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

Altassan, Ruqaiah; Péanne, Romain; Jaeken, Jaak; Barone, Rita; Bidet, Muad; Borgel, Delphine; Brasil, Sandra; Cassiman, David; Čechová, Anna; Coman, David; Corral, Javier; Correia, Joana; Morena‐Barrio, María Eugenia de la; Lonlay, Pascale de; Reis, Vanessa dos; Ferreira, Carlos R.; Fiumara, Agata; Francisco, Rita; Freeze, Hudson H.; Funke, Simone; Gardeitchik, Thatjana; Matthijs, Gert; Girad, Muriel; Girós, M.; Grünewald, Stéphanie; Hernández‐Caselles, Trinidad; Honzík, Tomáš; Hutter, Marlen; Krasnewich, Donna M.; Lam, Christina; Lee, Joy; Lefeber, Dirk; Marques‐da‐Silva, Dorinda; Martínez, Antonio; Moravej, Hossein; Õunap, Katrin; Pascoal, Carlota; Pascreau, Tiffany; Patterson, Marc C.; Quelhas, Dulce; Raymond, Kimiyo; Sarkhail, Peymaneh; Schiff, Manuel; Seroczyńska, Małgorzata; Serrano, Mercedes; Seta, Nathalie; Sykut-Cegielska, Jolanta; Thiel, Christian; Tort, Frederic; Vals, Mari Anne; Videira, Paula A.; Witters, Peter; Zeevaert, Renate; Morava, Éva

doi:10.1002/jimd.12024

Cited by 95 publications

(115 citation statements)

References 154 publications

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“…Because of the wide variety of CDG manifestations and poor prognosis in those patients, diagnosis of CDG is paramount. This is further supported by a recent PMM2‐CDG guideline where NIHF was the most common prenatal presentation . Several recommendations by this study emphasize the role of metabolic workup in identifying other causes of NIHF in addition to considering molecular PMM2 gene analysis in diagnostic panels for NIHF.…”

Section: Discussionsupporting

confidence: 70%

Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review

Makhamreh

Cottingham

Ferreira

et al. 2019

J of Inher Metab Disea

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Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF) including congenital disorders of glycosylation (CDG). Recognition of CDG in NIHF is challenging. This study reviews prenatal and neonatal characteristics of CDG presenting with NIHF. A systematic literature search was performed. Thirteen articles met the inclusion criteria. Twenty‐one cases with NIHF associated with a CDG were reported. There were 17 live births, three pregnancy terminations, and one fetal demise. Timing of CDG diagnosis was reported mostly postnatally (90%; 10/11). Postnatal genetic testing was reported in 18 patients; three patients were diagnosed by isoelectric focusing of serum transferrin that showed a type 1 pattern. The genes reported for CDG with NIHF for 15 distinct families include: PMM2 in 47% (7/15), ALG9 in 20% (3/15), ALG8 in 13% (2/15), ALG1 in 7% (1/15), MGAT2 in 7% (1/15), and COG6 7% (1/15). In our review, 81% (17/21) reported facial dysmorphism, 52% (11/21) reported CNS abnormalities, most commonly cerebellar atrophy (64%; 7/11), and 38% (8/21) reported cardiovascular abnormalities, most commonly hypertrophic cardiomyopathy (63%; 5/8). Among live births, 71% (12/17) infants died at a median age of 34 days (range 1‐185). Thrombocytopenia was reported in 53% (9/17) patients. Of those who survived past the neonatal period, 80% (4/5) had significant reported developmental delays. CDG should be on the differential diagnosis of NIHF in the presence of cerebellar atrophy, hypertrophic cardiomyopathy, or thrombocytopenia. Our review highlights the poor prognosis in infants with NIHF due to CDG and demonstrates the importance of identifying these disorders prenatally to guide providers in their counseling with families regarding pregnancy management. Synopsis Poor prognosis in fetuses and infants with nonimmune hydrops fetalis due to congenital disorders of glycosylation highlights the importance of prenatal diagnosis of this disorder.

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Section: Discussionsupporting

confidence: 70%

Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review

Makhamreh

Cottingham

Ferreira

et al. 2019

J of Inher Metab Disea

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“…The main neurological symptom in our patients remained psychomotor retardation and cerebellar ataxia with cerebellar hypoplasia on brain MRI scans, observed in 83% of PMM2-CDG patients and all SRD5A3-CDG patients. This finding confirms the thesis that the cerebellum is regularly involved in PMM2-CDG and SRD5A3-CDG [14,[25][26][27]. Epilepsy is also a common symptom (almost one-third of patients with PMM2-CDG in the study by Monin et al [22]), in our cohort it was observed in ALG13-CDG patients.…”

Section: Discussionsupporting

confidence: 92%

“…Up to now, 14 patients have been reported with the X-linked ATP6AP1 deficiency and the key features were immunodeficiency and liver involvement ranging from a mild elevation of serum transaminases to liver failure [15,[29][30]. The clinical outcome of PMM2-CDG varies among patients [25]. Inverted nipples and abnormal fat distribution were reported as its characteristic features and were present in the majority of our patients.…”

Section: Discussionmentioning

confidence: 75%

Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up

Bogdańska

Lipiński

Szymańska-Rożek

et al. 2020

Preprint

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Background: Congenital disorders of glycosylation (CDG) result from defects in the synthesis of glycans and the attachment of glycans to proteins and lipids. Our study aimed to describe the clinical, biochemical and molecular findings of CDG patients, and to present the long-term follow-up. Material and methods: A single-centre study (1995-2019 years) of patients with congenital disorders of N-glycosylation and combined N- and O-hypoglycosylation, diagnosed based on the serum transferrin (Tf) and apolipoprotein C-III (apoC-III) isoforms analysis, and confirmed molecularly, was performed. Results: Among 32 patients included into the study, 24 had type I Tf isoform profile, in 12 of them deficient PMM2 activity was detected. Three patients were diagnosed with ALG13-CDG; serum Tf isoform profile was normal in one of them, in one other was indicative for type I. Four patients had type II Tf isoform profile. The phenotypic and genotypic spectrum of 32 patients with CDG during long-term (in some cases over 20 years) observation was characterised and several measurements of serum Tf isoforms taken. Statistical analysis revealed strong negative correlation between Asialo-Tf and Tetrasialo-Tf, as well as between Disialo-Tf and Tetrasialo-Tf. Positive correlation was shown between Tetrasialo-Tf and Penasialo-Tf. Within type I CDG, no difference in % Tf isoforms was revealed between PMM2-CDG and non-PMM2-CDG patients. However, these two groups differed significantly in the such diagnostic features as: cerebellar ataxia, failure to thrive, hypothyroidism, pericardial effusion, cardiomyopathy, inverted nipples, prolonged INR. The effect of treatment with mannose in 2 patients with MPI-CDG were assesed and we found that % of Asialo-Tf, Monosialo-Tf, and Disialo-Tf was significanty lowered, whereas Tetrasialo- Tf and Pentasialo-Tf rose, coming closer or falling into the reference range. Conclusions: The novel finding was an abnormal Tf IEF pattern in two ALG13-CDG patients and normal in one ALG1-CDG patient. Clinical manifestation of presented CDG patients was similar to that reported in the literature. Mannose supplementation in MPI-CDG patients, as well as galactose supplementation in PGM-CDG patient improved patients’ clinical picture and Tf isoform profiles.

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“…PMM2 gene sequencing results revealed two interesting points: First, the p.Val231Met variant was more common than p.Arg141His, which is by far the most common variant in the literature, detected in 60% of PMM2‐CDG patients. Although p.Val231Met is the second most common variant (10%), no patients homozygous for this variant had been previously reported (Altassan et al, ). In this article, we report four patients (P3, P9–P11) from three families homozygous for p.Val231Met.…”

Section: Discussionmentioning

confidence: 98%

“…Phosphomannomutase 2 (EC 5.4.2.8) deficiency (PMM2-CDG, OMIM #212065) is by far the most common CDG. Since its initial description in 1984 (Jaeken et al, 1984), over 900 patients have been diagnosed worldwide, mostly from Europe (Altassan et al, 2019;Peanne et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Genotypes and estimated prevalence of phosphomannomutase 2 deficiency in Turkey differ significantly from those in Europe

Yıldız

Arslan²,

Çelik

et al. 2020

American J of Med Genetics Pt A

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Phosphomannomutase 2 deficiency (PMM2‐CDG) is an autosomal recessive congenital disorder of glycosylation, characterized by multisystem phenotypes, mostly including neurological involvement. In Turkey, due to high rates of consanguinity, many patients with autosomal recessive disorders have homozygous variants and these diseases are more common, compared to Europe. However, published reports of PMM2‐CDG from Turkey are scarce. Here, we describe clinical and molecular characteristics of PMM2‐CDG patients diagnosed in three centers in Turkey, using data obtained retrospectively from hospital records. We also analyzed an in‐house exome database of 1,313 individuals for PMM2 variants and estimated allele, carrier and disease frequencies, using the Hardy–Weinberg law. Eleven patients were identified from 10 families, displaying similar characteristics to previous publications, with the exception of the first report of epilepsia partialis continua and increased prevalence of sensorineural hearing loss. p.Val231Met was the most common variant, and was homozygous in four patients. This novel genotype results in a neurological phenotype with subclinical visceral involvement. Exome database analysis showed an estimated prevalence of 1:286,726 for PMM2‐CDG, which is much lower than expected (1:20,000 in Europe) because of the lack of predominance of the common European p.Asp141His allele, associated with a severe phenotype (allele frequency of 1:2,622 compared to 1:252 in gnomAD). These data suggest that prevalence, phenotypes and genotypes of PMM2‐CDG in Turkey differ significantly from those in Europe: Milder phenotypes may be more common, but the disease itself rarer, requiring a higher clinical suspicion for diagnosis. The association of sensorineural hearing loss with PMM2‐CDG warrants further study.

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

Cited by 95 publications

References 154 publications

Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review

Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review

Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up

Genotypes and estimated prevalence of phosphomannomutase 2 deficiency in Turkey differ significantly from those in Europe

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