Cerebellar ataxia and congenital disorder of glycosylation Ia (CDG-Ia) with normal routine CDG screening

Abstract

Cerebellar ataxia can have many genetic causes among which are the congenital disorders of glycosylation type I (CDG-I). In this group of disorders, a multisystem phenotype is generally observed including the involvement of many organs, the endocrine, hematologic and central nervous systems. A few cases of CDG-Ia have been reported with a milder presentation, namely cerebellar hypoplasia as an isolated abnormality. To identify patients with a glycosylation disorder, isofocusing of plasma transferrin is routinely performed. Here, we describe two CDG-Ia patients,who presented with mainly ataxia and cerebellar hypoplasia and with a normal or only slightly abnormal transferrin isofocusing result. Surprisingly, the activity of the corresponding enzyme phosphomannomutase was clearly deficient in both leucocytes and fibroblasts. Therefore, in patients presenting with apparently recessive inherited ataxia caused by cerebellar hypoplasia and an unknown genetic aetiology after proper diagnostic work-up, we recommend the measurement of phosphomannomutase activity when transferrin isofocusing is normal or inconclusive.

A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype

“…For the most frequent CDG-I subtype, PMM2-CDG (formerly CDG-Ia), several adolescent patients have been reported presenting with cerebellar hypoplasia. 23,24 In addition, DPM3-CDG has been reported in a 27-year-old female with muscle dystrophy and dilated cardiomyopathy, 25 while DOLK-CDG has recently been associated with non-syndromic dilated cardiomyopathy in patients between 5and 18 years of age. 26 Moreover, TUSC3-CDG and MAGT1-CDG are implicated in non-syndromic ID patients, with the age range of 25-62 years.…”

DPAGT1 myasthenia and myopathy

“…The transferrin glycosylation pattern was abnormal in patient 3 but not in patient 1 because of normalization of the pattern with age. 35 In patient 2, the Val264Met mutation abolishes effective enzyme activity and the synonymous Leu120-Leu mutation causes excessive exon skipping, predicting premature termination of translation. Of note, she retains a low level of unskipped transcript, which partially rescues her phenotype, and on immunoblotting, she shows normal glycosylation of a 70-kDa protein ( figure 1F) but hypoglycosylation of STIM1 ( figure 1G) and abnormal glycosylation of serum transferrin (figure e-2).…”

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2

“…12,13 The phenotype of HIPKD appears to be restricted to kidneys and pancreatic β-cells with additional liver involvement, which is distinct from CDG1A, where visceral involvement is only noted in the severe early-onset form with neurological and dysmorphic manifestations. A potential explanation for this organ-specific involvement would be a unique sensitivity of kidney, pancreas and liver to impaired PMM2 function.…”

“…However, this is not consistent with observations in patients with CDG1A, as those with mild forms show isolated neurological involvement only. 12,13 This strongly suggests that the brain is most sensitive to loss of PMM2 function and mild impairment thus primarily causes neurological problems. The severity of manifestations seen in HIPKD patients in the three key organ systems involved, yet with no evidence of systemic involvement clearly argues for a tissue-specific effect of the promoter mutation.…”