- Email: [email protected]
Novel nonsense mutation (R194X) in the PMM2 gene in a Japanese patient with congenital disorder of glycosylation type Ia
Brain & Development 27 (2003) 525–528 www.elsevier.com/locate/braindev
Case report
Novel nonsense mutation (R194X) in the PMM2 gene in a Japanese patient with congenital disorder of glycosylation type Ia Hiroaki Onoa,*, Nobuo Sakuraa, Katsuko Yamashitab, Isao Yuasac, Kousaku Ohnod a
Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan b Department of Biochemistry, Sasaki Institute, Hiroshima, Japan c Department of Legal Medicine, Tottori University Faculty of Medicine, Tottori, Japan d Department of Child Neurology, Institute of Neurological Sciences, Tottori University Faculty of Medicine, Tottori, Japan Received 9 December 2002; received in revised form 11 March 2003; accepted 14 March 2003
Abstract A Japanese boy had clinical features of congenital disorder of glycosylation type Ia (CDG Ia, also known as carbohydrate-deficientglycoprotein syndrome, previously), and enzymatic and molecular assay of phosphomannomutase confirmed this diagnosis. During infancy, the patient showed delayed mental and motor development, hypotonia, ataxia, hepatomegaly, liver dysfunction, abnormal coagulation system and cerebellar hypoplasia. At present, though he is 3 years and 8 months old, he cannot utter meaningful words or sit by himself. These findings suggested that he had one of the severe phenotypes of Japanese CDG Ia. Mutational analysis demonstrated heterozygosity for the missense mutation in exon 4 (P113L) and a novel nonsense mutation in exon 7 (R194X). We report his clinical course and the results of molecular assay, and discuss correlation between clinical severity and genotype. q 2003 Published by Elsevier Science B.V. Keywords: Congenital disorder of glycosylation; Transferrin; Phosphomannomutase; PMM2; Nonsense mutation
1. Introduction Congenital disorder of glycosylation (CDG), also called carbohydrate-deficient-glycoprotein syndrome previously, represent defects in N-glycosylation. Several types of CDG have been described, of which CDG type Ia (CDG Ia) is the most frequent. Clinically, patients with CDG Ia show delayed mental and motor development, cerebellar hypoplasia, liver dysfunction and abnormal coagulation system in addition to other abnormalities [1]. This type is associated with an abnormal isoelectoric focusing (IEF) pattern of serum transferrin caused by a deficiency in phosphomannomutase (PMM) [2]. Several mutations of the PMM2 gene, which is involved in the disorder, have been described [3]. Most previously reported patients with CDG have been Caucasians. Until now, only about 10 cases of CDG Ia have been reported in Japan, and mutational analysis was performed only in a few cases [4]. We determined the *
Corresponding author. Tel.: þ81-082-257-5212; fax: þ 81-082-2575214. E-mail address: [email protected] (H. Ono). 0387-7604/03/$ - see front matter q 2003 Published by Elsevier Science B.V. doi:10.1016/S0387-7604(03)00063-9
DNA sequence of the PMM2 gene in a Japanese boy with CDG Ia and found a novel nonsense mutation.
2. Patient The patient was the first child born to healthy, unrelated parents after a normal pregnancy. Birth weight and gestational age was 2850 g and 36 weeks, respectively. At 11 months of age he was evaluated in our clinic because of delayed mental and motor development. His growth had been normal, but he exhibited hypotonia, ataxia, hepatomegaly (4 cm below the costal margin at the mid-clavicular line), internal strabismus, inverted nipples and diminished deep tendon reflexes. Abnormal laboratory values were aspartate aminotransferase (AST) 272 IU/l (normal , 40 IU/l), alanine aminotransferse (ALT) 268 IU/l (normal , 50 IU/l), partial thromboplastin time 48.8 s (normal 23– 35 s), and antithrombin III was not detected (normal 70– 120%). An echocardiogram showed moderate left ventricular hypertrophy and a small pericardial effusion, but he had no cardiac symptoms. The patient had three
526
H. Ono et al. / Brain & Development 27 (2003) 525–528
tonic –clonic seizures during the first year of life, but his EEG was unremarkable. Cranial magnetic resonance imaging (MRI) at 11 months of age demonstrated mild atrophy of cerebellar hemispheres. However, at 1 year and 7 months, this finding progressed, particularly evident centrally. At present he is 3 years and 8 months old, but he cannot utter meaningful words or sit by himself. Hepatomegaly resolved, and liver dysfunction gradually improved (AST 125 IU/l and ALT 203 IU/l). Plasma levels of antithrombin III are slightly increased (39%). Cranial MRI, EEG, and echocardiogram remain unchanged. His parents gave their informed consent for a genetic analysis.
3. Methods Isoelectoric focusing (IEF) of serum transferrin was performed as described previously [5]. Phosphomannomutase (PMM) assays using cultured skin fibroblasts were carried out according to the method of Ohkura et al. [6]. Genomic DNA was isolated from white blood cells by means of standard laboratory procedures. Mutations were identified by direct sequencing. Polymerase chain reaction (PCR) was used to amplify all eight exons, including the flanking introns, with primers designed by Matthijs et al. [7]. PCR products were separated on a 2% agarose gel and purified with GFX PCR DNA and Gel Band Purification Kit (Amersham Biosciences Corp, Piscataway, NJ, USA). Cycle sequencing was performed using a BigDye Terminator Cycle Sequencing Ready Reaction kit (Applied Biosystems, Foster City, CA, USA) and an ABI Prism 310 Genetic Analyzer (Applied Biosystems). PCR products of exon 7 were digested with Tsp45I (New England Biolabs, Beverly, MA, USA). Fragments were separated on a 3.5% agarose gel and visualized by ethidium bromide staining. F304S mutation of the ALG6 gene encoding an a1,3-glucosyltransferase has been suspected as a causitive factor in the severe CDG Ia phenotype. Therefore, this mutation was also investigated using the method of Westphal et al. [8].
The patient’s father was heterozygous for the P113L mutation and his mother was also heterozygous for the R194X mutation (Fig. 1). This R194X mutation creates a restriction site for Tsp45I. The patient and his mother were verified to be heterozygous for the R194X mutation by Tsp45I restriction fragment length polymorphism analysis (Fig. 2). The F304S mutation of the ALG6 gene was not found.
5. Discussion Grunewald et al. [9] reported that multiorgan involvement, convulsions, severe developmental delay, and inability to walk are consequences of CDG Ia. Our patient had all of these symptoms, along with another finding, undetectable antithrombin III at the time of the initial presentation to our clinic. In previously reported Japanese patients with CDG Ia [4,5], most patients could sit, stand, walk with or without support, and speak simple sentences by the time they were 3 or 4 years old. Our patient cannot, suggesting that he is one of the most severe phenotypes among Japanese patients with CDG Ia. Westphal et al. [8] reported that the presence of the F304S mutation might exacerbate the clinical condition, especially in severely affected patients. However, this mutation was not identified in our patient. Akaboshi et al. [10] reported neuroradiological findings in CDG patients seemed to progress throughout early childhood, consistent with MRI findings in our patient. Mader et al. [11] also reported a patient with normal cerebellar volume on the initial examination and benign clinical course, who developed marked atrophy in childhood. They speculated that in severe cases the atrophy starts
4. Results IEF of serum transferrin showed the typical abnormal pattern of CDG type 1a; namely, decreased tetrasialoband and increased asialo-, and disialobands. Reduced PMM enzyme activity was demonstrated in cultured skin fibroblasts (14 pmol/min per mg protein vs. control, 45; 31% of the control value). Mutational analysis demonstrated heterozygosity for the missense and nonsense mutation. The first was 338C . T mutation in exon 4, resulting in the P113L. The second was 580C . T mutation in exon 7, resulting in the R194X, which is a novel nonsense mutation.
Fig. 1. The sequence of exon 7 from the patient and his parents. Direct sequencing analysis demonstrated a heterozygous C to T substitution in the patient and his mother.
H. Ono et al. / Brain & Development 27 (2003) 525–528
Fig. 2. PCR-restriction fragment length analysis used to detect the R194X mutation. PCR products digested with Tsp45I showed that the patient and his mother were heterozygous for the R194X mutation.
early and the initial imaging might show an already atrophic cerebellum. To date, about 60 different mutations of the PMM2 gene have been reported in CDG Ia [3]. The relationship between missense mutations, such as R141H, and the phenotype has been studied [12]. Forty-three of the 132 patients had the F119L/R141H genotype, of which 13 (30%) died [3]. Combinations of D56Y with R141H, R123Q, or F157S result in severe phenotype with a death rate of four in five [3]. High mortality was observed in the patients with the D188G/R141H genotype, four of five patients died before the age of 2 years [7]. It has remained unclear that the genotype inducing the premature stop codon is related to the severity of the phenotype, because this genotype has been found only in a few cases. According to the report by Grunewald et al. [9], two patients with truncating mutations showed severe or moderate – severe phenotype. Recently, Marquardt et al. [13] reported that CDG Ia case with the frameshift mutation showed severe transient myocardial ischemia. The R194X mutation in our case is novel. This region belongs to one of three different motifs that are most likely involved in catalytic activity [14]. The severity of the phenotype in our patient might be associated with this mutation. Our case showed relatively high residual PMM activity in fibroblast, 31% of the control. Grunewald et al. indicated that the residual PMM activities in fibroblasts from patients with two allelic mutations in the PMM2 gene could be quite high, reaching 70% of the normal value in one patient [9]. They also indicated that there was some degree of correlation between the residual activity in fibroblasts and the clinical phenotype [9]. However, some patients with a severe phenotype have relatively high residual PMM activity in fibroblasts, as shown in our case. The two patients with truncating mutations and severe or severe – moderate phenotype described previously had also relatively high residual enzyme activity, about 20% of normal controls [9]. Of the 16 patients with the R141H/V231M genotype, nine have died. The V231M mutation has a residual activity of 38.5%, but the abnormal protein is extremely unstable [15]. P113L, which is a missense mutation and found relatively frequently worldwide [3], may have been responsible for the
527
residual enzyme activity in our case. On the other hand, in the truncated protein induced by R194X, a number of amino acids would be deleted from the C-terminal portion with this mutation. This protein conformation might affect enzyme stability or function, which might contribute to the severe phenotype. In the future, more detailed analysis of the abnormal protein, including enzyme stability, will be required to establish the impact of this novel mutation on enzymatic function. Measurement of PMM activity in leukocytes might also be useful to confirm correlation between enzyme activity and severe phenotype, since no residual activity was found in one severe CDG Ia case with a frame-shift mutation [13].
Acknowledgements This work was carried out at the Research Center for Molecular Medicine, Faculty of Medicine, Hiroshima University.
References [1] Jaeken J, Casaer P. Carbohydrate-deficient glycoconjugate (CDG) syndromes: a new chapter of neuropaediatrics. Eur J Paediatr Neurol 1997;1:61–6. [2] Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett 1995;377:318 –20. [3] Matthijs G, Schollen E, Bjursell C, Erlandson A, Freeze H, Imtiaz F, et al. Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia). Hum Mutat 2000;16:386– 94. [4] Kondo I, Mizugishi K, Yoneda Y, Hashimoto T, Kuwajima K, Yuasa I, et al. Missense mutations in phosphomannomutase 2 gene in two Japanese families with carbohydrate-deficient glycoprotein syndrome type 1. Clin Genet 1999;55:50–4. [5] Ohno K, Yuasa I, Akaboshi S, Itoh M, Yoshida K, Ehara H, et al. The carbohydrate deficient glycoprotein syndrome in three Japanese children. Brain Dev 1992;14:30–5. [6] Ohkura T, Fukushima K, Kurisaki A, Sagami H, Ogura K, Ohno K, et al. A partial deficiency of dehydrodolichol reduction is a cause of carbohydrate-deficient glycoprotein syndrome type I. J Biol Chem 1997;272:6868–75. [7] Matthijs G, Schollen E, Van Schaftingen E, Cassiman J-J, Jaeken J. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome Type 1A. Am J Hum Genet 1998;62:542 –50. [8] Westphal V, Kjaergaard S, Schollen E, Martens K, Grunewald S, Schwartz M, et al. A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. Hum Mol Genet 2002;11:599 –604. [9] Grunewald S, Schollen E, Van Schaftingen E, Jaeken J, Matthijs G. High residual activity of PMM2 in patients fibroblasts: possible pitfall in the diagnosis of CDG-Ia (Phosphomannomutase deficiency). Am J Hum Genet 2001;68:347–54. [10] Akaboshi S, Ohno K, Takeshita K. Neuroradiological findings in the carbohydrate-deficient glycoprotein syndrome. Neuroradiology 1995; 37:491–5. [11] Mader I, Dobler-Neumann M, Stibler H, Krageloh-Mann I.
528
H. Ono et al. / Brain & Development 27 (2003) 525–528
Congenital disorder of glycosylation type Ia: benign clinical course in a new genetic variant. Childs Nerv Syst 2002;18:77 –80. [12] Kjaergaard S, Schwartz M, Skovby F. Congenital disorder of glycosylation type Ia (CDG Ia): phenotypic spectrum of the R141H/ F119L genotype. Arch Dis Child 2001;85:236–9. [13] Marquardt T, Hulskamp G, Gehrmann J, Debus V, Harms E, Kehl HG. Severe transient myocardial ischaemia caused by hypertrophic cardiomyopathy in a patient with congenital disorder of glycosylation type Ia. Eur J Pediatr 2002;161:524–7.
[14] Aravind L, Galperin MY, Koonin EV. The catalytic domain of the P-type ATPase has the haloacid dehalogenase fold. Trends Biochem Sci 1998;23:127 –9. [15] Pirard M, Matthijs G, Heykants L, Schollen E, Grunewald S, Jaeken J, et al. Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of phosphomannomutase 2. FEBS Lett 1999;452:319–22.
Case report
Novel nonsense mutation (R194X) in the PMM2 gene in a Japanese patient with congenital disorder of glycosylation type Ia Hiroaki Onoa,*, Nobuo Sakuraa, Katsuko Yamashitab, Isao Yuasac, Kousaku Ohnod a
Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan b Department of Biochemistry, Sasaki Institute, Hiroshima, Japan c Department of Legal Medicine, Tottori University Faculty of Medicine, Tottori, Japan d Department of Child Neurology, Institute of Neurological Sciences, Tottori University Faculty of Medicine, Tottori, Japan Received 9 December 2002; received in revised form 11 March 2003; accepted 14 March 2003
Abstract A Japanese boy had clinical features of congenital disorder of glycosylation type Ia (CDG Ia, also known as carbohydrate-deficientglycoprotein syndrome, previously), and enzymatic and molecular assay of phosphomannomutase confirmed this diagnosis. During infancy, the patient showed delayed mental and motor development, hypotonia, ataxia, hepatomegaly, liver dysfunction, abnormal coagulation system and cerebellar hypoplasia. At present, though he is 3 years and 8 months old, he cannot utter meaningful words or sit by himself. These findings suggested that he had one of the severe phenotypes of Japanese CDG Ia. Mutational analysis demonstrated heterozygosity for the missense mutation in exon 4 (P113L) and a novel nonsense mutation in exon 7 (R194X). We report his clinical course and the results of molecular assay, and discuss correlation between clinical severity and genotype. q 2003 Published by Elsevier Science B.V. Keywords: Congenital disorder of glycosylation; Transferrin; Phosphomannomutase; PMM2; Nonsense mutation
1. Introduction Congenital disorder of glycosylation (CDG), also called carbohydrate-deficient-glycoprotein syndrome previously, represent defects in N-glycosylation. Several types of CDG have been described, of which CDG type Ia (CDG Ia) is the most frequent. Clinically, patients with CDG Ia show delayed mental and motor development, cerebellar hypoplasia, liver dysfunction and abnormal coagulation system in addition to other abnormalities [1]. This type is associated with an abnormal isoelectoric focusing (IEF) pattern of serum transferrin caused by a deficiency in phosphomannomutase (PMM) [2]. Several mutations of the PMM2 gene, which is involved in the disorder, have been described [3]. Most previously reported patients with CDG have been Caucasians. Until now, only about 10 cases of CDG Ia have been reported in Japan, and mutational analysis was performed only in a few cases [4]. We determined the *
Corresponding author. Tel.: þ81-082-257-5212; fax: þ 81-082-2575214. E-mail address: [email protected] (H. Ono). 0387-7604/03/$ - see front matter q 2003 Published by Elsevier Science B.V. doi:10.1016/S0387-7604(03)00063-9
DNA sequence of the PMM2 gene in a Japanese boy with CDG Ia and found a novel nonsense mutation.
2. Patient The patient was the first child born to healthy, unrelated parents after a normal pregnancy. Birth weight and gestational age was 2850 g and 36 weeks, respectively. At 11 months of age he was evaluated in our clinic because of delayed mental and motor development. His growth had been normal, but he exhibited hypotonia, ataxia, hepatomegaly (4 cm below the costal margin at the mid-clavicular line), internal strabismus, inverted nipples and diminished deep tendon reflexes. Abnormal laboratory values were aspartate aminotransferase (AST) 272 IU/l (normal , 40 IU/l), alanine aminotransferse (ALT) 268 IU/l (normal , 50 IU/l), partial thromboplastin time 48.8 s (normal 23– 35 s), and antithrombin III was not detected (normal 70– 120%). An echocardiogram showed moderate left ventricular hypertrophy and a small pericardial effusion, but he had no cardiac symptoms. The patient had three
526
H. Ono et al. / Brain & Development 27 (2003) 525–528
tonic –clonic seizures during the first year of life, but his EEG was unremarkable. Cranial magnetic resonance imaging (MRI) at 11 months of age demonstrated mild atrophy of cerebellar hemispheres. However, at 1 year and 7 months, this finding progressed, particularly evident centrally. At present he is 3 years and 8 months old, but he cannot utter meaningful words or sit by himself. Hepatomegaly resolved, and liver dysfunction gradually improved (AST 125 IU/l and ALT 203 IU/l). Plasma levels of antithrombin III are slightly increased (39%). Cranial MRI, EEG, and echocardiogram remain unchanged. His parents gave their informed consent for a genetic analysis.
3. Methods Isoelectoric focusing (IEF) of serum transferrin was performed as described previously [5]. Phosphomannomutase (PMM) assays using cultured skin fibroblasts were carried out according to the method of Ohkura et al. [6]. Genomic DNA was isolated from white blood cells by means of standard laboratory procedures. Mutations were identified by direct sequencing. Polymerase chain reaction (PCR) was used to amplify all eight exons, including the flanking introns, with primers designed by Matthijs et al. [7]. PCR products were separated on a 2% agarose gel and purified with GFX PCR DNA and Gel Band Purification Kit (Amersham Biosciences Corp, Piscataway, NJ, USA). Cycle sequencing was performed using a BigDye Terminator Cycle Sequencing Ready Reaction kit (Applied Biosystems, Foster City, CA, USA) and an ABI Prism 310 Genetic Analyzer (Applied Biosystems). PCR products of exon 7 were digested with Tsp45I (New England Biolabs, Beverly, MA, USA). Fragments were separated on a 3.5% agarose gel and visualized by ethidium bromide staining. F304S mutation of the ALG6 gene encoding an a1,3-glucosyltransferase has been suspected as a causitive factor in the severe CDG Ia phenotype. Therefore, this mutation was also investigated using the method of Westphal et al. [8].
The patient’s father was heterozygous for the P113L mutation and his mother was also heterozygous for the R194X mutation (Fig. 1). This R194X mutation creates a restriction site for Tsp45I. The patient and his mother were verified to be heterozygous for the R194X mutation by Tsp45I restriction fragment length polymorphism analysis (Fig. 2). The F304S mutation of the ALG6 gene was not found.
5. Discussion Grunewald et al. [9] reported that multiorgan involvement, convulsions, severe developmental delay, and inability to walk are consequences of CDG Ia. Our patient had all of these symptoms, along with another finding, undetectable antithrombin III at the time of the initial presentation to our clinic. In previously reported Japanese patients with CDG Ia [4,5], most patients could sit, stand, walk with or without support, and speak simple sentences by the time they were 3 or 4 years old. Our patient cannot, suggesting that he is one of the most severe phenotypes among Japanese patients with CDG Ia. Westphal et al. [8] reported that the presence of the F304S mutation might exacerbate the clinical condition, especially in severely affected patients. However, this mutation was not identified in our patient. Akaboshi et al. [10] reported neuroradiological findings in CDG patients seemed to progress throughout early childhood, consistent with MRI findings in our patient. Mader et al. [11] also reported a patient with normal cerebellar volume on the initial examination and benign clinical course, who developed marked atrophy in childhood. They speculated that in severe cases the atrophy starts
4. Results IEF of serum transferrin showed the typical abnormal pattern of CDG type 1a; namely, decreased tetrasialoband and increased asialo-, and disialobands. Reduced PMM enzyme activity was demonstrated in cultured skin fibroblasts (14 pmol/min per mg protein vs. control, 45; 31% of the control value). Mutational analysis demonstrated heterozygosity for the missense and nonsense mutation. The first was 338C . T mutation in exon 4, resulting in the P113L. The second was 580C . T mutation in exon 7, resulting in the R194X, which is a novel nonsense mutation.
Fig. 1. The sequence of exon 7 from the patient and his parents. Direct sequencing analysis demonstrated a heterozygous C to T substitution in the patient and his mother.
H. Ono et al. / Brain & Development 27 (2003) 525–528
Fig. 2. PCR-restriction fragment length analysis used to detect the R194X mutation. PCR products digested with Tsp45I showed that the patient and his mother were heterozygous for the R194X mutation.
early and the initial imaging might show an already atrophic cerebellum. To date, about 60 different mutations of the PMM2 gene have been reported in CDG Ia [3]. The relationship between missense mutations, such as R141H, and the phenotype has been studied [12]. Forty-three of the 132 patients had the F119L/R141H genotype, of which 13 (30%) died [3]. Combinations of D56Y with R141H, R123Q, or F157S result in severe phenotype with a death rate of four in five [3]. High mortality was observed in the patients with the D188G/R141H genotype, four of five patients died before the age of 2 years [7]. It has remained unclear that the genotype inducing the premature stop codon is related to the severity of the phenotype, because this genotype has been found only in a few cases. According to the report by Grunewald et al. [9], two patients with truncating mutations showed severe or moderate – severe phenotype. Recently, Marquardt et al. [13] reported that CDG Ia case with the frameshift mutation showed severe transient myocardial ischemia. The R194X mutation in our case is novel. This region belongs to one of three different motifs that are most likely involved in catalytic activity [14]. The severity of the phenotype in our patient might be associated with this mutation. Our case showed relatively high residual PMM activity in fibroblast, 31% of the control. Grunewald et al. indicated that the residual PMM activities in fibroblasts from patients with two allelic mutations in the PMM2 gene could be quite high, reaching 70% of the normal value in one patient [9]. They also indicated that there was some degree of correlation between the residual activity in fibroblasts and the clinical phenotype [9]. However, some patients with a severe phenotype have relatively high residual PMM activity in fibroblasts, as shown in our case. The two patients with truncating mutations and severe or severe – moderate phenotype described previously had also relatively high residual enzyme activity, about 20% of normal controls [9]. Of the 16 patients with the R141H/V231M genotype, nine have died. The V231M mutation has a residual activity of 38.5%, but the abnormal protein is extremely unstable [15]. P113L, which is a missense mutation and found relatively frequently worldwide [3], may have been responsible for the
527
residual enzyme activity in our case. On the other hand, in the truncated protein induced by R194X, a number of amino acids would be deleted from the C-terminal portion with this mutation. This protein conformation might affect enzyme stability or function, which might contribute to the severe phenotype. In the future, more detailed analysis of the abnormal protein, including enzyme stability, will be required to establish the impact of this novel mutation on enzymatic function. Measurement of PMM activity in leukocytes might also be useful to confirm correlation between enzyme activity and severe phenotype, since no residual activity was found in one severe CDG Ia case with a frame-shift mutation [13].
Acknowledgements This work was carried out at the Research Center for Molecular Medicine, Faculty of Medicine, Hiroshima University.
References [1] Jaeken J, Casaer P. Carbohydrate-deficient glycoconjugate (CDG) syndromes: a new chapter of neuropaediatrics. Eur J Paediatr Neurol 1997;1:61–6. [2] Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett 1995;377:318 –20. [3] Matthijs G, Schollen E, Bjursell C, Erlandson A, Freeze H, Imtiaz F, et al. Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia). Hum Mutat 2000;16:386– 94. [4] Kondo I, Mizugishi K, Yoneda Y, Hashimoto T, Kuwajima K, Yuasa I, et al. Missense mutations in phosphomannomutase 2 gene in two Japanese families with carbohydrate-deficient glycoprotein syndrome type 1. Clin Genet 1999;55:50–4. [5] Ohno K, Yuasa I, Akaboshi S, Itoh M, Yoshida K, Ehara H, et al. The carbohydrate deficient glycoprotein syndrome in three Japanese children. Brain Dev 1992;14:30–5. [6] Ohkura T, Fukushima K, Kurisaki A, Sagami H, Ogura K, Ohno K, et al. A partial deficiency of dehydrodolichol reduction is a cause of carbohydrate-deficient glycoprotein syndrome type I. J Biol Chem 1997;272:6868–75. [7] Matthijs G, Schollen E, Van Schaftingen E, Cassiman J-J, Jaeken J. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome Type 1A. Am J Hum Genet 1998;62:542 –50. [8] Westphal V, Kjaergaard S, Schollen E, Martens K, Grunewald S, Schwartz M, et al. A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. Hum Mol Genet 2002;11:599 –604. [9] Grunewald S, Schollen E, Van Schaftingen E, Jaeken J, Matthijs G. High residual activity of PMM2 in patients fibroblasts: possible pitfall in the diagnosis of CDG-Ia (Phosphomannomutase deficiency). Am J Hum Genet 2001;68:347–54. [10] Akaboshi S, Ohno K, Takeshita K. Neuroradiological findings in the carbohydrate-deficient glycoprotein syndrome. Neuroradiology 1995; 37:491–5. [11] Mader I, Dobler-Neumann M, Stibler H, Krageloh-Mann I.
528
H. Ono et al. / Brain & Development 27 (2003) 525–528
Congenital disorder of glycosylation type Ia: benign clinical course in a new genetic variant. Childs Nerv Syst 2002;18:77 –80. [12] Kjaergaard S, Schwartz M, Skovby F. Congenital disorder of glycosylation type Ia (CDG Ia): phenotypic spectrum of the R141H/ F119L genotype. Arch Dis Child 2001;85:236–9. [13] Marquardt T, Hulskamp G, Gehrmann J, Debus V, Harms E, Kehl HG. Severe transient myocardial ischaemia caused by hypertrophic cardiomyopathy in a patient with congenital disorder of glycosylation type Ia. Eur J Pediatr 2002;161:524–7.
[14] Aravind L, Galperin MY, Koonin EV. The catalytic domain of the P-type ATPase has the haloacid dehalogenase fold. Trends Biochem Sci 1998;23:127 –9. [15] Pirard M, Matthijs G, Heykants L, Schollen E, Grunewald S, Jaeken J, et al. Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of phosphomannomutase 2. FEBS Lett 1999;452:319–22.