The carbohydrate-deficient glycoprotein syndromes are a recendy discovered group of inherited multisystemic diseases characterized by abnormal glycosylation of several glycoproteins. At least four variants have been recognized. In the past decade, tiiree different subtypes of carbohydrate-deficient glycoprotein syndrome type I have been identified according to different enzyme deficiencies. The most prevalent phenotype, carbohydrate-deficient glycoprotein syndrome type Ia, results from a phosphomannomutase 2 deficiency. Clinical presentations are fully different in any type and even in me same variant of carbohydrate-deficient glycoprotein syndrome. Patients affected by carbohydrate-deficient glycoprotein syndrome type Ia usually present neurologic, cutaneous, cardiac, renal, and hepatic disturbances. Ocular involvements are also frequently associated, especially in the first mondis of life. We report the recognizable pattern of ophthalmic manifestations in a child with carbohydrate-deficient glycoprotein syndrome type Ia.
Figure 1 . Magnetic resonance imaging of the brain with marked cerebellar hypoplasia.
A 19-month-old boy was referred to our institution for strabismus associated with nystagmoid movements that began at the age of 2 months. His parents were healthy and the pregnancy had been uneventful. The diagnosis of carbohydrate-deficient glycoprotein syndrome was suspected on the basis of clinical features, facial dysmorphism with large ears, a nose with a high bridge, a prominent jaw, abnormal distribution of subcutaneous fat, and hepatomegaly. A neurologic examination showed hypotonia and ataxia. Magnetic resonance imaging disclosed cerebellar hypoplasia involving the hemisphere and vermis with a Dandy-Walker variant aspect (Fig. 1). At 11 months old, he developed epilepsy that was well controlled with an antiepileptic drug. Biological and genetic examinations confirmed the diagnosis of carbohydrate-deficient glycoprotein syndrome type Ia. Transferrin serum electrophoresis showed typical patterns with an increase of disialotransferrin fraction and a decrease of tetrasialotransferrin. Residual enzyme activity of phosphomannomutase in a fibroblast was inferior to 50%. Genetic nonaccommodative esotropia with an alphabetic "V" syndrome associated with saccadic eye pursuit in horizontal strabismus had been evident from the first months of life. The retinal examination showed normal vessels and optic disc nerves. A fundus examination showed normal retinal vessels and pallor of both optic discs. We also observed diffuse hypopigmentation that allows abnormal visibility of choroidal vessels (Fig. 2). The flash visual evoked potential was normal. An electroretinogram (ERG) showed both scotopic and photopic impairments. A scotopic ERG was almost extinguished in both eyes, whereas a photopic ERG showed a marked amplitude decrease of b-wave. The flicker response was also altered, especially in the left eye (Fig. 3).
Figure 2. Fundus photograph showing a pale optic nerve with poor pigmentation and a highly visible choroid. No bone spicules are seen.
Carbohydrate-deficient glycoprotein syndrome is a newly discovered group of autosomal recessive diseases.1,2 Carbohydrate-deficient glycoprotein syndrome type Ia is the most common subtype, caused by a deficiency of phosphomannomutase 2 to map 1612.3-pl3.2. Mutation of this cytosolic enzyme decreases the catalytic activity necessary for the synthesis of guanosine diphosphate-mannose, which participates in the formation of lipid-linked oligosaccharide anchored to the endoplasmic reticulum. Sugar molecules were later added to some proteins growing on asparagine to form N-linked glycoproteins, which finish their maturation in the Golgi apparatus. Therefore, phosphomannomutase deficiency leads to the synthesis of the vast array of abnormal proteins that caused the multisystemic disorders observed in patients. Few reports have been published on the ophthalmic aspects of carbohydrate-deficient glycoprotein syndrome. Patients usually present with squint, retinal degeneration, nystagmus, and electrophysiological abnormalities. In our patient, it was interesting to note early and markedly photopic and scotopic ERG impairments. Indeed, photopic ERG was relatively preserved in the first years of life with this disease. Fiumara et al. have described 4 patients from 9 to 2 1 years of age with extinguished scotopic ERG associated with a normal photopic ERG.3 Among 10 patients reviewed by Stromland et al., 2 of them younger than 4 years have had ERGs performed. The results showed subnormal ERG rods with normal cone responses for one child, and an absolutely normal ERG for the other child, despite retinal changes observed in funduscopy.4 Anáreasson et al. examined 5 patients 8 to 48 years old with characteristic tapetoretinal ERG disorders associated with typical fundus. Cone responses were in the lower normal range in the young patients.5 They suggested that retinal disorders in patients with carbohydrate-deficient glycoprotein syndrome were progressive according to a worsening of ERG findings. This was confirmed by Casteels et al., who reported progressive electrophysiological deterioration in sisters during a period of 14 years.6 In our case, photopic ERG was altered early, suggesting possible specific cone damage. The pathophysiology of retinal damage in this metabolic disease is still unclear. Dysglycosylation involving the glycoprotein opsin and the interphotoreceptor retinoid binding protein could be implicated. The diagnosis of carbohydratedeficient glycoprotein syndrome should be considered in cases with early strabismus followed by unexplained retinopathy and should lead to specific biochemical tests.
Figure 3. Scotopic and photopic electroretinograms in a (top) normal child and (bottom) our case affected by carbohydrate-deficient glycoprotein (CDG) syndrome.
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