GM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease) are unrelenting heritable neurodegenerative conditions of lysosomal ganglioside accumulation. Although progressive brain atrophy is characteristic, longitudinal quantification of specific brain structures has not been systematically studied. The goal of this longitudinal study has been to quantify and track brain MRI volume changes, including specific structure volume changes, at different times in disease progression of childhood gangliosidoses, and to explore quantitative brain MRI volumetry (qMRI) as a non-invasive marker of disease progression for future treatment trials. Brain qMRI studies were performed in 14 patients with gangliosidoses (9 infantile, 5 juvenile) yearly. Cerebellar cortex and white matter, caudate, putamen, corpus callosum, ventricles, total brain, and intracranial volumes were measured, as well as total brain volume. Age-matched controls were available for the patients with the juvenile phenotype. The infantile phenotype of all gangliosidoses showed a consistent pattern of macrocephaly and rapidly increasing intracranial MRI volume with both (a) brain tissue volume (cerebral cortex and other smaller structures) and (b) ventricular volume (P<0.01 for all). In contrast to apparent enlargement of the total brain volume, and chiefly the enlarged cerebral cortex, a subset of smaller brain substructures generally decreased in size: the corpus callosum, caudate and putamen became smaller with time. The volume of cerebellar cortex also decreased in patients with infantile GM1-gangliosidosis and juvenile GM1- and GM2-gangliosidosis; however, infantile GM2-gangliosidosis cerebellar cortex was the exception, increasing in size. Elevated intracranial pressure (estimated by lumbar spinal pressure) was a common finding in infantile disease and showed continued increases as the disease progressed, yet lacked MRI signs of hydrocephalus except for increasing ventricular size. Notably, in patients with juvenile gangliosidosis, macrocephaly and elevated intracranial pressure were absent and total brain volume decreased with time compared to controls (P=0.004). The disease course of infantile versus juvenile gangliosidoses is clearly distinguished by the rate of brain disease progression as characterized by qMRI. Assessments by qMRI represent a robust non-invasive method for monitoring CNS changes in the clinical course of gangliosidoses and is ideally suited to monitor effects of novel CNS-directed therapies in future clinical trials.

Mucopolysaccharidosis type I (MPS I) was added to the Recommended Uniform Screening Panel for newborn screening in 2016, highlighting recognition that early treatment of MPS I is critical to stem progressive, irreversible disease manifestations. Enzyme replacement therapy (ERT) is an approved treatment for all MPS I phenotypes, but because the severe form (MPS IH, Hurler syndrome) involves rapid neurocognitive decline, the impermeable blood-brain-barrier is considered an obstacle for ERT. Instead, hematopoietic cell transplantation (HCT) has long been recommended, as it is believed to be the only therapy that arrests neurocognitive decline. Yet ERT monotherapy has never been compared to HCT, because it is unethically unacceptable to evaluate a therapeutic alternative to one shown to treat Central Nervous System (CNS) disease. An unusual opportunity to address this question is presented with this clinical report of a 16-year-old female with MPS IH treated only with ERT since her diagnosis at age 2. Neurological functioning was stable until cervical spinal cord compression at age 8, hydrocephalus at age 11, and neurocognitive declines beginning at age 10. Somatic disease burden is significant for first degree AV block, restrictive lung disease, bilateral hearing loss, severe corneal clouding, joint pain/limitations requiring mobility assistance, and short stature. This patient's extended survival and prolonged intact neurocognitive functioning depart from the untreated natural history of MPS IH. Disease burden typically controlled by HCT emerged. Although not anticipated to provide benefit for CNS disease, ERT may have provided some amelioration or slowing of neurocognitive deterioration.

This follow-up study of a subgroup of the patients seen in a natural history study of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A) addressed the adaptive and medical characteristics of their advanced disease manifestations. Of the original 24 patients, specific data was collected on only 58% primarily due to difficulty in locating families and coordinating time for interviews two to four years after the original study. At the last contact with the patient, age range was 8 to 24years of age. Data were collected from telephone interviews from the Vineland Adaptive Behavior Scales II and medical and treatment history. We report the case data from rapid progressing and slow progressing patients separately. By the end of our data collection, 5 patients had died; 4 rapid progressing patients between 8 and 12years of age and 1 slow progressing patient at age 21. Two patients were in out-of-home placements in the year before they died. We found that the incidence of surgeries and epilepsy was relatively low and that behavior problems largely subsided. Adaptive levels were very low with children functioning at below a two-year age equivalent level in all adaptive functions, but motor skills were slightly more intact. Only one slow progressing patient was functioning above a three-year level. Parent burden had shifted from behavioral control to physical management. Although their quality of life was clearly negatively impacted by physical management and palliative care, parents were more able to cope and adapt to such demands than in the initial stages of the disease.

The mucopolysaccharidoses (MPSs) are a group of rare genetic lysosomal disorders with progressive multisystem involvement. An MPS-specific physical symptom scale was developed and introduced a Physical Symptom Score (PSS) to quantify the somatic disease burden across MPS I, II and VI. Somatic burden of disease in patients with attenuated MPS I, II and VI as measured by the PSS will be positively associated with age and negatively associated with neuropsychological functions [i.e. full scale intelligence quotient (FSIQ) and attention]. Forty-eight patients with attenuated MPS I (n = 24), II (n = 14), and VI (n = 10) aged 6 to 32 years on enzyme replacement therapy who were enrolled in "Longitudinal Studies of Brain Structure and Functions in MPS Disorders" across seven centers. Somatic disease burden was measured by the PSS. Neuropsychological functions were measured by the Wechsler Abbreviated Scale of Intelligence (WASI) and Test of Variables of Attention (TOVA). PSS was positively associated with age in attenuated MPS I (P < 0.001), MPS II (P < 0.01) and MPS VI (P < 0.05). There was a negative association of PSS with FSIQ in attenuated MPS I (P < 0.001) and in MPS VI (P < 0.001) but not with MPS II. Although attention scores were below average in all groups, a significant negative association between PSS and one measures of sustained attention (TOVA d prime) was found only in MPS VI. Physical Symptom Score increased with age in attenuated MPS I, II and VI, reflecting progressive somatic burden of disease despite treatment with enzyme replacement therapy. Furthermore, the association of increased somatic disease burden with decreased neurocognitive ability suggests that both measures reflect disease severity and are not independent.