ADULT POLYGLUCOSAN BODY DISEASE Heather A. Lau, MD MS Assistant - - PowerPoint PPT Presentation

ADULT POLYGLUCOSAN BODY DISEASE

Heather A. Lau, MD MS Assistant Professor Division of Neurogenetics NYU School of Medicine

Summer 2016

Disclosures

• Advisory Board Member
• Adult Polyglucosan Body

Disorder Research Foundation

• National Tay-Sachs & Allied

Diseases Association

• Consulting
• Biomarin
• Pfizer
• Sanofi
• Contracted Research
• Amicus
• Biomarin
• Glaxo Smith Kline
• Pfizer
• Sanofi
• Shire
• Ultragenyx
• Research Grants
• National Tay-Sachs & Allied

Diseases Association

• Sanofi

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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

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

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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

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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

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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

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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

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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

• f 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

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• 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

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

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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!

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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

• r saliva test

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Management of symptoms of APBD

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There is no cure for APBD at this time. Treatment is directed at managing the symptoms Management of APBD Requires a Multidisciplinary Approach

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

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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/

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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

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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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