Clinical and genetic characterization of PYROXD1‐related myopathy patients from Turkey

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.

PYROXD1-associated myopathy

“…The muscle biopsies previously reported showed mixed myopathic features including fibre size variability in 86%, internalised nuclei in 79%, fatty replacement and increased fibrosis in 71% central cores in 71%, myofibrillar inclusions in 64%, sarcomeric disorganisation in 50%, nemaline rods in 43% and thin filament accumulation 29%. The muscle biopsy features in our case showed many features in keeping with the previous published cases similar reported in PYROXD1 mutation 3 5 6. Although, initially, the features are thought to be of non-specific myopathy, the myofibrillar abnormality detected would correlate with genetic finding of PYROXD1 mutation detected in this patient.…”

“…Of the 23 patients previously reported, summarised by Daimagüler et al , 14 were homozygous for the c.464 A>G p.(Asn155Ser) identified here, with a further 6 compound heterozygous including this mutation 5. The patients with homozygous mutations were milder than the compound heterozygotes but still exhibited a broad range of ages of onset from childhood to 50s.…”

Genotype-phenotype correlations in ocular manifestations of Marinesco–Sjögren syndrome: Case report and literature review

“…Neuromuscular characteristics usually develop in early infancy. [2][3][4][5][6] The prominent cerebellar ataxia seen in patients with MSS is caused by cerebellar atrophy and generally appears in early childhood. 2,6 The present study and the literature review results clearly demonstrate that cataracts are typically absent in young infants and develop later in childhood.…”

“…The variant was classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines (PVS1, PS3, PM2, PM4, PP1, PP3) and had not been reported in any variant database (ExAC, gnomAD, 1000 genomes, ClinVar). 5…”