RESUMO
TIA1/SQSTM1 myopathy is one of the few digenic myopathies. We describe four new French adult male patients carrying the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variant and review the literature to include 20 additional cases to define the spectrum of the disease. These twenty-four patients (75% males) had late-onset (52,6 ± 10,1 years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and myopathic EMG. Two of the four French patients had sensorimotor axonal polyneuropathy and an additional one had neurogenic changes in muscle biopsy. Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1 p.Asn357Ser variant was present in all patients and the SQSTM1 p.Pro392Leu was the most frequent (71%) of the four reported SQSTM1 variants. We reviewed the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort finding a prevalence of 11/414=2.7% of the TIA1 p.Asn357Ser variant, with two patients having an alternative diagnosis (TTN and MYH7) with atypical phenotypes, resembling some of the features seen in TIA1/SQSTM1 myopathy. Overall, TIA1/SQSTM1 myopathy has a homogenous phenotype reinforcing the pathogenicity of its digenic variants. We confirm an increased burden of the TIA1 p.Asn357Ser variant in distal myopathy patients which could act as a genetic modifier.
RESUMO
OBJECTIVE: X-linked myopathy with excessive autophagy (XMEA) linked to the VMA21 gene leads to autophagy failure with progressive vacuolation and atrophy of skeletal muscles. Current knowledge of this rare disease is limited. Our objective was to define the clinical, radiological, and natural history of XMEA. METHODS: We conducted a retrospective study collecting clinical, genetic, muscle imaging, and biopsy data of XMEA patients followed in France and reviewed the literature for additional cases. RESULTS: Eighteen males had genetically confirmed XMEA in France, carrying four different VMA21 variants. Mean age at disease onset was 9.4 ± 9.9 (range 1-40) years. In 14/18 patients (77.8%), onset occurred during childhood (< 15 years); however in four patients, the disease started in adulthood. Patients had anterior and medial compartment thigh muscle weakness, distal contractures (56.3%), elevated CK levels (1287.9 ± 757.8 U/l) and autophagic vacuoles with sarcolemmal features on muscle histopathology. Muscle MRI (n = 10) showed a characteristic pattern of lower limb muscle involvement. In 11 patients, outcome measures were available for an average follow-up period of 10.6 ± 9.8 years and six of them show disease progression. Mean change of functional outcomes was 0.5 ± 1.2 points for Brooke and 2.2 ± 2.5 points for Vignos score, 7/16 patients (43.8%) needed a walking aid and 3/16 (18.8%) were wheelchair-bound (median age of 40 years old, range 39-48). The variant c.164-7 T > G was associated with a later onset of symptoms. Respiratory insufficiency was common (57.1%) but cardiac involvement rare (12.5%). INTERPRETATION: XMEA has variable age of onset, but a characteristic clinical, histopathological, and muscle imaging presentation, guiding the diagnosis. Although slowly, motor disability progresses with time, and relevant genotype-phenotype correlations will help design future clinical trials.