Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study

BACKGROUND: Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, non-inflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE, codes for UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two reactions in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as α-dystroglycan and neural cell adhesion molecule (NCAM), has been reported in HIBM. METHODS: We treated 4 HIBM patients with intravenous immune globulin (IVIG), in order to provide sialic acid, because IgG contains 8 μmol of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg at weekly intervals. RESULTS: For all four patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows. Objective measures of functional improvement gave variable results, but the patients experienced improvements in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of muscle biopsies for α-dystroglycan and NCAM did not provide consistent evidence for increased sialylation after IVIG treatment. Side effects were limited to transient headaches and vomiting. CONCLUSION: The mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management

P. W. is supported by the Clinical Research Fund, University Hospitals Leuven, Leuven, Belgium. This work is partially funded by the grant titled Frontiers in Congenital Disorders of Glycosylation (1U54NS115198-01) from the National Institute of Neurological Diseases and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), and the Rare Disorders Consortium Research Network (RDCRN) (E. M., K. R., C. F., H. F., C. L., and A. E.)Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.preprintpublishe

A Participatory Framework for Plain Language Clinical Management Guideline Development

Sandra Brasil was supported by CDG & Allies—PPAIN funding. Publisher Copyright: © 2022 by the authors.Background: Clinical management guidelines (CMGs) are decision support tools for patient care used by professionals, patients, and family caregivers. Since clinical experts develop numerous CMGs, their technical language hinders comprehension and access by nonmedical stakeholders. Additionally, the views of affected individuals and their families are often not incorporated into treatment guidelines. We developed an adequate methodology for addressing the needs and preferences of family and professional stakeholders regarding CMGs, a recently developed protocol for managing congenital disorders of glycosylation (CDG), a family of rare metabolic diseases. We used the CDG community and phosphomannomutase 2 (PMM2)-CDG CMGs as a pilot to test and implement our methodology. Results: We listened to 89 PMM2-CDG families and 35 professional stakeholders and quantified their CMG-related needs and preferences through an electronic questionnaire. Most families and professionals rated CMGs as relevant (86.5% and 94.3%, respectively), and valuable (84.3% and 94.3%, respectively) in CDG management. The most identified challenges were the lack of CMG awareness (50.6% of families) and the lack of plain language CMG (39.3% of professionals). Concordantly, among families, the most suggested solution was involving them in CMG development (55.1%), while professionals proposed adapting CMGs to include plain language (71.4%). Based on these results, a participatory framework built upon health literacy principles was created to improve CMG comprehension and accessibility. The outputs are six complementary CMG-related resources differentially adapted to the CDG community’s needs and preferences, with a plain language PMM2-CDG CMG as the primary outcome. Additionally, the participants established a distribution plan to ensure wider access to all resources. Conclusions: This empowering, people-centric methodology accelerates CMG development and accessibility to all stakeholders, ultimately improving the quality of life of individuals living with a specific condition and raising the possibility of application to other clinical guidelines.publishersversionpublishe

Allele-specific silencing of the dominant disease allele in sialuria by RNA interference

Dominant disease alleles are attractive therapeutic targets for allele-specific gene silencing by small interfering RNA (siRNA). Sialuria is a dominant disorder caused by missense mutations in the allosteric site of GNE, coding for the rate-limiting enzyme of sialic acid biosynthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase. The resultant loss of feedback inhibition of GNE-epimerase activity by CMP-sialic acid causes excessive production of free sialic acid. For this study we employed synthetic siRNAs specifically targeting the dominant GNE mutation c.797G>A (p.R266Q) in sialuria fibroblasts. We demonstrated successful siRNA-mediated down-regulation of the mutant allele by allele-specific real-time PCR. Importantly, mutant allele-specific silencing resulted in a significant decrease of free sialic acid, to within the normal range. Feedback inhibition of GNE-epimerase activity by CMP-sialic acid recovered after silencing demonstrating specificity of this effect. These findings indicate that allele-specific silencing of a mutated allele is a viable therapeutic strategy for autosomal dominant diseases, including sialuria.—Klootwijk, R. D., Savelkoul, P. J. M., Ciccone, C., Manoli, I., Caplen, N. J., Krasnewich, D. M., Gahl, W. A., Huizing, M. Allele-specific silencing of the dominant disease allele in sialuria by RNA interference

Dominant Inheritance of Sialuria, an Inborn Error of Feedback Inhibition

“French type” sialuria, a presumably dominant disorder that, until now, had been documented in only five patients, manifests with mildly coarse facies, slight motor delay, and urinary excretion of large quantities (>1 g/d) of free N-acetylneuraminic acid (NeuAc). The basic defect consists of the very rare occurrence of failed feedback inhibition of a rate-limiting enzyme, in this case uridinediphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase, by a downstream product, in this case cytidine monophosphate (CMP)–NeuAc. We report a new patient with sialuria who has a heterozygous G→A substitution in nucleotide 848 of the epimerase gene, which results in an R266Q change. The proband’s other allele, as expected, had no mutation. However, the heterozygous R266Q mutation was detected in the patient’s mother, who has similarly increased urinary levels of free NeuAc, thereby confirming, for the first time, the dominant mode of inheritance of this inborn error. The biochemical diagnosis of the proband was verified by the greatly increased level of free NeuAc in his cultured fibroblasts, the NeuAc distribution, mainly (59%) in the cytoplasm, and by the complete failure of 100 μM CMP-NeuAc to inhibit UDP-GlcNAc 2-epimerase activity in the mutant cells. These findings call for expansion of the phenotype to include adults and for more-extensive assaying of free NeuAc in the urine of children with mild developmental delay. The prevalence of sialuria is probably grossly underestimated