Mild Clinical and Biochemical Phenotype in Two Patients with PMM2-CDG (Congenital Disorder of Glycosylation Ia)

Abstract

Phosphomannomutase 2 deficiency (PMM2-CDG) patients may present as mild phenotypes, with the cerebellum frequently involved. In those cases, false-negative results in screening may occur when applying conventional biochemical procedures. Our aim was to report two patients with a diagnosis of PMM2-CDG presenting with mild clinical phenotype. Patient 1-at 9 months of age, she presented with just psychomotor delay, tremor, hypotonia, and slight lipodystrophy. Patient 2-she presented at 8 months of age with psychomotor delay, hand stereotypes, hypotonia, convergent bilateral strabismus, and tremor but no lipodystrophy. Routine biochemical parameters including blood count, clotting factors, proteins, and thyroid hormone were normal in both cases. Cranial MRI evidenced mild cerebellar atrophy with moderate vermis hypoplasia. In case 1, sialotransferrin pattern showed very slightly increased disialotransferrin with no asialotransferrin, and in case 2, the transferrin pattern was impaired in the first study but nearly normal in the second. Nevertheless, in all the samples, quantification of the patterns obtained by capillary zone electrophoresis analysis gave results out of the control range. High residual PMM2 activity was observed in both cases and the genetic analysis showed that patient 1 was heterozygous for c.722G>C (p.C241S) and c.368G>A (p.R123Q) mutations, and patient 2 showed the c.722G>C and the c.470T>C (p.F157S) mutations in the PMM2 gene. We would like to stress the importance of the use of sensitive semiquantitative methods of screening for CDG in order to achieve early identification of patients with mild phenotypes. Intentional tremor was an atypical but remarkable clinical feature in both cases, and the global cerebellar atrophy with vermis hypoplasia reinforced the early clinical suspicion of a PMM2-CDG disease.

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.…”

Neurology of inherited glycosylation disorders

“…Two infants with absent or mild lipodystrophy were reported to have only subtle biochemical alterations and one of these children showed loss of purposeful hand movements and stereotypes similar to those reported in Rett’s disorder, plus intention tremor. 40 Patients with mild phenotypes who survive to adulthood might have borderline cognitive impairment, with or without strabismus. In one report, all three affected adults were in full-time employment.…”

Hyperkinetic movement disorders in congenital disorders of glycosylation

“…Some patients may have a milder phenotype, as illustrated in patient #4 [9,21]. Whilst dystonia was anecdotally reported in PMM2-CDG [10,[17][18][19], it was detected in all four patients in this study, associated with choreo-athetosis. Asparagine-linked glycosylation 6 CDG is the second most common type of CDG.…”