The adult galactosemic phenotype

Abstract

BackgroundClassic 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.MethodsThirty‐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.ResultsThe 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.ConclusionsTaken 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.

Developmental Outcomes of School-Age Children with Duarte Galactosemia: A Pilot Study

“…These problems were similar to those reported previously in individuals with classic galactosemia (Antshel et al 2004;Bosch et al 2004;Ryan et al 2013;Waisbren et al 2012). Parent reports on the SSIS Autism Spectrum subscale indicated that one of five control children and three of seven DG children in the study scored in the "concern" range.…”

“…Specific symptoms of concern assessed in this section of the SSIS survey included heightened anxiety, social problems, and social withdrawal. As noted above, these same sorts of internalizing behaviors have also been reported for patients with classic galactosemia (Antshel et al 2004;Bosch et al 2004;Ryan et al 2013;Waisbren et al 2012). Children in the DG, no parental concerns group did not exhibit these issues, which is not surprising considering that both the CBCL and SSIS are parent-response surveys, and earlier parent reports were used to stratify the DG children into "parental concern" and "no parental concern" groups.…”

Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model

“…5 Despite early dietary management, chronic complications such as intellectual deficits, ataxia, speech dyspraxia, premature ovarian insufficiency (POI) and decreased bone mineralization occur in many adults. [10][11][12][13][14][15][16][17][18][19] Different cell and animal models have been utilized to understand the pathogenic mechanisms of the acute neonatal lethality and the long-term complications associated with Classic Galactosemia. Early genetic studies in the yeast Saccharomyces cerevisiae showed that GALT-deficient mutant yeasts are sensitive to galactose in growth medium; but disruption of galactokinase (GALK) function in these yeasts reversed their galactose sensitivity.…”

Functional correction by antisense therapy of a splicing mutation in the GALT gene

“…12 Classic galactosemia (MIM #230400), which affects about 1/47 000 live-births, results from deficient activity of galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12), an ubiquitous key enzyme in galactose metabolism, essential for nursing infants, as lactose represents their primary carbohydrate source. 13,14 The present gold standard of care is a lifelong dietary galactose restriction, which has, however, proven to be insufficient to prevent the long-term sequelae. [13][14][15][16][17] The disorder is caused by mutations in the GALT gene, which profoundly impair GALT enzymatic activity.…”

“…13,14 The present gold standard of care is a lifelong dietary galactose restriction, which has, however, proven to be insufficient to prevent the long-term sequelae. [13][14][15][16][17] The disorder is caused by mutations in the GALT gene, which profoundly impair GALT enzymatic activity. 15,18,19 GALT is located in chromosome 9p13, arranged into 11 exons spanning about 4.0 kb of genomic sequence, and encodes a 379 amino-acid polypeptide, which is assembled as a B87 kDa homodimer.…”