Identification of neuronal structures and pathways corresponding to clinical functioning in galactosemia.

Classic galactosemia (OMIM# 230400) is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase deficiency. Newborn screening and prompt treatment with a galactose-free diet prevent the severe consequences of galactosemia, but clinical outcomes remain suboptimal. Five men and five women with classic galactosemia (mean age = 27.2 ± 5.47 years) received comprehensive neurological and neuropsychological evaluations, electroencephalogram (EEG) and magnetic resonance imaging (MRI). MRI data from nine healthy controls (mean age = 30.22 ± 3.52 years) were used for comparison measures. Galactosemia subjects experienced impaired memory, language processing, visual-motor skills, and increased anxiety. Neurological examinations revealed tremor and dysarthria in six subjects. In addition, there was ataxia in three subjects and six subjects had abnormal gait. Mean full scale IQ was 80.4 ± 17.3. EEG evaluations revealed right-sided abnormalities in five subjects and bilateral abnormalities in one subject. Compared to age- and gender-matched controls, subjects with galactosemia had reduced volume in left cerebellum white matter, bilateral putamen, and left superior temporal sulcus. Galactosemia patients also had lower fractional anisotropy and higher radial diffusivity values in the dorsal and ventral language networks compared to the controls. Furthermore, there were significant correlations between neuropsychological test results and the T1 volume and diffusivity scalars. Our findings help to identify anatomic correlates to motor control, learning and memory, and language in subjects with galactosemia. The results from this preliminary assessment may provide insights into the pathophysiology of this inborn error of metabolism.

The adult galactosemic phenotype.

BACKGROUND: Classic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression. METHODS: Thirty-three adults (mean age = 32.6 ± 11.7 years; range = 18-59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures. RESULTS: The sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55-122). All subjects followed a dairy-free diet and 75-80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression. CONCLUSIONS: Taken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.

Stability of blood phenylalanine levels and IQ in children with phenylketonuria.

Variability of metabolic control in phenylketonuria (PKU) potentially affects cognitive outcome in early and continuously treated children with this condition. The possibility that homeostasis is more important than the absolute level of exposure to phenylalanine (phe) has not previously been examined. A meta-analysis of 40 studies showed that in children with phenylketonuria (PKU), mean lifetime blood phe levels were significantly correlated with Full Scale IQ (FSIQ) (r=-0.34). A similar correlation (r=-0.35) was found between FSIQ and mean exposure during 0-12 years of age. Most of the studies in the meta-analysis, however, included children who had discontinued the phe restricted diet. None examined the impact of fluctuations in metabolic control in continuously treated children. This is important because new therapies may increase stability in blood phe levels. The question has arisen whether these therapies are beneficial in children whose blood phe levels are generally within the recommended range of 120-360 micromol/L. In this study, we describe the relationship between FSIQ and two parameters of metabolic control: (1) mean blood phe level of all reported specimens for each subject, and (2) variability of the blood phe level as indicated by the standard deviation of blood phe levels for each subject. Analyses were performed using lifetime phe levels and levels during three periods (0-6 years, 0-10 years, and >10 years of age). The most recent FSIQ for each child was used in the correlation analyses. Data were collected from medical records on all 46 children born between 1999 and 2006 with early and continuously treated PKU followed at the Metabolism Program at Children's Hospital Boston. The mean age of the children at the time of their most recent FSIQ test was 7.5+3.3 (2.9-15.5) and their mean FSIQ was 104+15 (68-143). The mean lifetime blood phe level in these children was 312+132 micromol/L (125-852). The standard deviation of blood phe levels was 182+72 micromol/L (96-336). The correlation between lifetime blood phe levels and most recent FSIQ was -.17 (p=0.38) and the correlation between standard deviation of blood phe levels and most recent FSIQ was -.36 (p=.058), not reaching significance, but indicating a trend. These results indicate that stability of blood phe levels may be more important to cognitive functioning than overall exposure to phe in early and continuously treated PKU. In treating PKU, attention should be given to variability in blood phe levels as well as maintenance of phe levels within the recommended range.

Improved Measurement of Brain Phenylalanine and Tyrosine Related to Neuropsychological Functioning in Phenylketonuria.

INTRODUCTION: Researchers hypothesized that in phenylketonuria (PKU) high brain phenylalanine (Phe) levels and low brain tyrosine (Tyr) levels affect neuropsychological functioning. However, traditional magnetic resonance spectroscopy (MRS) yielded uncertain results of brain Phe and could not adequately measure brain Tyr. This pilot study examined the potential of correlated spectroscopy (COSY) to quantify these biomarkers and explain variability in neuropsychological functioning. METHODS: Nine adults with early treated classic PKU received magnetic resonance imaging (MRI) with COSY and a battery of neuropsychological tests. Brain Phe and Tyr in parietal white matter (PWM) were compared to results in gray matter of the posterior cingulate gyrus (PCG). RESULTS: Brain Phe ranged from 101 to 182 (mean = 136.76 ± 23.77) µmol/L in PCG and 76 to 185 (mean = 130.11 ± 37.88) µmol/L in PWM. Brain Tyr ranged from 4.0 to 7.4 (mean = 5.44 ± 1.01) µmol/L in PCG and 4.1 to 8.4 (mean = 5.90 ± 1.48) µmol/L in PWM. Correlation coefficients were largest for brain Phe PWM and measures of auditory memory (rho = -0.79), anxiety (rho = 0.79), and executive functioning (rho = 0.69). Associations were in the expected direction, with higher brain Phe and lower brain Tyr related to poorer functioning. The two participants with severe structural MRI abnormalities had low brain Tyr levels in PCG and 3/5 of the participants with moderate to severe MRI abnormalities had higher than average brain Phe levels. CONCLUSION: COSY has the potential to quantify brain Phe and Tyr at low concentrations and in specific brain regions. In this pilot study, these biomarkers were associated with indices of neuropsychological functioning. Additional studies are needed to validate the COSY results.