Table 2

Conditions already diagnosed with worsening respiratory muscle weakness as part of their natural history

Multiple acyl-CoA dehydrogenase deficiency (MADD)MADD (glutaric aciduria type 2) is a disorder of fatty and organic acid metabolism that may present late, with severe axial and proximal weakness as well as respiratory muscle and bulbar weakness, sometimes precipitously.
There is:
  • An abnormal acylcarnitine profile (all sizes acylcarnitines are increased)

  • Fat infiltration in the posterior compartment of thighs (visible on MR)

  • Muscle biopsy shows massive deposits in myofibres with Oil red O staining

Importantly, it responds to riboflavin 400 mg/day
Muscle diseases with contractures71
Contracture—inability to stretch a muscle passively to its proper length because of fibrosis. Early and prominent contractures developing while muscles remain relatively strong occur only in a few myopathies
Collagen VI-related disorders
  • Bethlem myopathy—slowly progressive proximal limb weakness

  • Long finger flexor contractures—‘prayer sign’

  • About 10% develop respiratory insufficiency, which is related to the severity of limb weakness

  • Ullrich congenital muscular dystrophy—proximal joint contractures, hyperlaxity of distal small joints and often hip dislocation at birth. Respiratory involvement is common with nocturnal respiratory support required in the first or second decade.

Emery-Dreifuss muscular dystrophy
  • X-linked recessive—mutations in STA gene (protein emerin)

  • Autosomal dominant—mutations in LMNA gene on chromosome 1; LMNA encodes both lamins A and C—by alternative splicing

  • Triad of early muscle contracture, early humeroperoneal weakness and potentially serious cardiac complications

  • Contractures of neck extensors, elbows and ankles

  • Atrophy and weakness of humeral muscles and peroneal muscles (humeroperoneal distribution weakness)

  • Cardiomyopathy

Some Limb-girdle muscular dystrophies (LGMDs) that may potentially decompensate, requiring ICU
LGMDs are divided into two groups: autosomal dominant (LGMD 1) and autosomal recessive (LGMD 2). LGMD 1 is rare, accounting for 10% of LGMD cases
I would highlight the following:
  • LGMD2I

  • Sarcoglycanopathies

  • LGMD2A (rarely can have respiratory muscle involvement late in natural history)

  • (LGMD 2C–2F) present similarly to the dystrophinopathies.

  • >70% of cases have respiratory muscle involvement

  • Serum creatine kinase often >5000 U/L

Calpainopathy (LGMD 2A)
  • Scapular winging (but without medial rotation of the lower scapular border, unlike facioscapulohumeral muscular dystrophy)—the medial scapular border is straight and there is no facial weakness

  • Pelvic girdle weakness that spares the hip abductors with elbow flexion weakness

  • Sometimes ankle joint contractures and calf atrophy (can walk on the toes but not the heels)

  • Late respiratory muscle involvement with sparing of the cardiac muscles (described although rare)

  • Serum creatine kinase is roughly 1500–3000 U/L.

LGMD 2I (mutations in the fukutin-related protein gene)
  • Presents in adulthood with proximal limb muscle weakness

  • Respiratory muscle weakness often occurs, even in ambulant patients

  • Pseudohypertrophy of the calves and/or tongue

  • Scapular winging

  • Cardiac involvement

  • Serum creatine kinase 1000–5000 U/L (but sometimes normal in older patients)

Dystrophinopathies (X-linked recessive with absence or alteration in dystrophin protein), including
  • Duchenne muscular dystrophy. Dystrophin is almost entirely absent from the subsarcolemmal surface (1:3500 male births)

  • Becker muscular dystrophy has significant amounts of functioning dystrophin present. It is a rarer allelic disorder (one-third as common as Duchenne) and milder (but variable phenotype.

Duchenne muscular dystrophy
Diagnosis in childhood (between ages 3 and 5 years).
Loss of ambulation usually between 10 and 11 years.
Corticosteroids (Cooperative Investigation in Duchenne Dystrophy) consortium, 1989 was a landmark study revealing the benefits of corticosteroids in Duchenne.
They maintain ambulation by 1–3 years, and continued use reduces scoliosis (that begins when a boy becomes a wheelchair user) and maintains ventilatory muscle strength.
Respiratory failure is the major cause of death in patients with Duchenne muscular dystrophy, declining after loss of ambulation with respiratory impairment clinically manifest in the late teens. Pneumonia requiring ICU is a potential and frequent cause of death.
Life expectancy is improving with ventilatory support - patients born after 1990 have a median life expectancy of 28.1 years.72
Becker muscular dystrophy
Most have relatively mild disease before adulthood
Limb girdle weakness, calf pseudohypertrophy (prominent quadriceps weakness)
Restrictive lung disease occurs as a late complication in a small percentage of Becker cases, but the severity does not approach that seen in Duchenne.
Facioscapulohumeral muscular dystrophyWeakness of:
  • Facial muscles

  • Scapular fixator muscles: the lower medial scapular border rotates medially with arms outstretched

  • Biceps

  • Finger extensors

  • Abdominal and hip-girdle muscles

  • Foot drop

  • Extraocular, bulbar and respiratory muscles are usually spared but

  • 1% of patients require ventilatory support, invariably only when there is severe weakness elsewhere, with wheelchair dependence and often kyphoscoliosis.

Hereditary myopathy with early respiratory failure
Mutational hotspot is in exon 343 of the titin gene (TTN)
Slowly progressive myopathy that starts in young or middle-aged people with distal leg weakness that later generalises.
Calf hypertrophy and atrophy may occur
The respiratory muscles are very weak at the time a person is can still walk
Serum creatine kinase is raised, up to about 1000 U/L
Biopsy shows myofibrillar myopathic changes
Hereditary (usually transthyretin) and acquired systemic amyloidosis myopathyCan present with worsening dyspnoea and require respiratory support.
History of dysautonomia, weight loss, shoulder pad sign, organomegaly, periorbital bruising, pseudohypertrophy and macroglossia.73
Spinal muscular atrophy linked to chromosome 5q (autosomal recessive)
Disruption of survival motor neurone (SMN1) gene, which produces SMN protein. The SMN protein is produced in small quantity by the SMN2 gene (arose during an evolutionary duplication). There are variable numbers of the SMN2 gene – the more copies the less severe the disease.
Nusinersen, onasemnogene abeparvovec and oral risdiplam modify SMN2 pre-messenger RNA splicing to include exon 7, increasing concentration of functional SMN protein, and altering the natural history of the condition.
Type 0—reduced fetal movements in utero, severe weakness and hypotonia at birth
Infantile form, type 1—presents at birth or by 6 months, babies do not reach developmental milestone of sitting unassisted
Childhood type, type 2—onset after 6 months, children do not reach developmental milestone of walking unaided
Juvenile type, type 3—SMA type 3 usually starts after 18 months (usually between 5 and 15). Initially, patients can walk but many lose the ability. Proximal limb weakness and enlarged calf muscles are common, with areflexia, normal sensation, tremor and fasciculation.
Kyphoscoliosis and tongue fasciculation appear late.
SMA Type 4—onset is in adulthood, usually after aged 30 years. Generally, patients maintain mobility throughout life.
Respiratory complications are inevitable in children with type 1 spinal muscular atrophy; they occur to a variable extent in type 2 but are rare in type 3.
Intercostal muscles are weak, so inspiration depends on the diaphragm.
Serum creatine kinase is approximately 1000 U/L.
Postpolio syndromePostpolio syndrome affects poliomyelitis survivors 20–30 years after their acute illness. There is a slowly progressive loss of function and weakness in previously affected muscles. It is distinguished from motor neurone disease by:
  • Lack of upper neurone signs

  • History of poliomyelitis

  • Very slow progression with prolonged survival, even after respiratory failure is established

Spinobulbar syndromes
X-linked bulbospinal neuronopathy (Kennedy’s disease)
Brown-Vialetto-van Laere syndrome may present relatively abruptly with respiratory muscle and bulbar weakness, with pre-existing deafness; it is an important diagnosis since it may respond to riboflavin 400 mg/day.74
X-linked bulbospinal neuronopathy
Hand tremor begins in the 30 s.
Limb weakness often begins in the legs, before involving the arms and bulbar muscles (dysarthria then dysphagia)
Perioral and chin fasciculation (or myokymia) occurs at rest; asking the patient to whistle may accentuate this
Loss of vibration sensation distally
Serum creatine kinase can be very elevated, at times>1000 U/L.
Respiratory insufficiency may follow a lower respiratory tract infection or surgery; there is potential for acute respiratory insufficiency, requiring intensive care
Genetic neuropathiesPes cavus, distal atrophy and weakness
Respiratory involvement rarely occurs in CMT1A, and often when limbs are severely affected.
Other form of Charcot-Marie-Tooth disease (for example, CMT 4J and CMT2Z) may cause respiratory weakness and often have proximal as well as distal weakness. CMT4J can suddenly progress or resemble Guillain-Barré or chronic inflammatory demyelinating polyradiculoneuropathy (or motor neurone disease)