CoPAN

An ultra-rare form of NBIA known as CoPAN, or COASY Protein-Associated Neurodegeneration, is caused by a mutation in the COASY (Coenzyme A Synthase) gene on chromosome 17. CoPAN is so rare that only a few cases have been identified in the world.

Onset typically occurs in childhood, presenting first with spasticity and dystonia of the lower limbs and later with dystonia of the mouth and jaw. Speech problems also occur, including stuttering and slurring words caused by dysarthria (weakened muscles needed for speaking).

Clinical Diagnosis

CoPAN can be diagnosed through an MRI (T2-weighted) scan of the brain.

Based on one individual’s scan, the MRI showed hypointensity, or a darkened area that can indicate iron deposits, in the brain’s substantia nigra and globus pallidus. In another case, the scan showed hyperintensity (white spots that highlight problematic regions) and swelling in the brain’s caudate nuclei, putamina and thalamus. A third individual’s scan showed calcifications in the globus pallidus.

The diagnosis of CoPAN can be confirmed through genetic testing of the COASY gene to identify mutations.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with CoPAN, the following evaluations may be useful:

• A neurologic examination for dystonia, rigidity, spasticity and parkinsonism, including a formal evaluation for walking (ambulation) and speech.
• An informal developmental assessment, with a referral for more formal testing if a delay is indicated.
• An assessment for physical therapy, occupational therapy, and/or speech therapy, as well as appropriate assistive devices.
• A psychiatric assessment for possible obsessive-compulsive behavior.

Management

While there is no standard treatment for CoPAN, symptom management is available. Most are aimed at dystonia, which can be debilitating. Management tactics used with varying degrees of success include:

• Oral medications: baclofen, anticholinergics, tizanidine and dantrolene
• Botox: focal injections of botulinum toxin into muscles affected by dystonia. Botox can provide relief for several months from involuntary contractions, twisting, abnormal posture or changes in a person's voice or speech. Because each affected muscle must be injected, this is most practical when an individual has dystonia significantly affecting a specific body area, such as the hand or jaw. Resistance to Botox is a phenomenon, which may cause the treatment to lose its effectiveness over time. This occurs because the body makes antibodies to combat the toxin.
• Intrathecal baclofen therapy: Although baclofen is usually taken orally, a baclofen pump may be an option for some individuals. An evaluation can be done to determine whether a patient would respond positively to a pump, which is surgically implanted under the skin of the abdomen.
• DBS: deep brain stimulation. This involves placing electrodes in the brain and attaching the wires to a battery-operated neurostimulator implanted in the chest. The neurostimulator sends pulses to targeted areas in the brain and takes “offline” the part sending too many signals and causing the muscles to move in painful ways. DBS is the most commonly performed surgical treatment for Parkinson's disease.

The symptoms of parkinsonism in NBIA individuals can be treated with the same medications used in Parkinson’s disease.

More information on these therapies can be found in the Medical Information section of our website.

Notice if the individual has problems swallowing to prevent aspiration. Additionally, pay attention to diet and regularly measure height and weight in children to assure adequate nutrition. A gastrostomy tube can be placed if needed. Clinicians also recommend assessing ambulation and speech and communication needs. While the symptoms of CoPAN typically progress slowly, individuals in their 30s often have lost their ability to walk and must use a wheelchair.

Genetics

CoPAN is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one from the mother, one from the father), we normally carry two working copies of each gene. When a person has one copy of a recessive gene with a change (mutation) in it, the individual is not affected by the disease. That person is called a carrier.

Recessive diseases only occur when both parents are carriers for the same diseaseand pass their mutated genes onto their child. Statistically, there is a one in four chance that two carriers would have an affected child. The chance is two in four that two carriers would have a child who is also a carrier, and it’s one in four that the child will not have the mutation. Carrier testing for relatives and prenatal testing for at-risk pregnancies are suggested if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

When the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks of gestation.

Alternatively, the chorionic villus, the tiny finger-like projections on the edge of the placenta, are tested, usually at 10 to 12 weeks gestation. Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families.

Natural History Studies

Researchers conduct natural history studies to understand changes in disease-affected individuals over time. The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany and was created under an EU grant from 2011-2015 called Treat Iron-Related Childhood-Onset Neurodegeneration.

The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 16 countries have provided patient clinical data. There are over 750 entries consisting of NBIA patients and controls as of September 2021. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry.

CoPan Research

The recessive mutations in CoA Synthase (COASY) that cause COPAN were first uncovered in 2013 by Sabrina Dusi of The Firc Institute of Molecular Oncology, a research center in Milan, Italy. This study used exome sequencing for individuals who had an NBIA clinical presentation and neuroimaging indications but lacked the mutations in previously discovered genes. It resulted in this publication:Exome Sequence Reveals Mutations in CoA Synthase as a Cause of Neurodegeneration with Brain Iron Accumulation

Coenzyme A (CoA) is important to all living organisms because of its involvement in numerous enzymatic reactions. It is a key molecule for metabolizing fatty acids, carbohydrates, amino acids and ketone bodies. The last two steps of its biosynthesis are carried out by CoA Synthase, where the COPAN mutation occurs. Normal Coenzyme A Synthase is crucial for healthy nervous system function.

Because CoPAN is so rare, more studies are needed to better understand it.

Idiopathic NBIA

Idiopathic NBIA is of unknown origin, although it is suspected to be genetic. For many families, the person diagnosed with NBIA is the first and only affected individual, so it is difficult to know whether there is a specific pattern of inheritance. It is thought that most of these cases are probably recessive because some families have more than one affected child and idiopathic NBIA is more common in families in which the parents are related, such as distant cousins. That would make it more likely that they share a recessive gene.

The symptoms are more varied because there are probably several different causes of neurodegeneration for individuals in this group. As with other forms of NBIA, the idiopathic form features early- and late-onset types. Currently, about five percent of those diagnosed with NBIA are believed to be in this group.

Clinical Diagnosis

Suspicion of NBIA usually arises when an MRI of the brain shows excessive iron accumulation, along with a movement disorder. Depending on symptoms, genetic testing is done to rule out other forms of NBIA or other genetic disorders. If all are negative, but the findings are characteristic of NBIA, then the diagnosis of Idiopathic NBIA is given until further evidence of the genetic origin or another cause is determined.

Evaluations Following Initial Diagnosis

• Neurologic examination for movement disorders, including dystonia, rigidity, spasticity and choreoathetosis, which are involuntary movements that include contractions, twisting and writhing. Walking ability and speech also are assessed.
• An eye exam to check for such problems as retinopathy (damage to the small blood vessels in the retina) and optic atrophy (the loss of some or most of the fibers of the optic nerve).
• Developmental screening, with referral for more formal testing if delay is indicated.
• Assessment to see if physical therapy, occupational therapy and/or speech therapy are warranted.
• Assessment of behavior and neuropsychiatric changes.
• Medical genetics consultation.

Management

Doctors treat patients with medication when appropriate. Also, affected individuals may need a feeding tube or other assistance to achieve adequate nutrition. Other therapies might also be warranted.

Genetics

Testing to find the gene responsible for an individual’s form of NBIA may be pursued.

Prenatal Testing

In the absence of a known genetic mutation, testing during pregnancy to assess risk is not possible.

Research

Researchers continue their search for remaining genes that cause NBIA disorders, and much progress is being made with new technology. If a new gene is found by researchers, the person’s samples will be examined to see if they have mutations and their form of NBIA identified. Affected individuals diagnosed with Idiopathic NBIA might want to participate in the TIRCON International Patient Registry.

Beta-propeller
Protein-associated
Neurodegeneration (BPAN)

Beta-propeller Protein-Associated Neurodegeneration

(BPAN) is caused by mutations in the WDR45 gene on the X chromosome. It is inherited in an X-linked dominant manner, meaning that a single copy of the mutated gene is enough to cause disease in both males and females. Most affected individuals identified so far have been simplex, or isolated, cases; they are the only person in their family to have the disease. The majority are females, indicating the mutations are new, or de novo, and suggesting that mutations may be lethal in most males before birth. Rarely, the disorder may also occur in a sibling. In these cases, the mutation was inherited from a mildly affected parent. BPAN is the most common NBIA disorder at 35-45% of the NBIA population, with an estimated prevalence of 2 to 3 per million individuals.

Clinical Features

BPAN has a wide phenotypic spectrum, meaning that symptom presentation and severity can vary greatly among patients. The disease progresses in two stages. The first stage occurs in childhood and is characterized by developmental delay and intellectual disability. Most children are described as clumsy with an ataxic, or unsteady, staggering gait. In addition, children with BPAN usually show expressive language delay disproportionate to their other disabilities. Consequently, most individuals with BPAN can only speak a few words.

Several other common features are sleep disorders, seizures and ocular defects, such as retinal and optic nerve disease. Individuals may present with some autistic features, such as involuntary, repetitive and seemingly meaningless hand movements and other repetitive behaviors.

Many families report that their young children with BPAN have difficulty falling asleep and staying asleep, and thus tend to sleep in spurts. The abnormal sleep patterns may be caused by unrecognized nocturnal seizure activity, dysregulation of the sleep cycle, sleep-disordered breathing, reflux or spasticity.

Seizures are a common symptom of BPAN. Beginning in infancy and early childhood, they occur in about two-thirds of children with BPAN and typically cease in adolescence. They often start as febrile, or fever, seizures in a young child. Other types of seizures in BPAN individuals include generalized seizures, focal seizures with impaired consciousness, and epileptic spasms. Focal seizures begin in one area of the brain, while generalized seizures occur in both hemispheres of the brain at the same time. Generalized seizures can be categorized in the following ways:

• Absence: brief, sudden lapses of consciousness
• Tonic: sudden tension or stiffness that may affect the arms, legs or body, lasting about 20 seconds and occurring typically during sleep
• Tonic-clonic: loss of consciousness in which muscles stiffen and jerking movements last one to three minutes
• Myoclonic: brief, shock-like jerks of a muscle or group of muscles, in which the person is usually awake and able to think clearly

Seizure patterns can be similar to those of epileptic syndromes such as West syndrome and Lennox-Gastaut syndrome. Seizures are typically worse in early childhood and lessen with age.

Typically, BPAN individuals lose brain cells and tissue in the cerebral area of the brain, a condition called generalized cerebral atrophy. During adolescence or adulthood, affected individuals experience a relatively sudden onset of progressive dystonia-parkinsonism and cognitive decline.

Parkinsonism is caused by the degeneration of nerve cells in the brain and is characterized by tremors and shaking, slow movements, stiffness in the arms, legs or trunk, instability while standing, and frozen gait, which is a pause in one’s attempt to move forward when walking.

Dystonia, a movement disorder in which a person’s muscles contract uncontrollably, also is common. The affected body part will twist involuntarily, resulting in repetitive movements. This can affect a single muscle, a muscle group or the entire body.

BPAN is progressive, meaning the symptoms worsen over time.

Clinical Diagnosis

Delayed development and other symptoms often lead to genetic testing to uncover a diagnosis. Since BPAN is very rare and often not suspected, it typically is diagnosed with Whole Exome Sequencing (WES), which looks at all the protein-coding regions of the genome. Whole Genome Sequencing (WGS) is becoming more common, as this test looks at the entire genome and is the most extensive one currently available.

As a child progresses into adolescence, evidence of the disease can be seen in a brain MRI that shows iron accumulation in the basal ganglia, specifically in the substantia nigra and globus pallidus. Early imaging findings include mild white matter volume loss, delayed myelination and a thin corpus callosum. However, a young child with BPAN may have a normal brain MRI.

One possibly unique feature of BPAN can be detected on an MRI of the brain: the presence of a bright halo seen in a certain view (T-1 weighted) in the substantia nigra and cerebral peduncles. Hyperintense signal (an abnormality that shows as bright white on an MRI) in this region seems to appear at the same time or soon after the symptoms of progressive dystonia-parkinsonism emerge. On an MRI T-2 weighted view, a hypointense signal (an abnormality that appears dark on the MRI) appears in the substantia nigra that is usually detectable early in the second decade of life and possibly sooner.

Symptom Management

Various types of treatments help manage symptoms. Because symptom severity and complexity varies widely, management should be tailored to the individual. Individuals will benefit from routine follow-up by a neurologist for medication management and interval assessment of neurological regression, ambulation, seizure activity, speech, sight and swallowing.

Anti-seizure medication is recommended for children with recurrent, unprovoked seizures. Many children will outgrow their seizures and may be taken off the medication in adolescence as directed by their doctor.

Dopaminergic drugs, which mimic the effects of dopamine, a chemical involved in movement, are sometimes given for parkinsonism. Those drugs need to be further monitored for adverse neuropsychiatric effects and disabling motor fluctuations and dyskinesias (abnormal, uncontrollable, involuntary movements).

Other therapies that can help BPAN individuals include physical therapy to address gross motor dysfunction, maximize mobility and reduce the risk of later-onset orthopedic complications. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function, such as feeding, grooming and dressing. Feeding therapy, by an occupational or speech therapist, is recommended for difficulty feeding due to poor oral motor control.

Since most individuals are nonverbal or can only say a few words, speech therapy is recommended to help with augmentative and alternative communication. If the child also has autism symptoms, a comprehensive treatment model is recommended that may include applied behavior analysis and developmental approaches to support communication. All children with BPAN should have a formal audiological evaluation.

Developmental delays and intellectual disabilities are often managed in school through an individualized education plan (IEP).

Genetics

With genetic testing available, a BPAN diagnosis during childhood is now possible. Earlier detection also gives families an opportunity to find others with the same diagnosis for emotional support and advice on therapies. It further enhances the ability to participate in research and may enable earlier intervention for subtle symptoms of parkinsonism.

After a child is diagnosed, parental testing is recommended. Though most cases are simplex and de novo (only one individual is affected in the family because of spontaneous mutation in the germ cell), cases have been reported in which parents have another child with BPAN.

While many individuals with BPAN do not have children, mildly affected individuals that choose to conceive should seek genetic counseling. The chance to pass on a WDR45 mutation (pathogenic variant) is as great as 50%.

The main resource for the clinical information provided here is BPAN - GeneReviews. GeneReviews is primarily used by genetics professionals, so the terminology and information may be difficult for the general public.

All information is for informational purposes only. We do not endorse specific studies or clinical trials, experimental drugs, procedures, biotech or pharmaceutical companies.

Natural History Studies

BPANready

Oregon Health & Science University has a registry and conducts natural history studies that involve patients or guardians entering data remotely by phone, paper or online. It involves the retrospective use of medical records as well as listing BPAN milestones and patient (or parent) reported outcome measures.

The research team is using Latent Growth Models (LGM) in which latent growth curves model disease progression. Understanding the progression of the disease and how it manifests in different cases will increase clinical knowledge and help researchers identify important avenues for study and treatment.

BPAN families wishing to participate can find more information and register at NBIAcure.

RARE-X BPAN Data Platform

RARE-X is a nonprofit created to accelerate rare disease research, treatments, and cures by removing barriers for data collection and sharing. The Rare-X platform is designed to encourage data-sharing and thus quicken the speed of information and the pace of research into BPAN.

The platform is currently open to BPAN families that speak English, with plans to expand to other languages in the future. Those wishing to participate can access the site at https://bpan.rare-x.org.

The platform is free for families to use. It keeps health information confidential by providing only data that is not attached to individual names. BPAN families and individuals control whether to allow or deny access to their personal health information for any research project.

RARE-X BPAN asks BPAN families about their experiences with the condition through various structured and standardized surveys on various topics which can be updated by families as needed. A researcher who is studying mitochondria for example, can do a query for all relevant information on a specific symptom and might find similarities across various diseases that provide insights into new treatment pathways.

RARE-X provides support, technology, tools and resources necessary for successful data collection, and secure but open data sharing on a global scale.

The platform does not replace other forms of data collection that we have available in our NBIA community such as BPANready, Citizen and the TIRCON International NBIA Registry and Biobank. In fact, these existing projects can be connected to the RARE-X platform and expand the data available to interested researchers.

It is hoped that RARE-X BPAN will enhance our readiness for clinical trials and engage new researchers and biotech companies. It is cloud-based and researchers can query the database in many ways to find data that is brought together rather than in separate silos. The de-identified data never leaves the system. Researchers can link to it but cannot download it.

TIRCON International NBIA Registry

The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany, and was created under an EU grant from 2011-2015 called Treat Iron-Related Childhood-Onset Neurodegeneration.

The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 16 countries have provided patient clinical data. There are over 750 entries consisting of NBIA patients and controls as of September 2021. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry.

Articles

Research

The WDR45 gene was discovered in 2012 by Dr. Tobias Haack of Helmholtz Zentrum München, a German research center. The discovery resulted from a collaborative study involving the lab of Dr. Susan Hayflick at the Oregon Health & Science University. It applied next generation sequencing to individuals suffering from NBIA with no known genetic cause. This study resulted in the finding of the WDR45 gene, causing BPAN, with the findings reported in December 2012 in the American Journal of Human Genetics entitled "Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA."

The focus of the following research has been on finding suitable model organisms to perform pre-clinical testing. These organisms can provide important clues on the cause of disease as well as help develop and test potential treatments through drug screening that can be later translated to clinical trials. It is important that the model mimics the condition seen in patients. Below are various study models for BPAN.

• C. elegans - roundworm
• Drosophila - fruit flies
• Mice
• Pluripotent Stem Cells - skin cells from BPAN patients reprogrammed into neurons to model the disease. This enables scientists to learn more about the progression of the disease and to screen large numbers of small molecule drugs for potential treatment.

Other research areas focus on understanding the role of iron in BPAN and how a WDR45 mutation leads to neurodegeneration.

Many research efforts have indicated that BPAN causes impaired autophagic activity. Autophagy is essential for maintaining a stable environment in cells. It is the process by which cells clean out waste materials. In normal cells, waste materials are aggregated into a sac called the autophagosome and are transported to an organelle called the lysosome. The autophagosome and lysosome fuse and become an autolysosome. The waste is then broken down by enzymes that can digest the waste products and recycle them for further use in the cell.

When neural-specific depletion of genes for autophagosome formation occurs in the brain, it leads to massive neuron loss and axonal degeneration. Neurons and axons are fundamental units of the brain responsible for sending electrical signals to receive sensory information and motor commands to muscles.

Researchers want to understand the role that WDR45 plays in the incredibly intricate cascade of genes and proteins in the autophagy process. Once the precise mechanisms are determined, therapeutic drugs can be tested to target the specific pathways necessary to restore autophagy function in the cell.

Several potential pathways to treatments exist. One is testing known drugs that target neuroinflammation, oxidative stress and mitochondrial dysfunction. Another is gene therapy. This would involve providing a working copy of the WDR45 gene into cells or activating the inactive copy of WDR45 on the X chromosome. Scientists have yet to establish if these are viable options for BPAN.

The 7th International Symposium on NBIA & Related Disorders held Sept. 30 to Oct. 3, 2020, has recorded sessions #14-16 pertaining to BPAN research.

BPAN Research Articles:

Following is a list of BPAN research articles published recently and early papers after the gene discovery. Other free access BPAN articles can be found at Pub Med Central.

Kufor-Rakeb Syndrome, also known as Parkinson’s Disease 9 (PARK9), is an ultra-rare form of NBIA inherited in an autosomal-recessive manner. It is characterized by juvenile-onset parkinsonism and dementia.

Kufor-Rakeb is named for the village in Jordan where it was first described in 1994. In 2006, a mutation in the ATP13A2 gene was deemed responsible. Fewer than 50 affected individuals have been diagnosed with Kufor-Rakeb. They live in the US, Italy, South America, the Middle East and Asia.

Clinical Diagnosis

Brain CT and MRI scans may show diffuse, or widespread, moderate cerebral, cerebellar and brain stem atrophy. Iron accumulation in the basal ganglia affecting the putamen and caudate is present in some, but not all, individuals.

Disease onset is usually in adolescence. Parkinsonism is caused by the degeneration of nerve cells in the brain and is characterized by tremors and shaking; slow movements; stiffness in the arms, legs or trunk; instability while standing; and freezing of gait.

Key Clinical Manifestations:

• Parkinsonism
• Dementia (progressive cognitive decline)
• Supranuclear gaze palsy (inability to look in a particular direction because of cerebral impairment)
• Facial-faucial-finger myoclonus (involuntary jerking of the facial and finger muscles)
• Visual hallucinations
• Oculogyric dystonic spasms (involuntary intermittent or sustained deviation of the eyes in a usually upward direction)

Symptom onset often leads to genetic testing to search for a diagnosis. Because Kufor-Rakeb is so rare and not often suspected, it is often diagnosed with Whole Exome Sequencing (WES), which looks at all the protein coding regions of the genome. Whole Genome Sequencing (WGS) is becoming more common. It looks at the entire genome and is the most extensive test available at this time.

Genetics

Kufor-Rakeb is caused by a mutation in the ATP13A2 gene and is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change (mutation) in it, the person should still have normal health. That person is called a carrier.

Recessive diseases only occur when both parents are carriers for the same condition and pass their changed genes on to their child. Statistically, there is a one in four chance that two carriers would have an affected child. There is a two in four chance the parents will have a child who is also a carrier. The chances are one in four that the child will not have the gene mutation. Carrier testing for relatives and prenatal testing for at-risk pregnancies are suggested if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

When disease-causing mutations are identified in a family, prenatal diagnosis for pregnancies can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation. Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families.

Treatments

There is no cure for Kufor-Rakeb syndrome, but treatments are available to manage symptoms. As symptom severity and complexity varies widely, management should be tailored to the individual. Individuals will benefit from routine follow up by a neurologist for medication management and interval assessment of motor and cognitive functioning.

Treatment of Kufor-Rakeb syndrome often resembles treatment of typical Parkinson’s disease. Commonly, two medications, levodopa (L-DOPA) and carbidopa, are combined.

Other therapies also may benefit individuals with Kufor-Rakeb Syndrome. Physical therapy often is recommended to address gross motor dysfunction, maximize mobility and reduce risk of later onset orthopedic complications. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function, such as feeding, grooming and dressing. Feeding therapy by an occupational or speech therapist is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Clinical Trials

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies as they become available.

Research Articles:

Following is a list of relevant published research articles. Other free access articles can be found at Pub Med Central.

2020 - Kufor-Rakeb Syndrome/Parkinson Disease Type 9

2018 - Action Myoclonus and Seizure in Kufor-Rakeb Syndrome

2015 - The role of ATP13A2 in Parkinson's disease: Clinical phenotypes and molecular mechanisms

2014 - Mutations in the ATP13A2 Gene and Parkinsonism: A Preliminary Review

2012 - Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis | Human Molecular Genetics | Oxford Academic

2011 - Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein

2006 - Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase

Woodhouse-Sakati

Woodhouse-Sakati Syndrome (WSS) is caused by a mutation in the DCAF17 gene, which causes malformations in the body and deficiencies in the endocrine system. The endocrine system normally has feedback loops of hormones released by the body’s internal glands, but when that loop is disrupted, a variety of body functions can be affected.

WSS is ultrarare, with fewer than 100 affected individuals reported in the medical literature. Two types of WSS have been described with varying prognoses, and both can occur within the same family:

• Type 1: Severe and progressive neurologic disability at a younger age, which causes significant impairment to the individual’s quality of life
• Type 2: Absent or mild neurological involvements that do not have a profound impact on the individual’s quality of life

Clinical Features

Woodhouse-Sakati Syndrome is a multisystem disorder featuring such symptoms as hypogonadism (too little hormone for normal sex gland functioning), alopecia (hair loss), diabetes, intellectual deficits and dystonia, a movement disorder common in NBIA. Individuals with WSS present endocrine findings of hypogonadism during puberty. These affected individuals also have progressive childhood-onset hair thinning that will oftentimes develop into alopecia in adulthood. Patients may also experience slurred or slowed speech because of weakness in mouth muscles, known as dysarthria; difficulty swallowing, called dysphagia; seizures; and sensory polyneuropathy, the simultaneous breakdown of many peripheral nerves, making it difficult for individuals to move or feel physical sensations.

People with WSS may experience sensorineural deafness — hearing loss caused by dysfunction of the vestibulocochlear (auditory) nerve, inner ear, or central processing center of the brain. Hearing loss can range from mild to total.

Craniofacial abnormalities also may be present, including a high forehead, triangular face, prominent nasal root, an increased distance between the eyes and a flattened occiput (back of the head). Also possible are scoliosis, a sideways curvature of the spine; hyperreflexia, or overactive reflexes, and camptodactyly, a condition in which the finger(s) stay in a bent position.

Clinical Diagnosis

T2 weighted imaging, which is a basic pulse sequence on an MRI, can indicate iron accumulation in the brain. When that coincides with hair loss, diabetes, hearing loss, gonadal dysfunction and intellectual disabilities Woodhouse-Sakati Syndrome is indicated. Onset is typically in adolescence. An ECG may also pick up flattened T waves in WSS individuals.

Neuroimaging findings on an MRI include:

• Partially empty sella, the compartment that houses the pituitary gland. The space is often filled with cerebrospinal fluid, and the pituitary gland is smaller than normal.
• Progressive white matter lesions in the brain’s frontoparietal region.
• Iron deposits in the brain’s globus pallidus as well as in the substantia nigra (the part of the basal ganglia that controls movement) and, to a less extent, the red nucleus, part of the ventral midbrain that controls limb movements, especially when reaching.

Symptom Management

Various treatments can help manage different symptoms, and oversight by a multidisciplinary team is needed.

Hypogonadism requires hormone replacement therapy to develop secondary sex characteristics and aid bone health during puberty. Alopecia is treated on a symptomatic basis and is done only for cosmetic reasons. Speech therapy can be beneficial to dysarthria. Dysphagia typically requires extra measures to lower oral secretions, such as pureed food and thick liquids to avoid aspiration, and, potentially, a gastrostomy (direct access to stomach for a feeding tube). Standard treatments also are available for symptoms such as diabetes, hypothyroidism, hearing loss and intellectual disabilities.

Options for managing dystonia include oral medications, botox injections to help relieve involuntary contractions and deep-brain stimulation.

Please see our Medical Information section for more in-depth information on these therapies.

Monitoring symptoms is recommended as follows:

• Hypogonadism: beginning at ages 12-14
• Diabetes/hypothyroidism: starting at age 20
• Insulin-like growth factor (IGF-1): every three to five years after diagnosis
• Dystonia: annual neurological assessments
• Dysarthria/dysphagia: assessments as needed
• Intellectual development: annual assessments throughout childhood
• Hearing loss: annual audiology evaluations

Genetics

Woodhouse-Sakati Syndrome is an autosomal recessive disorder, meaning it is passed to the offspring when both parents are carriers. Statistically, there is a one in four chance that two carriers will have a child with WSS; a two in four chance that their child will be a carrier; and a one in four chance that their child will not receive the gene mutation.

Carrier testing for at-risk relatives and prenatal testing for pregnancies are suggested if there is an affected family member.

Prenatal Testing

If the disease-causing genetic mutation has been identified within the family, prenatal diagnosis for at-risk pregnancies can be done. DNA can be extracted from fetal cells and then analyzed around 15 to 18 weeks gestation. Alternatively, sampling of the chorionic villus, the tiny projections on the edge of the placenta, can be done around 10 to 12 weeks gestation.

Embryo screening, also known as preimplantation genetic diagnosis, may be an option for some families.

Note

The main resource for this clinical information is Woodhouse-Sakati Syndrome - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult for the general public to understand.

Natural History Studies

TIRCON International NBIA Registry

The TIRCON International NBIA Registry was created under a European Union grant called Treat Iron-Related Childhood-Onset Neurodegeneration to act as a clearinghouse for data on NBIA disorders. Grant funding ran from 2011 to 2015, and the project is housed at Ludwig Maximilian University of Munich, Germany. The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 12 countries take part in the registry by entering their patient data. As of September 2021, over 750 entries were in the registry consisting of NBIA patients and controls. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA. For more information on the registry, contact Anna Baur-Ulatowska Anna.Baur@med.uni-muenchen.de.

Research Publications and Articles

Following is a list of some recent research articles. Others can be found at PubMed Central.

2021 - A Deletion Variant in the DCAF17 Gene Underlying Woodhouse-Sakati Syndrome in a Chinese Consanguineous Family

2019 - Patterns of neurological manifestations in Woodhouse-Sakati Syndrome

2018 - Brain MR Imaging Findings in Woodhouse-Sakati Syndrome

2017 - Endocrine manifestations of Woodhouse-Sakati Syndrome – a Portuguese case

2008 - Mutations in C2orf37, Encoding a Nucleolar Protein, Cause Hypogonadism, Alopecia, Diabetes Mellitus, Mental Retardation, and Extrapyramidal Syndrome

Neuroferritinopathy

Neuroferritinopathy is a genetically dominant form of NBIA. That means it can be inherited if only one parent has the mutated gene. Although the prevalence is unknown, only about 100 cases have been reported, and most share the same gene change, suggesting a common ancestor. It is caused by mutations in the FTL gene, which stands for ferritin light. This is one of two sub-proteins that make up ferritin, a protein in the body that helps store and detoxify iron. MRIs are different from those of other NBIA patients.

Clinical Diagnosis

The effects of neuroferritinopathy typically begin around age 40, although onset in the early teenage years and in the sixth decade have been recorded. A family history consistent with autosomal dominant transmission are indicative of this disorder.

Individuals with neuroferritinopathy typically present with either dystonia or chorea. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. This usually affects one or two limbs. Mild changes in thinking (cognitive effects) can also occur at this time.

Within 20 years of onset, neuroferritinopathy usually begins to affect movement in all the limbs. It also causes difficulty speaking and resembles Huntington’s disease. Cognitive deficits and behavioral issues worsen over time.

Serum ferritin concentration may be low. Eye movements are usually not affected throughout the disease course. Axonal swellings (neuroaxonal spheroids) may be present.

From the onset, all affected individuals have evidence of excess brain iron accumulation on T2-weighted MRI views of the brain. Later stages are associated with high signal on T2-weighted MRI in the caudate, globus pallidus, putamen, substantia nigra and red nuclei. This is followed by cystic degeneration in the caudate and putamen.

a. Non-contrast brain CT symmetric low signal in the putamina

b. T2-weighted MRI image showing cystic change involving the putamina and globus pallidi and with increased signal in the heads of the caudate nuclei [Crompton et al 2005]

Table taken from Neuroferritinopathy - GeneReviews® - NCBI Bookshelf

Evaluations Following Initial Diagnosis

Psychometric, physiotherapy, speech therapy and dietary assessments should be made.

Management

The movement disorder is particularly resistant to conventional therapy, but records show some patients have responded to levodopa, tetrabenazine, orphenadrine, benzhexol, sulpiride, diazepam, clonazepam and deanol in standard doses. [Chinnery et al 2007, Ondo et al 2010]. Botulinum toxin is helpful for painful focal dystonia.

Dietary assessment is helpful. Affected individuals should be evaluated to ensure that they maintain caloric intake. Physiotherapy can help maintain mobility and prevent tightening of muscles, ligaments or skin.

Genetics

Because neuroferritinopathy is inherited in an autosomal dominant manner, a person affected with neuroferritinopathy has one working copy of the affected gene and one copy that has a change or mutation. This single mutation is enough to cause the disease. There is a one in two chance (50%) that an affected individual will pass the gene change on to his or her children. Most individuals diagnosed with neuroferritinopathy have one affected parent. The proportion of cases caused by de novo (new) mutations is unknown.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.

Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.

Note

A main resource for this clinical information is Neuroferritinopathy - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult for the general public to understand.

TIRCON International NBIA Registry

The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany, and was created under an EU grant from 2011-2015 called Treat Iron-Related Childhood-Onset Neurodegeneration.

The NBIA Alliance and other sources have provided funding since 2015. Clinical centers from 16 countries have provided patient clinical data. There are over 750 entries consisting of NBIA patients and controls as of September 2015. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni.muenchen.de for more information on this registry.

Clinical Trials

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies.

Neuroferritinopathy Research Publications and Articles

Other research articles and studies can be found at Pub Med Central.

Following is a list of recent Neuroferritinopathy research articles:

2021 - Pathogenic mechanism and modeling of neuroferritinopathy

2021 - New Insights into the Role of Ferritin in Iron Homeostasis and Neurodegenerative Diseases

2020 - Neuropathological and biochemical investigation of Hereditary Ferritinopathy cases with ferritin light chain mutation: Prominent protein aggregation in the absence of major mitochondrial or oxidative stress

2019 - Stem Cell Modeling of Neuroferritinopathy Reveals Iron as a Determinant of Senescence and Ferroptosis during Neuronal Aging

2016 - Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy

2016 - Neuroferritinopathy: Pathophysiology, Presentation, Differential Diagnoses and Management

2015 - Neuroferritinopathy: From ferritin structure modification to pathogenetic mechanism

Aceruloplasminemia

Aceruloplasminemia was first described in 1987 as an autosomal recessive disease, meaning that an affected individual has inherited the defective gene from both parents. The disorder is caused by a mutation of the ceruloplasmin gene (CP), which is inactivated. The estimated prevalence of this disease is about one in 2 million. It has been mainly studied in Japan, where it is most prevalent.

While other NBIA disorders cause iron accumulation in the brain, aceruloplasminemia is unique in that it causes iron overload not only in the brain but also in other organs such as the liver, pancreas and heart.

The main symptoms are retinal degeneration, diabetes and neurologic disease related to iron build-up in the brain’s basal ganglia. Movement problems include face and neck dystonia (involuntary muscle contractions, with repetitive movements or painful postures), blepharospasm (eyelid spasms), tremors and jerky movements.

Clinical Diagnosis

Individuals with aceruloplasminemia often present to doctors with anemia before the onset of diabetes mellitus or neurologic symptoms. Physical traits, known as phenotypic expression, vary, even within families.

The classical disease triad of aceruloplasminemia is diabetes, retinopathy and neuropathy. Diabetes mellitus is considered an early sign. It was reported as the first symptom in 68.5% of patients at a median age of 38.5 years (Vroegindeweij et al., 2015). Retinal symptoms are reported in over 75% of Japanese patients (Kono, 2012). These retinal manifestations do not affect visual acuity.

Neurological symptoms usually appear in the fifth decade of life and vary within a wide spectrum that includes cerebellar ataxia (sudden, uncoordinated muscle movement), involuntary movements, parkinsonism (movement disorder), mood and behavior disturbances, and cognitive impairment.

Physicians may do an MRI to assist in diagnosing patients. The MRI will show signs of iron accumulation in the brain (striatum, thalamus, dentate nucleus) and liver on both T1- and T2-weighted images. The images also will indicate the absence of serum ceruloplasmin, a copper-containing protein, and some combination of the following: low serum copper concentration, low serum iron concentration, high serum ferritin (a protein that enables cells to store iron) concentration and increased iron concentration in the liver. Laboratory blood tests can also test these concentrations.

Age at onset is 25 to 60, and older. Psychiatric problems in patients include depression and cognitive dysfunction in individuals older than 50.

When phenotypic and laboratory findings suggest the diagnosis of aceruloplasminemia, molecular genetic testing can include single gene testing, multigene panels or comprehensive genomic testing.

Evaluations Following Initial Diagnosis

To establish the extent of disease and the individual’s needs, evaluations for the following are recommended:

• Iron deposits. Serum ferritin concentration, brain and abdomen MRI findings, and hepatic (liver) iron and copper content by liver biopsy
• Neurologic findings. Brain MRI and protein concentration in cerebrospinal fluid
• Diabetes mellitus. Blood concentrations of insulin and HbA1c, a test of blood sugar levels
• Retinal degeneration. Examination of the optic fundi, the interior linking of the eyeball, and fluorescein angiography, a test to examine blood vessels in the retina, choroid and iris of the eye
• Anemia. Complete blood count
• Medical genetics consultation

Annual glucose tolerance tests starting at age 15 are recommended to evaluate the onset of diabetes mellitus. A cardiac evaluation should be performed early in the course of the disease and repeated every year. Finally, evaluation of thyroid and liver function and complete blood count are indicated annually starting at the time of diagnosis.

Management

Treatment is focused on reducing iron overload using iron chelating agents, such as desferrioxamine, deferasirox and deferiprone. While iron chelation therapy (ICT) was effective in reducing systemic iron overload, it was not effective on neurological symptoms [Kono 2013; Dusek et al., 2016]. It also must often be discontinued due to iron deficiency anemia.

More research needs to be done on the therapeutic efficacy of ICT in aceruloplasminemia. There is no information on whether it can improve glucose metabolism and retinopathy, and only short-term studies have been done on the effect on neurological symptoms. It is possible that the treatment would be more effective if started in the window between the appearance of the first signs of disease and the neurological symptoms. Zinc sulfate and minocycline have been proposed as alternatives to ICT due to their antioxidant properties. The results are promising but are limited to only two patients [Kuhn et al. 2007; Hayashida et al., 2016].

In some cases, ICT was combined with fresh-frozen plasma (FFP) administration. FFP can partially/temporarily restore circulating ceruloplasmin (Cp). A 2017 case report suggests that the early initiation of combined treatment with FFP and iron chelation may be useful to reduce the accumulation of iron in the central nervous system and improve neurological symptoms.

Genetics

Aceruloplasminemia is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change or mutation, the person should still have normal health. That person is called a carrier.

Recessive diseases only occur when both parents are carriers for the same condition and then pass their changed genes onto their child. Statistically, there is a one in four chance that two carriers would have an affected child. The chance is one in four that their child will not be a carrier.

Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are possible if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells through amniocentesis (usually at 15 to 18 weeks’ gestation) or sampling of the chorionic villus - the finger-like projections that emerge from the outer sac surrounding the fetus - (usually at 10 to 12 weeks’ gestation).

Screening embryos before they become implanted may be an option for some families in which the disease-causing mutations have been identified.

Note

A main resource for this clinical information is Aceruloplasminemia - GeneReviews - NCBI Bookshelf. GeneReviews is primarily for the use of genetics professionals so the terminology and information may be difficult to understand for the general public.

TIRCON International NBIA Registry

The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany, and was created under an EU grant from 2011-2015 called Treat Iron-Related Childhood-Onset Neurodegeneration.

The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 16 countries have provided patient clinical data. There are over 750 entries consisting of NBIA patients and controls as of September 2021. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry. 

Clinical Trials

Clinical trial information can be found at ClinicalTrials.gov by searching for aceruloplasminemia. Currently, one study is in the recruitment process at First Affiliated Hospital of Fujian Medical University. More information can be found at Clinical Curative Effect Evaluation Study of Treatment of Oral Deferiprone Tablets in Aceruloplasminemia.

Aceruloplasminemia Research Publications and Articles

Following is a list of recent aceruloplasminemia research articles. Other research articles and studies can be found at Pub Med Central.

2020 - Genetic and Clinical Heterogeneity in Thirteen New Cases with Aceruloplasminemia. Atypical Anemia as a Clue for an Early Diagnosis

2020 - Deferasirox Might Be Effective for Microcytic Anemia and Neurological Symptoms Associated with Aceruloplasminemia: A Case Report and Review of the Literature

2019 - Aceruloplasminemia: A Severe Neurodegenerative Disorder Deserving an Early Diagnosis

2018 - Aceruloplasminemia: Waiting for an Efficient Therapy

2018 - Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia

2017 - Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment

2016 - Iron chelation in the treatment of neurodegenerative diseases

2016 - Aceruloplasminemia With Psychomotor Excitement and Neurological Sign Was Improved by Minocycline (Case Report)

2015 - Combination‐therapy with concurrent deferoxamine and deferiprone is effective in treating resistant cardiac iron‐loading in aceruloplasminaemia

2015 - Aceruloplasminemia presents as Type 1 diabetes in non‐obese adults: a detailed case series

2013 - Aceruloplasminemia: an update

2012 - Aceruloplasminemia

2007 - Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate

2006 - Molecular and pathological basis of aceruloplasminemia

Cited on Page

Dusek P., Schneider S. A., Aaseth J. (2016). Iron chelation in the treatment of neurodegenerative diseases. J. Trace Elem. Med. Biol. 38 81–92. 10.1016/j.jtemb.2016.03.010 [PubMed]

Hayashida M., Hashioka S., Miki H., Nagahama M., Wake R., Miyaoka T., et al. (2016). Aceruloplasminemia with psychomotor excitement and neurological sign was improved by minocycline (case report). Medicine 95:e3594. 10.1097/MD.0000000000003594 [PubMed]

Kuhn J., Bewermeyer H., Miyajima H., Takahashi Y., Kuhn K. F., Hoogenraad T. U. (2007). Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate. Brain Dev. 29 450–453. 10.1016/j.braindev.2007.01.001 [PubMed]

Kono S. (2012). Aceruloplasminemia. Curr. Drug Targets 13 1190–1199. 10.2174/138945012802002320 [PubMed]

Kono S. (2013). Aceruloplasminemia: an update. Int. Rev. Neurobiol. 110 125–151. 10.1016/B978-0-12-410502-7.00007-7 [PubMed]

Vroegindeweij L. H., Van Der Beek E. H., Boon A. J., Hoogendoorn M., Kievit J. A., Wilson J. H., et al. (2015). Aceruloplasminemia presents as Type 1 diabetes in non-obese adults: a detailed case series. Diabet. Med. 32 993–1000. 10.1111/dme.12712 [PubMed]

Fatty Acid
Hydroxylase-Associated
Neurodegeneration (FAHN)

FAHN

Fatty Acid Hydroxylase-associated Neurodegeneration (also known as HSP35), is caused by a mutation in the fatty acid 2-hydroxylase (FA2H) gene found on chromosome 16.

FAHN is ultra-rare; with approximately 5% of NBIA Individuals having the diagnosis. Onset usually occurs in childhood, or within the first or second decade of life. FAHN affects the central nervous system (brain and spinal cord) and causes problems with the corticospinal tract, which is the path of communication between the brain and limbs. This communication problem results in spasticity of the limbs.

Ataxia is also common, which is impaired coordination, balance and speech, Ataxia and spasticity share some of the same symptoms. Individuals with spasticity can have difficulty walking and doing other tasks because of muscle stiffness, spasms and contractions. Often, these individuals also experience dystonia, which are involuntary movements and prolonged muscle contractions that result in twisting body motions, tremors and abnormal posture.

Affected FAHN individuals also experience optic atrophy, profound cerebellar atrophy and white matter changes in the brain, in addition to high iron levels in the brain. Later in the disease course, individuals experience progressive intellectual impairment and seizures. Life expectancy varies among individuals.

Clinical Diagnosis

FAHN is diagnosed through an MRI of the brain. A common type of MRI known as a T2-weighted scan will show abnormalities in FAHN individuals: hypointensity (darkness) of the globus pallidus and possibly variable unilateral or bilateral symmetric white matter hyperintensity (brightness). There may be progressive atrophy (wasting away or diminution) of various regions of the brain and spinal cord, as well as thinning of the corpus callosum, which is the thin separation between the brain’s two hemispheres. Bone marrow biopsy, although not necessary for diagnosis, may demonstrate accumulation of granular histiocytes, which are immune cells.

The diagnosis of FAHN may be suspected in individuals with the onset of hallmark features in the first or second decade: spasticity, ataxia, dystonia, optic atrophy, eye movement abnormalities early in the disease course and progressive intellectual impairment and seizures later in the disease course. Other features are spastic paraplegia or quadriplegia and pyramidal tract signs (problems, such as spasticity, caused by dysfunction of the motor neurons that originate in the cerebral cortex and terminate in the spinal cord); dysarthria (difficulty pronouncing words); and dysphagia (difficulty swallowing).

Note: Because very few individuals with FAHN have been documented, the phenotype (disease characteristics) is likely to expand as more cases are ascertained, and thus the designation of any phenotypic feature as ‘hallmark’ may be premature.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with FAHN, the following evaluations may be useful:

• Neurologic examination for dystonia, ataxia and spasticity, including formal evaluation of ambulation, speech and feeding
• Ophthalmologic assessment for evidence of optic atrophy or eye movement abnormalities
• Screening developmental assessment, with referral for more formal testing if developmental delay is observed or suspected
• Assessment for physical therapy, occupational therapy, and/or speech therapy and appropriate assistive devices

Management

Symptomatic treatment is aimed primarily at the dystonia, which can be debilitating. Therapies used with varying success include the oral medications baclofen, anticholinergics, tizanidine and dantrolene; focal injection of botulinum toxin; intrathecal baclofen; and deep brain stimulation.

More information on these therapies can be found in the Medical Information section of our website.

Attention should be given to diet and swallowing to prevent aspiration. Children with FAHN should have regular measurement of height and weight to assure adequate nutrition, with gastrostomy tube placement as needed. Assessment of ambulation and speech and communication needs, and ophthalmologic examination also are recommended.

Since most individuals with FAHN lose the ability to walk and speak, independence should be encouraged when possible. Adaptive equipment and devices that can help include walkers or wheelchairs and augmentative communication aids.

Genetics

FAHN is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change, or mutation, the person should still have normal health. That person is called a carrier.

Recessive diseases only occur when both parents are carriers for the same condition and then pass their mutated genes onto their child. Statistically, there is a one in four chance that two carriers would have an affected child. There is a two in four chance the parents will have a child who is also a carrier. The chances are one in four that the child will not have the gene mutation. Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are suggested if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.

Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.

Note

A main resource for the clinical information provided here is FAHN - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult to understand for the general public.

Research

Research grants have been awarded to various studies to help understand the disease. A focus of the research has been creating disease models which will allow scientists to perform studies testing possible drug therapies to see if effective in the disease models. It is important that the model mimic the condition seen in patients with FAHN.

A successful mouse model has been created to study the disease and research is underway to create a stem cell model. To develop these stem cells in the lab, cells will be taken from the connective tissue of FAHN patients. Researchers will then use a gene editing technology, CRISPR/Cas9, to add copies of certain genes to the cells, endowing them with a stem cell’s special characteristics. They can develop into central nervous system cells that may be affected by FAHN.

As research moves forward, these disease models could provide scientists important clues on the cause of disease as well as help develop and test potential treatments through drug screeningthat can be later used in clinical trials. trials.

Researchers are also gathering data to create a natural history of FAHN and are analyzing clinical, genetic and imaging data.

Natural History Studies

TIRCON International NBIA Registry

The TIRCON International NBIA Registry was created under a European Union grant called Treat Iron-Related Childhood-Onset Neurodegeneration. Grant funding ran from 2011 to 2015, and the project is housed at Ludwig Maximilian University of Munich, Germany. The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 12 countries take part in the registry by entering their patient data. There were over 750 entries consisting of NBIA patients and controls as of September 2021. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data is available to researchers studying NBIA disorders. For more information on the registry, contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de

Research Publications and Articles

Following is a list of some recent research articles. Others can be found at Pub Med Central.

2022 - Generation of the human iPSC line AKOSi010-A from fibroblasts of a female FAHN patient, carrying the compound heterozygous mutation p.Gly45Arg/p.His319Arg

2018 - Hereditary Spastic Paraplegia Type 35 with a Novel Mutation in Fatty Acid 2-Hydroxylase Gene and Literature Review of the Clinical Features

Mitochondrial-membrane
Protein-associated
Neurodegeneration (MPAN)

MPAN

Mitochondrial-membrane Protein-Associated Neurodegeneration is caused by mutations in the C19orf12 gene. This gene is found on chromosome 19 and is believed to play a role in fatty acid metabolism. Though ultra-rare, it is one of the more common forms of NBIA and has distinctive clinical symptoms that differentiate it from other forms of NBIA. The prevalence of MPAN is roughly estimated at less than one in 1 million.

Onset typically occurs in childhood (ages 3 to 16, considered juvenile onset) to early adulthood (ages 17 to 24, considered adult onset). However, some individuals are reported to have a much later onset, resulting in a slower progression and survival well into adulthood. There are a few instances of later onset with rapid progression of disease. It causes cognitive decline progressing to severe dementia.

MPAN is characterized by spasticity that is more prominent than dystonia. There is weakness in muscles caused by motor axonal neuropathy, optic atrophy, and neuropsychiatric (mental disorder due to disease of the nervous system) changes.

Most affected individuals are still able to walk as they reach adulthood. Psychiatric signs are common, including impulsive or compulsive behavior, depression and frequent mood changes. Unlike most other forms of NBIA, the vast majority of individuals with MPAN develop progressive cognitive decline.

Click on any of the thumbnail images below to view the photos in a larger size;
move cursor to upper right of picture to click on next and view as slideshow

Clinical Diagnosis

The following clinical findings are suggestive of a diagnosis of MPAN:

• MRI of the brain (T2 –weighted) that shows iron accumulation in the globus pallidus and substantia nigra
• Impaired gait, or an inability to walk normally
• Cognitive decline progressing to severe dementia
• Prominent neuropsychiatric abnormalities, exaggerated emotional responses, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention and hyperactivity
• Optic atrophy, a condition in which the optic nerve is damaged, causing vision to be affected
• Dystonia, a movement disorder in which a person’s muscles, often in the hands and feet, contract uncontrollably
• Upper motor neuron signs (spasticity, hyperreflexia [overactive reflexes], Babinski sign [when the big toe bends up and back and the other toes fan out]). The lower limbs are usually affected earlier and more significantly than the upper limbs.
• Lower motor neuron signs, such as muscle weakness and atrophy, hyporeflexia (muscles becoming less responsive to stimuli), and fasciculations (muscle twitches)
• Parkinsonism, a condition that causes movement abnormalities such as tremor, slow movement, impaired speech or muscle stiffness
• Dysarthria, a motor speech disorder that causes slow or slurred speech. This typically progresses to anarthria during end-stage disease, in which a person is unable to articulate speech.

Commonly, all age groups experience a decline in cognitive ability that progresses to dementia; prominent neuropsychiatric abnormalities; and movement problems caused by nerve-cell abnormalities. Studies reveal a loss of nerve cells, widespread iron deposits and abnormal axons (a part of nerve cells) called spheroid bodies, in the basal ganglia. Lewy neurites, which are abnormal clusters of protein that develop inside the nerve cells, are present in the globus pallidus, and Lewy bodies and neurites are widespread in other areas of the midbrain and in regions of the globus pallidus called the corpus striatum.

Management

Neuropsychiatric symptoms may require treatment by a psychiatrist.

Medical providers also may seek to manage the disease by performing regular eye exams, as well as neurological tests for dystonia, spasticity and parkinsonism. Children may benefit from a pediatric neurology assessment to establish care and continuity. Adults may benefit from a referral to a movement disorders neurologist or a neuromuscular clinic. This may include evaluation of the affected individual’s ability to walk and speak for possible physical, occupational and/or speech therapy.

For treatment of dystonia/spasticity, consider oral baclofen, trihexyphenidyl, intramuscular botulinum toxin or taking part in a trial of intrathecal baclofen under a physician’s guidance. For parkinsonism, consider pharmacologic treatment under physician guidance. For severe dysphagia (swallowing difficulties), consider nutritional and vitamin supplementation to meet dietary needs or a gastric feeding tube to minimize weight loss and decrease risk of aspiration.

Genetics

MPAN is inherited in an autosomal recessive, or less commonly, in an autosomal dominant manner. The phenotypes, or disease characteristics, are indistinguishable between the two types. Both cause a loss of the function of the C19orf12 protein.

Because most of our genes exist in pairs (one from the mother and one from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change (mutation) in it, the person should still have normal health. That person is called a carrier.

Recessive diseases only occur when both parents are carriers for the same condition and then pass their changed genes onto their child, resulting in two disease-causing mutations.

For autosomal recessive inheritance, there is statistically a 25% chance that two carriers would have an affected child. The chances are 50% that the parents will have a child who is an asymptomatic carrier and 25% that the child will not receive the gene mutation. Carrier testing for at-risk relatives and prenatal testing for pregnancies can be done if both disease-causing mutations have been identified in an affected family member.

When a disease is inherited in an autosomal dominant manner, only one copy of the mutated gene coming from either parent is needed to cause the disease. Each child of an MPAN-affected individual has a 50% chance of inheriting the mutation that causes the disorder.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.

Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.

Note

A main resource for the clinical information provided here is Mitochondrial Membrane Protein-Associated Neurodegeneration - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily for the use of professionals so the terminology and information may be difficult for the general public to understand.

Natural History Studies

The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany, and was created under an EU grant from 2011 to 2015 called Treat Iron-Related Childhood Onset Neurodegeneration (TIRCON ).

The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers in 16 countries are participants and provide patient clinical data. There are over 700 entries consisting of NBIA patients and controls as of September, 2021, including MPAN individuals. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data is available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry.

Therapies Under Investigation

Iron Chelation

Iron chelator drugs are being explored as a potential treatment for MPAN and other related NBIA disorders. One such drug, deferiprone, was used to treat two MPAN patients, including a 13-year-old. A two-year treatment in that person led to reduced iron content in the substantia nigra, while pallidal iron depositions and clinical status remained unchanged [Löbel et al 2014].

A study involving a related NBIA disorder, PKAN, explored whether deferiprone can reduce brain iron and slow disease progression. This study was done over the course of 18 months and was placebo-controlled. The treatment groups were randomized and the study was completed in a double-blind manner in which neither participants nor the researchers knew which patients were in which group. The results indicated that deferiprone did not lead to statistically significant clinical changes in PKAN individuals, although researchers reported a trend toward slower progression on the dystonia scale used for later onset individuals [Klopstock et al 2019].

MPAN Clinical Trials

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies.

MPAN Research Publications and Articles

Following is a list of recent MPAN research articles.

Other MPAN research articles and studies can be found at Pub Med Central.

2025 - Serum metabolomics indicates ferroptosis in patients with pantothenate kinase associated neurodegeneration

2024 - Nazo, the Drosophila homolog of the NBIA-mutated protein–c19orf12, is required for triglyceride homeostasis

2023 - Identification of Autophagy as a Functional Target Suitable for Pharmacological Treatment of Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) In Vitro

2020 - The Downregulation of c19orf12 Negatively Affects Neuronal and Musculature Development in Zebrafish Embryos

2020 - Is there heart disease in cases of neurodegeneration associated with mutations in C19orf12?

2020 - Brain iron and metabolic abnormalities in C19orf12 mutation carriers: A 7.0 tesla MRI study in mitochondrial membrane protein-associated neurodegeneration

2019 - Clinical and genetic spectrum of an orphan disease MPAN: a series with new variants and a novel phenotype

2019 - Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN)

2018 - Mitochondrial membrane protein-associated neurodegeneration: a case report and literature review

2017 - Evolution and novel radiological changes of neurodegeneration associated with mutations in C19orf12

2013 - New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN

PLA2G6-associated
Neurodegeneration (PLAN)

PLAN

PLA2G6-Associated Neurodegeneration, is named for the responsible gene: PLA2G6. This gene is thought to be important in helping cells maintain a healthy membrane (outer layer). It also is involved in lipid (fat) metabolism. It is not yet known how changes in this gene cause the symptoms of PLAN or the excess accumulation of iron in the brain in some affected individuals.

PLAN is made up of three distinct forms with differing characteristics:

• INAD, or Infantile Neuroaxonal Dystrophy: early onset, rapidly progressive disease
• Atypical NAD, or atypical neuroaxonal dystrophy: later childhood onset with slower progression and predominant extrapyramidal (nerves that regulate motor control) findings, such as dystonia (involuntary muscle contractions that cause repetitive or twisting movements) and dysarthria (difficulty pronouncing words). It includes a broad range of presentations
• PLA2G6-related dystonia-parkinsonism: adult-onset dystonia-parkinsonism accompanied by cognitive decline and neuropsychiatric changes (mental disorder due to disease of the nervous system)

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Infantile Neuroaxonal Dystrophy (INAD)

Classic INAD starts early in life and progresses rapidly. It usually develops between 6 months and 3 years of age. The first signs are often delays in developing skills, such as walking and talking. Children may be floppy or have low muscle tone early on (hypotonia), but this turns into stiffness (spasticity) as they age, especially in the arms and legs. Eye disease caused by the degeneration of the optic nerve (optic atrophy) is common later on and can cause poor vision and eventual blindness. Seizures and fast rhythms on an EEG may also result.

A loss of cognitive abilities occurs, and many affected children never learn to walk or lose that ability. Many affected children do not survive beyond their first decade, but some survive into their teens and beyond. Supportive care can contribute to a longer life span by reducing the risk of infection and other complications.

Clinical Diagnosis - INAD

An MRI of the brain and an eye exam are keys to diagnosing INAD. In addition to a loss of motor skills, affected individuals also experience cerebellar atrophy, strabismus (crossed eyes) and nystagmus (rapid involuntary eye movements). Abnormal axons (a part of nerve cells), called spheroid bodies, can be seen on biopsies but may not appear until later in the disease as they accumulate with age. Abnormal brain iron accumulation varies among affected individuals and may not be evident on MRI studies.

Management - INAD

Drugs are given to treat spasticity and seizures. Fiber supplements and/or stool softeners are used to treat constipation. A transdermal scopolamine patch may help with mouth secretions. Feeding modifications such as softer foods or a feeding tube may be required to prevent aspiration pneumonia and achieve adequate nutrition.

Atypical NAD

NAD usually starts in early childhood but can occur as late as the end of the second decade. It has a slower progression and a different variety of movement problems than INAD. At first, the individual may have delays in speaking or exhibit features similar to autism. Eventually, difficulty with movement develops, and these individuals usually have dystonia. Behavior changes are common, such as acting impulsively, not being able to pay attention for long periods of time or depression, which may require treatment by a doctor.

Clinical Diagnosis - Atypical NAD

Certain MRI views (T2-weighted images) of the brain show an abnormality in the globus pallidus, a part of the brain that controls movement. The abnormality, called hypointensity, indicates iron accumulation. Consequently, an MRI and eye exam are keys to establishing strong clinical features of NAD.

Predominant features of NAD are onset before age 20, psychomotor regression (i.e. loss of previously acquired skills), language difficulties, autistic-like behavior, cerebellar atrophy, optic atrophy, progressive dystonia and dysarthria. As with INAD, biopsies show evidence of abnormal axons called spheroid bodies. Other common features are psychiatric and behavior abnormalities, spasticity, joint contractures, seizures and nystagmus.

Management - Atypical NAD

Drug therapy is provided for spasticity and seizures. For dystonia associated with atypical NAD, oral or intrathecal baclofen may be tried. Treatment by a psychiatrist is indicated for those with later-onset neuropsychiatric symptoms. Fiber supplements and/or stool softeners are used to treat constipation. A transdermal scopolamine patch may help with mouth secretions. Feeding modifications such as softer foods or a feeding tube may be required to prevent aspiration pneumonia and achieve adequate nutrition.

PLA2G6-related dystonia-parkinsonism

The onset of PLA2G6-related dystonia-parkinsonism varies from childhood to second and third decade of life. These individuals experience dystonia, eye movement abnormalities, slowness, poor balance, rigidity and marked cognitive decline.

Clinical Diagnosis - PLA2G6-related dystonia-parkinsonism

Abnormal brain iron accumulation in the globus pallidus, substantia nigra and/or striatum varies among affected individuals and may not be evident on MRI studies until late in the disease.

The main features are variable onset from childhood to young adulthood; parkinsonism (tremor, bradykinesia [slow movements], rigidity and impaired postural responses); dystonia; cognitive decline; neuropsychiatric changes; and an initial dramatic response to dopaminergic (levodopa) treatment followed by the early development of dyskinesias (diminished voluntary movements and the presence of involuntary movements). Other common features are dysarthria, autonomic involvement and mild cerebral atrophy.

Management - PLA2G6-related dystonia-parkinsonism

Consider treating with dopaminergic agents. Consult a psychiatrist to treat neuropsychiatric symptoms. A physical therapy evaluation may help problems with posture and walking. Occupational therapy can help the person perform activities of daily living. Periodic assessment of vision and hearing may be needed. To prevent secondary complications: Start physical therapy early and orthopedic management to help prevent contractures (tightening of the muscles, tendons, skin and nearby tissues, which cause joints to stiffen) as the disease progresses.

Genetics

PLAN is inherited in an autosomal recessive manner, meaning the affected individual receives two mutated genes, one from each parent. This is how it works:

• Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change (mutation) in it, the person should still have normal health. That person is called a carrier.
• Recessive diseases only occur when both parents are carriers for the same condition and then pass their changed genes on to their child. There is a one in four chance that two carriers would have a child with the disorder. There is a two in four chance the parents will have a child who is also a carrier. The chances are one in four that the child will not have the gene mutation.

Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are suggested if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal testing for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.

Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.

Note

A main resource for the clinical information provided here is PLA2G6-Associated Neurodegeneration - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult to understand for the general public.

Research

The following discussion of research to better understand PLAN is for informational purposes only. We do not endorse specific studies or clinical trials, experimental drugs, procedures, biotech or pharmaceutical companies.

Research has been vital to understanding the role of PLA2G6 and how the loss of function affects nerve health. Understanding the role of this gene is an important step in finding ways to treat the disease. The function of the gene has been investigated in various animal models such as fruit flies and mice, as well as in induced pluripotent stem cell cultures (iPSCs). iPSCs are derived from skin (fibroblasts) or blood cells of healthy or affected individuals and converted to stem cells through overexpression of a group of genes known as Yamanaka factors. These cells can then be converted to any type of cell in the body. The relevant cell type that is used for PLAN research are dopamine neurons. The function of the protein produced by the gene, called iPLA2β, is not fully understood. According to preliminary research, it is thought to be a phospholipase enzyme that controls fatty acid levels in the brain. PLA2G6 mutations appear to cause a loss of catalytic activity and mislocalization of the protein, meaning the protein is not found where it normally is located, in the distal axons and dendrites.

Studies in patient cells show that the loss of PLA2G6 function causes an expansion of lysosomes (membrane-covered cell structures that break down cellular waste), aberrant morphology (abnormal shapes) and changes in the mitochondria, and accumulation of glucosylceramide (a basic component of the cell membrane). This is very similar to what is observed in fruit fly models, which suggests that drugs that work in the flies may work in humans. This opens up an avenue for screening drugs that alleviate neurodegeneration.

Researchers have been seeking therapeutic approaches to restore enzyme function in INAD. Potential therapeutic strategies may include gene therapy, enzyme replacement therapy through modification of the PLA2G6 protein so it can be delivered to the brain, use of pharmacological chaperones to improve the function of mutant PLA2G6 proteins, or stimulation of other enzymes to compensate for the loss of gene function such as Acyl CoenzymeA or other phospholipase enzymes. Challenges exist for each of these potential treatments, and all require extensive research before they can be tried in human subjects.

One of the potential therapeutic strategies, pharmacological chaperones, has shown potential in early research. As proteins are produced from DNA, they are folded into configurations that are required for proper function in the cell by small molecules called chaperones. Further research in this area would involve screening many drugs for the potential to act as a chaperone and to stabilize PLA2G6 protein folding.

Another potential therapeutic strategy is stimulation of other enzymes. Scientists have hypothesized that other enzymes called acyl CoA synthetases could compensate when mutations impair the enzyme. They have observed that a protein that stimulates the activity of acyl CoA synthetases has a beneficial effect on mice with a PLA2G6 mutation.

Gene Therapy

Research into gene therapy for INAD is in the early stages of development. The goal of gene therapy is to deliver healthy copies of PLA2G6 into a patient’s cells to treat the disease. Genes can be delivered through a viral vector, which is a virus that is scientifically engineered to carry the functional gene into the cell. Before a treatment can be tested in humans, it must first be used in animal models that are genetically engineered to have a PLA2G6 mutation. Scientists have developed a mouse model that is genetically engineered to have a PLA2G6 mutation. These mice develop movement and coordination problems similar to individuals with INAD. Researchers have found that when the mice receive the gene therapy, they have improved outcomes in length of life and mobility.

Researchers are now in a position to publish their findings and seek major grant funding to potentially investigate the therapy in human subjects. The researchers hope this strategy paves the way for future clinical trials in patients with PLAN.

PLAN Natural History Studies and Biobanks

PLANReady Natural History Study

The NBIA Research Group at Oregon Health & Science University has developed a study called PLANready. Its purpose is to help better understand the natural history of PLAN, meaning how symptoms appear and change over time. By studying individuals with PLAN, they also hope to identify disease markers that can be used in future clinical trials. A disease marker is any symptom or measurement that happens reliably in a disease, changes predictably with disease progression and becomes “better” with successful treatment. A disease marker could be an MRI finding, a protein level in the blood, or a rating scale to measure symptoms or function. Natural history studies provide data that serve as the foundation for future drug trials.

To find out more about this natural history study and to contribute to data collection go to: PLANready | NBIA.

TIRCON International NBIA Registry

The TIRCON International NBIA Registry was created under an EU grant called Treat Iron-Related Childhood-Onset Neurodegeneration. Grant funding ran from 2011 to 2015, and the project is housed at Ludwig Maximilian University of Munich, Germany. The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 12 countries currently take part in the registry by entering their patient data. There are over 700 entries consisting of NBIA patients and controls as of July 2020. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data is available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry.

The New York Stem Cell Foundation Research Institute (NYSCF)

The NYSCF’s mission is to accelerate cures for major diseases through stem cell research. The institute is collecting skin cell samples from patients and their families in addition to obtaining medical and family histories. The skin cells are then converted into induced pluripotent stem cells, which are cells that have the ability to differentiate into different types of cells such as neurons. This enables researchers to understand more about the disease and accelerate the rate in which treatments can be discovered. To learn more about this biobank, contact Geoff McGrane at gmcgrane@NYSCF.org

PLAN Clinical Trials

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies.

PLAN Research Publications and Articles

Following is a list of some recent research articles. Others can be found at Pub Med Central.

2025 - Consensus Clinical Management Guideline for PLA2G6-Associated Neurodegeneration (PLAN).

2023 - Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)

2021 - Compound heterozygous PLA2G6 loss-of-function variants in Swaledale sheep with neuroaxonal dystrophy

2020 - Lack of Association Between PLA2G6 Genetic Variation and Parkinson's Disease: A Systematic Review

2018 - PLA2G6-Associated Neurodegeneration (PLAN): Review of Clinical Phenotypes and Genotypes

2018 - Pantothenate Kinase-Associated Neurodegeneration (PKAN) and PLA2G6-Associated Neurodegeneration (PLAN): Review of Two Major Neurodegeneration with Brain Iron Accumulation (NBIA) Phenotypes

2017 - Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration