Neurodevelopmental profiles of 14 individuals with phosphomannomutase deficiency (PMM2-CDG)
Tara Weixel1,2, Dee Adedipe3,4, Glennis Muldoon3,5
1National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Insights
Phosphoglucomutase 2-congenital disorder of glycosylation (PMM2-CDG) causes complex neurodevelopmental issues, including intellectual disability and delayed milestones. This study quantifies these impairments to guide patient management.
Area of Science:
- Biochemistry
- Genetics
- Neuroscience
Background:
- PMM2-CDG is the most common congenital disorder of glycosylation, inherited autosomally recessively.
- It presents in infancy with multisystemic involvement, affecting over 1000 individuals globally.
- Limited natural history data exists on the neurodevelopmental aspects of PMM2-CDG.
Purpose of the Study:
- To conduct a prospective study with deep phenotyping, including neurodevelopmental assessments for PMM2-CDG.
- To systematically quantify the neurodevelopmental profile of individuals with PMM2-CDG.
- To expand understanding of PMM2-CDG impairments and inform management strategies.
Main Methods:
- Prospective study (NCT02089789) involving 14 participants (ages 2-33) with confirmed PMM2-CDG.
- Inclusion of comprehensive neurodevelopmental assessments within deep phenotyping protocols.
- Analysis of clinical features including growth, motor, language, and cognitive function.
Main Results:
- Participants exhibited neurodevelopmental disorders, faltering growth, hypotonia, cerebellar atrophy, peripheral neuropathy, movement disorders, and ophthalmological/auditory differences.
- All participants met criteria for intellectual disability or global developmental delay.
- Most participants had delayed gross motor and language milestones, with limited ambulation and verbalization.
Conclusions:
- PMM2-CDG presents a complex neurodevelopmental profile characterized by intellectual disability and multisystemic involvement.
- This study provides a systematic quantification of PMM2-CDG neurodevelopmental impairments.
- Findings will aid in guiding clinical management strategies for individuals with PMM2-CDG.
Abstract:
PMM2-CDG (formerly CDG-1a), the most common type of congenital disorders of glycosylation, is inherited in an autosomal recessive pattern. PMM2-CDG frequently presents in infancy with multisystemic clinical involvement, and it has been diagnosed in over 1000 people worldwide. There have been few natural history studies reporting neurodevelopmental characterization of PMM2-CDG. Thus, a prospective study was conducted that included neurodevelopmental assessments as part of deep phenotyping. This study, Clinical and Basic Investigations into Known and Suspected Congenital Disorders of Glycosylation (NCT02089789), included 14 participants (8 males and 6 females ages 2-33 years) with a confirmed molecular diagnosis of PMM2-CDG. Clinical features of PMM2-CDG in this cohort were neurodevelopmental disorders, faltering growth, hypotonia, cerebellar atrophy, peripheral neuropathy, movement disorders, ophthalmological abnormalities, and auditory function differences. All PMM2-CDG participants met criteria for intellectual disability (or global developmental delay if younger than age 5). The majority never attained certain gross motor and language milestones. Only two participants were ambulatory, and almost all were considered minimally verbal. Overall, individuals with PMM2-CDG present with a complex neurodevelopmental profile characterized by intellectual disability and multisystemic presentations. This systematic quantification of the neurodevelopmental profile of PMM2-CDG expands our understanding of the range in impairments associated with PMM2-CDG and will help guide management strategies.
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