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Adult-Onset Basal Ganglia Disease (Neuroferritinopathy)

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Adult-onset basal ganglia disease is a disease that affects the basal ganglia region of the brain due to an abnormal accumulation of iron in the brain.

Written byDr. Sameera Ashiqa. S

Medically reviewed byDr. Abhishek Juneja

Published At July 21, 2022
Reviewed AtMay 20, 2024

Introduction:

The term neuroferritinopathy (NF) is more commonly known as adult-onset basal ganglia disease. Neuroferritinopathy, or adult-onset basal ganglia disease, is characterized by the accumulation of abnormal amounts of iron in the brain, which results in damage to the basal ganglia region. This disease arises after the age of 40, hence the name adult-onset basal ganglia disease. Neuroferritinopathy (NF) belongs to a specific group of brain diseases, which is neurodegeneration with brain iron accumulation (NBIA). This read covers insight into neuroferritinipathy in general, its other common names, causes, clinical features, diagnosis, and treatment.

What Is Adult-Onset Basal Ganglia Disease or Neuroferritinopathy?

Neuroferritinopathy was first discovered in the year 2001 in England. It was diagnosed after a family was known to suffer from inherent damage to basal ganglia due to abnormal iron accumulation in the brain. This condition is characterized by damage to the basal ganglia region in the brain, the region that is responsible for controlled physical movements, and hence, the persons affected by NF experience progressive problems associated with physical movements.

What Are the Other Common Names for Adult-Onset Basal Ganglia Disease?

Various other names for adult-onset basal ganglia disease are as follows,

  • Ferritin-related neurodegeneration.

  • Neuroferritinopathy (NF).

  • Hereditary ferritinopathy.

  • NBIA3 (neurodegeneration with brain iron accumulation 3).

What Is the Pathophysiology Behind Adult-Onset Basal Ganglia Disease?

Iron is crucial for maintaining the respiratory needs of myelogenesis and the synthesis of neurotransmitters. However, localized iron accumulation is implicated in various neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and NF.

Ferritin, a key player in maintaining cellular iron balance, binds Fe(II), oxidizes it, and stores it within its internal cavity. Structurally, ferritin comprises a hollow, spherical shell formed by the symmetrical assembly of 24 subunits, with each containing up to 4,000 to 4,500 iron atoms. These subunits, termed heavy (H) and light (L) polypeptide chains, exhibit varying proportions depending on the tissue type. The H chain facilitates ferroxidase activity critical for storing iron in its Fe(III) oxidation state, while the L chain aids in iron nucleation on the cavity surface, supporting iron storage.

Alterations in Ferritin Structure and Neurodegenerative Diseases -

A common feature observed in many NF variants involves structural changes in exon 4, particularly affecting the C-terminal helix or E-helix of the L subunit. In the fully formed ferritin 24-mer, the E-helix of the L subunit contributes to the formation of hydrophobic pores along the fourfold symmetric axes of the ferritin molecule. However, mutations in the L subunits hinder the correct formation of these channels, resulting in larger pores incapable of effectively retaining deposited iron. Ferritin iron leakage and excess deposition may catalyze the production of reactive oxygen species, leading to oxidative cellular damage, which is particularly detrimental to the brain.

What Is the Inheritance Pattern Observed in Adult-Onset Basal Ganglia Disease?

The condition follows an autosomal dominant inheritance pattern, where possessing one altered gene copy in each cell is adequate to trigger the disorder.

Usually, affected individuals inherit the mutation from an affected parent, while in other instances, new mutations in the gene may occur. Such cases can arise in individuals with no family history of the disorder.

What Are the Causes of Adult-Onset Basal Ganglia Disease?

Adult-onset basal ganglia disease is an autosomal dominant disease, which means it is inherited. Mutations in the FTL (ferritin light chain) gene lead to the reduced ability to store iron, resulting in the formation and accumulation of iron in the brain, especially in the basal ganglia region. This region is responsible for the controlled movements of the body, and hence, those affected by this disease are known to have problems regarding physical actions.

How Common Is Adult-Onset Basal Ganglia Disease?

Adult-onset basal ganglia disease is not a very common disease, and only about 100 cases of neuroferritinopathy are known to be reported in medical history to date.

What Are the Common Signs and Symptoms of Adult-Onset Ganglia Disease?

The average age of onset of adult-onset ganglia disease is 40 years. The signs and symptoms of adult-onset ganglia disease can be categorized as physical and diagnostic signs and symptoms. Some of them are as follows,

Physical Signs and Symptoms: The physical manifestations of neuroferritinopathy or adult-onset basal ganglia disease are,

  • Involuntary muscle twitching or movements are known as chorea.

  • Involuntary muscular spasms and contractions.

  • The person involved might have muscular pain and might not be able to control the physical movements.

  • Usually, the physical signs and symptoms are often confined to one side of the body during the first few years after the onset of the disease.

  • Later, the symptoms progress and move to other parts of the body.

  • Most people do not experience any intelligence problems. However, some people can experience symptoms like the inability to reason or concentrate.

  • The progression of NF is slow, and it may ultimately lead to aphonia (inability to speak due to the damage caused to the larynx as a result of a disease) and dysphagia (inability to swallow).

Diagnostic Signs and Symptoms: The standard diagnostic sign is abnormal iron accumulation in the brain, mainly in the basal ganglia region.

  • Degeneration of neurons (brain cells) is also seen.

  • Basal ganglia cavitation and neurodegeneration can be noticed.

  • Neuronal damage or neuronal death is also evident.

How to Diagnose and Confirm Adult-Onset Basal Ganglia Disease?

In earlier times, all brain iron disorders were clubbed under a single category called pantothenate kinase-associated neurodegeneration called Hallervorden-Spatz syndrome. Later, after knowing the abnormal iron levels, brain iron disorders were categorized under the following three categories,

  • Genetic neurodegeneration with brain iron accumulation.

  • Genetic, systemic iron accumulation with neurologic features.

  • Acquired diseases associated with iron excess or iron deficiency.

  • Adult-onset basal ganglia disease is categorized under the first category, genetic neurodegeneration with brain iron accumulation.

  • Adult-onset basal ganglia disease is often diagnosed in older adults with Parkinson's or Alzheimer's.

The most commonly used diagnostic method for diagnosing adult-onset basal ganglia disease is MRI (magnetic resonance imaging) techniques.

  • MRI imaging helps diagnose abnormal iron deposits in the cerebellum and basal ganglia region.

  • MRI scanning technique also diagnoses neuro damage and neuronal death.

  • Blood tests do not usually help with diagnosing adult-onset basal ganglia disease. However, In some cases, a decrease in serum iron levels is noticed in the blood tests.

  • Ferritin aggregates in skin, kidneys, and muscle tissues can also help diagnose adult-onset basal ganglia disease or neuroferritinopathy (NF).

  • Genetic testing can confirm the diagnosis as it shows the mutation of the FTL gene.

How to Treat Adult-Onset Basal Ganglia Disease?

Neuroferritinopathy, unfortunately, has no cure at present. Also, the progression of this disease cannot be halted entirely as well. Only symptomatic treatments are practiced currently. Some of the commonly used symptomatic therapies are as follows,

  • Botox is used widely in treating focal dystonia (involuntary muscle contractions that may lead to twitching of the muscles).

  • Other drugs, such as Tetrabenazine, a dopamine depleter, are known to help with involuntary movements of the body.

  • Symptoms associated with involuntary muscle movements can also be treated with L-Dopa, Orphenadrine, Sulpiride, Clonazepam, Deanol, and Diazepam.

  • Iron supplements, if used, should be stopped immediately to stop worsening the disease.

  • L-Dopa is not known to help with Parkinson's disease.

Conclusion:

Adult-onset basal ganglia disease or neuroferritinopathy is a genetically inherited disease, and unfortunately, there is no cure for the condition yet. However, recent advances in science have developed many ways to maintain and manage the symptoms associated with adult-onset basal ganglia disease. In addition, diagnosing the condition earlier can help with better treatment and prognosis.

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Frequently Asked Questions

A series of uncommon hereditary illnesses known as NBIA (Neurodegeneration with Brain Iron Accumulation) is characterized by aberrant iron accumulation in the brain. These diseases are often incurable and might produce neurological symptoms that worsen with time. Exercise physiology, physical or occupational therapy, or speech pathology may all be used as symptomatic and supportive treatments.

Iron in the brain is not a temporary condition; rather, it is a defining trait of many illnesses. Depending on the particular subtype of the ailment, the course of the disease and the prognosis can differ dramatically. While some NBIA types advance gradually over many years, others may do so very quickly. Individual differences in the symptoms and severity are also rather significant.

Iron is necessary for the brain to operate normally because it is used to make neurotransmitters and myelin, which protects nerve fibers. The brain may not get enough oxygen and minerals when there is a serious iron deficit, which can have an impact on how well it functions. A lack of iron can affect different parts of the body, including the brain. Even though the severe and sustained iron shortage is not frequently linked to irreversible brain damage, it may cause some neurological issues.

Because there is presently no known therapy for these problems, treating iron accumulation in the brain, particularly in the setting of neurodegeneration with brain iron accumulation (NBIA) disorders, is difficult. However, therapeutic strategies mostly concentrate on symptom management and supportive care. Through chelation (binding to free iron atoms) and antioxidant activity, a number of nutrients can help lower the body's overall exposure to iron. These include milk thistle, quercetin, curcumin, and R-lipoic acid.

Iron is a necessary mineral that is vital for many body processes, including brain function. For the health and functionality of the brain to be at its best, iron levels must be adequate. Neurotransmitters are chemical messengers that enable communication between brain nerve cells, and iron plays a role in their creation. Both a lack of iron and an excess of iron can have a negative effect on how well the brain functions. Therefore, it is important for the body to control this process. In a social environment devoid of regular stimuli, brain iron shortage is linked to disturbance of neurophysiological systems that impair the development of motor and cognitive functions.

NBIA is typically predicated on an MRI of the brain that suggests aberrant iron deposition. Magnetic resonance imaging (MRI) characteristic changes and clinical findings can be used to distinguish the majority of neurodegeneration with brain iron accumulation (NBIA) illnesses.

NBIA is a rare condition. There are ten NBIA genes known so far, eight of which are autosomal recessive, one of which is autosomal dominant, and one of which is X-linked dominant. Although prevalence statistics are lacking, all forms of NBIA are regarded as affecting fewer than 1/1000000 people.

Dementia, known as limbic-predominant age-related TDP-43 encephalopathy (LATE), has only recently been identified. Although LATE affects memory and thinking issues, it differs from other types of brain illnesses, like Alzheimer's disease, regarding its underlying causes.

Yes, having too much iron in the brain has the potential to harm the brain. For many physiological functions in the body, including brain function, iron is a crucial mineral. However, when iron levels rise too high or become out of control, it can cause oxidative stress and brain cell damage.

Blood tests are frequently used to assess systemic iron levels in order to identify iron deficiency. However, clinical assessment and imaging methods may be used to infer brain iron insufficiency indirectly. Quantitative susceptibility mapping is a sort of MRI scan that examines various brain regions and counts the amount of iron in each one.

Yes, nerve damage can result from low iron levels in the body. Because iron is necessary for the nervous system to operate normally, low iron levels can prevent it from doing so, which could cause nerve injury. Myelin, a protective covering over nerve fibers that enables effective transmission of nerve signals, is produced in large part by iron. Myelin production and maintenance can be hampered by low iron levels, which can cause demyelination and consequent nerve injury.

Depending on the exact subtype of Neurodegeneration with Brain Iron Accumulation (NBIA), the age of onset, and the rate of illness development, the life expectancy of those with NBIA can vary greatly. The prognosis for the many subtypes of the rare genetic illnesses known as NBIA can vary. Although life expectancy varies, the average time after diagnosis is 10 to 12 years. Dystonia, difficulty swallowing, and aspiration pneumonia can all lead to death. Currently, there is no treatment for NBIA.

The term "late-onset NBIA" refers to a collection of hereditary illnesses that cause aberrant iron buildup in the brain, which causes neurodegeneration and a variety of neurological symptoms. Usually, specific gene mutations are linked to these illnesses. Late-onset Neurodegeneration with Brain Iron Accumulation (NBIA) is a term used to describe a subset of NBIA illnesses that develop symptoms and proceed later in life, usually after childhood or adolescence. The phrase "early-onset NBIA" is used, however, when symptoms start during childhood or adolescence.

Yes, an iron shortage may result in psychological issues. In order for the brain and neurological system to operate normally, iron, a vital nutrient, is required. On mental health and cognitive function, inadequate iron levels can have a variety of impacts. Low iron levels in the body may increase the risk for a wide range of mental health conditions, including anxiety and depression. Iron is an important ingredient for brain functions that might influence psychological behaviors.

Ceruloplasmin malfunction leads to an iron buildup in the brain and viscera. A low level of serum copper, iron, and ceruloplasmin contrasts with a high level of serum ferritin. Ceruloplasmin malfunction leads to an iron buildup in the brain and viscera. A low level of serum copper, iron, and ceruloplasmin contrasts with a high level of serum ferritin.

One surgical treatment for various neurological diseases, such as some types of Neurodegeneration with Brain Iron Accumulation (NBIA), is Deep Brain Stimulation (DBS). DBS includes implanting electrodes in particular brain regions, which are afterward attached to a neurostimulator that sends electrical impulses. Another alternative for treating dystonia in NBIA patients is deep brain stimulation (DBS), which is most frequently utilized in people with PKAN.

Iron deposition in brain cells must be strictly controlled to avoid harmful effects. Reactive oxygen species (ROS), particularly the hydroxyl radical, are produced by excess iron and can cause oxidative stress. The neurological movement illness known as neurodegeneration with brain iron accumulation (NBIA) is rare, hereditary, and characterized by aberrant iron buildup in the brain and advancing nervous system deterioration.

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Dr. Abhishek Juneja from iCliniq
Dr. Abhishek Juneja

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