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.

Web medical information produces anxiety in parents of infants with suspected galactosemia.

Parents had already taken information about galactosemia from web medical pages because they were asked for a second blood sample from their infant suspected for the disease. All enzyme types of this disorder are diagnosed by neonatal screening perinatally and treated with a galactose (GAL) free diet. The most frequent information about the disease was mental retardation (100%), eye cataracts (100%) liver dysfunction (90.5%), speech delay (76.1%), hypoglycemia (69.0%), seizures (31.0), etc. Most clinical and laboratory information about galactosemia taken from the Internet was correct for the classical type of the disorder. A differentiation of the galactosemia enzyme types is needed.

The need for additional care in patients with classical galactosaemia.

Purpose: Classical galactosaemia is an inborn error of galactose metabolism which may lead to impairments in body functions and accordingly, need for additional care. The primary aim of this study was to establish the type and intensity of this additional care. Materials and methods: Patients with classical galactosaemia aged ≥2 years were evaluated with the Capacity Profile, a standardised method to classify additional care needs according to type and intensity. Based on a semi-structured interview, current impairments in five domains of body functions were determined. The intensity of additional care was assessed (from 0, usual care, to 5, total dependence). Results: Forty-four patients with classical galactosaemia, 18 males and 26 females (median age 15 years, range 2-49 years), were included. There was a wide spectrum of impairments in mental functions. Motor function impairments were present in four patients, and mild speech impairments in eight patients. Additional care for sensory functions was uncommon. All patients needed a diet, which care is scored in the physical health domain. Conclusions: Apart from the diet all patients need, classical galactosaemia leads to the need for additional care mainly in the domains of mental functions and speech and voice functions. Implications for rehabilitation The Capacity Profile is a useful tool to demonstrate additional care needs in classical galactosaemia. In classical galactosaemia additional care is mostly indicated by mental impairments and speech and voice functions. One-fifth of patients have impairment of speech and voice functions at time of the study, and half of all patients had received speech therapy in childhood. Over 70% of patients need additional care/help due to impairment of mental functions, ranging from coaching due to social vulnerability to full day care.

Exploration of the Brain in Rest: Resting-State Functional MRI Abnormalities in Patients with Classic Galactosemia.

Patients with classic galactosemia, a genetic metabolic disorder, encounter cognitive impairments, including motor (speech), language, and memory deficits. We used functional magnetic resonance imaging to evaluate spontaneous functional connectivity during rest to investigate potential abnormalities in neural networks. We characterized networks using seed-based correlation analysis in 13 adolescent patients and 13 matched controls. Results point towards alterations in several networks, including well-known resting-state networks (e.g. default mode, salience, visual network). Particularly, patients showed alterations in networks encompassing medial prefrontal cortex, parietal lobule and (pre)cuneus, involved in spatial orientation and attention. Furthermore, altered connectivity of networks including the insula and superior frontal gyrus -important for sensory-motor integration and motor (speech) planning- was demonstrated. Lastly, abnormalities were found in networks involving occipital regions, linked to visuospatial capacities and working memory. Importantly, across several seeds, altered functional connectivity to the superior frontal cortex, anterior insula, parietal lobule and the (pre)cuneus was observed in patients, suggesting special importance of these brain regions. Moreover, these alterations correlated with neurocognitive test results, supporting a relation with the clinical phenotype. Our findings contribute to improved characterization of brain impairments in classic galactosemia and provide directions for further investigations.

White matter microstructure pathology in classic galactosemia revealed by neurite orientation dispersion and density imaging.

White matter abnormalities have been observed in patients with classic galactosemia, an inborn error of galactose metabolism. However, magnetic resonance imaging (MRI) data collected in the past were generally qualitative in nature. Our objective was to investigate white matter microstructure pathology and examine correlations with outcome and behaviour in this disease, by using multi-shell diffusion weighted imaging. In addition to standard diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI) was used to estimate density and orientation dispersion of neurites in a group of eight patients (aged 16-21 years) and eight healthy controls (aged 15-20 years). Extensive white matter abnormalities were found: neurite density index (NDI) was lower in the patient group in bilateral anterior areas, and orientation dispersion index (ODI) was increased mainly in the left hemisphere. These specific regional profiles are in agreement with the cognitive profile observed in galactosemia, showing higher order cognitive impairments, and language and motor impairments, respectively. Less favourable white matter properties correlated positively with age and age at onset of diet, and negatively with behavioural outcome (e.g. visual working memory). To conclude, this study provides evidence of white matter pathology regarding density and dispersion of neurites in these patients. The results are discussed in light of suggested pathophysiological mechanisms.

Living situation, occupation and health-related quality of life in adult patients with classic galactosemia.

BACKGROUND: Galactose-1-phosphate uridyltransferase deficiency is well known as the underlying defect in classic galactosemia. However, little is known about the consequences of this defect beyond physical disease. AIM: To evaluate psychosocial, educational and occupational outcome as well as health-related quality of life (HRQOL) in adult German patients with galactosemia and to compare information with data from patients with phenylketonuria as well as the general German population. METHODS: Members of the German patient support group for galactosemia received invitation, informed consent form and questionnaires by regular mail from the patient support group. Participation was voluntary. RESULTS: Forty-one out of 66 invited patients participated in this study. Nearly 2/3 of the patients were singles, and the majority of patients were still living with their parents. Frequently, patients had no school leaving certificate, and 30% of the patients had never started or never completed an apprenticeship. Getting along with galactosemia was rated as 'very good' or 'good' although following the diet was a burden. Social well-being and social functioning was lower compared to patients with PKU. DISCUSSION: Patients with galactosemia need a multi-professional team not only focusing on physical and/or biochemical aspects of disease but including also psycho-social dimensions of life.

Parenting a child with phenylketonuria or galactosemia: implications for health-related quality of life.

Parents of children with chronic disorders have an impaired health-related quality of life (HRQoL) compared to parents of healthy children. Remarkably, parents of children with a metabolic disorder reported an even lower HRQoL than parents of children with other chronic disorders. Possibly, the uncertainty about the course of the disease and the limited life expectancy in many metabolic disorders are important factors in the low parental HRQoL. Therefore, we performed a cross-sectional study in parents of children with phenylketonuria (PKU, OMIM #261600) and galactosemia (OMIM #230400), metabolic disorders not affecting life expectancy, in order to investigate their HRQoL compared to parents of healthy children and to parents of children with other metabolic disorders. A total of 185 parents of children with PKU and galactosemia aged 1-19 years completed two questionnaires. Parents of children with PKU or galactosemia reported a HRQoL comparable to parents of healthy children and a significantly better HRQoL than parents of children with other metabolic disorders. Important predictors for parental mental HRQoL were the psychosocial factors emotional support and loss of friendship. As parental mental functioning influences the health, development and adjustment of their children, it is important that treating physicians also pay attention to the wellbeing of the parents. The insight that emotional support and loss of friendship influence the HRQoL of the parents enables treating physicians to provide better support for these parents.

Psychosocial developmental milestones in men with classic galactosemia.

Patients with classic galactosemia suffer from several long term effects of their disease. Research in a group of mainly female patients has shown that these patients may also have a developmental delay with regard to their social aptitude. To study if male galactosemia patients achieve psychosocial developmental milestones more slowly than male peers from the general Dutch population, we assessed their development with the Course of Life Questionnaire (CoLQ). A total of 18 male galactosemia patients participated in this study (response rate 69%): 11 Dutch patients and seven American patients. We found severe delays in the social and psychosexual scales of this questionnaire, but not on the autonomy axis. These results are comparable to an earlier study with a limited number of male patients. The observed delays could be secondary to less developed social skills, cognitive dysfunction, or disrupted language development. We strongly recommend screening of galactosemia patients for developmental delays, to ensure early intervention through social skills training.

The neuropsychological profile of galactosaemia.

Long-term follow-up studies of individuals with galactosaemia have indicated that despite a strict galactose-free diet, cognitive functioning is often below average. This study was designed to examine the neuropsychological profile of individuals with galactosaemia in terms of IQ, memory, executive functioning, perceptual abilities and educational outcome. Twenty-eight people with classic galactosaemia and no comorbid neurological or psychiatric disorder took part. A battery of clinical neuropsychological tests was performed. Overall, findings were consistent with previous literature in showing galactosaemia to be linked to below-average functioning across a range of cognitive measures when mean scores were examined. Thus, the mean overall scores for verbal and performance IQ, memory, and executive functions were in the low average range. However, a range of ability was represented across individuals, with some achieving average or above scores and education to A level or above. Further work using longitudinal methodology is needed to address the issue of factors mediating any cognitive weaknesses and to establish the extent of any possible decline in functioning over time.

Remarkable differences: the course of life of young adults with galactosaemia and PKU.

Although the need for insight in factors influencing the quality of life of patients with an inborn error of metabolism is recognized, psychological adjustment of adults with metabolic diseases has not been properly studied. Adult patients with PKU were demonstrated not to differ from healthy controls in terms of their course of life (CoL) and health-related quality of life (HRQoL). However, adults with galactosaemia had a lower HRQoL with significant lower scores on the domains of cognitive and social function. This study investigated the CoL and the social demographical outcomes in these young adults with galactosaemia, and compared them with the general population and with PKU patients. A total of 15 (88%) adult patients with classical galactosaemia participated in this study. Classical galactosaemia patients had a delayed social and psychosexual development compared to their peers from the general population and to PKU patients. Also, they were significantly less frequently married or living together and significantly less frequently employed than the general population. Our study shows a stark contrast between patients with galactosaemia and patients with PKU, although both are diagnosed in the neonatal period and need life-long dietary restrictions. The observed difference is likely due to the long-term somatic complications frequently seen in galactosaemia and thus not due to the burden of a chronic disease necessitating life-long dietary restrictions. We conclude that it is essential that parents and clinicians encourage children with galactosaemia to participate in peer-related activities in order to stimulate social performance, which may result in a more normal CoL.

An updated review of the long-term neurological effects of galactosemia.

Classical galactosemia is an autosomal recessive condition in which there is near total absence of the activity of galactose-1-phosphate uridyltransferase. Patients with this condition have substantial motor, cognitive, and psychiatric impairments despite dietary treatment. A characteristic pattern of biochemical abnormalities is observed in patients with this disorder. Galactose-1-phosphate, the substrate of galactose-1-phosphate uridyltransferase, accumulates within cells, and surplus galactose is reduced to galactitol or oxidized to galactonate. Using sophisticated mass spectrometry, these compounds as well as free galactose can be measured in plasma and in urine. It is clear that initiation of dietary restriction of galactose in the newborn period produces reversal of hepatic, renal, brain, and immune dysfunction, along with reduction of the accumulated galactose metabolites. However, the neurologist should be aware that chronic and progressive neurologic impairments occur even in patients spared these neonatal symptoms. The purpose of this review is to summarize current information about neurologic complications of galactosemia and what is known, and still unknown, about its pathophysiology.

The impact of galactosaemia on quality of life--a pilot study.

Galactosaemia (galactose-1-phosphate uridyltransferase deficiency) is a pan-ethnic autosomal recessive disorder of galactose metabolism, with an estimated prevalence of 1 in 40-50000. In this pilot study, we aimed to examine the impact of galactosaemia on patients' everyday emotions, schooling, work, friendships, communication, physical activities, self-esteem and body image. We interviewed all patients with galactosaemia who attended our clinic over 2002-2003, aged 6 years and above (n = 13, age range 6-23 years) and, when possible, their parents (n = 12). The questionnaire used was based on an adaptation of the Minneapolis-Manchester QOL survey and the Australian Child Health Questionnaire. Interpersonal problems, bullying and having a hard time getting along with others, excessive anger on a regular basis, sleeping problems and problems with academic achievement, particularly with mathematics, were common. Significant differences were found between patients' and parents' perceptions, with 7/13 patients nominating the dietary restrictions and 4/7 parents nominating long-term issues as the most distressing aspect of having galactosaemia. In addition, most patients felt they were treated differently from their siblings by their parents, yet all parents felt they treated their child with galactosaemia as their other children. We conclude that galactosaemia has a significant impact on the psychosocial aspects of patients' lives. Clinicians should be aware that parents and patients can have different perspectives of the impact of galactosaemia on quality of life.

The relationship of genotype to cognitive outcome in galactosaemia.

AIMS: To evaluate the cognitive outcome of a cohort of children with galactosaemia in relation to genotype. METHODS: The cohort was drawn from children notified to the British Paediatric Surveillance Unit galactosaemia study which ran from 1988 to 1990. Cognitive outcome was assessed using the Wechsler Intelligence Scale for Children or the Wechsler Preschool and Primary Scale of Intelligence. Parents completed a questionnaire detailing educational status, and the attending paediatrician returned a questionnaire regarding age at diagnosis and biochemical outcome over the previous two years. RESULTS: A total of 45 children were genotyped: 30 were homoallelic for the Q188R mutation, the remainder being heteroallelic for Q188R with K285N (n = 4), L195P (n = 4), or other mutations (n = 7). Psychometric evaluation was available in 34 cases: mean full scale IQ was 79, verbal quotient 79, and performance quotient 82. Genotype was not related to galactose-1-phosphate (Gal-1-P) concentrations. However, children homoallelic for the Q188R mutation had significantly lower IQ scores than those who were heteroallelic (73. 6 v 94.8). This difference was independent of social and demographic influences and Gal-1-P concentrations over the previous two years. CONCLUSIONS: In children with galactosaemia, cognitive outcome appears to relate to genotype rather than metabolic control, as reflected by Gal-1-P concentrations. The value of measuring Gal-1-P concentrations routinely once successfully established on a galactosaemia diet is questionable as concentrations do not appear to affect outcome. In the UK population, homozygosity for the Q188R mutation is invariably associated with a poor outcome, and there is evidence that variability in neurocognitive outcome is at least part dependent on allelic heterogeneity.

A longitudinal study of cognitive functioning in patients with classical galactosaemia, including a cohort treated with oral uridine.

Existing longitudinal data on patients with classical galactosaemia suggests that neurocognitive functioning is impaired and, in isolated case reports, may show a decline in performance over time. The present study explored whether there are long-term changes in cognitive abilities in patients with galactosaemia and whether oral uridine can improve neurocognitive performance. Thirty-five patients (18 males, 17 females), 29 of whom received oral uridine powder at 150 mg/kg per day (divided dose, three times daily), were evaluated over a 2-5-year period with the Woodcock-Johnson Revised Cognitive Abilities Test, three academic achievement tests, and the Beery Test of Visual Motor Integration. Results showed that the uridine cohort and a comparison group that received only dietary restriction made small gains in cognitive performance over the treatment period and the size of the gains did not differ significantly. Seven subjects who started uridine prior to the age of 14 months did not differ significantly in their cognitive test scores at an average age of 3.5 years from a group of older children who had begun treatment at 4.5 years of age. These results provide no support for any developmental or uridine-treatment-related change in cognitive functioning for this sample of galactosaemic subjects.

Cognitive functioning, neurologic status and brain imaging in classical galactosemia.

A historical group of 45 children (4-18 years) and adults (18-39 years) with classical galactosemia had deficits of cognitive function that were variable and not related to the age at diagnosis or to severity of illness at presentation. There was a trend for patients to score highest on visual processing tasks. The standardized tests of speech and memory skills fell within the same range as the Broad Cognitive Ability score, indicating that the speech and language deficits may be part of a more global set of cognitive impairments. Scores on the Beery Visual Motor Integration and Block Design Tests fell in approximately the same range as other cognitive abilities. In addition, there was a high incidence of abnormality detected on MRI and 12 patients had neurologic symptoms that included ataxia, tremor and dysmetria. These abnormalities did not correlate with the age at diagnosis, severity of illness at presentation or scores on cognitive testing. The pathophysiology of neurologic and neuropsychologic impairments remains unknown. Since these appear to be unrelated to the duration of galactose exposure, other factors impacting on outcome need to be understood so that strategies can be developed to improve what appears to be a global impairment of cognitive function.

Correlation of cognitive, neurologic, and ovarian outcome with the Q188R mutation of the galactose-1-phosphate uridyltransferase gene.

This study was conducted to determine whether there is a genotype/phenotype correlation between aspects of cognitive, neurologic, and ovarian outcome in patients with galactosemia and the Q188R mutation of the galactose-1-phosphate uridyltransferase gene. The results showed that the Q188R mutation was found in 72% of alleles: 38 patients were homozygous and 21 were heterozygous for Q188R; eight patients did not have the mutation. The mean Broad Cognitive score for the group homozygous for Q188R was 75 (SD = 16), which was not statistically different from the outcome for the heterozygous group (mean score, 67; SD = 25) or the negative group (mean score, 88; SD = 21). Tremor, ataxia, and dysmetria were found in 12 subjects, and there was no association with Q188R status. Similarly, there was no association of this mutation with the development of primary amenorrhea (8 subjects) versus secondary amenorrhea (found in 14 women). Our findings suggests that the variability of outcome for patients with classic galactosemia cannot be explained by Q188R status alone, at least with regard to cognitive functioning, presence of neurologic symptoms, and timing of the onset of ovarian failure.

Verbal dyspraxia in treated galactosemia.

Galactosemia is an inborn error of metabolism that causes life-threatening illness a few days after galactose-containing milk is fed to a newborn. Early treatment with a strict lactose-free diet results in rapid improvement, and, until recently, it was thought that the long-term prognosis in such infants was usually good. The speech characteristics of 24 patients treated for galactosemia were examined. Fifty-four percent had the specific speech disorder, verbal dyspraxia. This finding was not related to age at diagnosis, severity of symptoms in the newborn period, or to biochemical control. There may be, however, a relation between dyspraxia and diminished IQ scores observed in the group of patients with dyspraxia judged as "severe." The findings indicate the association of a specific and unusual speech defect with a specific and rare metabolic disorder.

Developmental aspects of galactosemia from infancy to childhood.

The developmental status of 60 galactosemic infants, their subsequent intellectual level, school status, visual-perceptual skills, and EEG results were analyzed. In addition, the intelligence of the parents and the unaffected siblings, as well as the educational and vocational status of the parents, were also investigated. The results reveal that the highest level of mental development was in the preschool age group. The lowest level, and still within normal limits, was in the school-age children. The overall findings are consistent with earlier observations that better progress is found in those individuals whose dietary control is instituted at the youngest age level.