Table 1 Phenotypic characterization in a series of Limb Girdle Muscular Dystrophy LGMD R7 telethonin-related patients (Paim et al. 2013; Cotta et al. 2014; Winckler et al. 2019; current paper)
Individual | Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | Patient 6 | Patient 7 |
|---|---|---|---|---|---|---|---|
TCAP gene variant | Homozygous c.157C > T | Homozygous c.157C > T | Homozygous c.157C > T | Homozygous c.157C > T | Homozygous c.157C > T | Homozygous c.157C > T | Homozygous c.157C > T |
Gender/ age at admission (years) | M/ 14 | M/ 6 | M/ 22 | F/ 24 | M/ 29 | M/ 34 | F/ 54 |
Age at first symptoms (years) | 2 | 3 | 15 | 17 | 20 | 15 | 8 |
Age at muscle imaging (years) | 16 | 6 | 22 | 24 | 32 | 35 | 54 |
Disease duration at muscle imaging (years) | 14 | 3 | 7 | 7 | 12 | 20 | 46 |
Age at last examination (years) | 18 | 15 | 26 | 26 | 35 | 37 | 63 |
Ethnicity/ consanguinity/ affected relatives | Brazilian/ no/ one affected brother | Brazilian/ no/ single case in the family | Brazilian/ yes/ one brother and one female cousin | Brazilian/ unknown (probably yes because of affected relative)/ one cousin | Brazilian/ no/ single case in the family | Brazilian/ no/ single case in the family | Brazilian/ no/ single case in the family |
Age at first symptoms (years)/ first signs and symptoms | 2/ abnormal gait | 3/ difficulties climbing stairs and frequent falls | 15/ difficulties running and climbing | 17/ difficulties standing up and climbing stairs | 20/ gait disturbance, weakness in the lower limbs | 15/ weakness in the left lower limb | 8/ tiptoe walking, left lower limb deformity/ frequent falls |
Predominant distribution of weakness at admission | Proximal lower limbs with myopathic gait, lumbar hyperlordosis, and toe walking | Proximal lower limbs weakness, and tiptoe gait | Predominant proximal lower limbs weakness, and winged scapula | Proximal lower limbs weakness, right foot drop, waddling gait, and Gowers´ maneuver | Lower limbs proximal weakness | Global muscular atrophy, predominant proximal weakness, deep tendon reflexes could not be elicited | Winged scapula, fixed foot drop, and deep tendon reflexes could not be elicited |
Calf size | Slightly increased | Slightly increased | Prominently increased with larger diameter than the thighs | Moderately increased | Slightly increased with almost the same diameter of the thighs | Atrophy | Slightly increased |
Gait status | Myopathic gait | Tip toe walking | Unstable waddling gait | Unstable waddling gait | Unstable waddling gait | Wheel chair bound since 25 yo | Wheel chair bound at 41 yo |
CK (U/L)/times increased (x) | 694/ 3.7x | 981/ 4.4x | 218/ 1.1x | 1320/ 8x | 1438/ 7.5x | 358/ 1.9x | 269/ 2x |
Imaging asymmetric muscle fat replacement | Yes (subtle). Slight asymmetry of the glutei (smaller on the right side). No asymmetry in thighs and legs | No (absent). Symmetric involvement | Yes (moderate). Moderate asymmetry of the glutei (smaller on the right side). No asymmetry in thighs and legs | Yes (moderate). Asymmetric muscle fat replacement of semitendinosus severe at the right side and slight at the left side. Severe muscle fat replacement of the muscles of the peroneus group in the left side, absent in the right side | Yes (moderate). Gastroncemius medialis fat replacement severe in the right side, slight in the left side. Severe muscle fat replacement of the muscles of the peroneus group in the left side, absent in the right side | Yes (subtle) asymmetric preservation of the right tibialis posterior and left peroneus | Yes (subtle). Gastrocnemius medialis and gastrocnemius lateralis muscles fat replacement: severe at the right side and moderate at the left side |
Light microscopy morphologic findings | Atrophic lobulated fibres, internal nuclei, mitochondrial proliferation | Necrosis, phagocytosis, nuclear internalization above 60% | Lobulated (trabeculated) fibres | Necrosis, phagocytosis, rimmed vacuoles, core-like areas | Severe variation in fibre calibre, type 2 fibre predominance, endomysial fibrosis, rimmed vacuoles | Rimmed vacuoles, lobulated fibres | Necrosis, phagocytosis, lobulated (trabeculated fibres), nemaline bodies |
Fibre type morphometric study. Disproportion formula = (Type 2 mean diameter-Type 1 mean diameter)/Type 2 mean diameter. Criteria > 25% (Dubowitz et al. 2020), and > 35% (Clarke 2011) Mean fiber type diameter in micrometre (mean ± standard deviation) | 52% fibre type disproportion Type 1 = 210(± 69), Type 2 = 435(± 140) | No fibre type disproportion (8%) Type 1 = 35(± 7), Type 2 = 38 (± 8) | 57% fibre type disproportion Type 1 = 30(± 10), Type 2 = 71(± 11) | No fibre type disproportion (11%) Type 1 = 89(± 26), Type 2 = 100 (± 25) | No fibre type disproportion (11%) Type 1 = 40(± 8), Type 2 = 45 (± 34) | No fibre type disproportion (15%) Type 1 = 51(± 12), Type 2 = 60(± 16) | 34% fibre type disproportion (34%) Type 1 = 43(± 13), Type 2 = 67(± 18) |
Fibre type predominance (yes/no)/ Muscle biopsied/ percentage of Type 1 and Type 2 fibres/ Criteria for fibre type predominance for the specific muscle submitted to biopsy in the particular patient (Loughlin 1993; Dastgir et al. 2016; Cotta and Paim 2016; Cotta et al. 2021) | No fibre type predominance/ Right triceps brachialis/ Type 1 = 47.4%, and Type 2 = 52.6%/ Criteria Type 1 > 52.5% Type 2 > 87.5% | Yes: Type 1 fibre predominance/ Right vastus lateralis/ Type 1 = 57.9%, and Type 2 = 42.1%/ Criteria Type 1 > 57.8% Type 2 > 87.3% | No fibre type predominance/ Right biceps brachialis/ Type 1 = 49,6%, and Type 2 = 50,4%/ Criteria Type 1 > 62.3% Type 2 > 77.7% | No fibre type predominance/ Extensor longus digitorum of the right leg/ Type 1 = 52.4%, and Type 2 = 47.6%/ Criteria Type 1 > 67.3%, Type 2 > 72,7% | Yes: Type 2 fibre predominance (clinical information of left quadriceps femoris muscle biopsy)/ Type 1 = 2.5%, and Type 2 = 97.5% Criteria for vastus lateralis Type 1 > 57.8%, Type 2 > 87.3% Criteria for rectus femoris lateral head surface. Criteria Type 1 > 49.5%, Type 2 > 90.5% | Yes: Type 1 fibre predominance/ Right triceps brachialis/ Type 1 = 95.1%, and Type 2 = 4.9%/ Criteria Type 1 > 52.5% Type 2 > 87.5% | Yes: Type 1 fibre predominance/ Right deltoideus/ Type 1 = 90.3%, and Type 2 = 9.7%/ Criteria Type 1 > 73.3%, Type 2 > 66.7% |
Immunohistochemistry with anti-telethonin C- terminus antibody | Total absence of sarcomeric reaction | Total absence of sarcomeric reaction | Total absence of sarcomeric reaction | Total absence of sarcomeric reaction | Total absence of sarcomeric reaction | Total absence of sarcomeric reaction | Total absence of sarcomeric reaction |
Ultrastructural findings on transmission electron microscopy | Glycogen deposits | Nuclear pyknosis, invaginations, and pseudo-inclusions | Intrasarcoplasmic filamentous inclusions of 17 nm diametre, Nuclear invaginations, and pseudoinclusions | Nuclear pyknosis, autophagic vacuoles, multifocal sarcolemmal defects, and mitochondrial paracrystalline inclusions | Autophagic vacuoles, and atrophic fibres with myofibrillar disorganization | Autophagic vacuoles | Nemaline bodies, and mitochondrial paracrystalline inclusions |
Selected clinical findings that are uncommon in Limb Girdle Muscular Dystrophy | Divergent strabismus, long face, high arched palate, distal joint laxity, scoliosis, and elbow joint contracture | Slight bilateral eyelid ptosis | Orbicularis oris paresis, and limited abduction of the eyes | Absent uncommon clinical findings: no facial or ocular muscles abnormalities | Tremor on the hands, and difficulties performing extraocular eye movements | Tongue atrophy. Ten years after first symptoms (at 25 years old), he started strabismus, and severe worsening of lower limbs weakness, with loss of gait capacity in a period of months | Absent uncommon clinical findings: no facial or ocular muscles abnormalities |
Reference | Current paper | Winckler et al. 2019/ Current paper | Winckler et al. 2019/ Current paper | Current paper | Winckler et al. 2019/ Current paper |