Skeletal Dysplasia and Myelopathy in Congenital Disorder of Glycosylation Type IA

Westrum, S. M. Schade van; Nederkoorn, Paul J.; Schuurman, P. Richard; Vulsma, T.; Durán, Marinus; Poll-Thé, Bwee Tien

doi:10.1016/j.jpeds.2005.08.048

Cited by 14 publications

(13 citation statements)

References 8 publications

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“…In some instances, CA was detected prenatally or in the first 4 to 14 postnatal days . A few patients had initially a normal cerebellar magnetic resonance imaging (MRI) at first investigation between 2 days and 6 years of age . Global CA with enlarged hemispheric and vermian fissures, particularly of the anterior lobe of the vermis, are the most common presentations.…”

Section: Systems Summaries and Statementsmentioning

confidence: 99%

International clinical guidelines for the management of phosphomannomutase 2‐congenital disorders of glycosylation: Diagnosis, treatment and follow up

Altassan

Péanne

Jaeken

et al. 2019

J of Inher Metab Disea

101

126

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Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.

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Section: Systems Summaries and Statementsmentioning

confidence: 99%

International clinical guidelines for the management of phosphomannomutase 2‐congenital disorders of glycosylation: Diagnosis, treatment and follow up

Altassan

Péanne

Jaeken

et al. 2019

J of Inher Metab Disea

101

126

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“…Multiple (9 of 31; 29%) Pmm2 R137H/F115L mice also had various degrees of kyphosis (Supplementary Material, Fig. S4D), a disease feature documented in patients with PMM2-CDG (6,8,9). Two-dimensional (2D) micro-computed tomography (CT) imaging revealed a more pronounced curvature of the spine in Pmm2 R137H/F115L mice compared with WT (Supplementary Material, Fig.…”

Section: Resultsmentioning

confidence: 88%

A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2

et al. 2016

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The most common congenital disorder of glycosylation (CDG), phosphomannomutase 2 (PMM2)-CDG, is caused by mutations in PMM2 that limit availability of mannose precursors required for protein N-glycosylation. The disorder has no therapy and there are no models to test new treatments. We generated compound heterozygous mice with the R137H and F115L mutations in Pmm2 that correspond to the most prevalent alleles found in patients with PMM2-CDG. Many Pmm2R137H/F115L mice died prenatally, while survivors had significantly stunted growth. These animals and cells derived from them showed protein glycosylation deficiencies similar to those found in patients with PMM2-CDG. Growth-related glycoproteins insulin-like growth factor (IGF) 1, IGF binding protein-3 and acid-labile subunit, along with antithrombin III, were all deficient in Pmm2R137H/F115L mice, but their levels in heterozygous mice were comparable to wild-type (WT) littermates. These imbalances, resulting from defective glycosylation, are likely the cause of the stunted growth seen both in our model and in PMM2-CDG patients. Both Pmm2R137H/F115L mouse and PMM2-CDG patient-derived fibroblasts displayed reductions in PMM activity, guanosine diphosphate mannose, lipid-linked oligosaccharide precursor and total cellular protein glycosylation, along with hypoglycosylation of a new endogenous biomarker, glycoprotein 130 (gp130). Over-expression of WT-PMM2 in patient-derived fibroblasts rescued all these defects, showing that restoration of mutant PMM2 activity is a viable therapeutic strategy. This functional mouse model of PMM2-CDG, in vitro assays and identification of the novel gp130 biomarker all shed light on the human disease, and moreover, provide the essential tools to test potential therapeutics for this untreatable disease.

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“…Features of dysotosis multiplex have been reported in CDG‐Ia [Garel et al, 1998]. Another case of CDG‐Ia involved an 11‐year‐old male with acute spinal cord compression and atlantoaxial subluxation with a thickened ligament and platyspondyly of all vertebrae [Schade van Westrum et al, 2006]. In a patient with CDG‐Id, radiological evaluation showed “short vertebral bodies” (most marked in cervical and thoracic spine), and short ribs, radii, ulnae, femurs, tibiae and fibulae, along with paddle‐shaped iliac wings, and bilateral small scapulae [Sun et al, 2005].…”

Section: Discussionmentioning

confidence: 99%

Expanding spectrum of congenital disorder of glycosylation Ig (CDG‐Ig): Sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality

Kranz

Basinger

Güçsavaş-Çalıkoğlu

et al. 2007

American J of Med Genetics Pt A

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In this report, we describe a brother and sister who presented at birth with short-limb skeletal dysplasia, polyhydramnios, prematurity, and generalized edema. Dysmorphic features included broad nose, thick ears, thin lips, micrognathia, inverted nipples, ulnar deviation at the wrists, spatulate fingers, fifth finger camptodactyly, nail hypoplasia, and talipes equinovarus. Other features included short stature, microcephaly, psychomotor retardation, B-cell lymphopenic hypogammaglobulinemia, sensorineural deafness, retinal detachment and blindness, intestinal malrotation with poor gastrointestinal motility, persistent hyponatremia, intermittent hypoglycemia, and thrombocytopenia. Cardiac anomalies included PDA, VSD, hypertrophic cardiomyopathy, and arrhythmias. The brother had a small penis with hypospadias, hypoplastic scrotum, and non-palpable testes. Skeletal findings included absent ossification of cervical vertebral bodies, pubic bones, knee epiphyses, and tali. Both sibs died before age 2 years, one of overwhelming sepsis and the other of cardiorespiratory failure associated with her cardiomyopathy. Metabolic studies showed a type 1 pattern of abnormal serum transferrin glycosylation. Fibroblasts synthesized truncated LLOs, primarily Man(7)GlcNAc(2), suggestive of CDG-Ig. Both sibs were compound heterozygotes for a novel 301 G > A (G101R) mutation and a previously described 437 G > A (R146Q) mutation in ALG12. Congenital disorders of glycosylation should be considered for children with undiagnosed multi-system disease including neurodevelopmental delay, skeletal dysplasia, immune deficiency, male genital hypoplasia, and cardiomyopathy.

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Skeletal Dysplasia and Myelopathy in Congenital Disorder of Glycosylation Type IA

Cited by 14 publications

References 8 publications

International clinical guidelines for the management of phosphomannomutase 2‐congenital disorders of glycosylation: Diagnosis, treatment and follow up

International clinical guidelines for the management of phosphomannomutase 2‐congenital disorders of glycosylation: Diagnosis, treatment and follow up

A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2

Expanding spectrum of congenital disorder of glycosylation Ig (CDG‐Ig): Sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality

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