Journal of Inherited Metabolic Disease

, Volume 35, Issue 2, pp 279–286

The adult galactosemic phenotype

Authors

    • Children’s Hospital Boston
  • Nancy L. Potter
    • Washington State University
  • Catherine M. Gordon
    • Children’s Hospital Boston
  • Robert C. Green
    • Boston University School of Medicine
  • Patricia Greenstein
    • Beth Israel Deaconess Medical Center
  • Cynthia S. Gubbels
    • Maastricht University Medical Center
  • Estela Rubio-Gozalbo
    • Maastricht University Medical Center
  • Donald Schomer
    • Beth Israel Deaconess Medical Center
  • Corrine Welt
    • Massachusetts General Hospital
  • Vera Anastasoaie
    • Children’s Hospital Boston
  • Kali D’Anna
    • Children’s Hospital Boston
  • Jennifer Gentile
    • Children’s Hospital Boston
  • Chao-Yu Guo
    • Children’s Hospital Boston
  • Leah Hecht
    • Children’s Hospital Boston
  • Roberta Jackson
    • Eastern Washington University
  • Bernadette M. Jansma
    • Maastricht University
  • Yijun Li
    • Children’s Hospital Boston
  • Va Lip
    • Children’s Hospital Boston
  • David T. Miller
    • Children’s Hospital Boston
  • Michael Murray
    • Brigham and Women’s Hospital
  • Leslie Power
    • Washington State University
  • Nicolle Quinn
    • Children’s Hospital Boston
  • Frances Rohr
    • Children’s Hospital Boston
  • Yiping Shen
    • Children’s Hospital Boston
  • Amy Skinder-Meredith
    • Washington State University
  • Inge Timmers
    • Maastricht University Medical Center
  • Rachel Tunick
    • Children’s Hospital Boston
  • Ann Wessel
    • Children’s Hospital Boston
  • Bai-Lin Wu
    • Children’s Hospital Boston
  • Harvey Levy
    • Children’s Hospital Boston
  • Louis Elsas
    • University of Miami
  • Gerard T. Berry
    • Harvard Medical School, The Manton Center for Orphan Disease Research, Children’s Hospital Boston
Original Article

DOI: 10.1007/s10545-011-9372-y

Cite this article as:
Waisbren, S.E., Potter, N.L., Gordon, C.M. et al. J Inherit Metab Dis (2012) 35: 279. doi:10.1007/s10545-011-9372-y

Abstract

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.

Introduction

Hereditary galactosemia (OMIM 230400; Fridovich-Keil and Walter 2008; Elsas 2010; Berry and Walter 2011) is an autosomal recessive disease due to galactose-1-phosphate uridyltransferase (GALT) deficiency (EC 2.7.7.12), with an incidence of 0.020/1,000 births (1:50,000) in newborn infants in the United States (National Newborn Screening and Genetics Research Center 2009). Classic galactosemia is due to severe GALT gene mutations such as Q188R, K285N and the Ashkenazi Jewish Δ5.2 kb deletion, and is associated with absent or barely detectable GALT enzyme activity in erythrocytes. Untreated patients with classic galactosemia in the newborn period manifest poor feeding, failure to thrive, jaundice, liver disease, cataracts, E. coli sepsis, and neonatal death (Berry and Walter 2011). Newborn screening for galactosemia or prompt diagnosis following clinical presentation for galactosemia largely eliminate neonatal deaths through early treatment, including immediate removal of lactose (found in all dairy products and breast milk) and replacement with soy formula.

Yet galactosemia remains a disease that is incompletely treated by diet as evidenced by the common occurrence of central nervous system problems in both sexes (Waggoner et al. 1990) and primary ovarian insufficiency (POI) in women (Kaufman et al. 1981; Rubio-Gozalbo et al. 2010). Neuroimaging studies confirm poor myelination, scattered white matter abnormalities, cerebral atrophy, and cerebellar atrophy in some patients, as well as abnormalities in glucose uptake of metabolism in many brain regions (Dubroff et al. 2008). Patients experience learning disabilities, diminished IQ, executive functioning deficits and speech/ language disorders (Waisbren et al. 1983; Waggoner et al. 1990; Antshel et al. 2004; Potter et al. 2008; Schadewaldt et al. 2010; Shriberg et al. 2011). Some reports raise the specter of progressive cognitive dysfunction (Doyle et al. 2010). Bone turnover may also be impaired (Gajewska et al. 2008).

Despite the evidence for long-term diet-independent effects of galactosemia, there are no comprehensive multi-disciplinary evaluations of an adult cohort. Because there are few cross sectional studies of the complete phenotype of affected adults with classic galactosemia at different ages, clinicians, scientists and families cannot predict the adult prognoses for newly diagnosed patients whose lives will be characterized by significant dietary restrictions. To address this gap, we conducted medical, nutritional, genetic, neurological, speech/language, and psychological examinations in 33 adults with classic galactosemia. The research was conducted over one weekend, with all subjects receiving standardized evaluations by one team of investigators. With this method, we could also study how specific issues previously examined in isolation might influence the overall health and well-being of adults with galactosemia. Moreover, we aimed to determine if older adults experienced more symptoms or evidenced greater cognitive dysfunction than younger adults. The hypothesis to be tested was whether classic galactosemia is a progressive disease that includes neurodegeneration.

Methods

Subjects were adults with galactosemia recruited from throughout the United States as self- referral or through the Parents of Galactosemic Children Association. Subjects and their families received scholarships or paid their own ways to participate in the research and attend educational workshops on galactosemia. The Institutional Review Board (Committee on Clinical Investigations) at Children’s Hospital Boston approved the study. Informed consent was obtained from each subject. Forty-one researchers and support personnel from Boston, Miami, the state of Washington, and the Netherlands conducted the evaluations or obtained and analyzed laboratory specimens.

Subjects received the following evaluations, described in Table 1: structured physical and neurological examinations, endocrine testing, GALT enzyme assay in erythrocytes and GALT gene sequencing, fertility history, bone density measures, psychological evaluation, speech/language assessment, and nutritional evaluation. In addition, a subset of six subjects received a scalp-electrode based electroencephalogram (EEG) while performing a language production task and a separate subset of eight males agreed to donate semen for analysis.
Table 1

Methods

Evaluation

Method

# Subjects

Health history

Medical records and interview provided health information.

33

Physical Exam

Physical examination by a physician as well as a neurological examination by an adult neurologist.

33

GALT enzyme

Blood was assessed via a new LC-MS/MS-based assay (Li et al, 2010).

33

GALT gene mutation

Genomic DNA was obtained from subjects for GALT gene sequencing if genotype was not available from medical records.

33

Endocrine and fertility

Blood samples were obtained and evaluated for estradiol, follicle stimulating hormone (FSH), leutinizing hormone (LH), Inhibin B and anti-mullerian hormone (AMH) in women and testosterone, FSH, LH and Inhibin B in men

33

Semen

Semen samples were collected and analyses were made on pH, viscosity, agglutination, red cells, leucocytospermia, motility, VEL , LIN, morphology, percent heads, and percent tails.

8

Reproductive history

Standardized interview and review of medical records provided information on cytorchidism at birth, age at puberty, spontaneous menarche, attempts to conceive, length of time attempted to conceive, number of pregnancies, and number of children.

33

Bone mineral density

Dual-energy x-ray absorptiometry (DXA) scan of hip, neck, and spine.

33

Psychological

Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler 1999), Behavioral Rating Inventory of Executive Functioning-Adult Version (BRIEF-A) (Gioia et al. 2000), Adaptive Behavior Assessment System-Second Edition (ABAS-II) (Harrison and Oakland, 2003), Beck Depression Inventory-Second Edition (BDI-II) (Beck et al. 1996), Beck Anxiety Inventory (BAI) (Beck and Steer 1993)

33

Health quality of life

Interview questions regarding health quality of life, including occupation, education, marital status, and living situation.

13

Speech and language

Tongue strength (Stierwalt and Youmans 2007), Maximum phonation duration (Kent 1994), Goldman-Fristoe Test of Articulation-2 (Goldman and Fristoe 2000), Dysarthria and apraxia of speech (Duffy 2005), Peabody Picture Vocabulary Test-IV (Dunn and Dunn 2007), Hearing

33

Nutrition

Structured interview and 3-day food diary for assessing intake of galactose, calories, calcium and other nutritional parameters.

33

BMI: Underweight = <18.5; Normal weight = 18.5-24.9 ; Overweight = 25–29.9; Obesity = BMI of 30 or greater.

Laboratory

Results from blood samples were compared to reference values for: calcium (Ca), Phosphorous (P), 25-hydroxy vitamin D, Glucose, Glutamic-pyruvate transaminase/alanine amniotransferase (GPT ALT), Alk-Phosphatase, cyclomaltodextrin glucanotransferase (CGT), and Bilirubin (total, direct, and indirect).

33

Electroencephalography (EEG)

Electroencephalography (EEG) recordings were obtained in subjects in conjunction with the performance of a language task to study the brain’s reaction to or execution of this task in the form of event related potentials (Luck 2005). A portable electroencephalogram machine was transported from the Netherlands. Electrodes were placed on the head and the recordings were made while subjects completed the task.

6

Descriptive analyses included means and standard deviations for continuous variables, and frequency and percentages for categorical variables. Exploratory analyses using multiple logistic regression analyses assessed associations of outcomes with age and biologic parameters. Data were analyzed using the SAS Statistical System v9.2 (SAS Institute 2010). Unless otherwise noted, all tests were two-sided with significance level 0.05.

Results

Subjects (17 males and 16 females; 97% Caucasian) ranged in age from 18 to 59 years (mean age = 32.6 ± 11.7 years; median age = 31 years). Individual subject results for key variables are presented in Table 2. All subjects received a galactose-restricted diet when they were infants and followed this regimen with varying degrees of rigor through adolescence and into adulthood.
Table 2

Sample population sorted by age

Sex

Age

GALT gene mutation

Tremor

Ataxia

FSIQ

Depression

Anxiety

Dysarthria

Apraxia of Speech

Children

Low BMD

HT (cm)

BMI kg/m2

Female

18

p.Q188R/p.Q188R

no

No

92

no

yes

no

no

no

yes

161.05

19.4

Female

18

p.Q188R/p.Q344K

postural

No

66

no

yes

yes

no

no

no

176.7

26.9

Female

18

p.Q188R/p.Q188R

no

No

69

no

yes

no

no

no

no

179.8

16.5

Male

20

p.K285N/p.L95P

no

No

107

no

no

no

no

no

no

174.5

19.3

Female

20

p.Q188R/Insertioin (c.70InsA)

no

No

93

yes

yes

yes

yes

no

no

159

22

Male

21

p.Q188R/p.W154X

intention

Yes

122

no

yes

no

no

no

no

175.6

20.3

Male

21

p.Q188R/Deletion

postural

No

83

yes

no

no

no

no

no

180.3

26.4

Male

23

p.Q188R/p.Q188R

no

No

93

no

yes

no

no

no

no

178.1

23.6

Female

23

p.Q188R/p.R259W

no

No

75

no

yes

Not done

Not done

no

no

170.9

20.1

Male

23

p.Q188R/p.R333Y

no

No

112

no

no

no

no

no

no

167.4

20

Male

25

p.Q188R/Deletion

both

Yes

55

no

no

yes

no

no

no

178.3

20.4

Female

25

p.Q188R/Deletion

no

No

79

no

yes

no

no

no

yes

172.5

16.4

Male

25

p.K127Q/Deletion

no

No

112

no

yes

no

no

no

no

169.8

22.6

Male

27

p.Q188R/p.Q188R

no

No

99

no

yes

no

no

no

yes

171.2

20

Female

29

Deletion/Deletion

both

No

106

yes

yes

no

no

no

yes

165.1

22.7

Male

29

p.Q188R/p.K285N

intention

No

55

no

yes

yes

no

no

no

190.5

24.6

Female

31

p.Q188R/ Unclassified mutation

intention

Yes

55

yes

yes

yes

no

no

no

169.6

19.8

Female

31

p.Q188R/p.Q188R

no

No

57

no

no

no

yes

no

no

168.5

20

Male

32

p.Q188R/p.Q188R

postural

No

72

no

yes

no

yes

yes

no

187.8

34.7

Female

32

p.Q188R/p.Q188R

intention

No

88

no

yes

no

no

yes

no

167.4

36.5

Male

33

p.Q188R/p.K285N

intention

No

109

yes

yes

no

no

no

yes

168.5

25

Female

34

p.Q188R/p.Q188R

intention

No

101

no

no

yes

no

no

no

171.6

30.9

Male

34

p.Q188R/p.Q188R

intention

Yes

74

no

yes

yes

no

no

no

176.9

23.6

Female

36

p.Q188R/p.K285N

no

No

96

yes

yes

no

no

no

yes

173.5

29.7

Female

37

p.Q188R/p.Q188R

no

No

97

yes

yes

no

no

no

no

166.05

19.8

Male

45

p.Q188R/p.Q188R

no

No

99

yes

yes

no

no

no

yes

166.9

27.3

Male

45

p.Q188R/p.Q188R

no

No

107

yes

no

no

no

no

no

177.2

22.4

Male

48

p.Q188R/p.N97S

postural

No

66

yes

yes

no

no

no

yes

185

23.5

Female

48

p.Q188R/p.Q188R

no

No

86

no

no

no

no

no

no

150.1

43.1

Female

49

p.Q188R/p.Q188R

no

No

109

yes

yes

no

no

no

no

170.7

28.7

Male

51

p.Q188R/p.Q188R

no

No

107

no

no

no

no

yes

no

172.4

25.5

Female

55

Deletion/Deletion

postural

No

108

yes

no

no

no

no

no

155.7

27.7

Male

59

Deletion/Deletion

no

Yes

67

yes

no

yes

no

no

no

172.6

22

FSIQ = Full scale IQ derived from Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler 1999)

Depression: Score greater than 13 on the Beck Depression Inventory, Second Edition (BDI-II) (Beck et al 1996)

Anxiety: Score greater than 7 on Beck Anxiety Inventory (BAI) (Beck and Steer 1993)

Low BMD = Low bone mineral density, defined as z-scores greater than 2 standard deviations below the normative mean (Kelly 1990; Looker et al. 1995)

Genotype analyses revealed 15 subjects who were homozygous for the p.Gln188Arg mutation (here referred to as p.Q188R by tradition), 13 with p.Q188R on one allele and a severe mutation, including three deletions, one insertion, and one unclassified mutation, on the other allele. One subject possessed a p.K127Q/deletion genotype and there were three subjects with homozygous deletions. Deletions were noted to be large Δ5.2 kb deletions common in Ashkenazi Jewish individuals (Elsas and Lai 1998; Berry et al. 2001; Goldstein et al. 2011).

Using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method of Li, (Li et al. 2010) enzyme activity was non-detectable in all subjects, with limit of detectability (LOD) of 0.01 μmol/g Hgb/hour (0.07% of normal control values).

Cataracts in adulthood were noted in medical records or reported during the medical history by 21% of subjects. Nystagmus, irregular pupulatory border, and need for bifocals were noted in 1 subject each. Fifteen subjects (45%) had broken a bone, six during childhood and the others at ages 20 to 46 years. Slight pharyngeal erythema was noted in two subjects. Other medical issues, each noted in only one subject, included joint pain, musculoskeletal scoliosis, kidney stone, adult onset seizures, poor dental condition, café au lait spots, systolic heart murmur, high blood pressure, and mitral valve replacement.

Tremor was noted in 15 subjects (46%), with intention tremor in eight (24%), postural tremor in five (15%), and both kinds of tremors in two (6%) subjects. Ataxia was noted in five subjects (15%) and two subjects (6%) manifested dystonia. Two subjects were left handed (6%).

Full scale intelligence quotient (FSIQ) derived from the Wechsler Abbreviated Scales of Intelligence (Wechsler 1999) ranged from 55–122, with a mean of 88 ± 20. Thirteen subjects (39%) attained scores ≤85, with eight (24%) of these subjects attaining scores ≤70 (indicating intellectual disability). Scores on the verbal (vocabulary) and nonverbal (matrix reasoning) subtests did not differ, with means of 42 ±15 for vocabulary and 42 ± 14 for matrix reasoning (normal mean = 50). Deficits in executive functioning, as indicated by scores above 65 on the Behavior Rating Inventory of Executive Function (Gioia et al. 2000) were noted in 5 (15%) subjects. Seven (21%) subjects attained scores less than 85 on the Adaptive Behavior Assessment System. (Harrison and Oakland 2003). Fifteen subjects (46%) lived independently, including nine who were either married or living with partners. Average schooling was 1–2 years of college. Seven subjects (21%) were unemployed (and not in school). The typical occupational level was that of skilled manual laborer.

At the time of the study visit, depression, characterized by scores greater than 13 on the Beck Depression Inventory (Beck et al. 1996) was present in four individuals (12%), two of whom were being treated with anti-depressant medication. Six subjects reported having received anti-depressant medication at some point in their lives, including a young man who received electro-convulsive therapy. Three additional subjects reported suffering from depression in the past, raising the total number of subjects with observed or reported depression to 13 (39%) compared to 16.2% lifetime prevalence in the general adult population in the US (Kessler et al. 2003). Anxiety, indicated by scores greater than seven on the Beck Anxiety Inventory, (Beck and Steer 1993) was reported by 17 subjects (52%) (three were taking medication for anxiety) compared to 16.4% yearly prevalence of anxiety in the general adult population in the US (Surgeon General 2009). Five additional subjects had received medication for anxiety in the past, raising the total number of subjects with a history of anxiety to 22 (67%).

The majority of subjects exhibited deficits in motor speech function as defined by scores of 1 standard deviation or more below the mean of healthy controls on standardized measures. Reduced tongue strength, as measured by the Iowa Oral Performance Instrument (Stierwalt and Youmans 2007), was noted in 24 (73%) subjects. Breath support for speech, as measured by decreased phonation duration (Kent 1994), was decreased in 21 (64%) subjects, and articulation proficiency (Goldman and Fristoe 2000) was reduced in four (12%) subjects. Dysarthria, a sensorimotor speech disorder due to weakness, incoordination, involuntary movements, or abnormal muscle tone (Duffy 2005), was observed in eight subjects (24%). Apraxia of speech, affecting the planning and programming of speech movements (Duffy 2005), was noted in three subjects (9%). Receptive vocabulary (Dunn and Dunn 2007) was reduced in 14 (42%) subjects. Three men (and no women) had mild-moderate high frequency hearing loss (two unilateral; one bilateral). Preliminary analyses of event-related potentials (ERPs) derived from the continuous EEG (Luck 2005) in a subset of subjects, showed a deviant pattern compared to healthy adults in terms of the brain’s reaction to a language task. Error and voice onset data revealed a difference (p < .001) between the six subjects and a normative sample (errors: 20.8% vs. 6.4%; voice onset latency: 5.5 seconds vs. 1.5 seconds, respectively).

All female subjects had previously been diagnosed with POI. Consistent with that diagnosis was the finding of reduced serum AMH levels well below 0.3 ng/ml (mean = 0.025 ± 0.022 ng/ml; range = 0.01-0.07 ng/ml). Additional endocrine studies also indicated ovarian insufficiency in females not receiving estrogen replacement therapy. Estradiol in females ranged from 10 pg/mL to 129 pg/mL (mean = 33 ± 36; reference range = 21–649 pg/mL). FSH in female subjects ranged from 0.14-109.44 (mean = 32.77 ± 32.99; reference range = 1.38-16.69 mlU per mL). Eleven women experienced spontaneous menarche. The average age of menarche was 15.1 ± 1.8 years for women, including those receiving hormonal treatments to induce menstruation. In men, average age of self-reported puberty was 13.7 ± 1.8. Average age of puberty in the general population is currently about 13 years for girls and 14 years for boys (http://www.mgh.harvard.edu/children/ adolescenthealth/articles/aa_puberty.aspx). In male subjects, FSH ranged from 1.31-8.49 mlU per mL (mean = 4.33 ± 2.6; reference range = .95-11.95 mlU per mL). Testicular abnormalities (cryptorchidism) had occurred in one male at birth. Testicular size was within normal range (mean = 28 ±4.06 cc, range = 25–35 cc). Of the eight men who provided a semen sample, one had a low sperm count and two had low percent normal morphology. Among the 12 male and 10 female subjects who responded to the question about sex, five (42%) men and seven (70%) women reported having had intercourse. Three women in the total sample tried to conceive without achieving pregnancy. One woman became pregnant after trying for 60 months and gave birth to a healthy child. Two men were fathers, with one child each.

Bone density was, on average, greater than a standard deviation below the normal mean (z = −1.1) (Kelly, 1990; Looker et al. 1995). A total of eight subjects (24%) had a z score greater than 2 standard deviations below the mean on bone mineral density measurements.

Nutritional evaluations indicated that all subjects reported following a lactose-restricted or dairy-free diet with avoidance of milk and milk products. Forty-one percent of subjects referred to written diet guidelines, but the majority (90%) no longer received nutritional counseling. Two-thirds of subjects took calcium supplements and 38% took vitamin D supplements, but did so irregularly. Dietary records showed an average intake (without supplementation) of 675 mg calcium, 3.8 mcg vitamin D, 1110 mg phosphorus, and 282 mg magnesium. Eighty percent of subjects had intakes below the daily recommended intake (DRI) for calcium and 75% had intakes below the DRI for vitamin D. Mean plasma 25-hydroxy vitamin D level was 27 ± 11 ng/ml (reference range 32–100 ng/ml), with 80% of subjects below the sufficient range (Stoffman and Gordon 2009). Average height was 167.39 ± 7.77 cm for females (US 50th% for women = 165.5 cm) and 176.06 ± 6.90 cm for males (US 50th% for men = 179 cm) (Center for Disease Control and Prevention 2000). Body mass index results indicated that the majority of subjects (58%) maintained weights within the normal range for height and sex. Two women (13%) were underweight, four (25%) were overweight and two (13%) were obese. Among male subjects, four (24%) were overweight and one (6%) was obese.

Bilirubin (direct) was normal in all subjects and the mean bilirubin indirect was well within the average range (0.39 ± 0.28 mg/dl, range = 0.12-1.06 mg/dl; reference range = 0.1-0.8 mg/dl).

Logistic regression analyses revealed few significant associations between potential predictors and outcomes (Table 3). Age was not related to IQ, anxiety, tremor, ataxia, dysarthria, apraxia of speech, or whether or not the subject had a child. Each 10- year increment of age was associated with a 3-fold increase in odds of depression at some point in life. However, age was not associated with scores on the Beck Depression Inventory measuring depressive symptoms at the time of the study (r = 0.14, 95% CI (−0.22, 0.46), p = 0.56). Older individuals exhibited a higher body mass index (r = 0.41, 95% CI (0.08, 0.66), p = 0.02).
Table 3

Results of logistic regression analyses to assess the association of genotype, gender, and age with several study outcomes. Individual fixed effects are reported as odds ratios (ORs) with 95% confidence interval and p-value. Overall model significance was determined using the likelihood ratio test

 

Age (10 yr increase)

Gender (male vs. female)

Genotype (deletion/ no deletion)

Overall model significance

IQ < 85

0.75 (0.39, 1.41)

1.17 (0.27, 4.96)

2.73 (0.47,15.82)

0.57

p = 0.37

p = 0.83

p = 0.26

Depression

2.98 (1.23, 7.17)

0.51 (0.10, 2.70)

3.45 (0.42, 28.55)

p = 0.02

p = 0.02

p = 0.43

p = 0.25

Anxiety

0.53 (0.10, 1.12)

0.48 (0.09, 2.43)

0.27 (0.04,1.75)

p = 0.11

p = 0.25

p = 0.37

p = 0.17

Tremor

0.88 (0.47, 1.63)

1.47 (0.36, 6.04)

2.16 (0.39,12.07)

p = 0.75

p = 0.68

p = 0.59

p = 0.38

Ataxia

1.11 (0.49, 2.49)

4.55 (0.43, 47.58)

2.97 (0.36,24.75)

p = 0.38

p = 0.81

p = 0.21

p = 0.31

Apraxia of speech

0.62 (0.17, 2.30)

0.45 (0.03, 5.97)

- - - -

p = 0.46

p = 0.48

p = 0.55

Dysarthria

0.87 (0.43, 1.77)

0.85 (0.17, 4.23)

1.31 (0.20,8.70)

p = 0.97

p = 0.70

p = 0.84

p = 0.78

Had child

1.90 (0.57, 6.34)

1.89 (0.14, 25.47)

----

p = 0.38

p = 0.29

p = 0.63

Males and females exhibited similar rates of anxiety, depression, speech deficits and neurological signs and did not differ in terms of IQ or becoming parents.

Whether or not a subject had a ∆5.2 kb deletion on one or more alleles was not predictive of any examined outcome (Table 4). The percentage of subjects with tremor, ataxia, or speech defects was not associated with genotype. Subjects homozygous for the common p.Q188R genotype experienced a similar range of scores on IQ tests and measures of depression and anxiety as subjects with deletions or unclassified mutations on one allele.
Table 4

Genotype and frequency of IQ ≤85, and presence of tremor, dysarthria/dyspraxia, depression, and anxiety

Genotype (n)

IQ

Tremor

Dysarthria or apraxia

Depression (BDI > 13)*

Anxiety (BAI > 7)**

p.Q188R/p.Q188R (15)

57-109

27%

27%

27%

20%

p.Q188R/Unclassified (1)

55

yes

yes

No

yes

p.Q188R/p.W154X (1)

122

yes

no

No

no

p.Q188R/Deletion (3)

55,79, 83

67%

33%

33%

33%

p.Q188R/p.R259W (1)

75

no

-

No

no

p.Q188R/p.N97S (1)

66

yes

no

No

yes

p.Q188R/p.K285N (3)

55,96,109

67%

33%

67%

67%

p.Q188R/p.R333Y (1)

112

no

no

No

no

p.Q188R/p.Q344K (1)

66

yes

yes

Yes

yes

p.Q188R/Insertion (c.70InsA) (1)

93

no

yes

No

no

K285N/p.L95P (1)

107

no

no

No

no

K127Q/Deletion (1)

112

no

no

No

no

Deletion/Deletion (3)

55,79,83

67%

33%

33%

33%

*BDI = Beck depression inventory

*BAI = Beck anxiety inventory

Discussion

This study documents the occurrence of tremor, nutritional deficits, reduced bone density, diminished cognitive functioning, speech abnormalities, depression, and anxiety in association with galactosemia in adulthood. There were women experiencing primary ovarian insufficiency and many men who did not engage in sexual relationships. Also included in this sample were college students and teachers, and individuals in successful marriages. What may be most significant and what has not been described before is that symptoms did not go hand-in-hand. For example, individuals with tremor did not necessarily exhibit diminished cognitive functioning. Those with speech deficits were not necessarily depressed or anxious. A second significant finding was that older subjects compared to younger subjects did not exhibit poorer physical or mental health or a lower level of cognitive functioning. Thirdly, the predominance of dysarthria with vocal characteristics indicative of cerebellar dysfunction suggests central nervous system involvement of the cerebellum and its relative circuitry. The timing of this injury to the central nervous system needs to be established. Finally, genotypes, predominantly p.Q188R alleles, were uninformative in predicting examined outcomes in patients with zero residual GALT enzyme activity. Other studies described similarly variable outcomes in subjects with classic galactosemia associated with severe GALT mutations (Shield et al. 2000).

Possibly, genotype had an indirect effect on health and quality of life outcomes in our sample. For example, few men in our study had experienced sexual relations and even fewer tried to become fathers. Perhaps they were overly reserved or delayed in their psychosexual development, as has been suggested by Bosch et al. (2004). Or perhaps, expressive language difficulties may have interfered with their ability to initiate that first overture or sustain conversations with a date. Whether anxiety and depression, common among adults of either sex in this sample, resulted from hormonal variations associated with galactosemia or reflected discouragement and worry over infertility or cognitive, speech and motor challenges is not yet known.

Our study was limited due to sample size and the accrual process through the parent organization. There was an absence in this study of less severe mutant alleles such as the S135L seen predominantly in patients with African ancestry. Comparisons between individuals with mild and severe genotypes may be worthwhile in future studies.

The results of our study indicate a need to address psychosocial as well as medical issues when treating individuals with galactosemia. Greater attention to depression, anxiety, and social relationships may do much to relieve the impact of this disorder in adults.

Prospective studies that include individuals identified by newborn screening as well as individuals identified because of clinical signs are needed to assess the development and progression of symptoms over time. While it is tempting to focus on genotype-phenotype relationships in galactosemia, future studies need to take a broader perspective that includes interrelationships among the genetic (including whole genomic modifiers), epigenetic, and environmental factors that influence long-term outcomes in this disorder. Lastly, taken together, the data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease.

Acknowledgments

This project was funded in part by a research grant from the Parents of Galactosemic Children, USA, and in part by the grant UL1 RR025758-01 from the National Center for Research Resources, National Institutes of Health, to the Harvard Catalyst Clinical & Translational Science Center (Harvard Catalyst). The authors thank the CTSU staff of Children's Hospital Boston for their superb assistance and the patients with galactosemia and their families who traveled to Boston from around the U.S.A. and participated in this study. We thank the Parents of Galactosemic Children, USA for their support. We also thank Al Ozonoff, Linda Manis, Michelle Fowler, Judith Muir, Catherine Arnold, Brian Deutsch, Stephanie Kon, Anya Kwasnik, and Rebecca Owen for their invaluable help.

Copyright information

© SSIEM and Springer 2011