Can serial cerebral MRIs predict the neuronopathic phenotype of MPS II?

OBJECTIVE: To advance the prediction of the neurocognitive development in MPS II patients by jointly analyzing MRI and neurocognitive data in mucopolysaccharidosis (MPS) II patients. METHODS: Cognitive ability scores (CAS) were obtained by neuropsychological testing. Cerebral MRIs were quantified using a disease‐specific protocol. MRI sumscores were calculated for atrophy, white‐matter abnormalities (WMA) and Virchow‐Robin spaces (VRS). To distinguish between atrophy and hydrocephalus the Evans' index and the callosal angle (CA) were measured. A random effects repeated measurement model was used to correlate CAS with the three MRI sumscores. RESULTS: MRI (n = 47) and CAS scores (n = 78) of 19 male patients were analyzed. Ten patients were classified as neuronopathic and nine as non‐neuronopathic. Neuronopathic patients had normal cognitive development until age 3 years. Mental age plateaued between ages 3 and 6, and subsequently declined with loss of skills at a maximum developmental age of 4 years. MRIs of neuronopathic patients showed abnormal atrophy sumscores before CAS dropped below the threshold for intellectual disability (<70). White‐matter abnormalities (WMA) and brain atrophy progressed. The calculated sumscores were inversely correlated with CAS (r = −.90 for atrophy and −.69 for WMA). This was not biased by the influence of hydrocephalus as shown by measurement of the Evans' and callosal angle. Changes over time in the Virchow‐Robin spaces (VRS) on MRI were minimal. CONCLUSION: In our cohort, brain atrophy showed a stronger correlation to a decline in CAS when compared to WMA. Atrophy‐scores were higher in young neuronopathic patients than in non‐neuronopathic patients and atrophy was an important early sign for the development of the neuronopathic phenotype, especially when observed jointly with white‐matter abnormalities

Can serial cerebral MRIs

OBJECTIVE: To advance the prediction of the neurocognitive development in MPS II patients by jointly analyzing MRI and neurocognitive data in mucopolysaccharidosis (MPS) II patients. METHODS: Cognitive ability scores (CAS) were obtained by neuropsychological testing. Cerebral MRIs were quantified using a disease‐specific protocol. MRI sumscores were calculated for atrophy, white‐matter abnormalities (WMA) and Virchow‐Robin spaces (VRS). To distinguish between atrophy and hydrocephalus the Evans' index and the callosal angle (CA) were measured. A random effects repeated measurement model was used to correlate CAS with the three MRI sumscores. RESULTS: MRI (n = 47) and CAS scores (n = 78) of 19 male patients were analyzed. Ten patients were classified as neuronopathic and nine as non‐neuronopathic. Neuronopathic patients had normal cognitive development until age 3 years. Mental age plateaued between ages 3 and 6, and subsequently declined with loss of skills at a maximum developmental age of 4 years. MRIs of neuronopathic patients showed abnormal atrophy sumscores before CAS dropped below the threshold for intellectual disability (<70). White‐matter abnormalities (WMA) and brain atrophy progressed. The calculated sumscores were inversely correlated with CAS (r = −.90 for atrophy and −.69 for WMA). This was not biased by the influence of hydrocephalus as shown by measurement of the Evans' and callosal angle. Changes over time in the Virchow‐Robin spaces (VRS) on MRI were minimal. CONCLUSION: In our cohort, brain atrophy showed a stronger correlation to a decline in CAS when compared to WMA. Atrophy‐scores were higher in young neuronopathic patients than in non‐neuronopathic patients and atrophy was an important early sign for the development of the neuronopathic phenotype, especially when observed jointly with white‐matter abnormalities

Classic infantile Pompe patients approaching adulthood : a cohort study on consequences for the brain

AIM: To examine the long-term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy. METHOD: Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years. RESULTS: From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white-matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white-matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities. INTERPRETATION: As treatment enables patients with classic infantile Pompe disease to reach adulthood, white-matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow-up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease. WHAT THIS PAPER ADDS: In our long-term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white-matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities