Objective. Classical galactosemia (McKusick 230400) is an autosomal recessive disorder of galactose metabolism caused by a deficiency of galactose-1-phosphate uridyltransferase (EC 2.7.712). Treatment, consisting of a severe restriction of dietary galactose, is life saving, but most patients develop abnormalities despite this diet. The aim of this study was to study the influence of galactosemia on the patients’ health-related quality of life (HRQoL), on educational levels, and on the specific galactosemia-related concerns of these families.
Methods. Age-specific HRQoL questionnaires, a classical galactosemia-specific questionnaire designed by the authors, and a list of questions regarding educational attainment were handed out or sent to all 75 members of the Dutch Galactosemia Society and their families.
Results. Sixty-three (84%) patients with classical galactosemia from 58 families returned the questionnaire. Concerning HRQoL, significant differences between patients aged 1 to 5 and healthy children were found on the domains of abdominal complaints and communication. Patients aged 8 to 15 years differed from their healthy peers on the domain of cognitive function. Mothers of patients aged 6 to 15 reported a significantly lower HRQoL on the domains of motor and cognitive function. Patients 16 years and older had significant lower scores on the domains of cognitive and social function. The percentage of patients who attend special schools is significantly higher than in the general population, and the educational attainment is significantly lower in patients with classical galactosemia.
Conclusions. This is the first study to describe the HRQoL of patients with classical galactosemia using well-developed and validated instruments in different age groups. The results of the present study indicate that having galactosemia negatively influences the HRQoL. Early and regular evaluation and support of possible cognitive problems should be a major part of the protocol for the follow-up of patients with classical galactosemia.
- classical galactosemia
- galactose-1-phosphate uridyltransferase deficiency
- health-related quality of life
- educational attainment
Classical galactosemia (McKusick 230400) is an autosomal recessive disorder of galactose metabolism caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT; EC 2.7.712). Incidence in the Netherlands is 1:33 000 with an average of 6 new patients per year.1 Most patients present in the neonatal period, after ingestion of galactose, with icterus, hepatosplenomegaly, liver failure, food intolerance, hypoglycemia, renal failure, muscle hypotonia, sepsis, and cataract. Treatment, consisting of a severe restriction of dietary galactose, is life saving.2 For many years, elimination of galactose from the diet was considered to be an effective therapy to prevent complications. However, long-term follow-up of patients with classical galactosemia has shown that, despite a strict diet, most patients develop abnormalities such as in mental development, language development, cognitive and motor function, and hypergonadotropic hypogonadism.3–8 Long-term complications have been a target of clinical studies so far; however, the patients’ own experience of their disease has not been investigated. The interests of this study were 3-fold: 1) the influence of galactosemia on the patients health-related quality of life (HRQoL), 2) the educational levels of galactosemia patients, and 3) the specific galactosemia-related concerns of these families. Because patients with galactosemia, although having a normal life expectancy, are impaired by late complications that cannot yet be prevented, we believe that it is highly relevant to have better insight into the patients’ quality of life, to try to provide better support, and to facilitate a development as normal as possible.
All 75 patients who have classical galactosemia and are members of the Dutch Galactosemia Society and their families received questionnaires and were asked to return them by mail after completion. All patients were supposed to follow the strict galactose-restricted dietary recommendations as used in the Netherlands. No data about time of diagnosis were available.
Most of the questionnaires were handed out with instructions at an annual meeting of the members of the Dutch Galactosemia Society. Members not present at the meeting received the questionnaires and written instructions a few days later by mail.
For all of the patients aged 1 to 20 years, both parents were asked to complete a questionnaire. Mothers were asked to complete an HRQoL questionnaire, and both parents completed a classical galactosemia-specific survey. All patients 8 years and older completed a questionnaire themselves, including an HRQoL questionnaire and a classical galactosemia-specific survey. In the case of 2 affected siblings in 1 family, mothers were asked to fill out HRQoL questionnaires for each child separately. Patients were asked to complete the questionnaire within 3 weeks. Instructions included completing the entire questionnaire at the same time, to answer the questions without discussion with others, and to assist young children with difficult questions when necessary without influencing them.
For the evaluation of the quality of life and the classical galactosemia-related concerns of children and their parents, we used 2 questionnaires: the HRQoL questionnaires and a classical galactosemia-specific survey developed by the authors.
The TNO Institute of Prevention and Health and the Leiden University Hospital (TNO-AZL) designed questionnaires for measuring HRQoL for different age groups: TNO-AZL Preschool Children Quality of Life (TAPQOL)9 for preschool children, the TNO AZL Children’s Quality of Life questionnaire (TACQOL)10–12 for children aged 6 to 15 years with a child and a parent form, and the TNO-AZL Adult Quality of Life questionnaire (TAAQOL) for 16 years and older.13 The questionnaires focus on health problems in the past 3 months or the last weeks, and, if present, the well-being in relation to this health problem is assessed. The responses are the health-related component of the instrument, which is subsequently reported, with the exception of scales measuring emotional functioning (eg, social functioning TAPQOL, vitality TAAQOL).
The TAPQOL contains 43 items in 12 scales divided over 4 domains: 1) physical function, 2) social function, 3) cognitive function, and 4) emotional function. Scales that measure motor function, social function, and communication are applicable only to children 1.5 years and older.
The TACQOL contains 7 scales of 8 items: 1) physical symptoms, 2) motor function, 3) autonomy, 4) cognitive function, 5) social function, 6) positive emotions, and 7) negative emotions. Maximum domain scores are 32 for the first 5 domains and 16 for the emotional scales.
The TAAQOL comprises 12 scales: gross motor function, fine motor function, cognitive function, sleeping, pain, social function, limitations of daily activities, sexuality, vitality, happiness, depressive moods, and aggressiveness. In all scales, except in the scales concerning vitality, happiness, depressive moods, and aggressiveness, each item consists of 2 questions. For the TAPQOL and TAAQOL, the scale scores are obtained by adding item scores within scales and transforming crude scale scores to a 0 to 100 scale. For all questionnaires, higher scores indicate a better quality of life.
Galactosemia Quality of Life Survey
This unvalidated questionnaire was developed to obtain an impression of the effects of the disorder on the daily lives of the patients and their families. Item lists were developed from clinical experience and from parent interviews. A team of researchers (A.M.B, M.A.G., and B.F.L) collaborated on item development. Multiple items were generated for different domains of concern (knowledge of the disease, experience of the disease, diet, family communication, communication with health professionals). Items in each domain were reviewed and discussed by the other team members to ensure appropriateness. Questions were adjusted accordingly.
The final Dutch-language Galactosemia Academic Medical Center instrument has 52 items in the children’s (patients’) form and 59 items in the parents’ form. For the patients of 8 to 15 years and 16 years and older, equivalent versions were used. Items are expressed as statements in the first person and in the present tense. Children and parents were asked to indicate whether they agree with a given statement on 2 different 4-point scales. For this report, we focus on the questions regarding experience of the disease, with 17 items in the patients’ survey and 19 items in the parents’ survey. Nine items in the patients’ survey and 12 items in the parents’ survey could be answered by an agreement scale (totally agree, agree, disagree, or totally disagree). A frequency scale (almost never, sometimes, often, or almost always) was used for 8 items in the patients’ survey and 7 items in the parents’ survey.
Added to the mothers’ survey was a short list of questions about the educational level of their child. Patients 18 years and older were asked additional questions about educational level (completed level) and whether patients received special education as a result of learning disabilities.
One-sample t tests were performed to test the differences between patients with classical galactosemia and Dutch published norms on the TAPQOL and TAAQOL questionnaires.9,13 HRQoL of the children with classical galactosemia and their parents on the TACQOL was compared with that of an available norm group of healthy Dutch children. Means on the TACQOL of the healthy children and the patients with galactosemia were compared using t tests. For avoiding analyses with a large norm population and possible overrepresentation of younger children, an available random sample of 200 healthy Dutch children was used. Of this group, child and parent data were available.14 Data were collected in 12 municipal health services spread over the Netherlands.
The Dutch school system is divided into 3 phases. During the first phase (4–12 years), children attend primary school or, in case of learning disabilities, special schools with specially adapted programs. The second “high school” phase consists of preeducational programs for low-skilled professions and intermediate-skilled professions, higher skilled professions, or academic professions. These diplomas give access to schools for low-, intermediate-, and high-skilled professions and to university. Dutch Health Statistics provide reliable data only on the completed levels of schooling for different age groups. Therefore, we categorized the educational attainment according to the highest successfully completed level of schooling: low vocational training, intermediate vocational training, or high vocational training. Differences in educational levels between patients with galactosemia and healthy control subjects were analyzed with χ2 tests. From the galactosemia-specific survey, all questions in Dutch regarding the experience of the disease were selected and translated for presentation in this article, and frequencies are shown.
Sixty-three (84%) patients with classical galactosemia returned the questionnaire. Patient ages and the questionnaires completed by them and their families are shown in Table 1. As 5 pairs of affected siblings participated, 63 patients from a total of 58 families participated in the study. Because classical galactosemia is a relatively rare disease with an average of 6 new cases per year in the Netherlands, the patient group participating in this study is small. When calculated from Dutch incidence and birth rate, we included 73% of Dutch patients aged 1 to 5 (n = 22), 58% of patients aged 6 to 7 (n = 7, and at least 35% of patients aged 8 to 15 (n = 7). Two (17%) patients aged 16 to 17 and 15 patients over 18 were included. As in the recent past, many patients died before the proper diagnosis was made; this percentage is likely to be much higher in the older age groups.
There were 24 (38%) male and 39 (62%) female patients. Ages ranged from 1 to 41 years. Ninety-seven parents completed the questionnaire: 51 mothers and 46 fathers. One patient aged 8 was not able to complete the questionnaire because of mental retardation, and 2 mothers and 1 patient returned the questionnaire incomplete for unknown reasons.
Twenty-one mothers of children aged 1 to 5 years completed the TAPQOL questionnaire. Significant differences between patients with classical galactosemia and healthy control subjects were found on 2 domains: abdominal complaints (higher frequency of abdominal pain and colic) and communication (more problems with understanding what others say, problems with speaking clearly, and more difficulties with active and passive use of language). Mean scores are presented in Table 2.
Sixteen children aged 8 to 15 years completed the TACQOL questionnaire, and they differed from their healthy peers on the domain of cognitive function (understanding, learning, reading, mathematics, memory, concentration) showing impaired HRQoL (Table 3). Twenty-three mothers of patients aged 6 to 15 reported a significantly lower HRQoL on the domains of motor function (walking, running, standing, ascending stairs, balance, endurance, playing, handiness) and cognitive function (learning, concentration, reading, writing, mathematics, memory, verbal expression; Table 3). Quality of life measured with the TAAQOL showed that patients of 16 years and older had significantly lower scores on the domains of cognitive function (memory, concentration, attention) and social function (visiting other people, talking to other people, having fun with other people, having meaningful conversations; Table 4).
Of the age group 6 to 11 years, 16 mothers completed the questions regarding educational levels. According to their report, 44% of the children in this group attend special schools as opposed to 3% of the general population (data from Ministry of Education Culture and Science). As levels in Dutch secondary education are much more differentiated, almost everyone is able to attend a regular school.
Fifteen patients over the age of 18 completed the additional questions about their educational level. Of these patients, 28% attended special schools, significantly different from the general population as described above. Current educational attainment is significantly lower than the attainment of the general population with 61.5% completing basic school and low vocational training only, compared with 27.2% of the general population (Table 5).
All questions regarding experience of the disease are listed in Table 6 (parents) and Table 7 (patients 8 years and older). Ninety-seven parents completed the questionnaire. Although most parents reported treating their child with galactosemia the same way as their healthy children (69%) and raising their child with galactosemia in the same way as their healthy children (77%), many parents (73%) believe the galactosemia influences their contact with the child. Sixty percent of the parents believe that it is a burden to take care of a child with galactosemia. Most parents of girls (55%) frequently worry about possible infertility, and almost 40% of the parents report that their child experiences speech problems. Still, 86% believe that one can live a good life with this disorder.
Thirty-three patients aged 8 and older completed the questionnaire. Galactosemia is seen as a burden by 39% of patients. Some (34%) feel different because of having galactosemia, and 22% believe that their disease is not well understood by others. However, few patients worry frequently about their future, and most patients (91%) believe that one can live a good life with galactosemia. Most patients (80%) report being treated by their parents the same way as their healthy siblings. Worries about possible infertility are reported by 28% of the girls aged 8 and older (n = 22).
This is the first study to describe the HRQoL of patients with classical galactosemia using well-developed and validated instruments in different age groups. The results of the present study indicate that having galactosemia negatively influences the HRQoL. In all age groups, we found a consistently lower reported HRQoL, most strikingly on the cognitive domain but also on the domain of communication and social function. The consistently low scores on the cognitive domain correspond well with the finding that these patients have much lower educational levels and educational attainment than their healthy peers. Our results are consistent with the reports of late complications in patients with classical galactosemia in the literature. Two large long-term outcome studies show below-average IQ scores for patients with galactosemia as a group with a decline in group scores in groups of increasing age.6,8 However, no consistent decline in IQ was shown in patients who had been tested repeatedly with the same IQ test.8
Other effects of galactosemia on the reported specific concerns of the patients and their families were found. The majority of parents and of patients of all ages believe that patients with galactosemia can live a good life. However, many patients feel different from other people as a result of their disease. Most parents believe that galactosemia affects their contact with the child, and many frequently worry about their child’s future and their fertility.
In our study, no data were available on the neonatal symptoms and the age of the start of dietary treatment of the included patients. However, previous studies showed no significant correlation among mean IQ, development and the neonatal history, and initiation time of dietary treatment, except for patients in whom treatment was started after the age of 8 weeks.4,6,8 In addition, siblings with galactosemia, of whom the oldest had experienced clinical symptoms whereas the younger siblings were detected antenatally, had the same outcome of IQ and development.8 We know that classical galactosemia in 81% of the Dutch patients who were born in 1992-1997 was diagnosed within the first 2 weeks of life, and in all but 1 patient, who was homozygous for a mutation known for its mild presentation, within 40 days.15 We do not suspect a later start of dietary treatment in patients who are younger than 18 years and were born before 1992 or after 1997, and therefore we do not expect our data to be affected by differences in time of the start of dietary treatment.
As classical galactosemia is a relatively rare disorder with an average of 6 new cases per year in the Netherlands, the patient group participating in this study is small. However, we included >50% of the Dutch patients under age 16. We do not know whether the fact that all participants were members of the Dutch Galactosemia Society creates a bias. Potentially, patients with a lesser outcome are more likely to become a member of such a society. However, most patients who participated in the study are too young to draw conclusions about their long-term outcome, and most members joined the society in the neonatal period.
We believe that the strong correlation of the HRQoL over the different age groups and the correlation with the educational attainment strongly validates our results. The cognitive problems in all ages as well as the social problems reported by the patients over 18 should be a major factor of concern for medical specialists who are involved in the care of patients with classical galactosemia. As survival in patients with classical galactosemia is high, we now are confronted with an increasing group of patients who experience late complications that cannot be prevented with the present medical knowledge. In the Dutch protocol for the follow-up of patients with classical galactosemia, evaluation of cognitive skills and educational possibilities does not have a prominent place. We now believe that the attention should not be only on biochemical evaluation but that the focus during follow-up should shift to supporting the patients to attain the best achievable quality of life. Although patient numbers are small, the severe effects of classical galactosemia on the cognitive skills of the patients demand additional research on the effects of early intervention on the late effects of classical galactosemia.
- Received August 26, 2003.
- Accepted December 17, 2003.
- Address correspondence to Martha A. Grootenhuis, PhD, Pediatric Psychosocial Department, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands. E-mail:
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- ↵Gibson JB. Gonadal function in galactosemics and in galactose-intoxicated animals. Eur J Pediatr. 1995;54(suppl 2) :s14– s20
- ↵Kaufman FR, McBride-Chang C, Manis FR, Wolff JA, Nelson MD. Cognitive functioning, neurologic status and brain imaging in classic galactosemia. Eur J Pediatr. 1995;154(suppl 2) :s2– s5
- Nelson D. Verbal dyspraxia in children with galactosemia. Eur J Pediatr. 1995;154(suppl 2) :s6– s7
- ↵Verrips EGH, Vogels TGC, Koopman HM, et al. Measuring health-related quality of life in a child population. Eur J Public Health. 1999;9 :188– 193
- ↵Vogels AGC, Bruil J, Stuifbergen M, Koopman HM, Verrips GHW. Validity and reliability of a generic health-related quality of life instrument for adolescents, the TACQOL. Q Life Res. 1999;8 :630
- ↵Bosch AM, De Klerk JBC, Poll-The BT, Van Spronsen FJ, Wanders RJA, Bakker HD. Galactosemie in Nederland, opnieuw beschouwd. Tijdschr Kindergeneesk 2003;71 :2– ,49– 53
- Copyright © 2004 by the American Academy of Pediatrics