Monday, May 4, 2015

I am appalled

Many years ago, I was caring for an 8 month old patient with episodic respiratory difficulties, feeding difficulties and ptosis due to congenital myasthenia.  After a number of crises, the patient's parents entertained the option of not supporting him during future episodes of respiratory deterioration. On the eve of a "care" conference, I wrote to the parents (edited):

"Quite frankly, I am appalled that nonsupport has been entertained as an option.  There is no question that he experiences a variety of handicaps and difficulties.  On the other hand, the difficulties he faces are capable of significant remediation.  There is no reason to believe that his underlying disease is relentlessly progressive.

Of greatest importance, there is no reason to believe at present that he suffers from cognitive handicap. There is every reason to believe that he is capable of a full spectrum of cognitive and interpersonal interactions.  There is every reason to believe that he has a great deal to give to others and a great deal to receive from them...

He, like you and I, is capable of giving and receiving, loving and being loved, learning and teaching.  It is my conviction that he wants to do these things.  It is my conviction that he should be given every opportunity to do so."

The intensivist with whom I was working was incredulous about my saying, "I am appalled."

The ethics committee, of course, said,  "The committee is aware that there is potential for both a positive future but also the potential for a bleak future since his case seems to be a more affected case than even a series of known patients.  The committee also concludes that it would  be ethically appropriate for parents to be allowed the option to decline aggressive therapy."

The patient was defined as having congenital myasthenia due to endplate acetylcholinesterase deficiency (see Ohno K, Brengman J, Tsujino A, Engel AG. Human endplate acetylcholinesterase
deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the
asymmetric enzyme. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9654-9.  This patient is patient 3. Also: Camp S, Bon S, Li Y, Getman DK, Engel AG, Massoulié J, Taylor P. Patients with
congenital myasthenia associated with end-plate acetylcholinesterase deficiency
show normal sequence, mRNA splicing, and assembly of catalytic subunits. J Clin
Invest. 1995 Jan;95(1):333-40.  This patient is patient 4.)

The parents decided to proceed with further care, including tracheostomy.  By 17 months of age, the patient was being treated with a novel regimen of nightly paralyzation and ventilation at home (see Breningstall GN, Kurachek SC, Fugate JH, Engel AG. Treatment of congenital endplate
acetylcholinesterase deficiency by neuromuscular blockade. J Child Neurol. 1996 Jul;11(4):345-6.)

Eventually, he was weaned from this intervention.  At 16 years of age he used BiPAP at night without positive pressure assistance.  His tracheostomy was removed long before this.  He ambulated independently, but used a wheelchair for traversing distances.

More recently, it was discovered that, of all things, albuterol provided significant benefit for him.  He went to college.


  1. Also, patient 4 in: Hutchinson DO, Engel AG, Walls TJ, Nakano S, Camp S, Taylor P, Harper CM, Brengman JM. The spectrum of congenital end-plate acetylcholinesterase deficiency. Ann N Y Acad Sci. 1993 Jun 21;681:469-86 and Hutchinson DO, Walls TJ, Nakano S, Camp S, Taylor P, Harper CM, Groover RV,
    Peterson HA, Jamieson DG, Engel AG. Congenital endplate acetylcholinesterase
    deficiency. Brain. 1993 Jun;116 ( Pt 3):633-53.

  2. Chan SH, Wong VC, Engel AG. Neuromuscular junction acetylcholinesterase
    deficiency responsive to albuterol. Pediatr Neurol. 2012 Aug;47(2):137-40.

    Congenital myasthenic syndrome caused by endplate acetylcholinesterase deficiency constitutes a rare autosomal recessive disease. We describe a child with early-onset ptosis, complete ophthalmoplegia, facial and proximal muscle weakness, easy fatigability, a decremental electromyographic response, and a repetitive compound muscle action potential not improved by anti-acetylcholinesterase medication. Mutation analysis of the collagenic tail of endplate acetylcholinesterase (COLQ) that encodes the collagenic structural subunit of acetylcholinesterase revealed two canonic splice-site mutations: a previously identified IVS15 + 1G>A mutation and a novel IVS2 - 1G>A mutation. Treatment with albuterol resulted in progressive improvement of muscle strength, exercise tolerance, and ophthalmoplegia. Further studies are needed of the efficacy of albuterol in different types of congenital myasthenic syndrome and the physiologic basis of its beneficial effects.

  3. Liewluck T, Selcen D, Engel AG. Beneficial effects of albuterol in congenital
    endplate acetylcholinesterase deficiency and Dok-7 myasthenia. Muscle Nerve. 2011 Nov;44(5):789-94.

    Congenital myasthenic syndromes (CMS) are disabling but treatable disorders. Anticholinesterase therapy is effective in most of them, but is contraindicated in endplate (EP) acetylcholinesterase (AChE) deficiency, the slow-channel syndrome, Dok-7 myasthenia, and β(2) -laminin deficiency, and is not useful in CMS due to defects in muscle-specific kinase (MuSK), agrin, and plectin. EP AChE, Dok-7, and β(2)-laminin deficiencies respond favorably to ephedrine, but ephedrine can no longer be prescribed in the USA.
    We used albuterol, another sympathomimetic agent, to treat 3 patients with EP AChE deficiency and 15 with Dok-7 myasthenia. Response to therapy was evaluated by a 9-point questionnaire pertaining to activities of daily life.
    Comparison of the pre- and posttreatment responses indicated a beneficial response to albuterol (P < 0.001) in both patient groups. The adverse effects of therapy were like those of ephedrine.
    Our observations should spur controlled, prospective clinical trials of albuterol in these as well as other CMS.

  4. The patient is patient 2 in the Liewluck reference above.