Late-onset Pompe Patients Show No Major Brain, Cognitive Deficits in Study

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by Marta Figueiredo PhD |

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People with late-onset Pompe disease (LOPD) do not show significant brain abnormalities or general cognitive impairment, in contrast with some patients with the classical infantile-onset form, a study shows.

The study, “Is the brain involved in patients with late-onset Pompe disease?,” was published in the Journal of Inherited Metabolic Disease.

Pompe disease is caused by low to no levels of working acid alpha-glucosidase (GAA) — an enzyme that breaks down a large sugar molecule called glycogen — due to mutations in the GAA gene.

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GAA deficiency leads to the toxic buildup of glycogen in several tissues, most often muscle, “but it has also been found in the brain of patients with the relentlessly progressive classic-infantile [form of Pompe],” the researchers wrote.

Despite long-term enzyme replacement therapy (ERT), the mainstay and only therapeutic approach approved for Pompe, some patients with the most severe, classic infantile-onset form show extensive abnormalities in their brain white matter and impaired cognitive function.

White matter is made up of nerve cell fibers and it is one of the two kinds of tissues in the central nervous system (CNS, involving the brain and spinal cord), the other being gray matter, which is comprised of nerve cell bodies.

ERT delivers a lab-made version of GAA directly to a patient’s bloodstream to prevent further damage, but it cannot cross the blood-brain barrier and thereby reach the CNS. The blood-brain barrier is a highly selective membrane that prevents potentially harmful microbes and large molecules in circulation from reaching the CNS.

Whether brain involvement is confined to classical infantile-onset Pompe disease remains controversial. While some studies have reported brain abnormalities in LOPD, a milder form, others argue that such observations are age-related and similar to those seen in age-matched unaffected people.

To clarify this, a team of researchers at Erasmus University Medical Center Rotterdam, in the Netherlands, analyzed the brain structure and vasculature (blood vessels), and cognitive function in 19 children and adults with LOPD.

All patients, followed at the university’s Center for Lysosomal and Metabolic Diseases, were younger than 60, so as to minimize age-related vascular abnormalities, and did not have significant cerebrovascular risk factors.

Brain structure and vasculature were assessed with imaging tools, while cognitive function was evaluated through several validated tests of general intelligence and specific domains, such as verbal fluency, cognitive flexibility, attention, memory, and visuospatial abilities.

The patients’ ages ranged from 11 to 56 years, with an age at symptom onset ranging from 1 to 37 years, and a median disease duration of 18 years. Three patients (age range 11 to 23 years) were still without symptoms, having been diagnosed early due to an affected sibling or disease-specific findings in routine blood testing.

All of those experiencing symptoms were receiving ERT, for a median duration of 10 years (range of 4–14 years).

Educational level ranged from primary school to university and none of the patients reported any cognitive problems.

Results showed that most patients (63.2%) had no abnormalities in their white matter or cerebrovascular impairments.

Two patients (10.5%), between 40 and 50 years old, showed mild white matter abnormalities that were considered to be within normal range for their age. Another patient, a young adult (23 years old at symptom onset), had mild-to-moderate shrinkage of certain brain regions.

Cerebrovascular changes, specifically dilation and elotion of a particular brain artery, were detected in two (11%) of the 18 patients with available imaging data, one being the patient with brain shrinkage. No other blood vessel abnormalities were observed.

“The lower prevalence of vascular abnormalities we find compared to other studies is likely due to the fact that patients were younger and without respiratory failure,” the researchers wrote.

In cognitive function, most patients “performed within the normal range on measures of general intelligence or processing speed — domains that are commonly affected in classic-infantile patients,” the team wrote.

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Slightly sub-normal visuospatial function was detected in a subset of patients: nine out of 14 in a complex figure test and eight out of 10 in a cube-copying/clock drawing test. One of these patients also had white matter abnormalities. No participant exhibited muscle weakness of the hands.

Future, larger studies using additional cognitive tools are needed to better understand these findings, the team noted.

“Contrary to the findings in a subset of classic-infantile patients, we did not find substantial brain lesions or signs of general cognitive impairment in this group of patients with late-onset Pompe disease,” the researchers wrote.