Table 1.
Clinical Characteristics of Affected Individuals with PYROXD1 Variants
| ID | Family A-II1 | Family A-II2 | Family B-II2 | Family B-II3 | Family C-II1 | Family C-II2 | Family D-II1 | Family D-II3 | Family E-II2 |
|---|---|---|---|---|---|---|---|---|---|
| Gender, current age | male, 29 y | male, 26 y | male, 31 y | male, 21 y | female, 9 y | male, 7 y | female, 22 y | male, 17 y | female, 15 y |
| Ethnicity; consanguinity | European descent; no | European descent; no | Turkish; yes | Turkish; yes | Persian Jewish; no | Persian Jewish; no | Turkish; yes | Turkish; yes | Turkish; yes |
| PYROXD1 variants | c.285+1G>A (chr12: g.21598401G>A), c.116G>C (p.Gln372His, chr12: g.21615796G>C) | c.285+1G>A (chr12: g.21598401G>A), c. 0.116G>C (p.Gln372His, chr12: g.21615796G>C) | Hom. c.464A>G (p.Asn155Ser, chr12: g.21605064A>G) | Hom. c.464A>G (p.Asn155Ser, chr12: g.21605064A>G) | c.414+1G>A (chr12: g.21602626G>A), c.464A>G (p.Asn155Ser, chr12: g.21605064A>G) | c.414+1G>A (chr12: g.21602626G>A), c.464A>G (p.Asn155Ser, chr12: g.21605064A>G) | Hom. c.464A>G (p.Asn155Ser, chr12: g.21605064A>G) | Hom. c.464A>G (p.Asn155Ser, chr12: g.21605064A>G) | c.464A>G (p.Asn155Ser, chr12: g.21605064A>G), c.1159_1160insCAAA, chr12: g.21620457_21620458insCAAA) |
| Onset/progression | onset 5 y, difficulty running; slowly progressive weakness from 20 y; unable to climb stairs from 24 y; slow walk with a cane | onset 8 y; stable in childhood; mild progression from teenage years; increasing difficulty with stairs | onset 10 y; ambulant with difficulty ascending stairs | onset 10 y; ambulant | congenital onset; hypotonia; mild gross motor delay; walked age 20 mo; weakness from 6 y; increasing difficulty with stairs | infantile onset with hypotonia; walked age 13 mo; stable strength; difficulty with stairs | onset 2 y; ambulant; difficulty running and climbing; frequent falls; slowly progressive weakness from 20 y | onset 2.5 y; ambulant; difficulty climbing; stable in childhood | onset 4 y; easy fatigue; frequent falls; difficulty on stairs; slowly progressive; increasing difficulty with stairs |
| Pattern of limb weakness (HP:0001324) | symmetrical; UL, LL, axial; P, D | symmetrical; UL, LL, axial; P, D | symmetrical; UL, LL, axial; P UL, D LL | symmetrical; UL, LL, axial; P | symmetrical; UL, LL, axial | symmetrical; UL, LL, axial | symmetrical; UL, LL, axial; P | symmetrical; UL, LL, axial; P | symmetrical: UL, LL; P, D |
| Severity of limb weakness | all 4− and 4/5, except deltoid 2/5, shoulder abduction 1/5 | all 4+ and 5/5, except deltoid 2/5, ADM 3/5, APB 0/5; lower limbs 4/5 except hip flex 3/5 | – | – | all 4+ and 4−/5, except shoulder abd. 3/5, wrist flex 3+/5, neck flex 2/5, hip abduction 3/5 | all 4 and 4−/5, except deltoid 3+/5, finger spread 3+/5, neck flex 2/5; hip extension 5−/5 | proximal 4−, distal 4+/5, lower limbs more affected | proximal 4+ and 5−/5, distal 5/5 | proximal 4− and 4+/5; hip flexion 3/5; thenar wasting |
| Hyporeflexia (HP:0001265) | reduced or absent | reduced or absent | reduced or absent | reduced or absent | reduced or absent | reduced or absent | reduced or absent | reduced or absent | reduced or absent |
| Achilles contractures (HP:0001771) | yes | no | no | no | yes | no | no | no | no |
| Joint contracture 5th finger (HP:0009183) | yes | no | no | no | yes | no | no | no | no |
| Joint hypermobility (HP:0001382) | distal laxity, resolved with age | distal laxity, partial patella subluxations | no | no | elbow and MCP joints | mild at elbow, wrist, and MCP joints | no | no | no |
| Facial weakness (HP:0002058) | yes | yes | yes | yes | yes | yes | yes | yes | yes |
| Ptosis (HP:0000508) | no | no | no | mild | no | no | mild | mild | no |
| Ophthalmoplegia (HP:0000602) | no | no | no | no | no | no | no | no | no |
| High arched palate (HP:0000218) | yes | yes | no | no | yes | yes | yes | yes | yes |
| Additional facial features | dental malocclusion (HP:0000689), elongated face | dental malocclusion (HP:0000689), elongated face | no | micrognathia and retrognathia (HP:0000308) | int. exotropia, surgical correction (HP:0000577) | no | elongated face (HP:0000276) | elongated face (HP:0000276) | no |
| Dysphagia (HP:0002015) | present from 12 y; improved | yes, plus nasal regurgitation from 9 y; surgery for VPI | yes | no | no | no | yes | yes | yes |
| Chewing difficulties (HP:0030193) | no | no | no | no | yes | yes | no | no | no |
| Nasal speech (HP:0001611) | yes | yes | yes | yes | yes | yes | yes | yes | yes |
| Scoliosis (HP:0002650) | mild thoracic scoliosis from 20 y | no | no | no | mild scoliosis from 7 y | no | no | no | no |
| Spinal rigidity (HP:0003306) | no | no | no | no | thoracolumbar rigidity | thoracolumbar rigidity | no | no | no |
| Pectus excavatum (HP:0000767) | yes | no | no | no | yes | no | no | no | no |
| Scapular winging (HP:0003691) | yes | no | mild | mild | mild | mild, asymmetric | no | no | no |
| Pes cavus (HP:0001761) | yes | no | no | no | no | no | no | no | no |
| Pes planus (HP:0001763) | no | yes | yes | yes | no | no | yes | yes | no |
| Restrictive lung disease (HP:0002091) | yes, from 15 y | no | no | yes | no | no | no | no | no |
| Recurrent infections (HP:0002783) | no | no | no | no | yes | yes | yes | no | yes |
| Cardiac disease | abnormal septal motion and low normal ejection fraction at 27 y | no | no | no | mild to moderate pulmonic insufficiency | no | no | no | mild mitral and tricuspid insufficiency (HP:0001653) |
| Elevated CK (IU/L) (HP:0040081) | no (148–262) | yes (118–1,051) | yes (500–700) | yes (700–800) | no | no | yes (400–700) | no (290–376) | no |
| Histology | 11 y | not performed | not performed | 16 y | not performed | 4 y | not performed | 13 y | 10 y |
| Internalized nuclei | yes | – | – | yes | – | yes | – | yes (>50% of fibers) | yes |
| Central cores | yes | – | – | yes | – | yes | – | yes on NADH and SDH stains | yes |
| Myofibrillar inclusionsa | yes | – | – | yes | – | yes | – | EM not performed | EM not performed |
| Sarcomeric disorganization | yes | – | – | yes | – | yes | – | – | – |
| Thin filament accumulations | yes | – | – | yes | – | – | – | – | – |
| Nemaline rods | yes | – | – | yes | – | – | – | – | – |
Abbreviations are as follows: UL, upper limb; LL, lower limb; P, proximal; D, distal; ADM, abductor digiti minimi; APB, abductor pollicus brevis; MCP, metocarpophalyngeal; VPI, velopharyngeal insufficiency; CMAP, compound muscle action potential; EMG, electromyography; NCS, nerve conduction studies; NCV, nerve conduction velocity; y, year; mo, month.
a
Myofibrillar inclusions were positive to desmin, myotilin, alpha-actin, and αB crystallin.