1. Past, Pilot, and Proposed

2.   Over one weekend in Boston, we conducted medical, nutritional, genetic, neurological, speech/language, laboratory, and psychological examinations in 33 adults with classic galactosemia. I. PAST Supported by Parents of Galactosemic Children, Inc (Galactosemia Foundation) And New England Genetics Collaborative

3.   Full Scale IQ 88 (range: 55-122)  Tremor 46%  Employed 79%  Married or living with partner 27%  Anxiety (Currently or in the past) 52%  Depression (Currently or in the past) 39%  Low bone density 24% RESULTS

4.   Reduced tongue strength 73%  Decreased phonation duration 64%  Reduced articulation 12%  Dysarthria 24%  Apraxia of speech 9% SPEECH

5.   WOMEN  Primary ovarian insufficiency 100%  Average age of menarche 15 years  Pregnancy 1  Births 1  MEN  Average age of puberty 13 years  Fathered children 2 FERTILITY & REPRODUCTION

6.   Low calcium intake 80%  Low vitamin D intake 75%  Normal height for males & females  Normal body mass index (BMI) 58%  Underweight 13% (females only)  Overweight 25% females/24% males  Obese 13% females/6% males NUTRITION

7.   Adult Phenotype  height is well within average range  Speech issues resolve  46% had tremor  Few men engage in sexual relationships and father children  Underlying deficit may be motor  No genotype/phenotype correlation  Older subjects no worse than younger subjects WHAT WE DIDN’T KNOW BEFORE

8.   Specific aims  Assess the relevance of neuroimaging and electroencephalogram (EEG) measurements in adults with galactosemia in explaining the pathogenesis and timing of neurocognitive impairments and neurological symptoms in galactosemia.  To determine if there is evidence for a right hemispheric developmental deficit in galactosemia. II. PILOT STUDY Supported by The Galactosemia Foundation and, in part, by New England Genetics Collaborative.

9.   10 Adults with galactosemia (5 males/5 females)  Neuroimaging Study – MRI  Structural  DTI  Functional MRI (fMRI)  EEG  Neuropsychological Evaluation  Neurological Assessment METHODS

10.   Specific aim #1 Recruit 2,200 subjects with hereditary galactosemia from North America and Europe over a five year period of time.  Specific aim #2 Perform comprehensive phenotyping on 150 adult subjects with galactosemia.  Specific aim #3 Establish a data coordinating center for an International Galactosemia Research Consortium and Galactosemia Bio-repository at the Manton Center for Orphan Disease Research at Children's Hospital Boston  Specific aim #4 Perform whole genomic DNA sequencing on 10 subjects with Q188R/Q188R genotype and severe neurological complications and on 10 subjects with Q188R/Q188R genotype and little or no chronic complications. III. PROPOSED STUDY

11.   STAY TUNED!