[CASE REPORT] Homozygous N-terminal missense variant in PLEKHG5 associated with intermediate CMT: a case report

Mutations in PLEKHG5, a pleckstrin homology domain containing member of the GEF family, are associated with distal spinal muscular atrophy and intermediate Charcot-Marie-Tooth disease. Here, we describe an isolated case with distal intermediate neuropathy with scapular winging. By whole exome sequencing, we identified the homozygous PLEKHG5 Arg97Gln missense mutation, located in the N-terminal region of the protein. This mutation resides between a zinc-finger motif and a RBD domain, involved in binding rnd3, a RhoA effector protein. We conclude that based on the characteristic phenotype presented by the patient and the supportive genetic findings, the PLEKHG5 mutation is the causative variant.

Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India

Calpainopathy is caused by mutations in the CAPN3. There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5–20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique CAPN3 variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051–1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802–9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.

Scapular Winging following Sports-Related Injury in a Rugby Player

The most common cause of medial scapular winging is long thoracic nerve palsy (LTN) and subsequent serratus anterior muscle dysfunction. A 16-year-old right-handed male high-school rugby player developed severe right-sided neck and shoulder pain after tackling an opponent while playing rugby. Six weeks after initial injury, the patient observed shoulder muscle weakness when performing his daily activities. On physical examination, limited active elevation of the right shoulder in the scapular plane and scapular winging was observed. Magnetic resonance imaging revealed atrophy of both the SA and subclavius muscles on the right side, and we initially suspected an LTN injury sustained. However, while detailing his history, the patient explained that he also had noted difficulty sucking high viscosity drinks such as shakes and smoothies since childhood. In addition, physical examination showed weakness of the orbicularis oculi muscle. Considering the facial muscle weakness, facioscapulohumeral dystrophy (FSHD) was also suspected, and genetic testing showed chromosome 4q35 deletion with restriction fragments 17 kb and 3 tandem repeated DNA confirming the diagnosis of FSHD. Clinicians should be aware that FSHD could be one of the differential diagnoses of scapular winging after sports injury, and surgeons should rule out the diagnosis of FSHD before performing any surgical treatment for SA palsy.