specifically Juvenile NCL, include progressive vision loss, seizures, and ataxia or clumsiness.

Is Batten disease autoimmune?

It is unclear if autoimmunity causes Batten disease or is a result of its symptoms. 

Has anyone survived Batten disease?

Life expectancy for Batten disease varies by type. Congenital Batten disease is the most severe and rare, with affected infants typically dying soon after birth. Infantile Batten disease appears before age two, and patients usually do not survive beyond age five.

What medication is used for Batten disease?

Brineura (cerliponase alfa) is the only FDA-approved treatment for Batten disease. It replaces the TPP1 enzyme and helps slow the loss of walking ability in children with late infantile Batten disease (CLN2).