Diagnosing Late-Onset Pompe Disease


Estimates of late-onset Pompe disease (LOPD) incidence are varied across ethnic groups. For example, LOPD has been estimated to affect as many as 1 in 60,000 Caucasians while incidence is expected to be higher in African-Americans as Pompe disease in general has been projected to affect 1 in 14,000 African-Americans.

Clinical Presentation

Late-onset Pompe disease is differentiated from the “classic” infantile-onset form (IOPD) by the age of symptom onset and type of symptoms and their severity. Late-onset Pompe disease can present >12 months of age or as late as the second through sixth decades of life and is characterized by progressive muscle weakness and respiratory insufficiency. No matter the presentation or the subtype, Pompe disease is caused by the same underlying pathology: acid alpha-glucosidase (or GAA enzyme) deficiency, which leads to intralysosomal accumulation of glycogen. However, LOPD encompasses a broad spectrum of clinical phenotypes that differ in terms of age of onset, degree of severity, and rate of disease progression. This, and the relative rarity of the disease, makes diagnosis challenging. The course of disease is progressive, however, and symptoms correlate less with the age of the patient (Fig. 1A) than they do with disease duration (Fig. 1B). Table 1 summarizes some general characteristics of LOPD.

Figure 1A

This figure displays wheelchair use and respiratory support use in late-onset Pompe disease patients based on age and disease duration

Figure 1B

This figure displays wheelchair use and respiratory support use in late-onset Pompe disease patients based on age and disease duration

Figure 1.Wheelchair use (green bars) and respiratory support use (yellow bars) in LOPD patients based on (A) age and (B) disease duration.

Table 1.General Characteristics of LOPD


Age at symptom onset

>1 year to second through sixth decades of life and later

GAA enzyme activity

Variable, 2%–~40%

Major symptoms

  • Musculoskeletal Symptoms are the most common:
  • Pelvic girdle and trunk muscle weakness
  • Back pain
  • Muscle cramps
  • Respiratory Symptoms:
  • Distress/insufficiency
  • Frequent infections
  • Sleep disordered breathing
  • Gastrointestinal Symptoms:
  • Difficulties eating/swallowing
  • Poor weight gain/overweight
  • Cardiac hypertrophy is rare, but some patients may have abnormal heart rhythm

Rate of progression

Variable, slow to rapid, but progressive


Variable, age of death varies from >1 year to late adulthood; cause is usually respiratory failure, but cerebral aneurysm has been reported

Signs and Symptoms

Although the symptoms of classic IOPD are generally homogeneous, the same is not true for symptoms of LOPD. One of the challenges in diagnosing LOPD is that the constellation of symptoms is heterogeneous, often mimicking other neuromuscular disorders.  The most common symptoms of LOPD are musculoskeletal and respiratory. Progressive muscle weakness and atrophy, mainly affecting the limb girdle, proximal, and paraspinal muscles, lead to mobility problems. Difficulties running, lifting, or climbing stairs may be a patient’s primary complaint.

Respiratory symptoms are very common in LOPD patients; about 33% present with respiratory failure, and this is the most common form of death in these patients. Signs of chronic respiratory insufficiency include fatigue, headaches, daytime sleepiness, and decreased sleep quality. 

Many other symptoms are associated with LOPD; see Table 2 for a more comprehensive list of some of the common and less common signs and symptoms of LOPD.

Table 2.Signs and Symptoms of LOPD


  • Weakness in proximal, limb girdle, lower extremity, and paraspinal musculature, as well as in respiratory, shoulder girdle, neck flexors, bulbar, and facial/ocular muscles


  • Fatigue
  • Exercise intolerance
  • Reduced endurance
  • Waddling gait
  • Loss of ambulation and independent transition between positions
  • Difficulties lifting or with bed mobility
  • Dysarthria
  • Oropharyngeal dysphagia
  • Hypernasal or low volume speech
  • Uni- or bilateral ptosis
  • Ophthalmoplegia with inability of eyes to fixate on one point


  • Diaphragm muscle weakness leads to respiratory insufficiency and potentially failure characterized by: sleep apnea, sleep-disordered breathing, decreased vital capacity, postural decrease in forced vital capacity (>25% from upright to supine position), REM sleep hypopneas, impaired cough, dyspnea


  • Fatigue
  • Headaches
  • Daytime sleepiness
  • Decreased sleep quality
  • Requirement for assisted ventilation (CPAP, BiPAP, airway clearance, cough assist devices)


  • The mechanisms for GI and GU symptoms in LOPD have yet to be fully elucidated; glycogen deposition in smooth muscle may contribute to the pathology. These symptoms generally have a negative impact on patient’s quality of life


  • Abdominal discomfort
  • Hepatomegaly
  • Chronic diarrhea or constipation
  • Bloating
  • Cramps
  • Early satiety
  • Difficulties feeding and swallowing
  • Weight loss/overweight
  • Decreased gag reflex
  • Urinary/bowel incontinence


  • Underlying muscle weakness and lack of flexibility and extensibility can lead to a variety of musculoskeletal manifestations
  • Scoliosis can contribute to respiratory insufficiency and increases the risk for requiring respiratory support
  • Reduced flexibility of the neck and trunk muscles leads to rigid spine syndrome


  • Osteoporosis
  • Osteopenia
  • Low bone mineral density
  • Increased incidence of fractures
  • Scoliosis and other abnormal curvatures of the spine (lordosis, kyphosis)
  • Chest wall abnormalities
  • Rigid spine syndrome
  • Asymptomatic vertebral fractures


  • Lysosomal glycogen accumulation in the central and peripheral nervous systems, including the brain, brainstem nuclei, and anterior horn cells have been reported
  • Impairment of the stapedius muscular function in the middle ear may lead to hearing loss (another of the proposed mechanisms)


Small fiber neuropathies may result in:

  • Painful paresthesias in the extremities
  • Muscle cramps
  • Dry eyes
  • Sensorineural hearing loss
  • Sexual dysfunction


  • Glycogen deposits in vessel walls of cerebral arteries may result in vacuolar degeneration and reduction of smooth muscle integrity, potentially leading to the propensity for aneurysms


  • Headaches
  • Dizziness
  • Intracranial aneurysms
  • Microhemorrhages
  • Basilar artery dolichoectasia


  • Mainly a major pathology in IOPD, but LOPD patients can develop cardiac symptoms; greater GAA enzyme activity and differences in storage capacity and metabolism in heart vs skeletal muscle may account for disparities between IOPD and LOPD
  • WPW syndrome may be explained by disruption of the annulus fibrosis by glycogen-filled cardiac myocytes, thus allowing ventricular preexcitation


  • Isolated cases of cardiomyopathy and cardiac hypertrophy
  • Abnormal heart rhythm (supraventricular tachycardia, sick sinus syndrome, WPW syndrome)

Patient Case Studies

Below are examples of different patient case studies that illustrate the range of symptoms Pompe patients may have on clinical presentation and examination. These may be helpful to review to gain a better understanding of the varied symptoms at disease presentation, the signs of disease progression, and the challenges of making a timely and accurate diagnosis.

PatientCase_1  PatientCase_2  PatientCase_3 

Diagnosing LOPD

A thorough diagnostic workup of LOPD may include a physical exam, a host of laboratory evaluations (creatine kinase levels, nerve conduction and electromyography, muscle imaging/biopsy, pulmonary function tests, and other assessments such as glucose tetrasaccharide tests [for glycogen burden], GAA enzyme activity assays [dried blood spot (DBS), purified lymphocytes, or whole blood, or from purified fibroblasts or muscle biopsy], and gene mutation analysis/sequencing).

Table 3 lists some common diagnostic tests, what they are able to measure, and their potential strengths as diagnostic tools.

Table 3a.Common Diagnostic Evaluations for LOPD


  • Evaluation of muscle strength by manual (Medical Research Council [MRC] scale) or quantitative means
  • Screening for respiratory function (vital capacity)


  • Can provide useful information
  • Convenient, can be done in the office

Important points

  • Must assess muscle strength in multiple positions (sitting, supine, prone) to detect mild weaknesses
  • Vital capacity (counting aloud during exhalation) assessments should be done in seated and supine positions


  • Electrical activity of muscles at rest and during activity in response to nerve stimulation


  • More diagnostic than nerve conduction studies, which often yield normal results in LOPD patients
  • Myotonic or complex repetitive charges should strongly suggest the inclusion of Pompe disease in the differential diagnosis

Important points

  • Both the thoracic paraspinal muscles and proximal/distal muscles of upper/lower limbs should be measured
  • Myotonic discharges are often atypical
  • There may be no evidence of myotonia


  • Forced vital capacity (FVC)
  • Maximum inspiratory/expiratory pressure


  • Identifies respiratory muscle weakness and fatigability
  • MIP/MEP have greater sensitivity for detecting early respiratory muscle involvement

Important points

  • Measure FVC in the seated and supine positions; measurement may be normal in 1 but not the other
  • MIP helpful when FVC in supine position is not possible (ie, patient is wheelchair bound or has respiratory failure)


  • CK levels
  • Aspartate and alanine aminotransferases


  • Simple blood test
  • Persistent elevations of CK and/or transaminase levels in mildly symptomatic/ asymptomatic individuals should prompt further investigation of Pompe disease

Important points

  • CK levels can vary from 1.5 to 15 times ULN, or they can be normal
  • Serum transaminase levels may be increased


  • Histologic examination using PAS staining can identify glycogen accumulation and acid phosphatase in autophagic vacuoles
  • Electron microscopy, although not routinely used in clinical practice, can visualize cytosolic and lysosomal glycogen deposition


  • Muscle morphology can be highly abnormal in a high percentage of patients with Pompe disease

Important points

  • Invasive
  • Degree of muscle involvement varies from patient to patient and even within the same patient
  • There can be between 1% and 90% muscle involvement in LOPD patients
  • A normal biopsy does not rule out Pompe disease; histology alone cannot be used for accurate diagnosis. Vacuolization may be seen in up to 75% of fibers in affected muscles, but not at all in unaffected muscles, so the particular muscle biopsied and the site of biopsy can affect results


  • Non-specific biomarker of glycogen storage, elevated in patients with LOPD


  • Provides an overall indication of glycogen burden
  • May be valuable for monitoring disease progression

Important points

  • Further study required to determine utility in diagnosing Pompe disease

Table 3b. Common Diagnostic Tests for LOPD


  • Amount of GAA enzyme activity


  • The gold standard for diagnosing Pompe disease
  • Can be measured in multiple tissue samples: skin fibroblasts, muscle, whole blood samples, lymphocytes, and DBS
  • DBS and whole blood sampling are sensitive, reliable, non-invasive, and rapid

Important points

  • Most accurate measurements are made in DBS and purified lymphocytes
  • Whole blood may not be as accurate for diagnosing partial GAA enzyme deficiencies; requires inhibition of competing enzyme maltase-glucoamylase
  • Measurement of GAA activity in skin fibroblasts is relatively invasive, and requires time, lab resources, and skill
  • Muscle biopsy for GAA activity is relatively rapid and can provide information on tissue pathology, but is an invasive procedure. Vacuoles often, but not always, contain glycogen, and patterns can vary even within the same patient. Which muscle and the site of biopsy can affect results, so a normal biopsy does not rule out Pompe disease


  • Mutations in the sequence of the GAA gene that may (or may not) contribute to the Pompe phenotype


  • The leaky IVSI(-13T→G) splice site mutation is the most common in Caucasian LOPD patients (on 1 allele in >50% of LOPD patients)
  • Can confirm or clarify diagnosis (add clarity to discordant GAA enzyme results), assist family screening, identify carriers, identify novel mutations, and for research purposes

Important points

  • Not all mutations correlate with clinical phenotype

Diagnostic Algorithm

As mentioned, the variable course of LOPD, age of onset, wide spectrum of symptoms, and symptoms that closely resemble many other neuromuscular diseases all contribute to the difficulty in timely and accurate diagnosis of LOPD. To this end, the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) recommends that clinicians consider GAA enzyme activity testing when the following symptoms are observed: 

  • Limb girdle (especially pelvic) muscle weakness
  • Axial (especially paraspinal) muscle weakness
  • Mild scapular winging
  • Symptoms of orthopnea

A multigene testing panel can also be ordered to aid in diagnosis, and allows simultaneous testing for an alteration in several genes. Additionally, the AANEM have prepared a consensus algorithm for the diagnosis of LOPD. More recently, a modified algorithm has been proposed based on the observation that Pompe presenting symptoms tend to fall into 3 categories: proximal/axial weakness with or without respiratory symptoms, restrictive respiratory symptoms, and asymptomatic elevations in creatine kinase.

Diagnostic Delays and Differential Diagnosis

Achieving a timely and accurate diagnosis of LOPD is important because, while disease progression may be slow for some, it is relentlessly progressive for all. The delay in diagnosing patients with LOPD can vary between an immediate diagnosis (0 years) to 60 years or more after the onset of symptoms. A survey of the Pompe Registry evaluated a group of LOPD patients (onset of symptoms >12 years of age) and found a median time to diagnosis relative to onset of symptoms (diagnostic gap) of 6.0 years. When patients were stratified by presenting symptoms, those presenting with both musculoskeletal and respiratory symptoms had the shortest diagnostic gap (2 years) and patients presenting with neither of those symptoms had the longest delays in diagnosis (14+ years; Fig. 2).

Figure 2

This figure displays the time to diagnosis in late-onset Pompe disease patients based on presenting symptoms

Figure 2. The median number of years between onset of symptoms to diagnosis in 426 LOPD patients (LOPD defined as patients >12 years of age at onset of symptoms) from the Pompe Registry (a long-term,global, observational program started in 2004, sponsored and administered by Sanofi Genzyme® [Cambridge, MA]). The Pompe Registry was designed to develop a better understanding of the natural history and outcomes in patients with Pompe disease.The Registry contains the largest collection of data on patients diagnosed with Pompe disease. All patients with a confirmed diagnosis (confirmed and documented GAA deficiency from any tissue source and/or documentation of 2 GAA gene mutations) of Pompe disease, regardless of age, synptoms, or treatment status, can be enrolled by physician investigators worldwide. Patient participation in the Pompe Registry is voluntary, ans clinical information is reported voluntarily.

The consideration of the differential diagnosis in LOPD is crucial for a timely and accurate diagnosis because of the variability of symptoms, similarity of symptoms between LOPD and many other neuromuscular disorders, and the emergence in the literature of symptoms not usually associated with LOPD (rigid spine, basilar artery aneurysm, bulbar muscle weakness, ptosis, scoliosis, etc). LOPD may be considered in the differential diagnosis of the disorders listed in Table 4.

Table 4 Shared Symptoms Between LOPD and Other Disorders


  • Shared symptoms with LOPD

Limb girdle muscular dystrophies

  • Progressive muscle weakness in pelvis, lower limbs
  • Abnormal gait
  • Elevated CK

Becker/Duchenne muscular dystrophies

  • Progressive proximal muscle weakness (ie, shoulders)
  • Respiratory impairment
  • Elevated CK


  • Subacute proximal muscle weakness (ie, shoulders)
  • Difficulty swallowing
  • Elevated CK

Mitochondrial myopathies

  • Muscle weakness
  • Hypotonia
  • Exercise intolerance
  • Cardiomyopathy
  • Elevated CK

Glycogen storage diseases IIIa, IV

  • Hypotonia (in childhood)
  • Hepatomegaly (in childhood)
  • Muscle weakness
  • Exercise intolerance
  • Elevated CK

Glycogen storage disease V

  • Muscle weakness
  • Muscle cramps when exercising
  • Elevated CK

Danon disease

  • Muscle myopathy with glycogen accumulation
  • Elevated CK

Spinal muscular atrophy

  • Voluntary muscle weakness/atrophy
  • Elevated CK

Kennedy disease

  • Difficulty breathing
  • Difficulty swallowing
  • Elevated CK

Amyotrophic lateral sclerosis

  • Progressive muscle weakness
  • Respiratory impairment
  • Elevated CK

Scapulohumeral syndrome

  • Weakness of shoulder girdle
  • Scapular winging

Myasthenia gravis

  • Generalized muscle weakness
  • Fatigue
  • Respiratory insufficiency

Pompe Registry

If a diagnosis is eventually confirmed, consider the Pompe Registry for your patient and their family. Registries have proven to be especially valuable in gathering and disseminating information for rare diseases like Pompe disease.

The Pompe Registry is sponsored and administered by Sanofi Genzyme®. Information submitted to the Pompe Registry will be maintained as confidential.