The mystery of the missing smile (Moebius sequence) and autism

Many years ago while doing my residence training in Neurology I saw a patient that could not smile or frown. She had a blank stare on her face and had been like that ever since she was born. She was about 16 years of age when I first saw her at the outpatient clinics wondering whether I could do anything to help her. After taking the history and performing a physical/neurological examination I made the diagnosis of Moebius (also spelled Möbius) sequence. Unfortunately I could not do much for her. The masked facial expression wasn’t stoicism, but a neurological disability. She was truly hurting deep inside. I have always remembered her visit, the way she left my office, and my frustration at not being able to help her.


Figure: Paul Julius Moebius was a clinical neurologist and a researcher.  He made many contributions to medicine but his name is primarily associated with Moebius syndrome. Some of his work, unfortunately, was characterized by misogynistic attitude.

Moebius syndrome was first described by Harlan in 1880 but more extensively by the German neurologist Paul Julius Moebius (see figure above) in 1888 and later on in 1892. It is a congenital, static condition primarily affecting the muscles that control facial expression and eye movement. Patients can’t frown or grimace and many can’t move their eyes laterally. The combination of signs can be produced by multiple disorders affecting either the facial musculature, cells of the spinal cord, or the peripheral nerves. The fact that many known etiologies provide for the same constellations of signs makes the condition a “sequence” but, in the general literature, it is most commonly alluded to as a syndrome. (Note: In this regard autism per se should be considered a “sequence” not a syndrome. More on this in a later blog).

Moebius sequence is the result of underdevelopment of several brainstem nuclei. Usually the lower face is less involved than the upper face. Bilateral paralysis of the abducens nerve (cranial nerve VI) causes some affected individuals to have convergence of their eyes (their eyes turn inward, see banner image for this blog and the figure below). Dysfunction of other cranial nerves is common. Because multiple cranial nerves may be involved, patients may have a greater deficit in language and communication than predicted based on a normal intelligence quotient. Their blank facial expression is sometimes misinterpreted as dullness or unfriendliness. Other symptoms of the condition include atrophy of the tongue, paralysis of the soft palate, and deafness. Since the nerves that innervate the muscles of mastication are sometimes affected, the mandible may lack proper stimulation for growth during fetal development (micrognathia).

In some cases a period of hypotension (maternal hypotension, shock or a threatened abortion due to abruptio placenta) some 4 to 6 weeks before birth may provide for tissue injury within the areas of the brainstem in which the facial nerve is located. The end result is death of the cells that innervate the facial muscles and the gradual accumulation of mineral deposits as a tombstone to the hypotensive lesion. Since there is a close anatomical association between the facial nerve and cells that provide for lateral gaze both are usually affected concomitantly.

Several gene loci are involved and the literature now makes reference to Moebius syndromes 1, 2, and 3. However, these genetic cases only represent a tiny fraction of all Moebius cases. Prognosis depends on whether the brainstem centers for respiration and deglution/swallowing are affected.

Some research suggests that individuals with Moebius sequence are more likely to exhibit autistic symptoms than the general population. A study of 17 children and young adults with the condition revealed that 40% of them showed many of the symptoms of autism spectrum disorders (Gillberg and Steffenburg, 1989). The high prevalence has been corroborated in other series (Johansson et al., 2001) but downplayed in others (Briegel et al., 2009).

Sometime in the 1990’s Patricia Rodier created waves in the world of autism when she reported the case of an autistic individual whom at postmortem examination exhibited near-complete absence of several brainstem nuclei (facial and superior olive). It may well be that the patient she examined had Moebius sequence.  In her initial report  Dr. Rodier reported that similar neuropathological findings had been observed in mice where their genetic material had been manipulated (Hoxa-1 gene knockout mice).  She then took this observation and examined for variations of the Hoxa1 gene in ASD.  Her findings helped confirm that Hoxa1 is a susceptibility gene for autism. Neuropathological studies in ASD have not reported consistent abnormalities to help sustain a critical role of the brainstem nulei in autism, but more research is certainly needed in this area ( ).


Figure: The late Patricia Rodier died in 2012 at the age of 68 years. Dr. Rodier was an embryologist specializing in conditions of the nervous system.

What appears notewhorthy is that a large number of children exposed to cocaine or misoprostol in utero manifest autistic symptomatology.  It may not be coincidental that large number of patients with Mobius sequence are associated to prenatal exposure of the same chemicals (Kankirawaana et al., 1993; Bandim et al., 2003).

Bandim JM, Ventura LO, Miller MT, Almeida HC, Costa AE. Autism and Mobius sequence: an exploratory study of children in northeastern brazil. Arq Neuropsiquiatr 61(2A):181-6, 2003.
Briegel W, Schimek M, Kamp-Becker I< Hofmann C, Schwab KO. Autism spectrum disorders in children and adolecents with Moebius sequence. Eur Child Adoles Psychiatry 18(8):515-9, 2009.
Gillberg C, Steffenburg S. Autistic behavior n Moebius syndrome. Acta Paediatr Scand 78(2):314-6, 1989.
Johansson M. Wentz E, Fernell E., Stromland K, Miller MT, Gillberg C. Autistic spectrum disorders in Moebius sequence: a comprehensive study of 25 individuals. Dev Med Child Neurol 43(5):338-45, 2001.
Kankirwatana P, Tennison MB, D’Cruz O, Greenwood RS. Mobius syndrome in infant exposed to cocaine in utero. Pediatr Neurol 9(1):71-2, 1993.
Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J. Embyological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 370(2):247-61, 1996.

4 responses to “The mystery of the missing smile (Moebius sequence) and autism

  1. You might also be interested in a new study published by the CDC’s autism and developmental disability network who found that 8 year old children born in 2000 had an autism prevelance rate of 6.9%. This replicates a prior report by the same group using a differfent cohort, 8 year old children born in 1998 with cerebral pasly. In the earlier study they found that 8.1% of 8 year olds with cerebral palsy had a diagnosis of autism. The results of both studies were predicted by my model you cited above. It is the most consisently replicated autism phenomena and has been since Stella Chess finding of a 7.4% autism prevelance among 243 children diagnosed with congenital rubella syndrome in 1974.

    Thanks for posting my article 🙂


  2. Thank you for the information. As an aside most studies on the genetics of autism offer generic results with little in terms of explanation for clinical phenomena. It is difficult to find articles that have thought outside of the box and offered overarching explanations to autism as a whole. In this regard your article stands apart from many others. It is also highly readable:


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