Mixed-phenotype acute leukaemia is a generic classification item collecting leukaemias with two clones of different lineage or really abnormal cells expressing markers of several lineages. Their identification relies on both morphological and immunophenotypic features. From a cytogenetic/molecular point of view, their heterogeneity is amazing. Clinical management of such patients is getting progressively better stratified, allogeneic hematopoietic stem cell transplantation remaining the best option, with a possibly better approach for patients with Philadelphia chromosome. This is a typical example of the need for integrated diagnosis.

Currently, there is a rapid, ongoing increase in our understanding of genetic neuromuscular disorders at the molecular level: many causative genes have been found, giving hope for targeted genetic treatments, already proven effective in some diseases. In immune-mediated neuromuscular disorders, pathogenetic mechanisms are better understood, and this enables the development of more precise immunotherapies. Increased knowledge has led to a refinement of classifications and has added numerous subtypes to the already hundreds of possible neuromuscular diagnoses. Patients can only benefit from future targeted therapies if an accurate diagnosis is made. Moreover, a diagnosis needs not only to be precise; the diagnostic trajectory needs to be swift, as current and future treatments will be aimed at the prevention or the restriction of irreversible damage.

The best way to diagnose a neuromuscular disease at this point is probably to recognize the phenotypical pattern, to know its differential diagnosis, and to proceed from there.

A 64-year-old man with hypertension had acute-onset dysarthria and left-sided ataxia. A haematoma in the left cerebellar hemisphere was diagnosed. When he developed severe headaches and vertical gaze paresis, the neurosurgeon was consulted and a decision to evacuate the haematoma was made. After surgery, he acquired pneumonia, necessitating artificial ventilation. Further complications included metabolic alkalosis, sepsis, and haemodynamic instability. One week after surgery, he developed a tetraparesis.

A 36-year-old woman was concerned about being affected with a disease that ran in the family in an autosomal dominant (AD) manner. A few years before presentation, she noticed difficulty when walking in the mountains and this had gradually progressed to problems climbing stairs and an inability to run. She also noted that she could no longer lift her head when in supine position. Her mother had died of this disease in her early forties. She mentioned that many affected family members had been diagnosed with cardiac problems in addition to muscle weakness. Some were treated with an implantable cardioverter defibrillator. In elderly family members, cardiac enlargement was not uncommon.

A 60-year-old man reported slowly progressive symptoms over a period of five years. He experienced tingling in his toes that gradually spread halfway up the lower legs. He also developed a stiff feeling in his lower legs and nightly cramps in both calves, but no pain. For one year, he complained of numb fingertips with some loss of dexterity. He had no symptoms of autonomic dysfunction, was not known to have diabetes, ate a healthy, balanced diet, drank one glass of alcohol a day, and had not been treated with neurotoxic medication. His family history indicated no other relatives with similar complaints.

A 14-year-old girl born in Brazil who moved to Europe at a young age presented with weakness and a dull feeling in her right hand. The symptoms had been progressive over a period of one year. Initially, she had diminished sensation of her right index finger. This gradually progressed to affect the whole of her right hand, which eventually became numb. She was right-handed and could no longer use a pen for writing. Otherwise, her history was unremarkable.

At the age of 44 years, this now 57-year-old woman noticed myalgia and difficulty walking, progressing over weeks. Two weeks after the first complaints, lifting the arms became troublesome too. CK activity was found to be > 10,000 U/L. TSH was normal. A diagnosis of myositis was made, and prednisone was started at a dose of 60 mg daily (body weight 80 kg). CK decreased, but the complaints worsened. Six weeks after disease onset, she was presented at our hospital. She was otherwise healthy, apart from well-controlled Graves disease with orbitopathy at the age of 31 years.

A 33-year-old man was referred by his nephrologist who treats him with potassium supplementation for a hypokalaemic periodic paralysis, which had been diagnosed by the finding of heterozygosity for the missense mutation c.1853 G->A; p.Arg528His in the voltage-gated calcium channel (CAGNA1S) gene. He now visited our department in search of an explanation and treatment for an apparently fixed (permanent) weakness in his upper legs, which hampered climbing stairs.

The attacks of flaccid weakness had begun when he was 13 years old. The frequency had been increasing starting a few years ago. He now experiences mild attacks four to five times a week, with a heavy feeling in the affected limb during hours or a whole day.

A 44-year-old man was referred because of hyperCKaemia (elevated CK activity). CK ranged from 1300 to 2200 IU/L (normal < 171). Before referral some investigations were performed. TSH was normal. HyperCKaemia was initially considered to be related to the use of simvastatin, but four months after withdrawal of this drug, CK was still markedly elevated.

He did not complain about muscle weakness, muscle cramps, or myalgia. Previous history disclosed diabetes mellitus type 2, hypertension, and Asperger syndrome. Medication included metoprolol/hydrochlorothiazide, enalapril, and metformin. Family history was negative for neuromuscular disorders.

A 49-year-old man noticed a diminished sensation in his feet. Two months later, climbing stairs became difficult due to proximal muscle weakness of his legs. Over the next three months, sensory disturbances and both proximal and distal weakness progressed in arms and legs requiring the use of a walker or a wheelchair. Besides COPD, he was previously in a healthy condition. Based upon ancillary investigations, he was initially diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP), had received a course of intravenous Ig (IVIg), and was subsequently treated with high-dose corticosteroids (60 mg/day). He did not smoke or use drugs such as nitric oxide.

A five-month-old girl was referred with hypotonia and muscle weakness from birth onwards. She was born after an unremarkable pregnancy during a planned home birth at 40 weeks’ gestational age as the second child from healthy, unrelated parents. In the first days after her birth, they noted a paucity in movements and a low muscle tone. Breastfeeding failed, as she was unable to suck sufficiently. Bottle feeding with an adapted nipple also was a problem, and she often coughed or threw up after drinking. At the age of three months, a percutaneous endoscopic gastrostomy (PEG) probe had been placed to ensure caloric intake. Swallowing had gradually improved in the past month and now she managed to swallow small quantities of purified fruit and vegetables.

Major advances over the past decades have transformed the management landscape of neuromuscular disorders. Increased availability of genetic testing, innovative therapies that target specific disease pathways and mechanisms, and a multidisciplinary approach to care including both transitional and palliative care contribute to timely and more appropriate management of conditions that are associated with a severe disease burden and often also a reduction of life expectancy.

There is an increasing number of consensus recommendations/guidelines that are a useful adjunct for establishing a timely and accurate diagnosis, and enable prognostication of disease-related complications, are a guide for multidisciplinary care and treatment, and expedite initiation of disease-modifying interventions. A number of these guidelines have been referred to in various cases, such as myasthenia gravis (MG), myotonic dystrophy type 1 and 2, chronic inflammatory demyelinating neuropathies (CIDP), and Duchenne muscular dystrophy (DMD), to name a few.

A 40-year-old man was referred because he wished to be informed about the genetic nature of his disorder. He was diagnosed with Charcot–Marie–Tooth (CMT) disease. At 14 months of age, he started walking, but awkwardly due to a bilateral drop foot for which braces were prescribed. On first examination at age 2 years and 8 months, there was marked atrophy, hypotonia, and areflexia of the lower legs, and slight wasting of the thenar and hypothenar. At that time, nerve conduction studies showed normal motor conduction velocities of arm nerves. No motor unit action potentials could be recorded in the lower leg muscles on concentric needle examination.

Driven by technological advances, an ever-increasing number of genes and mutations are implicated in neuromuscular diseases. This has led to revised classifications of neuromuscular diseases and expanding phenotypic spectra related to single genes. As a result, gene-targeted therapies are emerging. Combined with the reduction in costs of genome sequencing, genetic testing plays an increasingly important role in the diagnostic process of neuromuscular diseases. Nevertheless, caution is warranted since results of genome sequencing can be challenging regarding the interpretation of the results. Here we discuss general principles that aid the efficient use of genetic testing that may improve the interpretation of results (see Table 7.1).

A 54-year-old man was referred by his GP. He had lived with his mother until her death when he was 47 years old. He then moved into an assisted living facility. His father had died in his early 30s in a car accident. A sister was said to have died of a muscle disease and a brother had reportedly died of a heart attack at age 35 years. A niece from his father’s side was also reported to have a muscle disease. Apart from having difficulties opening his hands since childhood (upon request) he had had no complaints until his late thirties, when he experienced muscle weakness. This hampered him during his full-time work as a groundskeeper in public gardens, but he continued working. Two months ago, however, he had to give up this job because of severe fatigue and increasing generalized weakness.