Introduction

A brief overview of pompe disease

Definition and cause

Pompe disease can also be known as an acid maltase deficiency or glycogen storage disease type II, this is because Pompe is an inherited genetic disorder due to the lack of the ‘acid alpha-glucosidase’ enzyme.¹ Pompe disease is known as an autosomal recessive disease, this is because when the offspring receives both copies of the gene they are affected. This occurs when both parents are known to be carriers who contain one copy of the genetic mutation which then leads the offspring to inherit both copies of the faulty gene. 

Types (infantile-onset and late-onset) 

There are two types of Pompe diseases known infantile-onset and late-onset. Infantile onset is the most common form of Pompe disease, which develops in the early stages of life. This leads to severe heart problems and hypotonia. Whereas, late-onset Pompe disease develops in adults, but can also occur during childhood or adolescence. Late-onset Pompe disease causes early motor problems.² Late-onset Pompe disease also can lead towards muscle weakness and respiratory failure. This article will focus on the effects of the infantile and late-onset Pompe disease and its effect on cognitive function. 

Importance of studying cognitive function in pompe disease

What is cognitive function?

The cognitive function is a mental process that contains memory, language or problem-solving skills. It allows people to think and process information. The part of the brain that is involved with these cognitive functions is the cerebral cortex.³ Studies have shown that cognitive impairment is more common in infantile-onset Pompe disease than late-onset Pompe disease.⁴

Importance of studying cognitive function

It is important to study cognitive impairments as they can cause a great amount of daily life challenges for patients, their families and friends. Therefore if early diagnosis of cognitive impairment is recognised then it allows for treatments to be discussed before it is too late and can cause a possibility to prevent further cognitive impairment.⁵ 

Implications for treatment and education

A current scheme of treatment for cognitive development is enzyme replacement therapy. If this treatment is used during the early stages of Pompe Disease then it is possible for normal cognitive development during early childhood stages up to 24 months.⁶ Enzyme replacement therapy involves the process of giving replacement enzymes to patients. The most common method is through IV fusions, where the replacement enzyme is infused directly into the bloodstream and by receiving these enzymes the body is able to perform cognitive functions normally.⁷  

Cognitive function and intellectual development

General cognitive development in children

Factors influencing cognitive development

Some key external factors that influence cognitive development are early experiences, nutrition, exercise, sleep and mindset. When children exhibit healthy nutrition, regular exercise and sufficient sleep it enables healthy brain development. When children approach learning tasks with a growth mindset it is believed that they are more likely to succeed academically and grow cognitively. ⁸ 

Research findings on cognitive function in pompe disease

Studies on infantile-onset pompe disease

In Europe in 2006, there was a trial carried out with enzyme replacement therapy and recombinant human alglucosidase alfa. The clinical trial observed the cardiac, respiratory, motor and cognitive function of 15 German patients who were aged 7 and older and began ERT at the age of 5 months. 

In the beginning, the starting dose was 20 mg/kg biweekly in 12 patients, 20 mg/kg weekly in 2 and 40 mg/kg in one patient. In this experiment, only 11 children did cognitive testing. The results of cognitive testing are explained below. ⁹

Cognitive outcomes:

For the 11 children who underwent cognitive testing, their IQ scores were measured. The results showed that 4 children had a normal IQ score (IG 117,102,96,94), and one child had an IQ score of 81 which meant that they had a mild developmental delay. Moreover, 6 of the patients had an IQ score ranging from 69 to less than 55 and this meant that they had intellectual disabilities. However, three patients were unable to meet the requirements for the standardised testing and one patient terminated the test early due to exhaustion. Therefore the study concluded that neurocognitive development is normal and is only mildly delayed in children. ¹⁰

Neurological and brain imaging findings

During the experiment 12 cMRI examinations were performed in 7 patients who were aged from 1.1 to 9.2 years. 4 of the patients had one MRI and 3 of them had 2-4 MRIs. In the results, white matter hyperintensities were found in 10/12 MRIs from the 6 patients, enlarged lateral ventricles in 3 MRIs from 2 patients, and abnormalities of the basal ganglia in 2 MRIs from 1 patient. The table below shows the results of the MRI scan and the abnormalities caused in the brain. 

The different shades of grey show the severity of involvement: light grey shade (indicates stage 1), dark shade (indicates stage 3). The numbers in the column indicate how much the section of the brain has been affected. 0 equals normal, 1 equals slightly abnormal and 2 equals abnormal. In stage 0 MRI white matter doesn’t change, in stage 1 the supratentorial region is affected, stage 2 the subcortical white matter and U-fibres is affected and in stage 3 the infratentorial region is affected.¹¹

Studies on late-onset pompe disease

A Study was done on 19 patients with late-onset Pompe disease (age range 11-56 years)  and the aim was to investigate the brain structure, cerebral vasculature and cognitive function in a cohort of patients with late-onset Pompe disease. The study consisted of brain imaging combined with cognitive testing of IQ and specific neuropsychological domains such as cognitive flexibility, attention and memory. 

Cognitive outcomes

At the end of the experiment, the two patients showed mild punctate WMA within normal range for age, with a Fazekas score of 1 to 2. Magnetic resonance angiography revealed a slight vertebrobasilar dolichoectasia in two patients but did not show any aneurysms or vascular dissections. Most of the patients had age-adjusted scores within the normal range and combined total intelligence (IQ) scores between 91-111. Therefore the results concluded that it showed no brain abnormalities other than minor microvascular lesions considered within normal range for age, or any signs of general cognitive impairment in late-onset Pompe patients. ¹²

Mechanisms behind cognitive impairment

Potential neurological pathways affected

Central nervous system involvement

The central nervous system is mainly involved in late-onset Pompe disease. Some autopsies have stated that there is a periodic acid-Schiff-positive vacuole within the smooth muscle cells. This suggests that there has been vacuolar degeneration and glycogen alter arterial wall architecture which can lead to the formation of aneurysms.¹³ When MRI scans are done on LOPD patients, they reveal cerebrovascular abnormalities in vertebrobasilar, cerebral and carotid arteries. Early detection of cerebrovascular malformations could help avoid life-threatening issues such as a subarachnoid haemorrhage or brainstem compression.¹⁴

Impact on learning and education

Challenges faced by children with Pompe disease in educational settings

Learning disabilities

Children who have Pompe disease are often faced with challenges in the central nervous system which then leads to secondary effects in cognitive functioning, academic, speech and language skills. In a study 5 children with infantile Pompe diseases were measured against the Adaptive Behaviour Scales and 4 out of the 5 were below average,¹⁵ which shows how Pompe disease affects a child’s ability to learn and communicate. In the follow-up study,¹⁶ 11 children with infantile disease were treated for attention-deficit/hyperactivity disorder 2 had shown levels of anxiety and one had autism. Therefore the disease clearly affects the cognitive functions within the brain which then leads to children with learning disabilities. 

Adaptations and interventions

In order to tackle these learning disabilities for children with Pompe disease an individualised education plan (IEPs) could be a possible solution.¹⁷ This is a plan where a teaching staff helps plan out a learning method which is best suited for each child it differs from person to person, therefore allowing for the appropriate amount of help to be reached for each child. Furthermore, another method that can be used is cognitive therapies and support,¹⁸ which allows for treatment for a range of mental and emotional health issues such as anxiety and depression. It aims to learn practical self-help strategies.¹⁹

Summary

Overall, Pompe disease causes impairment in cognitive function due to the effects it has on the central nervous system and the brain. This has a major effect on children causing intellectual disabilities and memory issues. Pompe disease can be treated with enzyme replacement therapy however the outcome varies from person to person.