G Burke

Dok-7 Mutations Underlie a Neuromuscular Junction Synaptopathy

Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission characterized by fatigable muscle weakness. One major subgroup of patients shows a characteristic “limb girdle” pattern of muscle weakness, in which the muscles have small, simplified neuromuscular junctions but normal acetylcholine receptor and acetylcholinesterase function. We showed that recessive inheritance of mutations in Dok-7, which result in a defective structure of the neuromuscular junction, is a cause of CMS with proximal muscle weakness.

Rapsyn mutations in hereditary myasthenia: distinct early- and late-onset phenotypes.

Rapsyn mutations in 16 unrelated patients with a congenital/hereditary myasthenic syndrome were identified, and a mutation (N88K) common to each of them was found. Two distinct phenotypes were noted: early and late onset. The former is frequently associated with arthrogryposis multiplex congenita and life-threatening crises. The late-onset phenotype developed in adolescence or adulthood and was initially mistaken for seronegative myasthenia gravis. Recognition of this late-onset phenotype should prevent inappropriate immunotherapy.

Distinct phenotypes of congenital acetylcholine receptor deficiency.

We contrast the phenotypes associated with hereditary acetylcholine receptor deficiency arising from mutations in either the acetylcholine receptor epsilon subunit or the endplate acetylcholine receptor clustering protein rapsyn. Mutational screening was performed by amplification of promoter and coding regions by PCR and direct DNA sequencing. We identified mutations in 37 acetylcholine receptor deficiency patients; 18 had acetylcholine receptor-epsilon mutations, 19 had rapsyn mutations. Mutated acetylcholine receptor-epsilon associated with bulbar symptoms, ptosis and ophthalmoplegia at birth, and generalized weakness. Mutated rapsyn caused either an early onset (rapsyn-EO) or late onset (rapsyn-LO) phenotype. Rapsyn-EO associated with arthrogryposis and life-threatening exacerbations during early childhood. Rapsyn-LO presented with limb weakness in adolescence or adulthood resembling seronegative myasthenia gravis. Awareness of distinct phenotypic features of acetylcholine receptor deficiency resulting from acetylcholine receptor-epsilon or rapsyn mutations should facilitate targeted genetic diagnosis, avoid inappropriate immunological therapy and, in some infants, prompt the rapid introduction of treatment that could be life saving.

Salbutamol benefits children with congenital myasthenic syndrome due to DOK7 mutations.

Congenital myasthenic syndromes due to DOK7 mutations cause fatigable limb girdle weakness. Treatment with ephedrine improves muscle strength. Salbutamol, a β(2)-adrenergic receptor agonist with fewer side effects and more readily available, has been effective in adult and anecdotal childhood cases. This study reports the effects of salbutamol on motor function in childhood DOK7 congenital myasthenic syndrome. Nine children (age range 5.9-15.1years) were treated with oral salbutamol, 2-4mg TDS. The effect on timed tests of motor function, pre- and up to 28months post-treatment, was audited retrospectively. All 9 reported functional benefit within 1month, with progressive improvement to a plateau at 12-18months. Within the first month, all 3 non-ambulant children resumed walking with assistance. Although improvements were seen in some timed tests (timed 10m, arm raise time, 6min walk time) this did not fully reflect the observed functional benefits in daily living activities. No major side effects were reported. We conclude that oral salbutamol treatment significantly improves strength in children with DOK7 congenital myasthenic syndrome and is well tolerated. Outcome measures need to be refined further, both to accurately reflect functional abilities in children and to document progress and treatment response.

Clinical features of congenital myasthenic syndrome due to mutations in DPAGT1

Background A newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles localised to the neuromuscular junction, DPAGT1 is ubiquitously expressed, modifying many proteins, and as such is an unexpected cause of isolated neuromuscular involvement. Methods We present detailed clinical characteristics of five patients with CMS caused by DPAGT1 mutations. Results Patients have prominent limb girdle weakness and minimal craniobulbar symptoms. Tubular aggregates on muscle biopsy are characteristic but may not be apparent on early biopsies. Typical myasthenic features such as pyridostigmine and 3, 4- diaminopyridine responsiveness, and decrement on repetitive nerve stimulation are present. Conclusions These patients mimic myopathic disorders and are likely to be under-diagnosed. The descriptions here should facilitate recognition of this disorder. In particular minimal craniobulbar involvement and tubular aggregates on muscle biopsy help to distinguish DPAGT1 CMS from the majority of other forms of CMS. Patients with DPAGT1 CMS share similar clinical features with patients who have CMS caused by mutations in GFPT1, another recently identified CMS subtype.

A treatable muscle disease

A 70-year-old woman presented with increasing weakness and fatigue over 4 years. She had suffered motor problems from birth with hypotonia and delayed motor milestones. She walked abnormally in childhood but appeared to show some improvement at the age of 10 years, remaining ambulant throughout her life. She was seen by an eminent neurologist at the age of 15 years who documented a waddling gait, and after investigation she was given a diagnosis of “amyotonia congenita”. At the age of 43 years she was reviewed; there had been no significant progression but she reported being intermittently worse during menstruation. Examination at that point revealed mild weakness of eye closure, mild right-sided ptosis, weakness and some wasting of the periscapular muscles and hip flexors. Investigations revealed mildly raised serum creatine kinase (CK) level (twice normal) and a myopathic electromyogram (EMG). Mild fibre hypertrophy and absence of type 2B fibres were noted on muscle biopsy and she was thought to have a form of congenital myopathy. However, from the age of 66 years she had increasing difficulty climbing stairs and could only walk for 60 m. She was unable to lift heavy objects or use her arms above her head, she had difficulty holding her head up, occasional choking and breathlessness on exertion and when lying flat. Examination revealed bilateral ptosis with little fatigability (fig 1), mild facial and neck weakness, and her tongue was weak and had a central furrow. There was no ophthalmoplegia. She had marked shoulder girdle weakness with some wasting and scapular winging. There was also marked weakness around the pelvic girdle; she walked with a waddling lordotic posture, was just about able to get out of a chair without using her arms and she could stand on her heels and toes. Her vital capacity was 80% of …

THE EYES HAVE IT: INITIAL GENETIC SCREENING IN SUSPECTED CONGENITAL MYASTHENIA

The congenital myasthenic syndromes (CMS) are a heterogenous group of inheritable disorders of neuromuscular transmission. Screening each of the eight genes thus far identified as commonly causing CMS in every suspected patient would be inefficient. We propose a strategy for targeted initial screening, based on the ophthalmoplegia present. The four most common syndromes (see Abstract PONM11 Table 1) account for 85% of genetically confirmed CMS and from our clinical database the presence of ophthalmoplegia and the mean fractional range of movement (ROM, 0 to 1) are: In those patients with ophthalmoplegia screening should begin with the AChR subunits, starting with CHRNE. For patients without ophthalmoplegia the RAPSN and DOK7 genes should be initially screened. This screening strategy without using other specific guiding features (e.g., pattern of weakness, presence of arthrogryposis and squint, response to treatment, childhood apnoeas, double response on electromyography) would identify the causative mutation in 88% of the individuals included in this study. Further refinements using the severity of the ophthalmoplegia may improve the screening process.Abstract PONM11 Table 1 Syndrome N Ophthalmoplegia Mean ROM in those with ophthalmoplegia AChR deficiency 35 94% 0.23±0.2 (N=33) Syndrome (SCS) 21 62% 0.7±0.2 (N=13) Dok7 CMS 24 21% 0.66±0.2 (N=5)