A 55-year-old man had had muscle complaints for as long as he could remember. He could not stretch his arms or walk without shoes due to deformities of the feet. Proximal muscle weakness was mild and slowly progressive over years, and contractures had always been prominent. His stamina was low, but he still worked full-time as a manual worker. He was otherwise healthy.

Family history revealed that his father was similarly affected. In addition, a half-brother and half-sister not only had contractures but also had muscle weakness. The latter underwent surgery for torticollis in the neonatal period.

While working is his garden, a 59-year-old man noticed pain in his neck and shoulders. He had some difficulty holding his head in an upright position and rising from a squat. The referring neurologist had performed an MRI scan of the cervical spine, which was normal. As his CK activity was moderately elevated and the EMG showed fibrillation potentials, myositis was suggested. On referral – six months after disease onset – he also mentioned difficulty climbing stairs. When walking, he experienced cramps in the calves. In recent weeks, he had developed a slurred speech and had problems fastening buttons. He had lost 10 kg (12% of his original weight). Pseudobulbar affect (forced laughter, yawning, or crying) was not mentioned at the time.

A 63-year-old woman was referred because of decreased strength of her right leg manifesting with buckling of the knee for the past five years. Sometimes this led to falls, which made her feel insecure while walking. She experienced some aching in her right heel and in her right knee after long walks. She was able to walk for two hours. She and her husband loved to walk in the mountains, and during those hikes she used a cane. The previous history is relevant because at age 5 years she had suffered from poliomyelitis anterior acuta, which had affected both legs. She had a partial recovery in the sense that she regained normal strength of her left leg and was left with residual weakness of her right leg. She underwent surgery at age 10 years (ankle arthrodesis on the right and epiphysiodesis of the left leg).

A 39-year-old man was referred because of three attacks of severe myalgia accompanied by ‘bloody urine’. There were no complaints about muscle weakness. There had been preceding exercise, but not excessively. Prior to one attack, he had suffered from a viral infection.

During childhood, at sports he had often noticed having muscle ache, once accompanied by ‘red urine’. There was no ‘second wind’ phenomenon. After three days, the muscle complaints usually disappeared. At age 20 years he had suffered a similar attack during a soccer game and again at age 37 after playing volleyball. On that occasion, CK was determined and found to be approximately 800,000 IU/L, which led to admission to hospital for hydration and monitoring of his kidney function. His CK normalized rapidly. At that time, a muscle biopsy was performed that showed no accumulation of fat or glycogen and no mitochondrial abnormalities.

A 48-year-old man had complained about the painful soles of his feet for several months. This pain was present constantly but increased on touch and when walking. He was a marathon runner but could no longer train or walk properly because of the pain. He did not report weakness, sensory disturbances, discoloration of his feet, or swelling of his joints. Otherwise, he was healthy. He was not known to have diabetes mellitus or any other chronic disorder, such as sarcoidosis, which can cause a painful neuropathy. There were no cardiovascular or intestinal complaints, and no symptoms of autonomic dysfunction. Symptoms that could suggest malignancy were absent. He did not use any medication, had not been treated with any neurotoxic drug earlier, did not smoke, and drank only very limited amounts of alcohol. There was no family history of neurological disorders.

A 20-year-old previously healthy man suddenly noticed that he was unable to run. The next day he could not climb the stairs and lost strength in his arms. He was admitted to hospital, and over the next hours he progressively lost muscle power in his arms and legs. Swallowing was progressively impaired, and he noticed minor tingling in both hands and feet. He had had a minor upper respiratory tract infection a week prior to admission.

A 7-year-old girl visited the outpatient clinic because of difficulty walking. She had never managed to run properly, and experienced frequent falls ever since she began walking independently at the age of 18 months. Jumping was not possible, and when stepping up or down, she needed support below her arms. There was no fluctuation of symptoms during the day, but she had suffered from periods that could last several weeks in which using the stairs was completely impossible. She was unable to blow up a balloon and her speech was slow and poorly articulated. There were no complaints about chewing or swallowing. She had a healthy non-identical twin sister and the family history was unremarkable.

A three-month-old boy was seen at the outpatient clinic because of reduced spontaneous movements, which his parents had noticed for a few weeks. His legs lay to the side, he barely moved his hands, and his parents had to increasingly support his head when feeding him. For the past two weeks. drinking became slower. He also drank less and he choked daily. Coughing and crying had become weak compared with the first two months of life. Pregnancy, birth, and family history were unremarkable. He was the second child of unrelated parents and had one healthy sister who was three years old.

A 53-year-old man developed a left-sided foot drop and a painful sensation on the ventral side of the foot and outer part of the lower leg. Two weeks later, the same symptoms also developed on the right side. In addition, he noticed progressive numbness of his lower legs. Three weeks later, he noticed weakness of his right hand, and was unable to spread his fingers. He had no other symptoms, and his medical history was not informative. He did not recall a tick bite or erythema migrans, or any pulmonary abnormality, and had not visited tropical countries. He does not sit with crossed legs.

After a normal pregnancy without hydramnios, delivery of a healthy-looking girl was uneventful. At four months of age, she had had a respiratory infection and was noted to have a weak cough. At eight months of age she was just able to keep her head in an upright position but was not able to sit unsupported. Her mother admitted that she had not been very active since birth, but there was no progressive muscle weakness and no swallowing difficulty. She was referred to a paediatric neurologist because of a suspected neuromuscular disorder. The parents were healthy and there was no consanguinity.

A 64-year-old man’s complaints had begun four years earlier with a burning pain at the glans of the penis, which lasted for several days, and was followed by a numb feeling that resolved after a few weeks. Some months later, there was an electric shock-like sensation at the side of his right lower leg, soon followed by numbness in that affected skin area. Over the ensuing years, there was a repeating pattern of a short-lasting sharp, burning pain, often during only one day, which evolved into a numb feeling that most of the time resolved completely in weeks to months. Several body parts had been affected in this way: the upper left leg, the fingers of his right hand, one by one, and the chest. Lately this had also occurred on his right cheek. The frequency of the attacks had not changed over the years.

A 66-year-old man with slowly progressive tingling and a dull feeling in his feet for two years visited our outpatient clinic. He noticed some imbalance when walking after rising from a chair or from bed. He had no complaints about his hands, and he did not notice weakness. He loved to play golf with his friends several times a week. He was known to have a steatotic liver and hypertension. He did not smoke, but he admitted that he had been drinking six glasses of beer or wine a day for many years. He used anti-hypertensive drugs and vitamin B complex.

A boy was referred at the age of 2 years and 8 months because of frequent falls. This occurred several times per day and he had hurt his head on multiple occasions. Earlier major motor milestones had been delayed by several months. He had achieved rolling over at 9 months, crawling at 15, and independent walking just before his second birthday. Speech and language development were also behind as his first word had been heard around the age of 2 and he now mastered no more than ten. He was friendly in his behaviour and made good eye contact. Pregnancy and birth had been unremarkable. His mother was 5 months pregnant with her second child. Family history was unremarkable.

A 70-year-old woman was referred by her GP because of progressive nasal speech and difficulties with chewing and swallowing, shortly after abdominal surgery because of a borderline malignant cystoadenofibroma of the uterus. Weeks later, she also noticed drooping of both eyelids and a tendency for her head to drop at the end of a day. In retrospect, mild nasal speech had been present for some months prior to surgery.

For decades, muscle biopsy has been considered an essential part of the work-up of patients suspected of a neuromuscular disease, alongside the physical examination, laboratory testing, electromyography, muscle imaging, and molecular investigations.

However, muscle biopsy is usually not the first diagnostic test requested when the clinical phenotype of a myopathic patient is clear (‘Gestalt’) and the molecular diagnosis is straightforward. For example, for patients with a phenotype of facioscapulohumeral dystrophy, Duchenne muscular dystrophy, or myotonic dystrophy, genetic investigations are the primary requested diagnostic tests. Since next-generation sequencing (NGS) has entered the diagnostic arena, a muscle biopsy is no longer a first-tier examination if a hereditary neuromuscular disorder – be it a myopathy, neurogenic disorder, or congenital myasthenic syndrome – is considered. Likewise, in patients with subacute weakness, especially if accompanied by skin abnormalities, the introduction of new serological markers has made the position of the applicability of muscle biopsy questionable according to some clinicians.

Over a period of months, a 45-year-old woman noticed that she had difficulty raising her arms. She also reported double vision in the evening that, in retrospect, had been present for some years. Three years later, it became difficult to keep her head up without support, to chew, and to swallow, which sometimes worsened over a period of weeks.

A 45-year-old man was referred by the internist because of a second episode of rhabdomyolysis. Motor milestones had been normal, and he had always been good at sports, although he was used to having stiff calves after skiing. At the age of 39 years he once experienced a sensation of ‘barbed wire’ in his upper legs, evolving in quite severe myalgia building up over days. This complaint dissolved in the course of three weeks. CK activity in this period increased to 23,094 U/L and normalized completely. There was no history of dark urine. In the absence of a metabolic cause or a history of the use of drugs, this was interpreted as having been caused by a viral infection. In the preceding months, he had been cycling fanatically daily, up to exhaustion. After this episode he had cut down on his sporting activities, but recently he had taken up mountain biking.