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

doi:10.1016/S0022-3476(94)70197-0

The Journal of Pediatrics

Volume 125, Issue 2, August 1994, Pages 225-227

https://doi.org/10.1016/S0022-3476(94)70197-0 Get rights and content

Abstract

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. (J PEDIATR 1994;125:225-7)

Section snippets

METHODS

Sixty-seven subjects (35 of whom were female) with the diagnosis of classic galactosemia and complete absence of GALT activity are currently followed at either Childrens Hospital Los Angeles or at the University of Wisconsin, Madison, Biochemical Genetics Clinic. These subjects have been available for determination of the Q188R mutation. From this cohort, 41 were given extensive neuropsychologic testing as previously described^5a; of the 26 subjects not tested, 14 were less than 4 years of age

RESULTS

The Q188R mutation was found in 72% of alleles. Homozygosity for Q188R was found in 38 subjects and heterozygosity in 21; 8 of those studied did not have the Q188R mutation. This distribution is similar to the distribution that we reported previously in a larger cohort of 132 patients, of whom 113 had no detectable GALT activity; Q188R was present in 67% of alleles.^6a

The Broad Cognitive score was relatively variable; scores ranged from the retarded to the above-average range.^5a The mean Broad

DISCUSSION

The clinical outcome for patients with classic galactosemia and absence of GALT activity is variable. The outcome does not appear to be related to the age at diagnosis of galactosemia or to the severity of illness⁷; it has been hypothesized that the variability might correlate with one or another of the mutations of the GALT gene. Because the Q188R mutation is found in a high percentage of affected alleles, and because homozygosity is seen in 57% of subjects, it was questioned whether

ACKNOWLEDGMENT

We thank Sriveda Koritala and Maurice Peters for excellent technical assistance.

References (13)

ND Leslie et al.
The human galactose-1-phosphate uridyl transferase gene
Genomics
(1992)
FR Kaufman et al.
Correlation of galactose-1-phosphate uridyl transferase levels and ovarian function in female patients with galactosemia
J PEDIATR
(1988)
JKV Reichardt et al.
Cloning and characterization of cDNA encoding human galactose-1-phosphate uridyl transferase
Molecular Biology Medicine
(1988)
JE Flach et al.
Sequence of cDNA encoding human galactose-1-phosphate uridyl transferase
Mol Biol Med
(1990)
JKV Reichardt et al.
Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyltransferase
Am J Hum Genet
(1991)
LJ Elsas et al.
Galactosemia: a molecular approach to the enigma
International Pediatrics
(1993)

There are more references available in the full text version of this article.

Cited by (50)

Pathophysiology of long-term complications in classic galactosemia: What we do and do not know
2022, Molecular Genetics and Metabolism
Citation Excerpt :
Some have stratified patients with confirmed CG on the basis of homozygosity, heterozygosity, or absence of Q188R (c.563A > G), a null variant of GALT that is especially common among patients of northern European ancestry [42]. One study concluded that homozygosity for Q188R was associated with more severe outcomes [49], but another concluded that it was not [50]. An alternative approach to testing the question of GALT genotype-phenotype relationships considers alleles as groups defined by whether or not they encode detectable residual GALT activity, and clusters all true null alleles into one comparison group, and all hypomorphic alleles into another.
Despite many decades of research involving both human subjects and model systems, the underlying pathophysiology of long-term complications in classic galactosemia (CG) remains poorly understood. In this review, intended for those already familiar with galactosemia, we focus on the big questions relating to outcomes, mechanism, and markers, drawing on relevant literature where available, attempting to navigate inconsistencies where they appear, and acknowledging gaps in knowledge where they persist.
Alterations of galactose metabolism caused by deficit of galactose-1-phosphate uridylyltransferase activity: An overview of galactosemia type I
2019, Molecular Nutrition Carbohydrates
Galactosemia type I is caused by a deficiency of the galactose-1-phosphate uridylyltransferase enzyme, encoding by the GALT gene. This pathology is inherited in an autosomal recessive pattern. Following galactose intake by galactosemic neonates, a toxic buildup of galactose metabolism intermediates is produced. Promptly, various signs appeared such as lethargy, poor feeding, jaundice, and hepatomegaly. Treatment is relatively easy to achieve to prevent acute symptoms and save the baby's life. However, even when patients undergo lifelong galactose dietary restrictions, some subjects develop mild to severe long-term complications. The mutational spectrum is characterized by allele heterogeneity, where few alleles have high frequency and a clear ethnic distribution. Missense mutations are the most common variants and are distributed along the whole GALT gene, altering functional and structural features of the enzyme. Dietary treatments consist of eliminating lactose- and galactose-rich foods and supplying formulas of soy milk. This diet should be maintained through the whole life of the patient. In contrast, the diet should be absolutely normal in the Duarte form of galactosemia. Experts reached a consensus and recommended the consumption of fruits, vegetables, legumes, unfermented soy products, and hard chesses.
Female Infertility
2019, Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management: Eighth Edition
Infertility affects approximately 13% of women and 10% of men. The major causes of female infertility are anovulation, fallopian tube disease, pelvic adhesions, endometriosis, and unexplained infertility. Initial treatment for women with anovulatory infertility involves a sequential approach, moving from less to more resource-intensive therapies. Interventions that increase fecundability in anovulatory women include optimization of weight, letrozole or clomiphene ovulation induction for women with the polycystic ovary syndrome, and gonadotropin injections or pulsatile gonadotropin-releasing hormone (GnRH) therapy for women with functional hypothalamic amenorrhea. For women with distal tubal disease, effective treatments include in vitro fertilization (IVF) or laparoscopic tubal surgery. For couples with unexplained infertility, clomiphene plus intrauterine insemination (IUI), gonadotropin plus IUI and IVF are effective treatments. Most women who are infertile will conceive with fertility therapy.
Hereditary galactosemia
2018, Metabolism: Clinical and Experimental
Citation Excerpt :
Psychiatric symptoms and emotional problems are more often reported in these patients and include depression, anxiety, obsessive-compulsive disorder and autism spectrum disorder [18,44]. Patients are also at risk of developing neurological complications and tremor, ataxia, dystonia, dysmetria and dysarthria have been repeatedly reported [18,22,27,30,45–50]. Current guidelines recommend periodic evaluation of cognitive abilities, executive functions, speech and language, psychiatric symptoms and development of social skills to assess the potential need for early intervention and special education services [51].
Hereditary galactosemia is an inborn error of carbohydrate metabolism. Galactose is metabolized by Leloir pathway enzymes; galactokinase (GALK), galactose-1-phosphate uridylyltransferase (GALT) and UDP-galactose 4-epimerase (GALE). The defects in these enzymes cause galactosemia in an autosomal recessive manner. The severe GALT deficiency, or classic galactosemia, is life-threatening in the newborn period. The treatment for classic galactosemia is dietary restriction of lactose. Although implementation of lactose restricted diet is efficient in resolving the acute complications, it is not sufficient to prevent long-term complications affecting the brain and female gonads, the two main target organs of damage. Implementation of molecular genetics diagnostic tools and GALT enzyme assays are instrumental in distinguishing classic galactosemia from clinical and biochemical variant forms of GALT deficiency. Better understanding of mechanisms responsible for the phenotypic variation even within the same genotype is essential to provide appropriate counseling for families. Utilization of a lactose restricted diet is also recommended for GALK deficiency and some rare forms of GALE deficiency. Novel modes of therapies are being explored; they may be beneficial if access issues to the affected tissues are circumvented and optimum use of therapeutic window is achieved.
Fertility in adult women with classic galactosemia and primary ovarian insufficiency
2017, Fertility and Sterility
Citation Excerpt :
Characteristics of patient subgroups were compared with the use of either a Mann-Whitney U test in case of numeric variables or a chi-square test/Fisher exact test in case of categoric variables. Potential predictive factors were formulated before start of the study (genotype p.Q188R/p.Q188R, GALT enzyme activity <0.4%, spontaneous menarche, low educational level, and galactose intake of >20 mg/d), based on previous literature (31, 33, 40, 42, 43), and subsequently evaluated with the use of Fisher exact test and odds ratios (ORs). Time to first pregnancy was evaluated with the use of a survival analysis and presented in a Kaplan-Meier curve.
To study pregnancy chance in adult women with classic galactosemia and primary ovarian insufficiency. Despite dietary treatment, >90% of women with classic galactosemia develop primary ovarian insufficiency, resulting in impaired fertility. For many years, chance of spontaneous conception has not been considered, leading to counseling for infertility. But an increasing number of reports on pregnancies in this group questions whether current counseling approaches are correct.
Multicenter retrospective observational study.
Metabolic centers.
Adult women (aged >18 y) with confirmed classic galactosemia and primary ovarian insufficiency were included.
Participants and medical records were consulted to obtain study data in a standardized manner with the use of a questionnaire.
Conception opportunities, time to pregnancy, pregnancy outcome, hormone replacement therapy use, fertility counseling, and the participants' vision of fertility were evaluated. Potential predictive factors for increased pregnancy chance were explored.
Eighty-five women with classic galactosemia and primary ovarian insufficiency participated. Twenty-one women actively attempted to conceive or did not take adequate contraceptive precautions. Of these 21 women, nine became pregnant spontaneously (42.9%). This was higher than reported in primary ovarian insufficiency due to other causes (5%–10%). After a period of 12 months, a cumulative proportion of 27.8% of couples had conceived, which increased to 48.4% after 24 months and 61.3% after 27 months. Predictive factors could not be identified. A considerable miscarriage rate of 30% was observed (6 of 20 pregnancies). Although a substantial proportion of women expressed a child-wish (n = 28/53; 52.8%), the vast majority of participants (n = 43/57; 75.4%) considered conceiving to be highly unlikely, owing to negative counseling in the past.
The pregnancy rate in women with classic galactosemia and primary ovarian insufficiency was higher than for women with primary ovarian insufficiency of any cause. This shifting paradigm carries significant implications for fertility counseling and potential application of fertility preservation techniques.
Female Infertility
2013, Yen and Jaffe's Reproductive Endocrinology: Seventh Edition

View all citing articles on Scopus

^☆: From the Departments of Pediatrics, Biochemistry and Molecular Biology and the Institute for Genetic Medicine, and Psychology, University of Southern California School of Medicine, Los Angeles, and the Departments of Pediatrics and Genetics, Waisman Center, University of Wisconsin, Madison

^☆☆: Supported in part by grant RO1-HD26401 from the National Institute of Child Health and Human Development and in part by a Basil O'Connor Award from the March of Dimes (5-FY93-0798) and by the James Zumberge Fund, University of Southern California.

^★: Reprint requests: Francine Ratner Kaufman, MD, 4650 Sunset Blvd., Box 61, Los Angeles, CA 90027.

^★★: 0022-3476/94/$3.00 + 0 9/20/55472

View full text

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

Abstract

Section snippets

METHODS

RESULTS

DISCUSSION

ACKNOWLEDGMENT

Genomics

J PEDIATR

Cloning and characterization of cDNA encoding human galactose-1-phosphate uridyl transferase

Molecular Biology Medicine

Sequence of cDNA encoding human galactose-1-phosphate uridyl transferase

Mol Biol Med

Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyltransferase

Am J Hum Genet

Galactosemia: a molecular approach to the enigma

International Pediatrics