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Neurodegeneration with brain iron accumulation 2 (PLA2G6)
NBIA2 is a progressive neurological disorder causing movement problems, speech difficulties, and cognitive changes. It is caused by genetic changes in the PLA2G6 gene and typically affects children and young adults.
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Overview
Neurodegeneration with brain iron accumulation type 2 (NBIA2) is a group of rare, inherited neurological disorders. It is characterised by the progressive build-up of iron in certain areas of the brain, particularly the basal ganglia, which are involved in controlling movement [PMID:36574345]. This iron accumulation contributes to a range of neurological symptoms that worsen over time.
NBIA2 is also known by the names infantile neuroaxonal dystrophy (INAD) and atypical neuroaxonal dystrophy (ANAD), which refer to different forms of the condition based on age of onset and severity. While INAD typically presents in infancy, ANAD may appear in childhood or early adulthood. The condition affects various neurological functions, impacting movement, speech, and cognitive abilities.
Symptoms & clinical features
The symptoms of NBIA2 can vary widely, even within the same family, and depend on the specific form of the condition. In the infantile form (INAD), early symptoms often include delayed development, muscle weakness (hypotonia), and problems with walking and balance. Children may also develop spasticity, which is muscle stiffness, and involuntary movements [PMID:33994645]. Eye movement abnormalities, such as nystagmus (involuntary eye movements), are also common.
In the atypical form (ANAD), symptoms might emerge later in childhood or adolescence. These can include speech difficulties (dysarthria), dystonia (sustained or repetitive muscle contractions leading to twisting and repetitive movements or abnormal fixed postures), and parkinsonism (symptoms similar to Parkinson's disease, such as tremors and rigidity). Cognitive decline and psychiatric features, such as behavioural changes, may also be observed [PMID:33994645].
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Affected organs
NBIA2 primarily affects the brain and the nervous system. The hallmark feature is the accumulation of iron in specific deep brain structures, notably the globus pallidus and substantia nigra within the basal ganglia. These regions play a crucial role in regulating movement, learning, and emotions. The iron build-up, alongside neurodegeneration (the progressive loss of nerve cells), disrupts the normal functioning of these brain areas.
Additionally, the peripheral nervous system, which includes nerves outside the brain and spinal cord, can also be affected, contributing to symptoms like muscle weakness and abnormal reflexes. Over time, the widespread impact on brain cells leads to the progressive neurological decline seen in individuals with NBIA2.
Risks & severity
NBIA2 is a rare and progressive condition, meaning symptoms typically worsen over time. The severity and rate of progression can differ significantly between the infantile (INAD) and atypical (ANAD) forms. INAD is generally more severe, with rapid neurological deterioration beginning in infancy, leading to significant disability early in life. Life expectancy for individuals with INAD is often reduced, with many not surviving beyond childhood.
ANAD has a later onset and a more variable course. While it is also progressive, the rate of decline can be slower, and individuals may live into adulthood, sometimes for many decades. The exact prevalence of NBIA2 is not well established, but it is considered one of the more common types of neurodegeneration with brain iron accumulation disorders. The condition does not typically lead to an increased risk of other non-neurological conditions, but the neurological symptoms can significantly impact quality of life.
Genetic causes
NBIA2 is caused by pathogenic variants in the PLA2G6 gene. This gene provides instructions for making an enzyme called phospholipase A2 group VI. This enzyme is crucial for breaking down phospholipids, which are essential components of cell membranes and are involved in various cellular processes, including inflammation and cell signalling [PMID:25641703].
When there are pathogenic variants in PLA2G6, the enzyme may not function correctly or may be entirely absent. This leads to a disruption in the normal metabolism of phospholipids, particularly in nerve cells. Research suggests that this disruption, along with impaired mitochondrial function and oxidative stress, contributes to the accumulation of iron and the subsequent damage to brain cells, ultimately causing the neurological symptoms observed in NBIA2 [PMID:36574345].
- PLA2G6 phospholipase A2 group VIThe PLA2G6 gene provides instructions for an enzyme crucial in fat metabolism and maintaining cell membrane health, and is associated with a spectrum of neurodegenerative disorders.
Inheritance pattern
NBIA2 is inherited in an autosomal recessive pattern. This means that a person must inherit two copies of the altered PLA2G6 gene - one from each parent - to develop the condition. Individuals who inherit only one copy of the altered gene are known as carriers. Carriers typically do not show any symptoms of NBIA2 themselves, but they can pass the altered gene on to their children.
If two carriers have children together, there is a 25% chance with each pregnancy that their child will inherit two altered copies of the gene and develop NBIA2. There is also a 50% chance that the child will be a carrier, and a 25% chance that the child will inherit two normal copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
A diagnosis of NBIA2 is usually suspected based on a person's clinical symptoms and findings from brain imaging, such as an MRI scan. MRI scans typically show characteristic iron accumulation in the basal ganglia, along with changes like cerebellar atrophy (shrinkage of the cerebellum).
Confirmation of NBIA2 requires genetic testing to identify pathogenic variants in the PLA2G6 gene. In the UK, genetic testing for NBIA2 is available through the NHS Genomic Medicine Service (GMS). Referral for genetic testing is typically made by a neurologist or a clinical geneticist. The relevant R-codes for genomic testing would be discussed as part of the GMS testing directory. A diagnosis can help guide management and provide important information for family planning.
Management & lifestyle
Currently, there is no cure for NBIA2, and management focuses on addressing the symptoms and improving quality of life. Treatment approaches are supportive and multidisciplinary, involving a team of healthcare professionals such as neurologists, physiotherapists, occupational therapists, speech and language therapists, and dietitians.
Physiotherapy can help maintain muscle strength and flexibility, while occupational therapy can assist with daily living activities. Speech and language therapy may be beneficial for communication and swallowing difficulties. Medications can be used to manage specific symptoms like dystonia, spasticity, or parkinsonism. Regular follow-up with a neurologist is important to monitor disease progression and adjust treatment strategies as needed. Genetic counsellors can provide support and information to affected individuals and their families.
UK care pathway
In the UK, individuals suspected of having NBIA2 would typically be referred to a neurologist for initial assessment and diagnosis. If NBIA2 is suspected, a referral for genomic testing will be made via the NHS Genomic Medicine Service (GMS). This is usually coordinated by a clinical genetics service or a specialist paediatric/adult neurology centre. The specific R-codes for testing can be found in the GMS Genomic Test Directory.
Following a confirmed diagnosis, ongoing care is generally managed by a specialist team, often involving multidisciplinary input. Genetic counsellors play a vital role in providing information about the condition, inheritance patterns, and support for family planning.
Frequently asked questions
What is the typical age of onset for NBIA2?
The age of onset for NBIA2 can vary. The infantile form (INAD) typically begins in infancy, usually between 6 months and 3 years of age. The atypical form (ANAD) has a later onset, often appearing in childhood or early adulthood, and its progression can be slower.
Is NBIA2 inherited?
Yes, NBIA2 is an inherited condition. It follows an autosomal recessive pattern, meaning a person must inherit a pathogenic variant in the PLA2G6 gene from each parent to develop the condition. Parents who each carry one altered gene copy are typically unaffected but can pass the gene on.
Can NBIA2 be cured?
Currently, there is no cure for NBIA2. Treatment focuses on managing the symptoms and providing supportive care to improve the individual's quality of life. This includes therapies such as physiotherapy, occupational therapy, and medications to help with specific neurological symptoms.
How is NBIA2 diagnosed?
Diagnosis of NBIA2 involves a combination of clinical assessment, brain imaging (MRI scans showing characteristic iron accumulation), and genetic testing. Genetic testing confirms the diagnosis by identifying pathogenic variants in the PLA2G6 gene, usually through the NHS Genomic Medicine Service in the UK.
What are the common symptoms of NBIA2?
Symptoms can include developmental delay, muscle weakness, spasticity, balance and walking difficulties, speech problems, and involuntary movements. In later-onset forms, features similar to Parkinson's disease and cognitive changes may also be present.