BPAN WARRIORS TERMS & CONDITIONS OF USE
Last Updated: January 7, 2020
WHAT IS BPAN | WDR45?
Beta-propeller protein-associated neurodegeneration (BPAN) is a disorder that damages the nervous system and is progressive, which means that it gradually gets worse. Affected individuals develop a buildup of iron in the brain that can be seen with medical imaging. For this reason, BPAN is classified as a type of disorder called neurodegeneration with brain iron accumulation (NBIA), although the iron accumulation may not occur until late in the disease.
This damage leads to delayed development and recurrent seizures (epilepsy) beginning in infancy or early childhood, movement problems that get worse over time, and a gradual loss of intellectual functioning in adulthood. Affected individuals eventually have a buildup of iron in the brain that can be seen with medical imaging; for this reason, BPAN is classified as a type of disorder called neurodegeneration with brain iron accumulation (NBIA).
The WDR45 gene provides instructions for making a protein called WD40 repeat protein interacting with phosphoinositides 4 (WIPI4).
WIPI4 is a member of a group of proteins each with a characteristic structure resembling a seven-bladed propeller. The WIPI4 protein is involved in the early stages of a process called autophagy, which helps clear unneeded materials from cells, including excess amounts of an iron storage protein called ferritin. In autophagy, worn-out cell parts (such as organelles, which are specialized structures that perform certain tasks within the cell) and other materials that are no longer needed are isolated in tiny compartments called autophagosomes.
The WIPI4 protein helps control (regulate) the production and elongation of autophagosomes to contain the materials. The autophagosomes are then transported to organelles called lysosomes, which act as recycling centers within cells. Lysosomes use digestive enzymes to break down waste substances and recycle worn-out cell components.
Most of the WDR45 gene mutations identified in people with BPAN are thought to result in the production of an unstable WIPI4 protein that is quickly broken down, leading to loss of WIPI4 protein function. Without functional WIPI4 protein, the process of autophagy is impaired, making cells less efficient at removing damaged organelles and waste materials. Researchers suggest that nerve cells (neurons) may be particularly vulnerable to impaired autophagy because they have long extensions (axons and dendrites), making it even more difficult to transport the waste materials from these structures to the lysosomes in the cell body for recycling. The waste materials can build up in these areas and damage them. Damage to neurons results in the neurological problems that occur in BPAN.
BPAN SIGNS AND SYMPTOMS
WHAT WE KNOW TODAY | AN EXPANDING PHENOTYPE
BPAN symptoms may vary greatly from patient to patient both in presentation and severity. The phenotype of BPAN patient symptoms is ever expanding and will require continued collection of data through standardized measures.
Advances in genetic technologies have accelerated gene discovery as well as identification of the now expanding BPAN phenotype. Symptoms vary based upon individual patient, however most scientists agree that the disease course is broken into two phases, Phase I typically appearing in early childhood (by age 1) and Phase II, typically appearing in late adolescence or early adulthood.
PHASE I SYMPTOMS: PRIMARY
Symptoms of BPAN typically start to appear in early childhood.
Pervasive Developmental Disorders including:
Gross and Fine Motor Delays
Coordination & Balance Problems
Attention & Concentration Problems
Speech/Communication Delays: Expressive language is significantly affected and kids may develop few to no words
Social and Behavioral Issues, sometimes associated with Autism
Some children may have multiple seizure types first appearing infancy or later in life and may develop into seizure disorders similar to West Syndrome and Lennox Gestault Syndrome
Abnormal Sleep Patterns (Disordered Sleep)
PHASE I SYMPTOMS: SECONDARY
Bruxism (Teeth Grinding)
Ophthalmologic - Retinal and Optic Nerve Disease
Orthopedic Dysfunction (Scoliosis)
Osteopenia and Osteoporosis
Autonomic Dysfuntion Including Body Temperature Regulation
Hypontonia or Muscle Rigidity
Oral-Motor Feeding Problems
Nociception - Impaired Perception of Pain
Psychiatric - Anxiety, Depression, Autism, and Behavioral Issues
Individuals with BPAN can also have some symptoms that are also shared with individuals with Rett Syndrome:
Stereotypes (repetitive, rhythmic motions)
Biting and mouthing of hands
Rett Breathing Patterns including breath holding, hyperventilation and hypoventilation
PHASE II SYMPTOMS
Symptoms do not typically appear until late adolescence or early adulthood.
Parkinsonism (symptoms similar to Parkinson’s disease)
Bradykinesia (slow movements)
Postural instability (loss of balance that causes unsteadiness)
Other muscle problems
Dystonia (involuntary muscle contraction and spasms)
Gait freezing (freezing while walking)
Spasticity (stiff, rigid muscles)
Cognitive (mental) decline with specific loss of expressive language skills
Can progress to dementia in adulthood
The first few days, weeks and months after a BPAN diagnosis can be overwhelming. The process of digesting the full implications of a BPAN diagnosis, understanding a condition which currently affects such few people worldwide, seeking sound medical direction while providing the quality daily medical care is no easy task. As with many ultra-rare medical conditions, resources may be limited or all-together unavailable.
Although we are all unique, our common experiences often provide us with invaluable information, direction, reassurance and most importantly HOPE. Each step we take towards connecting with others may help you move forward in this BPAN Journey and closer to understanding the vital role you play as a member of our community.
GENETIC TESTING AND MRI'S
Although clinical findings, MRI results and symptom reporting are important to support a BPAN diagnosis, only a genetic test can confirm a BPAN diagnosis.
BPAN is a monogenetic disease, that is inherited in an X-linked manner. Most reported cases of patients to date have been female, with a single occurrence a family, resulting from a de novo (spontaneous) pathogenic mutation of the WDR45 gene. There a few reported familial cases of germline mosaicism and transmission of a pathogenic variant from an asymptomatic mother to her offspring due to signfican X-skewing. With the exception of these reported cases, patients with BPAN are not thought to be able to reproduce.
Once a pathogentic variant has been reported in family, genetic counseling and prenatal may be recommended.
SOURCE | GENE REVIEW: Beta-Propeller Protein-Associated Neurodegeneration
Synonyms: BPAN, Neurodegeneration with Brain Iron Accumulation 5 (NBIA5)
As genetic testing become more common, major insurance companies have now started to cover genetic tests if they are deemed medically necessary and will provide pertinent information for the management of your medical condition. Each insurance policy is different, therefore it is important to check with your insurance company. Often the authorization process may take months to process and may require individuals and/or patient vendors to dispute denial of services. A genetic counselor may also be able to help with this process, and many testing labs facilitate the insurance prior authorization process.
CAN'T AFFORD TO HAVE GENETIC TESTING?
GENETIC TESTING COMPANIES:
BPAN AND SEIZURES
LEARN MORE ABOUT BPAN WARRIORS RECENT PARTICIPATION IN THE RARE EPILEPSY ANALYSIS SURVEY:
FINAL Rare Epilepsy Landscape Analysis
FINAL Rare Epilepsy Landscape Analysis Appendix
Value of RELA to Our Organization and Constituents:
Identify partners for collaboration based on priorities, size, interest, disease, comorbidities etc
Significantly raise awareness and the profile of the Rares among professionals, policymakers and the public
Pinpoint resources available and which ones to turn to when for organizational challenges around operations, advocacy, research and more
Benchmark your organization against other similarly situated organizations
Inspire new ideas for successful programs and services
Save you time and money and give you a running start when undertaking initiatives that others have developed before
Find collaborators and mentors
Impact of the RELA:
Already the RELA has had many positive impacts including:
Providing a first of its kind assessment of rare epilepsy organizations - founding, organization, staffing, reach, research funding, mission, priorities, infrastructure, assets, challenges
Identifying a community of 70+ rare epilepsy organizations - with even more on the horizon - and facilitating new opportunities to dialogue and exchange information
Identifying many shared opportunities and priorities for collaboration around research, information/support, professional education, and advocacy that can be pursued through existing coalitions like Rare Epilepsy Network (REN) and RSCS or new initiatives
Identifying gaps in prevalence/incidence and research funding to inform campaigns targeting NINDS/NIH, FDA, CDC, DOD etc to redress these gaps
Encouraging organizations like Epilepsy Foundation (EF) to complete an internal audit of their programs and services in relationship to Rares resulting in new efforts/discussions to explore meaningful ways to partner with Rare organizations
BPAN A RARE PEDIATRIC EPILEPSY
Many people with BPAN have recurrent seizures (epilepsy) beginning in infancy or early childhood. Several different types of seizures can occur in this disorder, even in the same individual. Often the first type to occur are febrile seizures, which are triggered by a high fever. Affected individuals can also experience generalized tonic-clonic seizures (also known as grand mal seizures). This type of seizure affects the entire body, causing muscle rigidity, convulsions, and loss of consciousness. Other seizure types that can occur in this disorder include short lapses in awareness that can have the appearance of staring spells or daydreaming (absence seizures, also called petit mal seizures), sudden episodes of weak muscle tone (atonic seizures), involuntary muscle twitches (myoclonic seizures), or more pronounced movements called epileptic spasms. Some individuals have seizure patterns that resemble those in epileptic syndromes, such as West Syndrome or Lennox-Gastaut Syndrome.
TYPES OF SEIZURES:
GENERALIZED (BILATERAL) TONIC-CLONIC SEIZURES (GRAND MAL)
RARE EPILEPSY NETWORK (REN)
The Rare Epilepsy Network, or REN for short, is a collaboration between the Epilepsy Foundation, RTI International, Columbia University and many different organizations that represent patients with a rare syndrome or disorder that is associated with epilepsy or seizures. The REN will establish a registry of these patients which includes patient or caregiver-reported data in order to conduct patient-centered research.
MRI'S AND BRAIN IRON ACCUMULATION
MRI FINDINGS OF BRAIN IRON ACCUMULATION
The acronym NBIA (neurodegeneration with brain iron accumulation) designates a clinically
and genetically heterogeneous group of neurodegenerative diseases, the majority of which is
hallmarked by iron deposits in the brain . Iron accumulation, is detected in vivo by MRI analysis,
and affects mainly the basal ganglia regions, such as globus pallidus (GP) and substantia nigra (SN),
although other regions including the cortex and cerebellum can be involved. These disorders are
inherited as Mendelian traits (autosomal recessive, dominant, or X-linked), and typical features are
extra pyramidal symptoms, namely, dystonia, parkinsonism, spasticity, variably associated with
neuropsychiatric abnormalities, and optic atrophy or retinal degeneration . Disorders belonging
to the NBIA group are rare, between one and three per million individuals in the general population,
and 15 causative genes, whose products are involved in a wide spectrum of biological activities,
have been so far discovered. Although the presence of brain iron accumulation enables the diseases
to be included in the NBIA group, the pathogenic mechanisms linking specific disease-genes
mutations to iron metabolism are unclear.
Iron overload in the brain is a distinct finding in rare neurodegenerative disorders classified as
NBIA, but is also observed in common neurodegenerative disorders, including Parkinson’s,
Alzheimer’s, and ALS. Two NBIA gene products play a direct role in iron homeostasis, but whether
other NBIA-related gene products also control iron metabolism in the human brain, and whether
high levels of iron contribute to the progression of neurodegeneration is still a matter of
investigation. An interesting study based on a systems biology approach aimed at clarifying the
pathogenic mechanisms of these disorders and identifying the network connecting known NBIA
transcripts with specific partners. This analysis indicated that multiple cell types contribute to the
clinically heterogeneous group of NBIA disorders, revealed strong links with iron metabolism and
demonstrated the presence of common pathways shared by NBIAs and overlapping
neurodegenerative disorders .
SOURCE: Levi, S.; Tiranti, V. Neurodegeneration with Brain Iron Accumulation Disorders: Valuable Models Aimed at Understanding the Pathogenesis of Iron Deposition. Pharmaceuticals 2019, 12, 27.
Iron accumulation may be visible in the progression of BPAN through MRI on FLAIR/T1 and T2 sequences; however, the a more sensitive SWI sequence may show blooming earlier in life (at 4 and 9 years of age) but not in early life. Thus, a normal MRI should not preclude consideration of WDR45 testing in patients with DEEs.
SOURCE: Carvill GL, Liu A,
Mandelstam S, et al. Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45. Epilepsia.
ONLINE PATIENT RESOURCES
RARE DISEASE | ADVOCACY | MEDICAL
Our BPAN Warriors community wants nothing more than to see patients with BPAN identified accurately and expeditiously, with the hopes that this may alleviate the emotional, physical and often financial burden that many families experience. To this end, we hope that the medical community will join us as we as we advocate and work to increase BPAN awareness throughout the world.
GLOBAL BPAN/NBIA COMMUNITY
THE NBIA ALLIANCE is an international umbrella organization for NBIA lay advocacy groups. It started in January, 2012, in conjunction with the kick-off meeting of the European Union funded project TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration).
THE NBIA DISORDERS ASSOCIATION (formerly Hallervorden-Spatz Syndrome Association) is a non-profit voluntary organization founded in 1996 and dedicated to families affected by neurodegeneration with brain iron accumulation and related disorders.
RARE DISEASE ADVOCACY AND EDUCATION
GLOBAL GENES is one of the leading rare disease patient advocacy organizations in the world. The non-profit organization promotes the needs of the rare disease community under a unifying symbol of hope – the Blue Denim Genes Ribbon®. What began as a grassroots movement in 2009 , with just a few rare disease parent advocates and foundations , has since grown to over 500 global organizations.
NORD, the National Organization for Rare Disorders is an American non-profit organization aiming to provide support for individuals with rare diseases by advocating and funding research, education, and networking among service providers.
EURODIS Rare Diseases Europe is a unique, non-profit alliance of 779 rare disease patient organisations from 69 countries that work together to improve the lives of the 30 million people living with a rare disease in Europe.
RareConnect is a place where rare disease patients can connect with others globally. RareConnect is a safe environment where privacy is respected and where trusted information is shared via real patient representatives.
Rare Disease Day takes place on the last day of February each year. The main objective of Rare Disease Day is to raise awareness amongst the general public and decision-makers about rare diseases and their impact on patients' lives.The campaign targets primarily the general public and also seeks to raise awareness amongst policy makers, public authorities, industry representatives, researchers, health professionals and anyone who has a genuine interest in rare diseases.
Rare Voices Australia, the national alliance of people living with a rare disease, will provide a unified voice to improve the lives of all Australians affected by rare diseases.
THRIVE is a collaborative initiative to engage, embrace and drive change in the rare disease community. By acknowledging the need to communicate and lean on the strengths of our allies, brighter futures will come.
EPILEPSY AND SEIZURE MANAGEMENT
THE EPILEPSY FOUNDATION, also Epilepsy Foundation of America, is a non-profit national foundation, headquartered in Landover, Maryland, dedicated to the welfare of people with epilepsy and seizure disorders. The foundation was established in 1968 and now has a network of 59 affiliates.
MICKIE'S MIRACLES creates global Pediatric Epilepsy awareness, education and advocacy in order to help families stop fighting a ghost.
THE ILAE, the International League Against Epilepsy was started in 1909. Its goal is to improve the lives of people with epilepsy through research. They run the medical journal Epilepsia, Epilepsia Open, and Epileptic Disorders.
THE INFANTILE SPASMS PROJECT is a program of the Division of Pediatric Neurology and Department of Pediatrics at the David Geffen School of Medicine and Mattel Children's Hospital at the University of California, Los Angeles (UCLA). The information presented here is intended as a straightforward and organized guide to parents and caregivers of children with infantile spasms, as well as practitioners. This site is supported by the Epilepsy Therapy Project, the Milken Family Foundation, and the Paul A. Hughes Family Foundation.
THE AES, American Epilepsy Society is one of the oldest neurological professional organizations in this country. The Society seeks to promote interdisciplinary communications, scientific investigation, and exchange of clinical information about epilepsy.
Membership consists of clinicians, scientists investigating basic and clinical aspects of epilepsy, and other professionals interested in seizure disorders. Members represent both pediatric and adult aspects of epilepsy.
THE CHILD NEUROLOGY FOUNDATION serves as a collaborative center of education and support for caregivers and their children with neurologic conditions.
THE EPILEPSY SOCIETY is the largest medical charity in the field of epilepsy in the United Kingdom, providing services for people with epilepsy for over 100 years.
THE LGSF, the Lennox-Gastaut Syndrome Foundation is a nonprofit organization dedicated to improving the lives of individuals with Lennox-Gastaut Syndrome through research, programs and education.
THE PARKINSON'S FOUNDATION is a national organization whose mission is to make life better for people with Parkinson’s disease by improving care and advancing research toward a cure.
THE MICHAEL J. FOX FOUNDATION for Parkinson's Research is dedicated to finding a cure for Parkinson's disease through funded research and ensuring the development of improved therapies for those living with Parkinson's today.
THE AMERICAN PARKINSON DISEASE ASSOCIATION (APDA), founded in 1961, is the nation's largest grassroots network dedicated to assist the more than 1 million Americans living with Parkinson's disease.
THE DAVIS PHINNEY FOUNDATION is a non-profit with a mission to help people with Parkinson's live well with the disease. It was founded in 2004 by Davis Phinney, the former professional road bicycle racer and Olympic medal winner. Phinney was diagnosed with young-onset Parkinson's disease in 2000 at the age of 40.
THE INTERNATIONAL PARKINSON AND MOVEMENT DISORDER SOCIETY (MDS) is a professional society of clinicians, scientists, and other healthcare professionals who are interested in Parkinson's disease, related neurodegenerative and neurodevelopmental disorders, hyperkinetic movement disorders, and abnormalities in muscle tone and motor control.
The assistance of our members, who work tirelessly to help further the Society's mission, enables MDS to educate and inform others around the world about the latest news, research, and advances in movement disorders.
MITOACTION's mission is to improve the quality of life for children, adults, and families living with mitochondrial disease.
THE UNITED MITOCHONDRIAL DISEASE FOUNDATION (UMDF) is a voluntary, non-profit organization dedicated to providing education and support to individuals diagnosed with, or suspected of having, mitochondrial diseases.
"Learn from yesterday, live for today, hope for tomorrow. The important thing is not to stop questioning"