Understanding Charcot-Marie-Tooth Disease, Dominant Intermediate B

Charcot-Marie-Tooth disease, dominant intermediate B (CMTDIB), is an inherited neuropathy caused by pathogenic variants in the DNM2 gene. It follows an autosomal dominant inheritance pattern, and some affected families also have neutropenia, a low level of infection-fighting white blood cells called neutrophils. Genetic testing can help confirm the diagnosis.

Understanding Charcot-Marie-Tooth Disease, Dominant Intermediate B

Charcot-Marie-Tooth disease (CMT) is a group of inherited conditions that damage the peripheral nerves. Intermediate forms have features of both the demyelinating type (CMT1), which damages the myelin coating, and the axonal type (CMT2), which damages the nerve fiber.

CMTDIB is caused by pathogenic variants in the DNM2 gene, which provides instructions for making dynamin 2. This protein helps form small sacs that move materials into cells and helps organize the cell’s internal support structure. Some affected families also have neutropenia, a low level of infection-fighting white blood cells called neutrophils. Early cataracts have also been reported.

Symptoms usually begin in childhood or early adulthood and include muscle weakness and wasting in the feet and lower legs, numbness and reduced reflexes.

Diagnosing Charcot-Marie-Tooth Disease, Dominant Intermediate B

Nerve conduction studies in intermediate CMT typically show signal speeds between the slower speeds seen in demyelinating CMT1 and the near-normal speeds seen in axonal CMT2. A blood count may also identify neutropenia in some people with CMTDIB. Genetic testing through a multigene panel, exome sequencing or genome sequencing can help confirm the diagnosis by identifying a pathogenic variant associated with CMTDIB in the DNM2 gene.

Uses of Genetic Testing for Charcot-Marie-Tooth Disease, Dominant Intermediate B

Genetic testing for CMTDIB can be helpful in several ways:

1. Confirming the diagnosis: Finding a disease-causing variant associated with CMTDIB in the DNM2 gene can help confirm the diagnosis and provide answers about the cause of symptoms.
2. Separating CMT subtypes: Many types of CMT have similar symptoms. A genetic result can identify the specific subtype and help doctors plan care.
3. Checking other features: Some DNM2 variants associated with CMTDIB have been linked to low levels of certain white blood cells (neutropenia) and clouding of the lens of the eye (cataracts). The result can help doctors decide whether additional checks are needed.
4. Family screening and counseling: Relatives of someone with a confirmed pathogenic variant associated with CMTDIB in the DNM2 gene can choose to have testing for that variant. A genetic counselor can explain what the result means for the family, including the 50% chance of passing the variant on with each pregnancy.
5. Research and clinical trials: Some research studies and trials enroll people by gene. A confirmed genetic diagnosis can make it easier to find studies that fit.

Advancements in Genetic Research for Charcot-Marie-Tooth Disease

Research on CMTDIB focuses on understanding how pathogenic variants in the DNM2 gene affect peripheral nerves. This work may help guide the development of future treatments.

Related Charcot-Marie-Tooth Articles

• Charcot-Marie-Tooth, Intermediate: forms with features of both CMT1 and CMT2.
• Charcot-Marie-Tooth Disease: an overview of CMT and its genetics.

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Frequently Asked Questions About Charcot-Marie-Tooth Disease, Dominant Intermediate B

What is CMT dominant intermediate B?

It is an inherited neuropathy with features of both demyelinating and axonal CMT. Some families also have neutropenia, a low number of neutrophils, which are white blood cells that fight infection.

What causes it?

It is caused by pathogenic variants in the DNM2 gene, which makes dynamin 2.

What are the symptoms?

Common symptoms include weakness and wasting of the feet and lower legs, high arches, trouble walking, reduced reflexes and sensory loss. Some people have neutropenia or early cataracts.

How is it inherited?

It is inherited in an autosomal dominant pattern. One altered copy of the gene is enough to cause the condition, so each child of an affected parent has a 50% chance of inheriting the variant. Some people have a new (de novo) variant that was not inherited from either parent.

How is it diagnosed?

A neurologist usually starts with a medical and family history and an exam of strength, reflexes and sensation. Nerve conduction studies and electromyography (EMG) show how well nerves carry signals and whether the problem mainly affects the myelin coating or the nerve fiber (axon). Genetic testing can then confirm the specific cause.

Is there a treatment?

There is currently no cure, but care can help people stay active and independent. Physical and occupational therapy, ankle-foot orthoses (braces), supportive footwear, orthopedic surgery for foot deformities and pain management are commonly used. Some medications can worsen CMT symptoms, so tell every doctor treating you if you have CMT. A neuromuscular specialist can build a care plan with you.

Does Sequencing test for this condition?

Whole genome sequencing reads 100% of your DNA, which includes the DNM2 gene discussed in this article. Sequencing's Kit Bundles include Next Gen Disease Screening, which analyzes your genome for more than 15,000 conditions. You can also upload DNA data from another test for free and search it in Genome Explorer. Results describe variants, not a diagnosis.

Where can I find support or a specialist?

Patient organizations such as the Charcot-Marie-Tooth Association, Hereditary Neuropathy Foundation, Immune Deficiency Foundation and Muscular Dystrophy Canada offer education and support for people and families affected by CMT, and several publish directories of CMT clinics or specialists. They are listed in the resources below, along with an expert written overview from GeneReviews.

Resources

These organizations and resources are provided for education and support. They are not endorsements or medical advice.

• Charcot-Marie-Tooth Association (United States): a patient and family organization for all types of CMT.
• CMTA: Find a specialist: the organization's directory of clinics or specialists.
• CMTA: Advisory Board: the medical and scientific advisors who guide the organization.
• Hereditary Neuropathy Foundation (United States): a patient organization for people and families affected by CMT and other inherited neuropathies.
• HNF: Find a specialist: the organization's directory of clinics or specialists.
• HNF: Scientific Advisory Board: the medical and scientific advisors who guide the organization.
• Immune Deficiency Foundation (United States): patient organization for immune conditions, with general information about neutropenia (low levels of a type of white blood cell) that is not specific to CMTDIB.
• IDF: Find a specialist: the organization's directory of clinics or specialists.
• IDF: Medical Advisory Committee: the medical and scientific advisors who guide the organization.
• Muscular Dystrophy Canada (Canada): a neuromuscular disease organization that supports people with CMT in Canada.
• Muscular Dystrophy Canada: Medical and Scientific Advisory Committee (MSAC): the medical and scientific advisors who guide the organization.
• GeneReviews: Charcot-Marie-Tooth Hereditary Neuropathy Overview (NCBI Bookshelf): an expert written clinical overview of CMT types and genes.

References

1. Züchner S, Noureddine M, Kennerson M, et al. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat Genet. 2005;37(3):289-294. doi:10.1038/ng1514

This article is for education and is not a substitute for professional medical advice, diagnosis, or treatment. Talk to a qualified healthcare provider about your own health.