What Are the Clinical Presentation of Charcot-Marie-Tooth Disease?

Patient Presentation
A 2-year-old male came to clinic for his health supervision. The mother was concerned that he was somewhat clumsy. “It’s always seems like he will just fall down for no good reason. He has bruises on his shins that I’ve noticed too,” she complained. “He’s pretty active and keeps up with his older sister and other kids though. Nothing stops him” she related. The past medical history showed a full-term infant without any pre- or peri-natal problems. His development had been tracking and by developmental screening questionnaire during the office visit was also on track. The review of systems was also normal. When reviewing the family history the mother became serious. “I wanted to bring up the falling down, because at our family reunion this summer I found out that one of my cousin’s sons has just been diagnosed with Charcot-Marie-Tooth disease. My cousin’s wife wasn’t worried about it, so I didn’t think anything at the time, but then I looked it up on the Internet and found out there can be real problems that get worse. It’s really bothering me and I’m wondering if we should test him for it?” she asked. The mother said that that the affected child was diagnosed at age 8 after he was noticed to have problems with writing that the teachers complained about. The mother said, “The boy’s father is my first cousin on my father’s side. The boy’s mother married into our family and said at the reunion that she has no problems.” The boy’s siblings are well also. The patient’s sister was a healthy 4 year old, and there were no neurological diseases in either side of the family that the mother was aware of or early infant deaths.

The pertinent physical exam showed a well-appearing male with normal vital signs and growth parameters. He scribbled on a chalkboard appropriately in the room, walked and climbed up onto the examination table and chair from the floor without difficulties. His extremities showed a few scattered bruises on his shins in various stage of healing. Cranial nerves III-XI were intact. He had good muscle bulk, strength, tone and normal deep tendon reflexes. No clonus or muscle wasting was noted. He was able to get up from a seated position on the floor without difficulties (i.e. no Gower sign) and appeared to have a normal gait for age walking and running. The rest of his examination was negative.

The diagnosis of a healthy 2 year old was made, but with a new diagnosis of Charcot-Marie-Tooth disease in a second cousin. The pediatrician said, “By what you’re telling me and his normal physical exam he looks like a healthy normal boy to me at this time. I haven’t read about Charcot-Marie-Tooth for quite a while so I would need to look that up to be able to know if your children should be tested. Do you think that your cousin would be willing to share more information about his son? Having the exact name, and what the boy’s doctors have told the parents about who else in the family might need to be tested would be really helpful.” The mother said she would talk with her cousin. A few weeks later, the patient’s sister returned for her own health supervision visit. The mother relayed that the affected boy had been diagnosed with a X-linked form of Charcot-Marie-Tooth and therefore the boy’s mother’s family was most likely affected and were being informed. “My cousin said that at this time the father’s family, like us, doesn’t need to be evaluated but I’m going to keep in touch with my cousin about this. They also said that the boy should do very well over time but will probably have more problems with handwriting and doing other things like tying shoes. I’m just glad that he will be OK,” the mother explained.

Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy, is the most common cause of inherited neuropathies affecting 10-82:100,000 individuals. CMT comprises a heterogeneous group of peripheral, chronic inherited neuropathies that affects both the motor and sensory neurons and which have different genetic causations. Charcot and Marie were both French neurologists and Tooth was a British neurologist who described distal muscle wasting in 1886. Dejerine and Sottas reported the infantile form in 1893 which bears their name for this more severe clinical subtype. CMT classification is advancing as new testing becomes available but currently is classified as:

  • CMT1
    • Most common variant of CMT (70%)
    • Autosomal dominant
    • Has different subgroups but the most common subgroup is CMT1A which codes for a peripheral nerve protein 22 on chromosome 17
    • Identified most often with classic clinical presentation (see below)
    • Has slow nerve conduction and demyelination
  • CMT2
    • Autosomal dominant
    • Clinical indistinguishable from CMT except for nerve conduction studies
    • Has near normal nerve conduction and no demyelination
  • CMT3 or Dejerine-Sottas disease
    • Autosomal dominant or recessive
    • Has hypertrophy of nerve fibers often described as an “onion-bulb” in appearance on biopsy
    • This is the classic infantile onset clinical presentation (see below)
    • Has very slow nerve conduction times and demyeliation
  • CMT4
    • Autosomal recessive
    • Rare with distinct phenotypes
  • CMTX
    • Second most common form of CMT (10%)
    • X-linked dominant
    • More severe in males than females. Females may have few symptoms.
    • Have slowed nerve conduction times

Learning Point
Clinical phenotypes of CMT are often describe as classic and then age based.

  • The classic phenotype is being able to walk on time around 12 to 15 months of age but with the development of weakness or sensory loss over the next 20 years. Symptoms slow after that time but patients usually require few ambulatory aids.
    This is commonly found for CMT1A and men with CMTX.

  • Infantile onset shows patients that do not begin walking on time. There are severely affected and likely to require ambulatory aids by the age of 20.
    Examples are some patients with CMT3 and CMT1.

  • Adult onset where patients may have no symptoms until middle age. This is common in some variations of CMT1 and women with CMTX.

“The neuropathy of CMT is length dependent, which means that the longest nerves in the body are affected first and most severely.” Lower extremities are usually affected before the upper extremities.

Symptoms vary greatly by individual and subtypes. Patients often come to attention because of difficulties in walking or running including toe walking, tripping or falling, or just general clumsiness for gross motor movement. There also may be foot (pes cavus or hammar toes) or ankle injuries because of the muscle weakness. Upper extremity symptoms may not come to attention until the child has to perform fine motor movements such as tying shoes, dressing or writing. Infants may have hypotonia, hip dysplasia and feeding problems.

On physical examination muscle weakness and wasting can be subtle or obvious. Wasting is often seen in the hands. Sensory nerve abnormalities are often less prominent but decreaseed joint position and vibration tend to be more affected than temperature or pin prick sensations. Gait abnormalities are common depending on severity and individual compensation.

After diagnosis which often requires neurology and genetic evaluations, patients and families may need treatment. Treatment has to be individualized to preserve quality of life, particularly mobility, being the most important. Multidisciplinary treatment including physical therapy (focusing on range of motion, strengthening and balance) occupational therapy (improving activities of daily living and handwriting) and orthopedic surgery (to maintain ambulation and decrease pain associated with structural and functional problems) are important for families.

Questions for Further Discussion
1. What are causes of peripheral neuropathy? See a Review here
2. What are distinguishing features between a neuropathy and a myopathy?
3. What data do you use to determine if a family member needs screening or diagnostic testing for a potential disease?
4. What are the ethical issues of genetic testing for minor children?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Charcot-Marie-Tooth Disease

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Yagerman SE, Cross MB, Green DW, Scher DM. Pediatric orthopedic conditions in Charcot-Marie-Tooth disease: a literature review. Curr Opin Pediatr. 2012 Feb;24(1):50-6.

Patzko A, Shy ME. Charcot-Marie-Tooth disease and related genetic neuropathies. Continuum (Minneap Minn). 2012 Feb;18(1):39-59.

Jani-Acsadi A, Ounpuu S, Pierz K, Acsadi G. Pediatric Charcot-Marie-Tooth disease. Pediatr Clin North Am. 2015 Jun;62(3):767-86.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital