Specialties piecing together the puzzle to spot Pompe disease early on

Thursday, 18 Feb 2021

Rare diseases can often present in a myriad of different ways, making it challenging for clinicians to diagnose. Yet, the goal of early diagnosis is an important one, particularly for treatable rare diseases such as Pompe disease. But what are the red flags?, when is the right time to stop and screen for a rare disease like Pompe disease? And whose responsibility is it to do the screening? Given Pompe disease can appear at any age and presents with generally non-specific symptoms, we spoke with leading Australian Pompe disease experts, Associate Professor Robert Henderson, a senior staff specialist in Neurology at the Royal Brisbane and Women’s Hospital, Dr Michel Tchan, clinical and metabolic geneticist at Westmead Hospital, and Associate Professor Andrew Kornberg, a paediatric neurologist at the Royal Children’s Hospital Melbourne.

What is Pompe disease and what makes it so hard to diagnose?

Pompe disease is due to biallelic pathogenic variants in the GAA gene. This autosomal recessive, lysosomal-storage disorder results in accumulation of lysosomal and non-lysosomal glycogen in skeletal, cardiac and smooth muscle tissues, which often impairs end-organ function.1,2

“It’s complicated by the variations in phenotypes that can present,” explained Dr Tchan who said, “the biggest challenge facing recognition of the disease is often that the symptoms are non-specific and there can be inconsistency in the presentation from one case to the next.” More than 450 GAA mutations have been discovered leading to either complete or partial deficiency in the GAA enzyme.1 The severity of the mutation determines when Pompe disease manifests:2,3

  • <1% of normal GAA activity leads to infantile-onset Pompe disease (IOPD) in children <1 year of age

This variable phenotype is one of the reasons Pompe disease is “underdiagnosed and for every patient there may be decades of symptoms,” said Associate Professor Henderson.  Dr Tchan added, “patients can been seen by 20–30 different medical professionals, all looking at slightly different aspects of their health. All it takes is for one to put the pieces of the puzzle together, but often for patients the diagnostic journey can be a long one.”

Infantile-onset Pompe disease (IOPD)

Associate Professor Kornberg specialises in managing the infantile presentation of Pompe disease, so he sees both IOPD and paediatric LOPD. In this setting “early diagnosis is important for mortality and morbidity. The problem is most people wouldn’t recognise the signs and symptoms as suggesting Pompe disease, but if you don’t keep it in mind as an option you could miss a case,” he explained.

His advice for different specialists who see infants is to keep Pompe in mind when other obvious causes are not able to explain non-specific symptoms. “In the infant who is ‘floppy’ or hypotonic, think could it be Pompe disease? For cardiologists who see heart abnormalities like cardiomyopathy in the young consider Pompe disease and referral to a neurologist.” Getting a diagnosis quickly is important in IOPD as “it is usually fatal around one year of age when left untreated,” he explained.

For juvenile onset (or paediatric LOPD) A/Prof Kornberg described how it can “present in numerous ways. Kids don’t present with weakness but may have muscle pain or fail to meet developmental milestones or fall behind their peers when it comes to physical activity. They rarely have respiratory issues.

Late-onset Pompe disease (LOPD)

Aside from infants, other patients living with Pompe disease may be seen by a wide variety of specialities for their non-specific symptoms, depending on the severity and the manifestations of the disease.3 Dr Henderson and Dr Tchan described a few of the common types of medical professionals who may be likely to encounter patients experiencing symptoms of Pompe disease:

Specialist Signs and symptoms of Pompe disease
Rheumatologist Aching discomfort in joints and muscles, particularly in the proximal or hip girdle muscles
Respiratory specialist Weakness in diaphragm muscle, sleep apnoea, daytime tiredness, morning headaches
Gastroenterologist AST/ALT elevations due to muscle breakdown
Neurologist Muscle weakness, chronic elevation in creatinine kinase, positive Gower’s manoeuvre


But as Dr Tchan pointed out, “each of these aspects could be indicative of several diseases, so what should be a ‘red flag’ to think of Pompe disease?”

A/Prof  Henderson said that while there is variation in its presentation, there are some clues that signal to him to consider Pompe disease. “Most adult patients have weakness of the muscles closer to the centre of the body. So tasks like sitting up in bed become difficult, or they present with a waddling gait,” he explained.

 Muscle weakness was also a hallmark symptom for Dr Tchan, who added “I check the creatine kinase (CK) levels in patients with Pompe disease – which can be up in the hundreds early on in the disease. Occasionally aspartate aminotransferase (AST)/alanine aminotransferase (ALT) is elevated too. Once other causes such as statin myopathy and thyroid disease have been excluded, we do a dried blood spot test to look for an absence of the GAA enzyme and then sometimes onto genetic sequencing. Of course it’s important to refer the patient who chooses this option to a genetics service for appropriate counselling around the results.”

Pompe disease is treatable

Enzyme replacement therapy is available for Pompe disease.1–3 Compared to the natural history of IOPD, this therapy is lifesaving,2,4,5 so it’s important to be able to diagnose Pompe disease as early as possible. For people with LOPD, diagnosing as early as possible could mean delaying progression.4 As Associate Professor Kornberg said “if you don’t make an early diagnosis patients may end up with end-organ issues, like cardiac impairment. The earlier you can diagnose and implement enzyme replacement therapy in patients, the better.”

In LOPD Dr Tchan described treatment as “disease-modifying, it’s not a cure. There is reasonable evidence that treatment slows down deterioration. Some adults respond well, usually within the first few months. But it is important to remember that treatment won’t bring muscle tissue back, so it’s important to get patients on treatment as soon as possible.”

Pompe may be rare, but you’re never alone

Associate Professor Henderson emphasised that “the Australian Pompe Association is very active and patients are also eligible for assistance through the NDIS.” Dr Tchan also pointed out the strength of patient support groups in Australia. The Australian Pompe Association can be contacted via their website: https://australianpompe.org.au.

Support for physicians also exists, as Dr Tchan highlighted “the importance of supportive care cannot be understated. This could include respiratory specialists, physiotherapists and occupational therapists. If you are ever unsure consider reaching out to someone who has experience in treating patients with Pompe disease or even referring your patient to them. You could also involve them as an advisor whilst patients remain under the care of their local neurologist.”


This article was sponsored by Sanofi Genzyme. The content is entirely independent and based on published literature, guidelines and authors’ opinion. The views expressed do not necessarily reflect the view of Sanofi Genzyme.


Dr Tchan has received travel funding support to attend educational meetings from Sanofi Genzyme and Shire Pharmaceuticals. Honoraria received by Dr Tchan from Sanofi Genzyme, Takeda and Amicus for speaking engagements and advisory boards are donated to research trusts.

Associate Professor Robert Henderson participates in advisory boards for Sanofi Genzyme and Biogen.

Associate Professor Andrew Kornberg participates in advisory boards with Sanofi Genzyme



  1. Dasouki M, et al. Pompe disease: literature review and case series. Neurol Clin 2014;32(3):751–76.
  2. National Organization for Rare Disorders. The Physician’s Guide to Pompe Disease 2013: Available from: https://rarediseases.org/physician-guide/pompe-disease/ [accessed Jan 2021].
  3. Cupler EJ, Berger KI, Leshner RT, et al. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve 2012;45(3):319–33.
  4. Chan EK and Kornberg AJ, Elevated Creatine Kinase in a 6-Year-Old Boy. Semin Pediatr Neurol 2018;26:46–49.
  5. Kishnani PS et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology. 2007 Jan 9;68(2):99-109. doi: 10.1212/01.wnl.0000251268.41188.04. Epub 2006 Dec 6. Erratum in: Neurology. 2008 Nov 18;71(21):1748. PMID: 17151339.


sanofi-aventis australia pty ltd, trading as Sanofi Genzyme ABN 31 008 558 807. Talavera Corporate Centre, Building D, 12-24 Talavera Road, Macquarie Park, NSW 2113. MAT-AU-2100027. Date of preparation January 2021.

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