Clinical and genetic characterization of PYROXD1-related myopathy

Abstract

Congenital myopathies (CMs) are a heterogeneous group of inherited muscle disorders characterized by muscle weakness at birth, while limb-girdle muscular dystrophies (LGMD) have a later onset and slower disease progression. Thus, detailed clinical phenotyping of genetically defined disease entities are required for the full understanding of genotype-phenotype correlations. A recently defined myopathic genetic disease entity is caused by bi-allelic variants in a gene coding for pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) with unknown substrates. Here, we present three patients from two consanguineous Turkish families with mild LGMD, facial weakness, normal CK levels, and slow progress. Genomic analyses revealed a homozygous known pathogenic missense variant (c.464A>G, p.Asn155Ser) in family 1 with two affected females. In the affected male of family 2, we found this variant in a compound heterozygous state together with a novel frameshift variant (c.329_332delTCTG, p.Leu112Valfs*8), which is the second frameshift variant known so far in PYROXD1. We have been able to define a large homozygous region in family 1 sharing a common haplotype with family 2 in the critical region. Our data suggest that c.464A>G is a Turkish founder mutation. To gain deeper insights, we performed a systematic review of all published PYROXD1-related myopathy cases. Our analysis showed that the c.464A > G variant was found in 87% (20/23) of the patients and that it may cause either a childhood- or adult-onset phenotype, irrespective of its presence in a homozygous or compound heterozygous state. Interestingly, only four patients had elevated CK levels (up to 1000 U/L), and cardiac involvement was found in few compound heterozygous cases.

C1 [Daimagueler, Huelya-Sevcan; Akpulat, Ugur; Oezdemir, Oezkan; Cirak, Sebahattin] Univ Cologne, Fac Med, Dept Pediat, Cologne, Germany.

[Daimagueler, Huelya-Sevcan; Akpulat, Ugur; Oezdemir, Oezkan; Thiele, Holger; Altmueller, Janine; Nuernberg, Peter; Cirak, Sebahattin] Univ Hosp Cologne, Kerpener Str 62, D-50937 Cologne, Germany.

[Daimagueler, Huelya-Sevcan; Akpulat, Ugur; Oezdemir, Oezkan; Nuernberg, Peter; Cirak, Sebahattin] Univ Cologne, Fac Med, Ctr Mol Med Cologne CMMC, Cologne, Germany.

[Akpulat, Ugur] Kastamonu Univ, Fac Med, Dept Med Biol, Kastamonu, Turkey.

[Yis, Uluc] Dokuz Eylul Univ, Fac Med, Dept Pediat Neurol Izmir, Izmir, Turkey.

[Gungor, Serdal] Inonu Univ Malatya, Fac Med, Turgut Ozal Res Ctr, Dept Paediat Neurol, Malatya, Turkey.

[Talim, Beril] Hacettepe Univ Ankara, Dept Pediat, Pediat Pathol Unit, Ankara, Turkey.

[Diniz, Gulden] Izmir Democracy Univ, Dept Pathol, Izmir, Turkey.

[Baydan, Figen] Tepecik Training & Res Hosp, Div Child Neurol, Izmir, Turkey.

[Baydan, Figen] Tepecik Training & Res Hosp, Neuromuscular Dis Ctr, Izmir, Turkey.

[Thiele, Holger; Altmueller, Janine; Nuernberg, Peter] Univ Cologne, Cologne Ctr Genom CCG, Cologne, Germany.