Cracking the Code: Understanding and Diagnosing Charcot-Marie-Tooth Disease, Dominant Intermediate B, with Neutropenia

Expert Reviewed By: ⁠Dr. Brandon Colby MD

Charcot-Marie-Tooth disease (CMT) is a group of inherited neurological disorders that affect the peripheral nerves, causing muscle weakness and sensory loss. Dominant intermediate B, with neutropenia, is a rare subtype of CMT, characterized by additional symptoms such as low white blood cell count (neutropenia). In recent years, advances in genetic testing have provided valuable insights into the underlying causes of this complex disorder and have paved the way for more accurate diagnosis and management. This article will explore the current understanding of dominant intermediate CMT, the role of genetic testing in diagnosis, and the potential benefits of genetic testing for individuals affected by this condition.

Understanding Dominant Intermediate Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease is a heterogeneous group of disorders, with various subtypes classified based on the specific genes involved and the pattern of inheritance. Dominant intermediate CMT refers to a group of CMT subtypes that have features of both demyelinating and axonal neuropathy, and are inherited in an autosomal dominant manner. This means that an affected individual has a 50% chance of passing the condition on to their offspring.

Mutations in the Dynamin 2 Gene

One of the key discoveries in understanding the genetic basis of dominant intermediate CMT was the identification of mutations in the pleckstrin homology domain of the dynamin 2 gene (DNM2) (source). This gene plays a crucial role in the formation and maintenance of nerve cells, and mutations in DNM2 can lead to impaired nerve function and the characteristic symptoms of CMT.

C1orf194 Deficiency

Another significant finding was the link between C1orf194 deficiency and dominant intermediate CMT. A study involving C1orf194 knockout mice demonstrated that the absence of this gene led to early embryonic lethality and motor and sensory defects, serving as a model for dominant intermediate CMT (source).

Diagnosing Charcot-Marie-Tooth Disease

Diagnosing CMT can be challenging due to its clinical variability and genetic heterogeneity. Clinical evaluation, nerve conduction studies, and electromyography are commonly used to assess the severity and type of neuropathy. However, genetic testing has become an increasingly important tool for confirming a diagnosis and identifying the specific subtype of CMT.

Genetic Testing for PMP22 Duplication and Deletion

One of the most common genetic causes of CMT is the duplication or deletion of the PMP22 gene. A study investigating the frequency of PMP22 gene alterations in a cohort of Egyptian patients with CMT found that genetic testing was a valuable tool for identifying the underlying genetic cause of the disease (source).

Identifying Mutations in the HSPB1 Gene

Another important genetic cause of CMT is missense mutations in the HSPB1 gene, which have been linked to axonal CMT and distal hereditary motor neuropathy (source). Genetic testing for HSPB1 mutations can help to confirm a diagnosis and provide valuable information for the management of the condition.

Benefits of Genetic Testing for Charcot-Marie-Tooth Disease

Genetic testing for CMT can provide several benefits for individuals and families affected by the condition:

Accurate Diagnosis

Identifying the specific genetic cause of CMT can help to confirm a diagnosis and provide a clearer understanding of the disease course and prognosis.

Family Planning

For individuals with a family history of CMT, genetic testing can provide information about their risk of passing the condition on to their children, allowing for informed family planning decisions.

Treatment and Management

Understanding the genetic basis of CMT can help to guide treatment and management strategies, including physical therapy, occupational therapy, and the use of assistive devices.

Future Research

As our understanding of the genetic basis of CMT continues to grow, there is hope that this knowledge will lead to the development of targeted therapies and potential cures for this complex condition.

About The Expert Reviewer

Dr. Brandon Colby MD is a US physician specializing in the personalized prevention of disease through the use of genomic technologies. He’s an expert in genetic testing, genetic analysis, and precision medicine. Dr. Colby is also the Founder of  and the author of ⁠⁠Outsmart Your Genes.

Dr. Colby holds an MD from the Mount Sinai School of Medicine, an MBA from Stanford University’s Graduate School of Business, and a degree in Genetics with Honors from the University of Michigan. He is an Affiliate Specialist of the American College of Medical Genetics and Genomics (⁠⁠ACMG), an Associate of the American College of Preventive Medicine (⁠⁠ACPM), and a member of the National Society of Genetic Counselors (⁠NSGC)