- Email: [email protected]
Untreated classical galactosemia patient with mild phenotype
Molecular Genetics and Metabolism 89 (2006) 277–279 www.elsevier.com/locate/ymgme
Brief communication
Untreated classical galactosemia patient with mild phenotype Bianca Panis
a,b
, Jaap A. Bakker b, Jean-Pierre J.E. Sels c, Leo J.M. Spaapen b, Luc J.C. van Loon d, M. Estela Rubio-Gozalbo a,b,*
a Department of Pediatrics, University Hospital Maastricht, Maastricht, The Netherlands Laboratory Genetic Metabolic Diseases, University Hospital Maastricht, Maastricht, The Netherlands c Department of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands Departments of Human Biology and Movement Sciences, Maastricht University, Maastricht, The Netherlands b
d
Received 3 February 2006; received in revised form 2 March 2006; accepted 2 March 2006 Available online 18 April 2006
Abstract Despite life-long galactose restriction, long-term complications generally occur in classical galactosemia. We report an adult male with classical galactosemia (Q188R homozygosity, severely reduced erythrocyte galactose-1-phosphate uridyltransferase activity) who has a surprisingly mild phenotype despite genotype and enzyme activity associated with severe phenotype. Moreover he has a normal galactose intake from the age of 3 years. This case is probably an example of the important role of yet unknown susceptibility and or modifier genes. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Classical galactosemia; Galactose oxidation; Mild phenotype
Introduction Classical galactosemia is an autosomal recessive disorder of galactose metabolism, caused by deficiency of galactose-1-phosphate uridyltransferase (GALT, McKusick 230400). It usually presents with a neonatal toxicity syndrome, a possibly lethal condition if undiagnosed and untreated [1]. Treatment consists of dietary restriction of galactose. Untreated patients who survive the neonatal period, often develop severe mental retardation, cataract, and neurological impairments [2]. Although early restriction of galactose improves prognosis, it cannot prevent long-term complications such as motor disabilities, speech deficits, hypergonadotrophic hypogonadism in females, and decreased bone mineral density (BMD) in both genders [3–6]. Diet relaxation leads to clinically observed complications like cataract and elevation of the galactose pathway metabolites. *
Corresponding author. Fax: +31 43 387 5246. E-mail address: [email protected] (M.E. Rubio-Gozalbo).
1096-7192/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2006.03.002
The pathogenesis of these long-term complications is not fully understood. The clinical outcome varies; important phenotype determining factors are genotype and residual GALT activity. Q188R mutation in the GALT gene is associated with a severe phenotype [7]. We report a 34 years old Caucasian male with classical galactosemia (Q188R/Q188R homozygosity, erythrocyte GALT activity: 0.5 lmol/h Æ gHb, normal 32.8 ± 5.4) and no complaints despite no galactose restriction since the age of 3 years. He is married and requested screening of his newborn daughter because he had been diagnosed with galactosemia, after experiencing a sepsis and liver failure as a neonate. His medical history revealed no symptoms related to his galactosemia. Ophthalmologic examination including slit lamp exam revealed no cataract. Neurological examination was unremarkable, with no signs of tremor and ataxia. Liver function parameters were all in the normal range. He has finished high school and has worked as a car mechanic for many years. After following several courses, he is now working at a logistics department.
278
B. Panis et al. / Molecular Genetics and Metabolism 89 (2006) 277–279
Patients and methods Index patient The study was approved by the Medical Ethical Committee of our hospital. Dietary intake was determined by a food frequency questionnaire and a 3 days food diary. Galactose metabolites and calcium, 25-hydroxy vitamin D (25OHD), insulin-like growth factor-I (IGF-I), and parathormone (PTH) were determined according to standard methods and compared to the reference ranges. BMD was assessed using the Dual energy X-ray Absorptiometry (DXA) technique (Hologic QDR-4500A, Waltham, USA).
Measurement of in vivo [1-13C]galactose oxidation Whole-body in vivo oxidative capacity of galactose of the index patient (34-year-old male, BMI 25.7 kg/m2) and an age, gender, and BMI matched healthy control subject (28-year-old male, BMI 24.6 kg/m2), were determined by intravenous bolus injection of 7 mg/kg [1-13C]galactose tracer (0.039 mmol/kg; Cambridge Isotope Laboratories, Andover, USA) [8,9]. Subjects were informed about the nature and risks of the experimental procedures before their written informed consent were obtained. Expired breath samples were collected from a 3.00 L mixing chamber into vacutainer tubes at 15-min intervals during the first 60 min after [1-13C]galactose administration. Thereafter, breath samples were collected every 30 min until t = 360 min. Whole-body oxygen uptake (VO2) and carbon dioxide production (VCO2) were measured during three 60-min periods using a ventilated hood system (Oxycon-ß, Mijnhart). During the entire study period, subjects rested supine and were allowed to drink only water. Expired breath samples were analyzed for 13C/12C ratio by gas chromatograph continuous flow isotope ratio mass spectrometry (GC-CIRMS; Finnigan MAT 252, Bremen, Germany). The 13CO2 production (Pr13CO2; in mol) from the oxidation of the infused [1-13C]galactose tracer was subsequently calculated as: Pr13 CO2 ¼ ðTTRCO2 VCO2 Þ=ðkÞ; where TTRCO2 is the breath 13C/12C ratio at a given time point, VCO2 is the carbon dioxide production (L Æ min1), k is the volume of 1 mol of CO2 (22.4 L Æ mol1). The 13CO2 production was calculated over each 15 or 30 min time-frame, after which the total amount of 13CO2, produced during the 360 min experimental period, was calculated. Total 13CO2 production represents a minimal estimate of the amount of [1-13C]galactose that was oxidized within the experimental period.
Results Index patient Analysis of the patients’ diet showed a daily intake of 9 g galactose (normal). There were no dietary deficiencies. Concentrations of galactose pathway metabolites are shown in Table 1. Serum concentration of calcium, 25OHD, and PTH were between reference ranges (data
not shown). IGF-I was 116 ng/ml and below reference range (135–449 ng/ml). The BMD T-score of lumbar spine and femoral neck were 1.5 (osteopenia) and 0.7, respectively. In vivo oxidation of [1-13C]galactose A total of 615 (3.4 mmol) and 595 mg (3.3 mmol) [1-13C]galactose was infused in the index patient and control subject, respectively. Over the 6 h period, 0.06 and 1.06 mmol 13CO2 were expired by the index patient and control subject, corresponding with a minimal oxidation of 12 (1.8%) and 191 mg (32.1%) [1-13C]galactose, respectively. Discussion This male classical galactosemia patient is presented because of his remarkable mild phenotype despite Q188R homozygosity (associated with severe phenotype) and no dietary galactose restriction. Surprisingly, he does not show cataract or neurological impairment [5,6,10,11]. Galactose oxidation metabolites in the index patient are within the range for treated patients, despite a normal galactose intake and a low galactose oxidation capacity. Galactose oxidation with intravenous administered [1-13C]galactose tracer showed an oxidation capacity within 6 h, comparable with other Q188R homozygous patients [12]. It is possible that a greater amount of oxidation beyond the 6 h study period accounts for enhanced galactose disposal, as has been reported for Q188R homozygous patients [8]. Alternative oxidation pathways can also account for galactose oxidation in galactosemia patients. The reduction of galactose to galactitol is catalyzed by aldose reductase [13]. Galactitol accumulation in lens tissue causes swelling and cataract. The index patient has no cataract and urinary galactitol concentrations are even below the values of treated patients so this pathway is not likely to play a major role in galactose disposal in the index patient. However, a less functional aldose reductase and other unknown modifier genes might also play a role in this patient. Two other alternative oxidation pathways are the pyrophosphorylase pathway and the galactonate pathway but the rates of metabolism by these pathways are limited [14]. Disaccharidase activity in the intestine might be decreased with a diminished galactose uptake. However, this patient has no symptoms of gastro-intestinal malabsorption. BMD of lumbar spine was diminished despite normal serum calcium, 25OHD, and PTH levels. Serum IGF-I
Table 1 Galactose oxidation metabolites
Red cell galactose-1-phosphate (lmol/g Hb) Plasma galactitol (lmol/l) Urinary galactitol (lmol/mmol creatinine) Urinary galactose (lmol/mmol creatinine)
Index patient
Reference range Q188R/Q188R
Reference range healthy controls
0.41 9.0 83.0 4.0
<0.58 11.0 ± 1.0 131.0 ± 22.0 5.1 ± 2.1
<0.05 <0.3 <5.0 0.2–25.6
B. Panis et al. / Molecular Genetics and Metabolism 89 (2006) 277–279
level (a key role player in bone metabolism) was in the range that we find in treated patients [3]. It is very interesting that this male galactosemia patient has fathered a child as most male patients do not reproduce. The lack of reproduction in males can be a result of social impairment or infertility as in female patients, but this is not likely as there is no evidence of endocrine or semen abnormalities. This index patient indicates that the former rather than the latter explanation accounts for their infrequent reproduction. Lee et al. [15] reported a female patient, homozygous for Q188R and a mild phenotype who had also withdrawn the diet at the age of 3 years. This patient had ovarian failure (a very common sign in females with galactosemia) and low verbal and performance IQ. However, she had been able to attend school, do full-time clerical work and live independently. Her outcome without diet does not seem to be more severe than that of many treated patients. Erythrocyte GALT activity and galactose pathway metabolites of both patients were in the same range. They both did not develop cataract despite normal galactose intake from the age of 3 years. The patient from Lee et al. showed mild neurological impairment. Both patients, with genotype and enzyme activity associated with severe phenotype, have a clinical course despite no diet after the age of 3 years which is milder than expected. This case and the one reported by Lee et al. are probably examples of the important role of yet unknown susceptibility and or modifier genes.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Acknowledgments [12]
We especially acknowledge the study persons. We furthermore thank Bart Kuijper for his practical work. This study was financially supported by a grant from the ‘‘Profileringsfonds’’ of the University Hospital Maastricht and by the Dutch Society for Galactosemia.
[13] [14]
References [1] J.B. Holton, J.H. Walter, L.A. Tyfield, Galactosemia, in: C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle (Eds.), The Metabolic and
[15]
279
Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, pp. 1553–1587. J.H. Friedman, H.L. Levy, R.M. Boustany, Late onset of distinct neurologic syndromes in galactosemic siblings, Neurology 39 (1989) 741–742. B. Panis, P.P. Forget, M.J. van Kroonenburgh, C. Vermeer, P.P. Menheere, F.H. Nieman, M.E. Rubio-Gozalbo, Bone metabolism in galactosemia, Bone 35 (2004) 982–987. S. Schweitzer, Y. Shin, C. Jakobs, J. Brodehl, Long-term outcome in 134 patients with galactosaemia, Eur. J. Pediatr. 152 (1993) 36– 43. D.D. Waggoner, N.R. Buist, G.N. Donnell, Long-term prognosis in galactosaemia: results of a survey of 350 cases, J. Inherit. Metab. Dis. 13 (1990) 802–818. K.R. Ridel, N.D. Leslie, D.L. Gilbert, An updated review of the longterm neurological effects of galactosemia, Pediatr. Neurol. 33 (2005) 153–161. L. Tyfield, J. Reichardt, J. Fridovich-Keil, D.T. Croke, L.J. Elsas 2nd, W. Strobl, L. Kozak, T. Coskun, G. Novelli, Y. Okano, C. Zekanowski, Y. Shin, M.D. Boleda, Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene, Hum. Mutat. 13 (1999) 417–430. G.T. Berry, R.A. Reynolds, C.T. Yager, S. Segal, Extended [13C]galactose oxidation studies in patients with galactosemia, Mol. Genet. Metab. 82 (2004) 130–136. G.T. Berry, R.H. Singh, A.T. Mazur, N. Guerrero, M.J. Kennedy, J. Chen, R. Reynolds, M.J. Palmieri, P.D. Klein, S. Segal, L.J. Elsas 2nd, Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes, Pediatr. Res. 48 (2000) 323–328. L.J. Sokoll, J.A. Sadowski, Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population, Am. J. Clin. Nutr. 63 (1996) 566–573. S.E. Waisbren, T.R. Norman, R.R. Schnell, H.L. Levy, Speech and language deficits in early-treated children with galactosemia, J. Pediatr. 102 (1983) 75–77. G.T. Berry, I. Nissim, A.T. Mazur, L.J. Elsas, R.H. Singh, P.D. Klein, J.B. Gibson, Z. Lin, S. Segal, In vivo oxidation of [13C]galactose in patients with galactose-1-phosphate uridyltransferase deficiency, Biochem. Mol. Med. 56 (1995) 158–165. N.D. Leslie, Insights into the pathogenesis of galactosemia, Annu. Rev. Nutr. 23 (2003) 59–80. S.L. Wehrli, G.T. Berry, M. Palmieri, A. Mazur, L. Elsas 3rd, S. Segal, Urinary galactonate in patients with galactosemia: quantitation by nuclear magnetic resonance spectroscopy, Pediatr. Res. 42 (1997) 855–861. P.J. Lee, M. Lilburn, U. Wendel, P. Schadewaldt, A woman with untreated galactosaemia, Lancet 362 (2003) 446.
Brief communication
Untreated classical galactosemia patient with mild phenotype Bianca Panis
a,b
, Jaap A. Bakker b, Jean-Pierre J.E. Sels c, Leo J.M. Spaapen b, Luc J.C. van Loon d, M. Estela Rubio-Gozalbo a,b,*
a Department of Pediatrics, University Hospital Maastricht, Maastricht, The Netherlands Laboratory Genetic Metabolic Diseases, University Hospital Maastricht, Maastricht, The Netherlands c Department of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands Departments of Human Biology and Movement Sciences, Maastricht University, Maastricht, The Netherlands b
d
Received 3 February 2006; received in revised form 2 March 2006; accepted 2 March 2006 Available online 18 April 2006
Abstract Despite life-long galactose restriction, long-term complications generally occur in classical galactosemia. We report an adult male with classical galactosemia (Q188R homozygosity, severely reduced erythrocyte galactose-1-phosphate uridyltransferase activity) who has a surprisingly mild phenotype despite genotype and enzyme activity associated with severe phenotype. Moreover he has a normal galactose intake from the age of 3 years. This case is probably an example of the important role of yet unknown susceptibility and or modifier genes. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Classical galactosemia; Galactose oxidation; Mild phenotype
Introduction Classical galactosemia is an autosomal recessive disorder of galactose metabolism, caused by deficiency of galactose-1-phosphate uridyltransferase (GALT, McKusick 230400). It usually presents with a neonatal toxicity syndrome, a possibly lethal condition if undiagnosed and untreated [1]. Treatment consists of dietary restriction of galactose. Untreated patients who survive the neonatal period, often develop severe mental retardation, cataract, and neurological impairments [2]. Although early restriction of galactose improves prognosis, it cannot prevent long-term complications such as motor disabilities, speech deficits, hypergonadotrophic hypogonadism in females, and decreased bone mineral density (BMD) in both genders [3–6]. Diet relaxation leads to clinically observed complications like cataract and elevation of the galactose pathway metabolites. *
Corresponding author. Fax: +31 43 387 5246. E-mail address: [email protected] (M.E. Rubio-Gozalbo).
1096-7192/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2006.03.002
The pathogenesis of these long-term complications is not fully understood. The clinical outcome varies; important phenotype determining factors are genotype and residual GALT activity. Q188R mutation in the GALT gene is associated with a severe phenotype [7]. We report a 34 years old Caucasian male with classical galactosemia (Q188R/Q188R homozygosity, erythrocyte GALT activity: 0.5 lmol/h Æ gHb, normal 32.8 ± 5.4) and no complaints despite no galactose restriction since the age of 3 years. He is married and requested screening of his newborn daughter because he had been diagnosed with galactosemia, after experiencing a sepsis and liver failure as a neonate. His medical history revealed no symptoms related to his galactosemia. Ophthalmologic examination including slit lamp exam revealed no cataract. Neurological examination was unremarkable, with no signs of tremor and ataxia. Liver function parameters were all in the normal range. He has finished high school and has worked as a car mechanic for many years. After following several courses, he is now working at a logistics department.
278
B. Panis et al. / Molecular Genetics and Metabolism 89 (2006) 277–279
Patients and methods Index patient The study was approved by the Medical Ethical Committee of our hospital. Dietary intake was determined by a food frequency questionnaire and a 3 days food diary. Galactose metabolites and calcium, 25-hydroxy vitamin D (25OHD), insulin-like growth factor-I (IGF-I), and parathormone (PTH) were determined according to standard methods and compared to the reference ranges. BMD was assessed using the Dual energy X-ray Absorptiometry (DXA) technique (Hologic QDR-4500A, Waltham, USA).
Measurement of in vivo [1-13C]galactose oxidation Whole-body in vivo oxidative capacity of galactose of the index patient (34-year-old male, BMI 25.7 kg/m2) and an age, gender, and BMI matched healthy control subject (28-year-old male, BMI 24.6 kg/m2), were determined by intravenous bolus injection of 7 mg/kg [1-13C]galactose tracer (0.039 mmol/kg; Cambridge Isotope Laboratories, Andover, USA) [8,9]. Subjects were informed about the nature and risks of the experimental procedures before their written informed consent were obtained. Expired breath samples were collected from a 3.00 L mixing chamber into vacutainer tubes at 15-min intervals during the first 60 min after [1-13C]galactose administration. Thereafter, breath samples were collected every 30 min until t = 360 min. Whole-body oxygen uptake (VO2) and carbon dioxide production (VCO2) were measured during three 60-min periods using a ventilated hood system (Oxycon-ß, Mijnhart). During the entire study period, subjects rested supine and were allowed to drink only water. Expired breath samples were analyzed for 13C/12C ratio by gas chromatograph continuous flow isotope ratio mass spectrometry (GC-CIRMS; Finnigan MAT 252, Bremen, Germany). The 13CO2 production (Pr13CO2; in mol) from the oxidation of the infused [1-13C]galactose tracer was subsequently calculated as: Pr13 CO2 ¼ ðTTRCO2 VCO2 Þ=ðkÞ; where TTRCO2 is the breath 13C/12C ratio at a given time point, VCO2 is the carbon dioxide production (L Æ min1), k is the volume of 1 mol of CO2 (22.4 L Æ mol1). The 13CO2 production was calculated over each 15 or 30 min time-frame, after which the total amount of 13CO2, produced during the 360 min experimental period, was calculated. Total 13CO2 production represents a minimal estimate of the amount of [1-13C]galactose that was oxidized within the experimental period.
Results Index patient Analysis of the patients’ diet showed a daily intake of 9 g galactose (normal). There were no dietary deficiencies. Concentrations of galactose pathway metabolites are shown in Table 1. Serum concentration of calcium, 25OHD, and PTH were between reference ranges (data
not shown). IGF-I was 116 ng/ml and below reference range (135–449 ng/ml). The BMD T-score of lumbar spine and femoral neck were 1.5 (osteopenia) and 0.7, respectively. In vivo oxidation of [1-13C]galactose A total of 615 (3.4 mmol) and 595 mg (3.3 mmol) [1-13C]galactose was infused in the index patient and control subject, respectively. Over the 6 h period, 0.06 and 1.06 mmol 13CO2 were expired by the index patient and control subject, corresponding with a minimal oxidation of 12 (1.8%) and 191 mg (32.1%) [1-13C]galactose, respectively. Discussion This male classical galactosemia patient is presented because of his remarkable mild phenotype despite Q188R homozygosity (associated with severe phenotype) and no dietary galactose restriction. Surprisingly, he does not show cataract or neurological impairment [5,6,10,11]. Galactose oxidation metabolites in the index patient are within the range for treated patients, despite a normal galactose intake and a low galactose oxidation capacity. Galactose oxidation with intravenous administered [1-13C]galactose tracer showed an oxidation capacity within 6 h, comparable with other Q188R homozygous patients [12]. It is possible that a greater amount of oxidation beyond the 6 h study period accounts for enhanced galactose disposal, as has been reported for Q188R homozygous patients [8]. Alternative oxidation pathways can also account for galactose oxidation in galactosemia patients. The reduction of galactose to galactitol is catalyzed by aldose reductase [13]. Galactitol accumulation in lens tissue causes swelling and cataract. The index patient has no cataract and urinary galactitol concentrations are even below the values of treated patients so this pathway is not likely to play a major role in galactose disposal in the index patient. However, a less functional aldose reductase and other unknown modifier genes might also play a role in this patient. Two other alternative oxidation pathways are the pyrophosphorylase pathway and the galactonate pathway but the rates of metabolism by these pathways are limited [14]. Disaccharidase activity in the intestine might be decreased with a diminished galactose uptake. However, this patient has no symptoms of gastro-intestinal malabsorption. BMD of lumbar spine was diminished despite normal serum calcium, 25OHD, and PTH levels. Serum IGF-I
Table 1 Galactose oxidation metabolites
Red cell galactose-1-phosphate (lmol/g Hb) Plasma galactitol (lmol/l) Urinary galactitol (lmol/mmol creatinine) Urinary galactose (lmol/mmol creatinine)
Index patient
Reference range Q188R/Q188R
Reference range healthy controls
0.41 9.0 83.0 4.0
<0.58 11.0 ± 1.0 131.0 ± 22.0 5.1 ± 2.1
<0.05 <0.3 <5.0 0.2–25.6
B. Panis et al. / Molecular Genetics and Metabolism 89 (2006) 277–279
level (a key role player in bone metabolism) was in the range that we find in treated patients [3]. It is very interesting that this male galactosemia patient has fathered a child as most male patients do not reproduce. The lack of reproduction in males can be a result of social impairment or infertility as in female patients, but this is not likely as there is no evidence of endocrine or semen abnormalities. This index patient indicates that the former rather than the latter explanation accounts for their infrequent reproduction. Lee et al. [15] reported a female patient, homozygous for Q188R and a mild phenotype who had also withdrawn the diet at the age of 3 years. This patient had ovarian failure (a very common sign in females with galactosemia) and low verbal and performance IQ. However, she had been able to attend school, do full-time clerical work and live independently. Her outcome without diet does not seem to be more severe than that of many treated patients. Erythrocyte GALT activity and galactose pathway metabolites of both patients were in the same range. They both did not develop cataract despite normal galactose intake from the age of 3 years. The patient from Lee et al. showed mild neurological impairment. Both patients, with genotype and enzyme activity associated with severe phenotype, have a clinical course despite no diet after the age of 3 years which is milder than expected. This case and the one reported by Lee et al. are probably examples of the important role of yet unknown susceptibility and or modifier genes.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Acknowledgments [12]
We especially acknowledge the study persons. We furthermore thank Bart Kuijper for his practical work. This study was financially supported by a grant from the ‘‘Profileringsfonds’’ of the University Hospital Maastricht and by the Dutch Society for Galactosemia.
[13] [14]
References [1] J.B. Holton, J.H. Walter, L.A. Tyfield, Galactosemia, in: C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle (Eds.), The Metabolic and
[15]
279
Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, pp. 1553–1587. J.H. Friedman, H.L. Levy, R.M. Boustany, Late onset of distinct neurologic syndromes in galactosemic siblings, Neurology 39 (1989) 741–742. B. Panis, P.P. Forget, M.J. van Kroonenburgh, C. Vermeer, P.P. Menheere, F.H. Nieman, M.E. Rubio-Gozalbo, Bone metabolism in galactosemia, Bone 35 (2004) 982–987. S. Schweitzer, Y. Shin, C. Jakobs, J. Brodehl, Long-term outcome in 134 patients with galactosaemia, Eur. J. Pediatr. 152 (1993) 36– 43. D.D. Waggoner, N.R. Buist, G.N. Donnell, Long-term prognosis in galactosaemia: results of a survey of 350 cases, J. Inherit. Metab. Dis. 13 (1990) 802–818. K.R. Ridel, N.D. Leslie, D.L. Gilbert, An updated review of the longterm neurological effects of galactosemia, Pediatr. Neurol. 33 (2005) 153–161. L. Tyfield, J. Reichardt, J. Fridovich-Keil, D.T. Croke, L.J. Elsas 2nd, W. Strobl, L. Kozak, T. Coskun, G. Novelli, Y. Okano, C. Zekanowski, Y. Shin, M.D. Boleda, Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene, Hum. Mutat. 13 (1999) 417–430. G.T. Berry, R.A. Reynolds, C.T. Yager, S. Segal, Extended [13C]galactose oxidation studies in patients with galactosemia, Mol. Genet. Metab. 82 (2004) 130–136. G.T. Berry, R.H. Singh, A.T. Mazur, N. Guerrero, M.J. Kennedy, J. Chen, R. Reynolds, M.J. Palmieri, P.D. Klein, S. Segal, L.J. Elsas 2nd, Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes, Pediatr. Res. 48 (2000) 323–328. L.J. Sokoll, J.A. Sadowski, Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population, Am. J. Clin. Nutr. 63 (1996) 566–573. S.E. Waisbren, T.R. Norman, R.R. Schnell, H.L. Levy, Speech and language deficits in early-treated children with galactosemia, J. Pediatr. 102 (1983) 75–77. G.T. Berry, I. Nissim, A.T. Mazur, L.J. Elsas, R.H. Singh, P.D. Klein, J.B. Gibson, Z. Lin, S. Segal, In vivo oxidation of [13C]galactose in patients with galactose-1-phosphate uridyltransferase deficiency, Biochem. Mol. Med. 56 (1995) 158–165. N.D. Leslie, Insights into the pathogenesis of galactosemia, Annu. Rev. Nutr. 23 (2003) 59–80. S.L. Wehrli, G.T. Berry, M. Palmieri, A. Mazur, L. Elsas 3rd, S. Segal, Urinary galactonate in patients with galactosemia: quantitation by nuclear magnetic resonance spectroscopy, Pediatr. Res. 42 (1997) 855–861. P.J. Lee, M. Lilburn, U. Wendel, P. Schadewaldt, A woman with untreated galactosaemia, Lancet 362 (2003) 446.