The patient was a 35-year-old Chinese male, with an unremarkable antenatal, perinatal and developmental history. He was physically active, and completed military service uneventfully at 20 years of age. He first developed symptoms in his early 20s, when he experienced gradually progressive difficulty extending his fingers, leading to difficulty in using his handphone. In his early 30s, he developed progressive difficulty lifting heavy objects, as well as distal lower limb weakness. Speech, swallowing and respiratory functions were normal. There was no parental consanguinity. His biological father had upper and lower limb weakness; patient is estranged from his biological father and could not provide further information. His biological mother and younger siblings (half-brother and half-sister, aged 33 and 29 respectively) were well. He was married, with no children. On examination, extraocular, facial, and bulbar muscle movements were normal. Muscle bulk was normal, with no wasting or hypertrophy observed. Muscle tone and deep tendon reflexes were also normal. Distal predominant muscle weakness was noted, most prominent in the bilateral index finger and left fourth and fifth finger extensors where differential weakness was seen (MRC grade 1–2; Fig. A-D). The distribution of weakness in the other muscle groups was as follows: In the upper limbs, finger abduction (MRC grade 2), elbow flexion (MRC grade 3), finger flexion and thumb abduction (MRC grade 4), wrist flexion and extension (MRC grade 5), shoulder abduction and elbow extension (MRC grade 4). In the lower limbs, ankle dorsiflexion (MRC grade 3), toe extension (MRC grade 3), knee flexion (MRC grade 5), Knee extension (MRC grade 4), hip flexion and extension (MRC grade 4). Mild muscle weakness was noted in axial muscles (neck flexion MRC grade 3, neck extension 4). Spine flexion and extension were intact. Sensory examination was normal. There were no skin, joint, or spinal abnormalities, and no tendon contractures seen. Serum creatine kinase was normal. Nerve conduction study was unremarkable, while needle electromyography (EMG) revealed myopathic changes as characterized by low amplitude, short duration, polyphasic motor unit potentials with early recruitment, increased insertion activities without fibrillation potentials or positive sharp waves. Pertinent findings of the lower body muscle MRI (Magnetic resonance imaging; encompassing the pelvis, thighs and calves; Fig. E-G) included: fatty infiltration in gluteus maximus/ medius, sartorius, adductor magnus, semimembranosus, biceps femoris, extensor digitorum longus, tibialis anterior, and soleus. Other than the sartorius and extensor digitorum longus, whereby fatty infiltration was moderate, involvement of other affected muscles was mild. No significant loss of muscle volume or muscle oedema were evident. An electrocardiogram showed normal sinus rhythm, and transthoracic echocardiogram was normal. Biceps brachii muscle biopsy showed variation of muscle fibre size. Scattered and clustered predominantly atrophic type 2 fibres, together with nuclear clumps were seen (Mean type 1 fibre diameter: 30 ± 13 μm, mean type 2 fibre diameter 19 ± 13 μm, type 2 fibre percent 48%, type 2 factor atrophy factor 2.0). Focal areas of endomysial and perimysial fibrosis, and increased adipose tissue were noted. Some fibres showed pale central areas on NADH and SDH stains but not on COX stain, suggesting regions with reduced oxidative enzyme activities. No necrosis or regenerating fibers were seen. There was no fibre type predominance. No abnormal inclusions were seen on Gömöri-trichrome stain. Electron microscopy showed atrophic fibers without the presence of nemaline rods. Genetic testing revealed a heterozygous p.Ser246Leu variant (NM_152263.4, c.737 C > T) in the TPM3 gene. No other pathogenic variants in other genes known to be associated with genetic muscle diseases were identified. Cascade testing could not be performed, as patient’s biological father was not contactable. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the c.737 C > T variant was inconclusive, showing overexpression of the TPM3 gene in muscle tissue as well as multiple regions of mRNA mis-splicing.