Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia

1 INTRODUCTION

Classical galactosemia (OMIM: 230400) is an inborn error of galactose metabolism, caused by a severe deficiency of the galactose-1-phosphate uridyltransferase (EC 2.7.7.12) enzyme. After ingestion of galactose in infancy, the accumulation of galactose-1-phosphate and its metabolites results in multi-organ failure with predominant involvement of the liver. In particular newborns are susceptible for severe Escherichia coli sepsis. The mainstay of treatment is a galactose-restricted and lactose free diet, which is lifesaving when started early.

Despite this treatment many patients develop long-term complications.1, 2 The most frequent and severe long-term complications are impaired cognition, speech and language deficits, and in women premature ovarian failure.3 Next to these well-known complications, galactosemia is increasingly being recognized as a neurometabolic disorder with significant motor involvement.3-5 In particular tremor and ataxia have been reported.1, 4, 6 However, in most papers, data were collected retrospectively or without formal neurological examination and quantification of the severity of symptoms.2, 6, 7 Two more detailed and recent papers evaluated movement disorders (MDs) in adult galactosemia patients by direct neurological examination. Waisbren et al studied 33 adult patients and found tremor being most frequent (46%), followed by ataxia (15%), and dystonia (6%).3 Rubio-Agusti et al investigated MDs in 47 adult patients.8 They reported motor dysfunction in 66%. Tremor was seen in 49%, ataxia in 13%, and a remarkably higher frequency of dystonia (49%) than earlier reported. Detailed information about MDs in particular in children with galactosemia is currently scarce and possible differences between children and adults are largely unknown.

In galactosemia a high prevalence of depression and anxiety has been reported. In patients with (primary) MDs there is also an increasing awareness of associated nonmotor neuropsychological symptoms.9-11 Whether these symptoms are secondary to the burden of a MD or part of the phenotype is still unsolved. It is interesting to evaluate whether the motor and nonmotor symptoms are associated in galactosemia patients.3, 8

The aim of this study is to systematically determine the frequency, classification and severity of MDs in a cohort of adult and pediatric galactosemia patients, and to assess the association with clinical characteristics, such as treatment variables. We will also evaluate nonmotor neuropsychological symptoms and daily functioning and analyze whether these are associated with the presence of MDs.

2 METHODS

Patients were recruited from the metabolic departments of five nationally endorsed centers of expertise in the Netherlands and two in the United Kingdom. All patients, both children (<18 years) and adults (≥18 years), with a genetically or enzymatically confirmed diagnosis of classical galactosemia were invited to participate. Written informed consent has been obtained from all participants or their official caregivers. This study was approved by the medical ethics committees of the participating centers, and carried out in accordance with the Declaration of Helsinki.

Self-perceived motor symptoms were evaluated with a structured interview. Demographic and disease characteristics were obtained by interviewing and/or from patient files. To determine the presence, classification and severity of MDs, a standardized videotaped neurological examination was performed (A.K.). This protocol included walking, posturing tasks, kinetic tasks, and functional tasks such as writing. The motor phenotype was scored during consensus meetings using the videos. The expert panel (M.T., T.K., R.Z., H.E., A.K.) was briefly informed about the clinical history and self-reported symptoms. The dominant and any associated MD types were identified. Severity of each MD was determined with the Clinical Global Impression severity scale (CGI, a 7-point Likert scale, higher scores indicate a more severe MD).12

Adaptive and daily functioning and psychiatric and behavioral problems were assessed with age-specific validated Dutch and English questionnaires. In children we assessed adaptive functioning with the Vineland Adaptive Behavior Scale,13 and scores were transformed in a developmental age equivalent. Subsequently, the percentage of age-appropriate functioning (developmental age/biological age × 100%) was determined. Daily functioning in adults was evaluated with the Health Assessment Questionnaire (HAQ),14 providing a Functional Disability Index (FDI, range 0-3, higher scores indicating more disability), and with the Sickness Impact Profile (SIP68, range 0-68, higher score indicating more disability).15 The presence of various domains of psychiatric and behavioral problems were identified with age-appropriate versions of the Achenbach questionnaires, using both a self-report and proxy version (Child Behavior Checklist and Youth Self Report, Adult Behavior Checklist, and Adult Self report).16-18

Statistical analyses were carried out using SPSS version 23. Univariate logistic regression was used to calculate odds ratios for MD presence according to clinical or demographic characteristics. To assess differences in MD frequencies, the Fisher's exact test was used. Differences in continuous variables between patients with and without MDs were analyzed with the Independent samples t test or Mann-Whitney U test, depending on normality of the data.

This study was approved by the medical ethics committees of the participating centers. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.

Written informed consent has been obtained from all participants included in the study or their official caregivers.

This article does not contain any studies with human or animal subjects performed by the any of the authors.

3 RESULTS

Thirty seven patients were recruited (15 males, 22 females), from 29 different families (eight pairs of siblings). The participation rate was 70% (37/53). The cohort contained 19 adult patients (mean age 32.6 years) and 18 children (mean age 11.0 years). Four of the adult patients reported here, were also included in the study by Rubio-Agusti et al8 Table 1 presents the demographic and disease characteristics.

4 DISCUSSION

This is the first comprehensive study reporting a systematic and detailed evaluation of MDs together with nonmotor neuropsychological symptoms and the impact on daily functioning in both children and adults with classical galactosemia.

MDs were found in almost half of the patients. This frequency is in line with the earlier reports in adults (45 and 66%) (3.8). The MD prevalence could be an overestimation since there might have been a selection bias; patients suffering from MDs may be more inclined to participate in research addressing this topic. The participation rate of our study was relatively high (70%), thereby reducing this possible selection bias. In respect of the prevalence and severity of MDs we found, it is remarkable that only one patient in our cohort received specific MD treatment.

Dystonia and tremor were the major MD types in adults, which is in accordance with the dominant MD types reported by Rubio-Agusti et al.8 Similar to what is known for other inborn errors of metabolism (IEM) with MDs,22 the majority of patients had a combined MD phenotype with different MD types being present simultaneously.

One of the strengths of the present study is the inclusion of both children and adults, allowing us to demonstrate remarkable differences in MD types. Dystonia and myoclonus dominated the phenotype in children, while in adults no myoclonus was detected. This suggests evolution of MDs over time. Possibly, MD appearance in childhood is influenced by development, immaturity, and ongoing myelination of the central nervous system (CNS), while later in life the MDs evolve to a more tremulous appearance. It would be interesting to see whether a similar difference between children and adults is seen in other IEM with MDs.

Next to the video assessment, we interviewed patients about self-perceived motor symptoms. We found less discrepancy between the self-report and the expert evaluation than in earlier reports.8 The majority of patients in our study indicate that their motor symptoms started in childhood, but later beginning was also described. Almost 40% of the patients with MDs report their motor symptoms to be progressive, remarkably only reported by adults. A limitation of this study is that data on the course of symptoms were collected retrospectively and were self-reported. Longitudinal studies are required to further clarify when MDs occur and whether these are indeed progressing or evolving in time.

It is not well understood why some galactosemia patients develop a severe neurological phenotype and others do not. In many IEM an early diagnosis and treatment is very important for the clinical (neurological) outcome. However, in our cohort this association was not found. This is in accordance with earlier studies in galactosemia.1, 8, 23 It seems that, although obviously of undisputed importance, early initiation of treatment does not always prevent MDs. Moreover, in our study there were two pairs of siblings of whom the youngest were diagnosed and treated from day one and had much more severe MDs than the late diagnosed older sibs. This was also described within a family reported by Hughes et al.6 Strict dietary adherence also cannot prevent MDs. Dietary adherence was very high in our patient group, but patients who had noncompliant periods did not have more MDs. Too strict dietary regimens with over-restriction of galactose might even have negative effects. This hypothesis has also been suggested by Knerr et al,24 and similar phenomena were also described in other IEM, like urea cycle defects.25 These findings might be explained by accumulation of toxic metabolites on one hand, and lack of relevant (intermediary) metabolites on the other hand. Based on current knowledge, we assume that both ends of the spectrum, late/no dietary treatment as well as a very restricted diet, would not lead to optimal (motor) functioning.

In our study we found an association between a history of delayed motor milestones and the occurrence of MDs. This is an important finding, as it can serve as a “red flag.” We advise extra alertness for the occurrence of MDs in children with galactosemia who have a delayed motor development. Based on our results, the occurrence of MDs seems to be based on an individual susceptibility rather than on treatment characteristics. Our findings might indicate that patients with MDs have a more severe phenotype in general, as we also observed a trend that MDs were more frequent in patients with speech problems, children who attend special education and in adults who are unemployed. Although we did not demonstrate statistically significant differences for these parameters, the found differences are of reasonable magnitude and should be interpreted in the light of the relatively small sample size. Despite lacking statistical power, the differences might very well be relevant.

Next to MDs, a high percentage of patients in our study had behavioral or psychiatric problems (47.2%), associated with the presence of MDs. Internalizing symptoms such as depression and anxiety, were most frequent (38.9%). This is in accordance with earlier reports on psychiatric comorbidity in galactosemia with high rates of anxiety and depression.3, 8 It is interesting to speculate whether these symptoms are a secondary phenomenon to physical or cognitive disability or if they are part of the disease itself. In recent years it has become clear that nonmotor neuropsychological symptoms form an integral part of several primary MDs such as idiopathic cervical dystonia or dopa-responsive dystonia.9, 10 The fact that in our study psychiatric and behavioral symptoms were associated with MDs and were often co-occurring outlines the possibility that in galactosemia there might also be a common pathophysiological pathway affecting both motor and nonmotor circuits. Unfortunately, in our study we had no electrophysiological registrations or magnetic resonance imaging (MRI) or neurotransmitter imaging data available. To further elucidate the pathophysiology of MDs and neuropsychological symptoms in patients with galactosemia, it is important to incorporate the results of these diagnostic tests and clinical data in future studies.

Impairment in daily and adaptive functioning was common in our cohort. Patients with MDs had lower levels of adaptive functioning; especially the communication domain appeared associated with MDs. To improve the level of functioning of our patients, MDs are important to take into account and should be considered for symptomatic treatment and supportive therapies.

In conclusion, hyperkinetic MDs are frequent in both children and adults with galactosemia. We found remarkable differences in the clinical presentation between children and adults. The occurrence of MDs seems to be based on an individual susceptibility rather than treatment characteristics. Longitudinal studies are needed to further elucidate the evolvement of MDs. We demonstrated an association between MDs and nonmotor neuropsychological symptoms and a lower level of daily functioning. Based on the results of our study, we recommend an increased awareness of both MDs and nonmotor neuropsychological symptoms in patients with galactosemia. When applicable, treatment of MDs should be considered. Patients would benefit from regular and detailed neurological and neuropsychological assessments; the inclusion of these assessments in galactosemia guidelines is supported by this research.

CONFLICTS OF INTEREST

The authors have no conflicts of interest to report.

AUTHOR CONTRIBUTIONS

1. Research project: A. Conception, B. Organization, C. Execution;

2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique;

3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

A.K.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B.

S.G.: 1A, 1B, 1C, 2C, 3B.

E.M.: 1A, 1B, 1C, 2C, 3B.

M.C.: 1B, 1C, 2A, 2B, 2C, 3B.

H.E.: 1C, 2C, 3B.

R.Z.: 1C, 2C, 3B.

M.R.: 1B, 2C, 3B.

A.B.: 1B, 2C, 3B.

M.W.: 1B, 2C, 3B.

T.D.: 1B, 2C, 3B.

R.L.: 1B, 2C, 3B.

M.B.: 1B, 2C, 3B.

M.J.: 1B, 2C, 3B.

M.T.: 1A, 1B, 2C, 3B.

T.K.: 1A, 1B, 1C, 2A, 2C, 3B.