ADULT POLYGLUCOSAN BODY DISEASE Heather A. Lau, MD MS Assistant Professor Division of Neurogenetics NYU School of Medicine Summer 2016
Disclosures • Advisory Board Member • Contracted Research • Adult Polyglucosan Body • Amicus • Biomarin Disorder Research Foundation • National Tay-Sachs & Allied • Glaxo Smith Kline • Pfizer Diseases Association • Sanofi • Consulting • Shire • Biomarin • Ultragenyx • Pfizer • Sanofi • Research Grants • National Tay-Sachs & Allied Diseases Association • Sanofi 2
Overview • What is APBD? • What are the symptoms and signs of APBD? • Misdiagnosis and its implications • What is the cause of APBD? • How is APBD diagnosed? • Management of symptoms of APBD 3
What is APBD and what are the symptoms?
APBD: Adult Polyglucosan Body Disease • An inherited adult onset progressive disorder that affects the nervous system • The disease may present in the 50s and 60s, but some patients may experience symptoms as early as age 35 5
Typical Symptoms of APBD • Reduced sensation in the legs – an early sign with numbness beginning in the toes/feet • Bladder dysfunction may also be an initial sign • Difficulty in controlling flow of urine (neurogenic bladder) • Frequent urination • Walking difficulties eventually leading to wheelchair use due to muscle weakness and stiffness (spasticity) in the legs • Memory difficulty may occur later in the disease in up to 50% of patients 6
Typical Signs of APBD • Neurologic examination: • Weakness in Legs • Spasticity in Leg (stiffness) • Abnormal deep tendon reflexes in lower extremity • Loss of sensation to vibration • Unsteady gait (walking) • Brain and Spine Imaging: • Atrophy in the Medulla • Cerebellar atrophy • White matter lesions in subcortical and periventricular white matter, and brainstem • Cervical Spinal Cord Atrophy • Nerve and Muscle Electrophysiologic studies (EMG/NCS) • Length-dependent axonal sensorimotor polyradiculoneuropathy • Urologic studies: post void residuals, urinary retention 7
APBD is frequently misdiagnosed! • Benign Prostatic Hypertrophy (BPH)* • Up to 50% of Men with APBD • Peripheral Neuropathy • Multiple Sclerosis (Autoimmune) • Cerebral Small Vessel Disease and Stroke • Amyotrophic Lateral Sclerosis (ALS) – Lou Gehrig’s Disease • Spine disease: “myelopathy” • Other “ leukodystrophies ” • Vasculitis and Other Inflammatory Causes • Complications of Diabetes • Side effects of Chemotherapy • Hereditary Spastic Paraparesis 8
Misdiagnosis May Lead To Patients Receiving Inappropriate Therapies and Expose Them to Risk of Complications Disease Modifying Medications For MS Immunosuppressive Therapy Spine Surgery Prostate surgery 9
What is the cause of APBD?
APBD is caused by a genetic mutation • Autosomal Recessive inheritance of a mutation in a gene called GBE1 • Both copies of the gene need to be mutated to cause disease • Couples who are both carriers of the abnormal gene have a 25% chance of having a child affected with the disease • APBD is pan-ethnic but more frequent in patients of Ashkenazi Jewish Heritage due to presence of founder mutations • A GBE1 pathogenic variant, p.Tyr329Ser (c.A986C), is the most common finding in the Ashkenazi Jewish patients • A new intronic mutation (c.691+2T>C) has recently been found in Ashkenazi patients by Dr. H. Orhan Akman 11
What does the GBE1 gene do? • GBE1 gene encodes a protein called Glycogen Branching Enzyme • Mutations in this gene lead to a deficiency of the Enzyme • Glycogen Branching Enzyme is important in the proper creation of glycogen , a storage form of glucose and an important source of energy for the body • Enzyme deficiency leads to the accumulation of abnormal glycogen molecules called “ Polyglucosan Bodies ” in the brain, spinal cord and peripheral nerves • These glycogen molecules cannot be used for energy and are thought to disrupt the normal function of nerve cells leading to the symptoms described 12
APBD is a type of Glycogen Storage Disorder • Glycogenoses are estimated to occur in 1 in 10,000 people • APBD accounts for about 3% of these glycogenoses • Roughly, 1 in 600,000 – 800,000 • Although APBD is a rare disorder: • Estimated carrier frequency in people with Ashkenazi Jewish Heritage is 1 in 35 - 1 in 68 • It may be underdiagnosed! 13
How is APBD diagnosed?
Triad of symptoms of Urinary dysfunction, Gait difficulty, & Sensory Loss should prompt a workup for APBD • Initial Diagnostic Testing Includes: • Neurologic Consultation and Examination • Urologic Consultation and Urologic Studies • Brain and Spine Imaging to evaluate for other causes • Nerve and Muscle Electrophysiology testing • Blood and Urine tests • Subsequent DNA analysis of the GBE1 gene in patients with low enzyme activity based on a blood or saliva test 15
Management of symptoms of APBD
There is no cure for APBD at this time. Treatment is directed at managing the symptoms Management of APBD Requires a Multidisciplinary Approach Presentation Title Goes Here 17
A Team Approach to Care for Patients with APBD • Geneticist to confirm diagnosis and provide counseling about inheritance and risk to family members • Neurologist • Baseline Brain MRI and Spine • Nerve and muscle Electrophysiologic studies • Memory assessments • Urologist • Assessment of bladder function • Management of urinary issues • Antispasmodic medications • Bladder catheterization • Prompt identification and treatment of recurrent bladder infections, a major cause of morbidity • Psychologist or Behavioral Neurologist : • Cognitive aids, Manage Mood disorder if develops • Physical Medicine Rehabilitation Physician: • Guide Physical Therapy • Assess for need of gait safety devices: canes, walkers, wheelchairs • Assist in prevention of falls and injuries 18
For More Information and how can you help?
For More Information: • Adult Polyglucosan Body Disease Research Foundation (APBDRF) funds both basic science and clinical studies to help delineate the pathophysiology of the disease and to identify potential therapies: http://apbdrf.org/ • The website maintains a database of physicians familiar with APBD for referrals • Information on how to obtain testing for APBD • Information for patients and family members about the disease and current research efforts • How can you help! • A Natural History Study is being conducted through APBDRF and head by Dr Salvatore DiMauro at the Mailman School of Public Health at Columbia University: http://www.sac-cu2.org/APBD/ 20
Summary • APBD is an adult onset disorder affecting urination, walking, sensation and memory • It is frequently misdiagnosed and likely underdiagnosed • It has a higher prevalence in the Ashkenazi Jewish population • Diagnosis is made by demonstrating low GBE1 enzyme activity and confirmed by genetic analyzing of the GBE1 gene • There is no current cure but treatment is symptomatic, and management requires a team of specialists • Research into the understanding the disease and potential therapeutic interventions is ongoing. • Participation in a natural history study is important in assisting scientists and physicians to learn about the disease and help guide research for possible treatments 21
Funding for this series is provided in part by: . A generous grant in honor of Beatrice Milberg Seed funding was provided by
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