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Hilary Feldman, PhD
Child Development Unit
Children’s Hospital of Pittsburgh

It is clear that early diagnosis and treatment of MSUD is critical in order to prevent permanent physical and neurological deficits. In their review of the developmental outcome of 22 patients with MSUD, Hilliges, Awiszus, and Wendel (1993), postulated that cognitive outcome is associated with exposure to excessively elevated branched-chain amino and oxoacid levels during the postnatal period. They found that children treated before 5 days of age have a higher likelihood of having a normal IQ.

Nord, van Doorninck, and Greene (1991) also found that children who were diagnosed at a younger age had a milder neonatal course. Children with more moderate or severe complications had lower IQs than those who were asymptomatic or only suffered mild complications. Those children with milder complications also required fewer special education services when they became school-aged.

Mazur, Field, Berlin, Berry, Heidenreich, Yudkoff, and Segal (1991) found that children who had IQs below average had been diagnosed later than those with normal IQs (mean of 3.5 days for normal IQs and mean of 10 days for below normal IQ). Children who had been treated before they had severe symptoms had higher IQ scores than their siblings with MSUD who were not treated until they became symptomatic. The most important influences on IQ were age at the time of diagnosis and long-term metabolic control, although it was felt that control at the time of diagnosis may also have had some effect.

Morton, Strauss, Robinson, Puffenberger, and Kelley (2002), reporting on their experience managing a group of patients over 11 years, note that when classical MSUD is well managed in the neonatal period, individuals can have normal growth and development and relatively few hospitalizations. Unfortunately, common infections and injuries at any age can result in medical complications which can lead to a decline in neurological functioning.

As they grow older, learning and behavioral problems have been identified in children suffering from this disease. While not well studied, Nyhan, Wulfeck, Tallal, and Marsden (1989) found deficits with cognitive and language functioning among children with MSUD. Clearly there is variability, with some children exhibiting significant deficits while others fall within the average range.

Hoffmann, Helbling, Schadewaldt, and Wendel (2006) looked at the effect of long term metabolic control on cognitive outcomes of 24 children with MSUD during their first 6 years of life. They focused on yearly medians of mean plasma leucine levels and identified three clusters of children: those with low, intermediate, and high levels. Those in the cluster with the lowest leucine levels had IQs that were statistically higher and close to the average range (median IQ = 102), while children with intermediate leucine levels had IQs which fell below average (median IQ = 76) and those with high leucine levels had IQs which were most significantly below normal (median IQ=57). They concluded that children can have normal cognitive functioning if longterm leucine levels are close to normal and if they have not had neonatal encephalopathy.

Cognitive and behavioral outcomes are assessed as part of the evaluation for individuals with MSUD being considered as transplant candidates at Children’s Hospital of Pittsburgh. Those who are accepted are evaluated again post-transplant. To date, 17 individuals have had psychological testing as part of the pre-transplant evaluation and five individuals have been evaluated post-transplant. We have looked at a variety of measures including cognitive functioning, receptive vocabulary, academic skills, verbal and visual memory skills, visual motor skills, fine motor speed, executive functioning skills, adaptive functioning skills, and parental report of behavior. Our findings support the literature indicating that there is significant variability in skills among individuals with MSUD.

Individuals evaluated as part of the pre-transplant assessment ranged in age from 17 months and 31 years. Individuals seen after transplant ranged in age from 3 and 27 years. Of the individuals who were evaluated as part of the pre-transplant protocol, IQs ranged from mental retardation to average. Of these individuals, 47% obtained scores within the average range, 29% obtained scores below the average range, and 24% obtained scores well below the average range. On testing of receptive vocabulary, scores ranged from well below average to above average, with 7% scoring above the average range, 64% of individuals scoring within the average range, 21% below the average range, and 7% of individuals scoring well below average.

On assessment of verbal and visual memory skills, individuals obtained scores ranging from well below average to above average. On a visual-motor task and testing of fine motor speed, scores ranged from well below average to average. Assessment of academic and early learning skills indicated that 60% of individuals obtained scores within the average to the above average range and 40% of individuals obtained scores below the average range.

Parents also were administered an adaptive functioning measure which measures the individual’s ability to function in the daily world (based on what is expected for the individual’s age). Individuals are assessed on performance within the areas of Communication, Daily Living Skills (e.g. dressing, bathing, and other activities of daily living), Socialization, and Motor Skills. In the current sample, 50% of individuals obtained scores within the average range, 13% obtained scores below the average range, and 37% of individuals obtained scores well below the average range. Behaviorally, of 12 individuals, ranging in age from 6 to 31, over 80% were described as having or having had significant behavioral or attentional difficulties.

There have been five individuals who have been evaluated post-transplant with an age range of 3 to 27 years. Due to the wide age range and the diversity of individuals in the group, it is difficult to compare individuals. However, all parents and patients who were old enough to assess their experience, reported satisfaction with the transplant decision. One mother stated that it felt like a "burden had been lifted." Another young adult reported that "I feel like a whole new man." All individuals and/or parents reported satisfaction about being able to eat a variety of foods and not having dietary restrictions. All individuals and/or parents reported feeling less stress regarding ongoing concerns about the possible negative consequences of illnesses.

Although the sample is very small, parents of preschoolaged children who obtained transplants report being extremely satisfied with their child’s developmental progress post-transplant. Parents report that their children seem to be "brighter" and more alert. One preschool-aged child was functioning at or above the average range on most measures, whereas prior to the transplant the child displayed developmental delays. In older individuals, while there may be permanent deficits based on the child’s medical complications prior to the transplant, a trend toward better behavioral functioning has been observed.

Individuals with MSUD are a diverse group. Of our current, limited sample, almost 50% of individuals with MSUD have average intellectual functioning and almost 70% of individuals have average receptive vocabulary skills. On testing of academic skills, 60% of individuals obtained scores within the average to the above average range and 40% of individuals obtained scores below the average (Feldman, Ph.D. cont. from page 5) range. On an adaptive functioning measure, which assesses daily functioning based on parental report, almost 50% of individuals fell within the average range, although 37% of individuals were reported to be functioning well below the average range. In addition, a significant number of individuals (greater than 80%) are reported to have behavioral difficulties.

It is clear that continued study and research is needed to further understand the effects of MSUD on cognition and behavior and to identify the role that transplantation can play in minimizing further medical complications as well as increasing the quality of life for individuals and their families. One of the challenges is to continue to support families and to help families encourage age appropriate independent and adaptive functioning of individuals with MSUD.

REFERENCES

Hilliges C, Awiszus D, Wendel (1993). Intellectual performance of children with maple syrup urine disease. Eur J Pediatr. Feb; 152(2): 144-7.

Hoffmann B, Helbling C, Schadewaldt P, Wendel U. (2006) Impact of longitudinal plasma leucine levels on the intellectual outcome in patients with classic MSUD. Pediatr. Res. Jan 59 (1): 17-20.

Kaplan P, Mazur A, Field M, Berlin JA, Berry GT, Heidenreich R, Yudkoff M, Segal (1991)

Intellectual outcome in children with maple syrup urine disease. J. Pediatr. Jul; 119 (1(pt 1)): 46-50.

Morton DH, Strauss K, Robinson D, Puffenberger E, Kelley R (2002). Diagnosis and treatment of maple syrup disease: A study of 36 patients. Pediatrics. 109 (6): 999-1008.

Nord A, van Doorninck WJ, Greene C (1991) Developmental profile of patients with maple syrup urine disease. Jl of Inherited Metabolic Disease. 14(6): 881-9.

Nyhan WL, Wulfeck BB, Tallal B, Marsden DL. (1989) Metabolic correlates of learning disability. Birth Defects Orig Artic Ser. 25 (6): 153-69.

Strauss KA, Mazariegos GV, Sindhi R, Squires R, Finegold DN, Vockley G, Robinson DL, Hendrickson C, Virji M, Cropcho L, Puffenberger EG, McGhee W, Seward LM, Morton DH (2006). Elective liver transplantation for the treatment of classical maple syrup urine disease. Am J Transplant. Mar; 6 (3): 557-64.

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