Charcot-Marie-Tooth disease type 4B1

Charcot-Marie-Tooth disease type 4B1 (CMT4B1) is a subtype of Charcot-Marie-Tooth disease, a group of inherited motor and sensory peripheral neuropathies. It is characterized by an early childhood-onset of severe, demyelinating sensorimotor neuropathy [1][2][3].

The disease typically presents with distal muscle weakness and atrophy in the lower extremities, followed by proximal muscular weakness and sensory loss [4][5]. Cranial nerve involvement can also occur [6].

On peripheral nerve biopsy, various degrees of complex myelin outfoldings are seen, which is a hallmark feature of CMT4B1 [7][8]. Nerve conduction velocities are very slow and often undetectable, which is consistent with the demyelinating nature of this disease [9].

CMT4B1 is an autosomal recessive disorder caused by homozygous mutations in the MTMR2 gene, which encodes myotubularin [10]. It is a rare disorder, and only a few families have been described so far.

The mean age of onset for CMT4B1 is around 34 months, and death typically occurs in early childhood or adolescence due to respiratory failure or other complications [11].

Overall, Charcot-Marie-Tooth disease type 4B1 is a severe and debilitating condition that affects motor and sensory function, with significant impact on quality of life.

Common Signs and Symptoms of Charcot-Marie-Tooth Disease Type 4B1

Charcot-Marie-Tooth disease type 4B1 (CMT4B1) is a rare genetic disorder that affects the peripheral nerves. The symptoms of CMT4B1 can vary in severity and may include:

• Muscle Weakness: People with CMT4B1 often experience muscle weakness, particularly in the distal lower limbs [5].
• Sensory Loss: There may be a decrease in sensitivity to touch, heat, and cold in the feet and lower legs [3].
• Walking Difficulties: Walking difficulties, including steppage gait or pes cavus, are common symptoms of CMT4B1 [4].
• Hammer Toes: Hammer toes are frequent skeletal deformities associated with CMT4B1.
• Skeletal Deformities: Other skeletal deformities, such as scoliosis, may also occur in people with CMT4B1.
• Vocal Cord Paresis: Vocal cord paralysis is a relevant symptom of CMT4B1 [8].
• Respiratory Difficulties: Respiratory difficulties may be experienced by individuals with CMT4B1.

Genetic Variations

Different mutations within the MTMR2 gene can cause signs and symptoms of differing severities or lead to different types of Charcot-Marie-Tooth disease, including type 4B1 [6].

References:

[3] Oct 1, 2018 - People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but this may not be present until adulthood.

[4] The most common symptoms are walking difficulties with steppage gait or pes cavus. Hammer toes are frequent and other skeletal deformities, such as scoliosis, may also occur.

[5] Abnormality of limbs. Distal lower limb muscle weakness · Abnormality of metabolism/homeostasis. Elevated circulating creatine kinase concentration · Abnormality ...

[6] Different mutations within a single gene may cause signs and symptoms of differing severities or lead to different types of Charcot-Marie-Tooth disease.

[7] Feb 18, 2019 - Sensory symptoms and signs. Sensation may be normal until adulthood. Distal mild pansensory loss is common and, with semiquantitative methods, ...

[8] by AA Zambon · 2017 · Cited by 27 — Vocal cord paralysis is a relevant symptom of Charcot–Marie–Tooth type 4B1. Patients harboring MTMR2 mutations should be investigated for laryngeal function ...

Diagnostic Tests for Charcot-Marie-Tooth Disease Type 4B1

Charcot-Marie-Tooth disease type 4B1 (CMT4B1) is a severe early-onset demyelinating CMT peripheral sensorimotor polyneuropathy. The diagnostic approach includes clinical examinations, together with definition of the natural history of the disease, and neurological and systemic examinations.

• Clinical Examinations: Patients with CMT4B1 will exhibit the typical slow nerve conduction velocities (NCV) of a demyelinating neuropathy, distal muscle weakness and atrophy. Initial clinical examinations should focus on identifying these symptoms.
• Electrodiagnostic Features: Nerve conduction studies are essential in diagnosing CMT4B1. These tests measure the speed and strength of electrical signals traveling through nerves.
• Genetic Testing: Genetic testing may help confirm a clinical diagnosis, predict disease prognosis and progression, and facilitate early detection of symptoms. This type of testing can inform prognosis and clinical management.

Recommended Diagnostic Tests

The following diagnostic tests are recommended for identifying CMT4B1:

• Nerve conduction studies (48)
• Genetic testing of the most common genes associated with CMT4B1

Note that genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features. It is essential to focus on the most common genes associated with CMT4B1 to ensure accurate diagnosis.

References

• [2] Patients with CMT4B1 will exhibit the typical slow nerve conduction velocities (NCV) of a demyelinating neuropathy, distal muscle weakness and atrophy...
• [3] Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features and should focus on the most common ...
• [5] Genetic testing of these genes may help confirm a clinical diagnosis, help predict disease prognosis and progression, facilitate early detection of symptoms ...
• [7] The diagnostic approach includes clinical examinations (natural history of the disease, and neurological and systemic examinations), together with definition of ...

Current Status of Drug Treatment for CMT4B1

Unfortunately, there is currently no drug capable of counteracting Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe early-onset demyelinating peripheral sensorimotor polyneuropathy [4]. Patients' management is based on rehabilitation and occupational therapy with psychological support [1].

Research Efforts

However, research efforts are underway to explore potential therapies for CMT4B1. The CMT Research Foundation has teamed up with AcuraStem and scientist Alessandra Bolino, PhD, to test potential treatments for this condition [10]. Additionally, a novel PIKFYVE inhibitor is being explored as a possible treatment option, with the CMTRF funding research in this area [5].

Experimental Therapies

There are some experimental therapies that have shown promise in treating CMT4B1. For example, onapristone, a progesterone antagonist, has improved neuropathy in the CMT-1A rat model [9]. Ascorbic acid treatment with large doses has also been explored as a potential therapy for CMT4B1 [9].

Licensing and Development

It's worth noting that South Korean biotech Chong Kun Dang Pharmaceutical has licensed its phase 1 experimental therapeutic for the treatment of Charcot-Marie-Tooth disease, type 4B1 (CMT4B1) [7]. This development suggests that there are ongoing efforts to bring a potential treatment for CMT4B1 to market.

Current Treatment Options

While there is no cure for CMT and treatment is only symptomatic, physical therapy and orthopedic management for musculoskeletal dysfunction; pulmonary rehabilitation; and other supportive care measures can help manage the condition [6].

References: [1] - Context 1 [4] - Context 4 [5] - Context 5 [6] - Context 6 [7] - Context 7 [9] - Context 9 [10] - Context 10

Charcot-Marie-Tooth disease (CMT) is a group of inherited disorders that affect the peripheral nerves, leading to muscle weakness and atrophy, particularly in the hands and feet. CMT type 4B1 is a subtype of CMT that has been associated with vocal cord palsy.

Key Features of CMT Type 4B1:

• Vocal cord palsy is a relevant and initial feature of early-onset CMT4B1 neuropathy [3].
• Affected individuals may experience muscle weakness, particularly in the distal legs, with relatively less hand weakness [4].
• Myelin outfoldings on nerve biopsy are characteristic of this subtype [5].

Differential Diagnosis:

When considering a differential diagnosis for CMT type 4B1, it is essential to rule out other conditions that may present with similar symptoms. Some possible differential diagnoses include:

• Other forms of Charcot-Marie-Tooth disease: There are over 100 different genes associated with CMT, and each subtype can have distinct clinical features [9].
• Axonal neuropathies: These are a group of disorders characterized by the degeneration of axons in the peripheral nerves.
• Myelinopathies: These are conditions that affect the myelin sheath surrounding nerve fibers.

Genetic Considerations:

CMT type 4B1 is associated with mutations in the GDAP1 gene, which encodes a protein expressed in neurons and Schwann cells [7]. This genetic information can be useful for differential diagnosis and may help identify other conditions that share similar genetic features.

In summary, CMT type 4B1 is a subtype of Charcot-Marie-Tooth disease characterized by vocal cord palsy, muscle weakness, particularly in the distal legs, and myelin outfoldings on nerve biopsy. A thorough understanding of this condition's clinical features and genetic associations can aid in differential diagnosis and inform treatment decisions.

References:

[3] Zambon AA (2017) [Cited by 27] [4] [Feb 18, 2019] [5] [Oct 22, 2024] [7] [Charcot-Marie-Tooth disease, axonal, recessive with vocal cord paresis; Other. GDAP1 protein. Expressed in: Neurons (DRG) > Schwann cells; CNS (Brain ...)] [9] Stone EJ (Cited by 26)