Limb-girdle muscular dystrophy due to GMPPB mutations: A case report and comprehensive literature review

Abstract

Mutations in the guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) gene are rare. To date, 72 cases with GMPPB gene mutations have been reported. Herein, we reported a case of a 29-year-old Chinese male presenting with limb-girdle muscular dystrophy (LGMD) who was found to have two heterozygous GMPPB mutations. The patient had a progressive limb weakness for 19 years. His parents and elder brother were normal. On examination he had a waddling gait, and absent tendon reflexes in all four limbs. Electromyography showed myogenic damage. Muscle magnetic resonance imaging (MRI) showed fatty degeneration in the bilateral medial thigh muscles. High throughput gene panel sequencing revealed that the patient carried compound heterozygous mutations in the GMPPB gene, c.553C>T (p.R185C, maternal inheritance) and c.346C>T (p.P116S, paternal inheritance). This case provides additional information regarding the phenotypic spectrum of GMPPB mutations in the Chinese population.

Consequences of GMPPB deficiency for neuromuscular development and maintenance

“…In agreement with a previous report for zebrafish ( Liu et al, 2021 ), GMPPB expression in mice increases during embryonal and postnatal development, which is accompanied by an increase in mannosylated glycans. Since GMPPB loss-of-function in humans manifests with variable muscular and neurological defects ( Belaya et al, 2015 ; Jensen et al, 2015 ; Rodriguez Cruz et al, 2016 ; Balcin et al, 2017 ; Luo et al, 2017 ; Sun et al, 2020 ; Chompoopong and Milone, 2023 ), we assessed the consequences of the knockdown of Gmppb in myoblasts or N2A cells. Indeed, knockdown of Gmppb in N2A cells and myoblasts affected both the development of dendrite-like protrusions in N2A cells as well as the differentiation of myotubes.…”

“…Notably, symptom severity correlates with enzymatic activity of mutated GMPPB: mutations in the N-terminal nucleotidyl-transferase domain of GMPPB seem to impair its activity more severely as mutations in its C-terminal beta-helix domain ( Liu et al, 2021 ). Hence, mutations in the catalytic domain of GMPPB normally result in CNS and muscle involvement, whereas mutations in the C-terminal part of GMPPB affect mostly only skeletal muscles ( Sun et al, 2020 ). Interestingly, the most common mutations in GMPPB are c.79G >C (p.Asp27His) in the N-terminal part and c.860G > A (p.Arg287Gln) in the C-terminal part.…”

“…Additional symptoms such as cerebellar hypoplasia, seizures, or cardiac involvement are reported for some patients. The age at onset and disease progression varies from early infancy to adulthood ( Belaya et al, 2015 ; Jensen et al, 2015 ; Rodriguez Cruz et al, 2016 ; Balcin et al, 2017 ; Luo et al, 2017 ; Sun et al, 2020 ; Chompoopong and Milone, 2023 ).…”