Trial Outcomes & Findings for Intervention and Outcomes in Duarte Galactosemia (NCT NCT02519504)

Families were recruited through collaboration with state new born screening programs or metabolic clinics. Those expressing interest were evaluated for eligibility and asked to complete an online survey.

Interest in participating was expressed by parents or caregivers for 600 children. Consent to participate was not given for 22 and consent was given for another 12 but the initial online survey was not completed.The case/control status and demographic information is unknown for these 34 children.

Intervention and Outcomes in Duarte Galactosemia

The Children's Memory Scale assesses memory and learning across three domains: auditory/verbal, visual/nonverbal, and attention/concentration. Each domain contains two core subtests and one supplemental subtest, each of which contain both an immediate and delayed memory portion. From these subtests, eight Index scores are derived: Visual Immediate, Visual Delayed, Verbal Delayed, Verbal Delayed, Delayed Recognition, Overall Learning, Attention/Concentration, and General Memory. The Index scores represent functioning within and across the domains. The scaled scores of the subtests relevant to each Index score are summed, and from this sum, a normed Index score is derived. Each Index score has a range of 50-150, and an average score of 100, with most children scoring between 85 and 115 (SD=15). Lower scores indicate impaired memory abilities.

Auditory working memory can be assessed using WISC-IV-Integrated: Digit Span test. The digit span test forward assesses attention and short-term memory while the digit span test backward assesses working memory. For the forward test, the examinee listens while examiner says a series of numbers and asks the participant to repeat them back in the same order. For the backward test, the examiner will ask the examinee to repeat the numbers backwards, that is, by starting with the last number said and going backwards to the first number said. This process continues until the examinee can no longer remember either the full sequence of numbers or the correct order. Both forward and reverse trials are given twice. The Digit Span test is scored by the amount of numbers the examinee was able to remember in each test. Scores could range from 0 to 16 with higher scores indicating better performance.

Spatial working memory was assessed using the Wechsler Intelligence Scale for Children IV-Integrated (WISC-IV-Integrated): Spatial Span During the forward task, participants are presented with a board containing blue blocks randomly arranged. The rater first taps out a pattern of blocks, beginning with two blocks and increasing the number of blocks in the pattern with participant proficiency, and the participant is tasked with tapping the same pattern. For the backwards test, the participant is tasked with tapping out the reverse pattern after the rater's demonstration. These patterns also begin with two blocks and increase with participant proficiency. The score is the number of patterns completed correctly. Scores can range from 0 to 16 with higher scores indicating better performance.

The word generation subtest is designed to assess verbal productivity through the ability to generate words within specific semantic and initial letter categories. The participant is given a semantic or initial letter category and asked to produce as many words as possible in 60 seconds. Scores represent the number of words generated and higher scores indicate better executive control of language production, better inhibition and ideation, or better vocabulary knowledge.

The route finding subtest is designed to assess knowledge of visual spatial relations and directionality, as well as the ability to use this knowledge to transfer a route from a simple schematic map to a more complex one. The participant is shown a schematic map with a target house and asked to find that house in a larger map with other houses and streets. Scores could range from 0 to 20 with higher scores indicating better performance with visuospatial relations and orientation.It's broken into percentile categories: \<2% =1, 2-10%= 2, 11-25%=3, 26-75%=4, \>75%=5. The scores from the percentile categories described are reported. Higher numbers in the percentile categories indicate better performance with visuospatial relations and orientation.

Behavior Rating Inventory of Executive Function (BRIEF) is a questionnaire composed of three indices: Global Executive Composite, Behavioral Regulation Index, and Metacognition Index. Items are rated in a Likert-scale with 1 (never), 2 (sometimes), and 3 (often). The Global Executive Composite consists of 72 items with scoring ranging from 72 to 216. The Behavioral Regulation Index score is the total of 28 items and ranges from 28 to 84. The Metacognition Index score is the total of 44 items and ranges from 44 to 132. Raw scores are standardized to t-scores with a mean of 50 with a standard deviation of 10. Scores above 50 suggest increased difficulty while scores under 50 reflect better functioning.

The WASI-II: Vocabulary subtest is a quick estimate of an individual's level of intellectual functioning. The subtest is comprised of 42 total items that require the subject to orally define 4 images and 37 words presented both orally and visually. Scores are scaled to a t-score with a mean of 50 and standard deviation of 10. Scores above 50 indicate greater intellectual ability.

The WASI-II: Matrix Reasoning subtest is a quick estimate of an individual's level of intellectual functioning. The subtest is comprised of 35 incomplete grid patterns that require the participant to select the correct response from five possible choices. Scores are scaled to a t-score with a mean of 50 and standard deviation of 10. Scores above 50 indicate greater intellectual ability.

The ABER measures the initial response of the auditory pathway to sounds by quantifying the cranial nerve 8 conduction and brain wave latency and amplitude. Three electrodes were attached, one on the forehead and one on each earlobe, to assess response to stimulation. Responses to a clicking sound are recorded by a computerized system.There is not a normative expected range - higher scores mean that the signal is being conducted slower and lower values means that it is being conducted faster.

Pure-tone hearing test measures both conductive and sensorineural hearing loss. In this procedure, sounds are presented at different frequencies and volumes through speakers, headphones, and small devices placed behind the ear while the participant stands in a soundproof booth. Pass "1" / Fail "2", scores are presented as % of case/control who failed the hearing screen. Hearing was screened in the right and then left ear at 500, 1000, 2000, and 4000 Hz at 30 DB using pure tones in a non-sound proof room. A child received a "1" if s/he responded to all frequencies in both ears and a "2" if s/he did not respond with 2 attempts at one or more frequencies.

The DEAP evaluates both articulation and phonological processes. The DEAP includes a Diagnostic Screen, a diagnostic Articulation Assessment, a diagnostic Phonology Assessment (with a phonological analysis), and an Oral Motor Screen. The Diagnostic Screen can determine whether a child has a speech difficulty. If all words were produced at least twice (2 of 3 possible trials), there were 25 targets available (25 points possible). Any difference across the 3 trials for 1 word counted as 1 point. For example, 4 instances of words produced differently is 4/25 = 16% occurrence. The test establishes "inconsistent production" at greater than or equal to 40%.

The Diadochokinetic (DDK) speech rate assesses speech and language problems. The DDK rate measures how quickly a participant can say a series of sounds. Scores are second/syllable. Lower value = faster talker. Lowest value of 2-3 trials, or only 1 trial provided/audible.

The Acoustic Voice Quality Index (AVQI) uses multiple acoustic markers to assess dysphonia. Scores can range from 0 to 10 and scores from 0 to 3 suggest normophonia while 10 represents severe dysphonia.

The OWLS-II: LC measures oral language reception, which is the understanding of spoken language. The examiner orally presents increasingly difficult words, phrases, and sentences to the participants and he/she responds by pointing to or stating which of the four pictures is correct. The raw score of the number of correct responses is converted to a standard score based on age. The mean standard score for this test is 100, with a standard deviation of 15 and a range of 50-150, with higher scores indicating better listening comprehension.

The OWLS-II: LC measures oral language expression, which is the use of spoken language. The examiner orally presents a verbal prompt along with a picture and the participant must respond orally to the prompt with increasingly difficult language. The raw score of the number of correct responses is converted to a standard score based on age. The mean standard score for this test is 100, with a standard deviation of 15 and a range of 50-150, with higher scores indicating better listening comprehension.

Movement ABC-2: Performance test is designed to identify and describe impairments in motor performance of children and adolescents 3-16 years of age. The Performance Test involves children completing a series of fine and gross motor tasks grouped into three categories: Manual Dexterity, Aiming and Catching, and Balance. A tester will observe and record how the child performs the task. The scores are given in percentiles, with 50% being the average score- below 50% means below average, and a range of 1%-99%. Children whose performance falls below the 15th percentile may benefit from intervention, with those between the 6th and 15th percentile being at risk for Developmental Coordination Disorder (DCD). Those whose performance is at or below the 5th percentile represent children with DCD if other criteria are also met.

IOPI is a hand held manometer which measures intraoral pressure generated by compression of an air filled bulb by the tongue against the palate. Strength is measured in kilopascal (kPa). Typically, tongue strength is decreased in subjects with classic galactosemia and can contribute to speech disorders.

TETRAS consists of 10 items that evaluate tremor in the head, arms, and legs. The rater assigns a score of 0 to 4 for each item, in ascending order of severity. Total scores range from 0 to 40 with higher scores indicating greater severity of tremors.

The SSIS is a parent-reported measure that evaluates Social Skills and Problem Behaviors. 38 items are rated in a Likert-scale of 0 (never) to 3 (very often). The raw scores are converted to scaled scores with a mean of 100, a standard deviation of 15, and a range of 50-150. Standard scores are derived from the scores of a large nationally representative sample of individuals having a similar age and the same sex. Higher standard scores for "Social Skills" indicate more positive social skills, while higher standard scores for "Problem Behaviors" indicates more maladaptive behaviors (i.e. lower scores indicate fewer problem behaviors).

The CBCL is a parent-reported measure that evaluates a child internalizing and externalizing behaviors and total problems. It consists of 140 questions on a Likert-scale: 0 = Not True, 1 = Somewhat or Sometimes True, 2 = Very True or Often True. Total raw scores are converted to t-scores with a mean of 50 and standard deviation of 10. Higher scores indicative of better behavior and less problems.

RCMAS measures for the presence of academic stress, test anxiety, peer and family conflicts, and drug problems in children. The test consists of 49 yes/no items and a total score is calculated by summing the number of yes responses. The total raw score is converted to a t-scores with a mean of 50 and a standard deviation of 10. Scores above 60 generally indicate that the child is experiencing some level of anxiety.

Questionnaire developed by project staff based on experiences of children, as reported by parents, with classic galactosemia with questions on specific problems experienced, when identified, placement or intervention, other problems.

The upper extremity steadiness assessment is the "dot task", where subjects are asked to hover a pen/stylus a dot steadily for 20 seconds without touching the page/screen and keeping the arm/elbow lifted off the table. Movement in the X, Y, and Z dimensions (left-right, up-down, vertical movement) are recorded on video and scored by overlaying a measurement onto the video to determine the extent of adventitious movement. A lower score indicates increased upper extremity steadiness, with 0 being no movement. 0 = no adventitious movement, 1. = adventitious movement is barely visible, 1.5 = adventitious movement is visible, but less than 1 cm, 2. = adventitious movement is 1- \< 3 cm amplitude, 2.5 = adventitious movement is 3- \< 5 cm amplitude, 3. = adventitious movement is 5- \< 10 cm amplitude, 3.5 = adventitious movement is 10- \< 20 cm amplitude, 4. = adventitious movement is \> 20 cm amplitude.

This measure involves using a stylus pen to draw an Archimedes spiral in between the lines of a spiral template that is displayed on the tablet screen. The drawn spiral is recorded by the Neuroglyphics software on a SurfacePro3 tablet which displays the spiral template and records position and pressure of the pen tip as the subject draws. The pen should be held such that no part of the hand or arm touches the table. The scoring for this measure is the root mean square (RMS) of the drawn spiral compared to the "ideal" spiral. The root mean square is the square root of the arithmetic mean of the squares of a set of numbers representing the distance between processive points on an actual spiral drawn by a participant and what would have been an "ideal spiral" drawn mid-way between the template outlines provided on the tablet. The closer the drawn spiral was to the "ideal spiral" the smaller the RMS value will be.

Hand strength will be assessed with a standard pediatric dynamometer. Pediatric reference ranges for hand strength vary depending on age and gender; for this study the hand strength of cases and controls are compared.

The Goldman Fristoe Test of Articulation-3 (GFTA-3) is a systemic measure of articulate consonant and vowel sounds for children. The average standard score for this test is 100, with a standard deviation of 15 and a range of 50-150, with higher scores indicating better articulation. The raw score of the number of speech errors during the test, and is converted to a standard score based on age and sex.

The Children's Depression Inventory-2 (CDI-2) is a screening measure for symptoms of depression in children. It is a self-report form and includes 12 items. Each item receives a score of 0-2, where 0 = the absence of depressive symptoms and 2 = definite symptoms of depression. Total raw scores are converted to t-scores, with a mean of 50 and a standard deviation of 10. T-scores between 45 and 55 are generally considered normal and higher scores indicates more depressive symptoms.

SFP is a non-standardized 53-item exam of the oral and facial structures (Structure), the range and speed of movement of the oral and facial structures (Function), and the ability to imitate non-speech single and sequential movements (Praxis). The Structure score had a range of 0-10, with 10 items scored as "0"-within functional limits, or "1"-deviant. The Function score had a range of 0-66, consisting of 33 items scored as "0"- within functional limits, "1"- mild/moderate impairment, or "2"- severe impairment. The Praxis score had a scale from 0-40, and consisted of 10 items scored as "0"- imitates immediately, "1"- mild groping; or delayed but successful, "2"- groping or sequential efforts, then success, "3"- could not achieve imitation with purposeful effort, or "4"- child does not/cannot attempt the task. The scores from the three domains are summed to create an overall SFP score, with a possible range of 0 -116. For this exam, the closer to zero, the better the score.