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  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
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Alternative titles; symbols

  • CDG It; CDGIt

▼ Description
Congenital disorder of glycosylation type It (CDG1T) is an autosomal recessive disorder characterized by a wide range of clinical manifestations and severity. The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism (summary by Tegtmeyer et al., 2014).

For a discussion of the classification of CDGs, see CDG1A (212065).

▼ Clinical Features
Stojkovic et al. (2009) reported a 35-year-old man with recurrent muscle cramps provoked by exercise. He had had 2 episodes of dark-brown urine after strenuous exercise, suggesting rhabdomyolysis. Neurologic examination showed mild weakness of the pelvic-girdle muscles; serum creatine kinase and ammonia were increased after strenuous exercise. Muscle biopsy showed abnormal subsarcolemmal and sarcoplasmic accumulations of normally structured, free glycogen. An in vitro muscle study of anaerobic glycogenolysis and glycolysis showed a metabolic block after formation of glucose-1-phosphate and before formation of glucose-6-phosphate, indicating a phosphoglucomutase deficiency. PGM1 activity was 1% of control values. Stojkovic et al. (2009) concluded that this disorder is a rare glycolytic disorder, which should be designated glycogenosis, or glycogen storage disease, type XIV. In a follow-up report, Tegtmeyer et al. (2014) found that the patient reported by Stojkovic et al. (2009) had abnormal liver enzymes and an abnormal pattern of transferrin glycosylation, consistent with a congenital disorder of glycosylation.

Timal et al. (2012) reported 2 unrelated children with congenital disorder of glycosylation type It. One boy was adopted and of Colombian origin. He had cerebral thrombosis and dilated cardiomyopathy, and died at age 8 years. Laboratory studies showed low levels of antithrombin III (SERPINC1; 107300) and elevated liver enzymes. The other child was a 16-year-old Caucasian girl who had Pierre Robin sequence, cleft palate, fatigue, dyspnea, tachycardia, dilated cardiomyopathy, and chronic hepatitis. Laboratory studies showed increased serum creatine kinase and liver enzymes. Transferrin isoelectric focusing in both patients showed abnormal N-glycosylation. In addition to the loss of complete N-glycans, there were minor bands of monosialo- and trisialotransferrin, suggesting the presence of incomplete glycans. Thus, the pattern could best be described as CDGI/II.

Tegtmeyer et al. (2014) reported 19 patients from 16 families with CDG1T, including the 3 patients reported by Stojkovic et al. (2009) and Timal et al. (2012). Patients displayed a wide range of clinical features, but all had signs of hepatopathy with abnormal liver enzymes and sometimes with steatosis and fibrosis. The majority of patients had muscle symptoms, including exercise intolerance and muscle weakness; 5 had a history of rhabdomyolysis. Serum creatine kinase was often elevated, and hypoglycemia was common. Most patients were noted to have cleft palate and bifid uvula at birth, and many of these patients had short stature later in life. Six patients developed dilated cardiomyopathy, including 3 who were listed for heart transplantation. Two patients developed malignant hyperthermia after the administration of general anesthesia. Two unrelated girls had hypogonadotropic hypogonadism with delayed puberty. Patient cells showed considerable variability in the transferrin-glycoform profile, with forms lacking one or both glycans as well as forms with truncated glycans, consistent with a mixed type I/II pattern. Cells also showed increased concentrations of galactose- and glucose-1-phosphate compared to controls. Addition of galactose to cell cultures enhanced glycosylation but did not affect glycogen content. A subset of patients treated with oral galactose showed improved transferrin glycosylation, and the 2 girls with delayed puberty showed resolution of hypogonadotropic hypogonadism after treatment with galactose.

Conte et al. (2020) reported clinical data on 54 patients, including 11 newly reported and 43 identified in a literature review. The most common clinical features were elevated transaminases in 96%, growth delay in 89%, hypoglycemia in 89%, and cleft palate or bifid uvula in 87%. Other common clinical features included abnormal cardiac function and dilated cardiomyopathy in 46%, hepatic defects in 46%, and myopathy or muscle symptoms in 57%. Neurologic symptoms, including seizures, paralysis, hypotonia, impaired intellectual development, and psychomotor impairment, were seen in 43%. In comparing features in early or later clinical presentation (before or after 1 year of age), respiratory tract symptoms and oral/gastrointestinal defects were reported significantly more frequently in the younger group. Thyroid hormone abnormalities were reported more frequently in female patients.

▼ Diagnosis
Tegtmeyer et al. (2014) developed a modified Beutler test using glucose-1-phosphate for the screening of PGM1 deficiency.

Conte et al. (2020) showed that the modified Beutler test was abnormal in dried blood spots from 2 neonates and 2 infants with CDG1T. Deficiency of PGM activity (less than 20 U/L) was detected in all 4 samples.

▼ Inheritance
The transmission pattern of CDG1T in the patients reported by Timal et al. (2012) was consistent with autosomal recessive inheritance.

▼ Clinical Management
Wong et al. (2017) treated 8 CDG1T patients with homozygous or compound heterozygous mutations in PGM1, aged 19 months to 21 years, with D-galactose supplementation. The dosage increased from 0.5g/kg/day to 1.5g/kg/day (maximum dose 50 g/day) in 3 increments over 18 weeks. All patients had abnormal baseline results of ALT, AST, and aPTT (alanine transaminase, aspartate transaminase, activated partial thromboplastin time), all of which improved or normalized using 1g/kg/day D-gal. Antithrombin-III levels and transferrin glycosylation showed significant improvements, and galactosylation and whole glycan content were increased. In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal lipid-linked oligosaccharide profile, and abnormal nucleotide sugars in patient fibroblasts. Most cellular abnormalities improved or normalized following D-gal treatment. D-gal increased both UDP-Glc and UDP-Gal levels and improved lipid-linked oligosaccharide fractions in concert with improved glycosylation. No adverse effects were reported. Wong et al. (2017) concluded that oral D-galactose supplementation is a safe and effective treatment for CDG1T in their pilot study and that transferrin glycosylation and ATIII levels were useful trial end points. They noted that larger, longer-duration studies were ongoing.

Conte et al. (2020) reported clinical and laboratory features in 11 patients with CDG1T before and after treatment with galactose. In the majority of neonatal patients, the D-galactose supplementation improved some of the most frequent symptoms, including hypoglycemic episodes, liver disease, endocrine dysfunction, and growth delay. Improvement was also seen in muscle symptoms in 3 patients after D-galactose treatment.

▼ Molecular Genetics
In a man with exercise intolerance and episodic rhabdomyolysis, Stojkovic et al. (2009) identified compound heterozygosity for mutations in the PGM1 gene (171900.0001 and 171900.0002). Each unaffected parent carried 1 of the mutations.

In 2 unrelated patients with CDG1T, Timal et al. (2012) identified 2 different homozygous mutations in the PGM1 gene (171900.0003 and 171900.0004, respectively). The mutations were identified by exome sequencing and confirmed by Sanger sequencing. Studies in patient fibroblasts showed 7 to 8% residual enzyme activity. The authors noted that the PGM1 enzyme, phosphoglucomutase, is involved in the cytoplasmic biosynthesis of nucleotide sugars needed for glycan biosynthesis.

In 19 patients from 16 families with CDG1T, Tegtmeyer et al. (2014) identified 21 different homozygous or compound heterozygous mutations in the PGM1 gene (see, e.g., 171900.0005-171900.0009). Three of the patients had previously been reported by Stojkovic et al. (2009) and Timal et al. (2012). The mutation in the first family identified by Tegtmeyer et al. (2014) was found by homozygosity mapping and whole-exome sequencing; mutations in additional families were found by Sanger sequencing. All patients studied had significantly decreased cellular PGM1 enzyme activity (range, 0.3-12% of controls).

Conte et al. (2020) reported molecular data in 54 patients with CDG1T, including 11 newly reported and 43 identified in a literature review. Forty-three individual mutations were identified in the PGM1 gene (see, e.g., 171900.0004, 171900.0010-171900.0013) and no genotype-phenotype correlation was found.

Tags: 1p31.3