Charcot-Marie-Tooth disease type 4J

Charcot-Marie-Tooth disease type 4J (CMT4J) is a rare subtype of Charcot-Marie-Tooth disease type 4, characterized by childhood- to adulthood-onset of variably severe symptoms [1]. It is an autosomal recessive progressive neurologic disorder with a highly variable phenotype and onset ranging from childhood to adulthood [6].

The symptoms of CMT4J include rapidly progressive sensorimotor neuropathy, delayed motor development, muscle weakness, and atrophy [8]. This subtype falls under the category of demyelinating forms of CMT, which are inherited in an autosomal recessive pattern [7].

CMT4J is a rare form of CMT, affecting only 0.24% of people with the disease [2]. It is caused by biallelic mutations in the peripheral myelin protein zero gene (Thr124Met) [3], which leads to the degeneration of peripheral nerves.

The symptoms and progression of CMT4J can vary significantly from person to person, making it a challenging condition to diagnose and manage. However, early diagnosis and treatment can help alleviate some of the symptoms and improve quality of life for those affected by this rare disease.

References: [1] - Context result 1 [2] - Context result 2 [3] - Context result 3 [6] - Context result 6 [7] - Context result 7 [8] - Context result 8

Common Signs and Symptoms of CMT4J

Charcot-Marie-Tooth disease type 4J (CMT4J) is a subtype of Charcot-Marie-Tooth disease type 4, characterized by childhood- to adulthood-onset of variably severe symptoms [1]. The most frequent signs and symptoms observed in both pediatric and adult patients are:

• Gross motor delay: A significant delay in developing gross motor skills, such as walking and running [3].
• Muscle weakness: Weakness in the muscles, particularly distal (far from the center of the body) but sometimes involving proximal (near the center of the body) muscles [2].
• Impairment or loss of reflexes: Decreased or absent reflexes in the affected limbs.
• Skeletal deformities: Abnormal curvatures of the spine (scoliosis), pes cavus (high arches), hammer toes, and other skeletal deformities [7].

Additional Symptoms

Other symptoms associated with CMT4J include:

• Decreased sensitivity to touch, heat, and cold: A decreased sensitivity to touch, heat, and cold in the feet and lower legs.
• Walking difficulties: Walking difficulties with steppage gait or pes cavus.
• Muscle wasting and contractures: Muscle wasting and contractures (permanent shortening of the muscles) that affect both lower and upper limbs [9].

References

[1] Childhood- to adulthood-onset of variably severe symptoms in CMT4J.

[2] Weakness, usually mostly distal but sometimes involving proximal muscles.

[3] Gross motor delay and muscle weakness, each noted in 14 patients.

[7] Walking difficulties with steppage gait or pes cavus, hammer toes, and other skeletal deformities.

[9] Muscle wasting and contractures that affect both lower and upper limbs.

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

Charcot-Marie-Tooth disease type 4J (CMT4J) is a subtype of Charcot-Marie-Tooth disease, and its diagnosis involves a combination of clinical features, family history, neurological examination, and specific diagnostic tests. Here are some of the key diagnostic tests used to diagnose CMT4J:

• Genetic testing: Genetic testing can help confirm a clinical diagnosis of CMT4J by identifying autosomal recessive variants in the Factor-Induced Gene 4 (FIG4) gene [5]. This test is usually done with a blood sample and can detect the most common genetic defects known to cause CMT4J [11].
• Nerve conduction velocity (NCV): NCV tests measure the speed at which electrical signals travel through nerves. Abnormal results can indicate nerve damage, which is characteristic of CMT4J [5].
• Electromyography (EMG): EMG tests measure the electrical activity of muscles and can help identify muscle weakness or atrophy, which are common symptoms of CMT4J [6].
• Clinical genetic test: A clinical genetic test offered by Molecular Genetics Laboratory for conditions such as Charcot-Marie-Tooth disease can also be used to diagnose CMT4J [4].

Diagnostic Teams

A diagnostic team for CMT4J may include:

• Genetics: Geneticists play a crucial role in diagnosing and managing CMT4J, particularly in identifying genetic variants that cause the condition.
• Neurology: Neurologists are essential in evaluating patients with suspected CMT4J, performing neurological examinations, and interpreting NCV and EMG results.

References

[1] - [15] refer to the search results provided in the context.

Current Status of Drug Treatment for CMT4J

Unfortunately, there is still no effective drug treatment available for Charcot-Marie-Tooth disease type 4J (CMT4J). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment [6][14].

Preclinical Studies and Gene Therapy

However, preclinical studies have shown promising results in testing gene-therapy approaches to restore FIG4 function, which is the underlying cause of CMT4J [5]. Additionally, a study demonstrated the potent beneficial effects of AAV9 gene therapy in a severe mouse model of CMT4J [7].

Potential Therapies

Researchers are exploring various potential therapies for CMT4J, including:

• Gene silencing and gene replacement therapies
• Small molecule treatments
• Curcumin, a low-affinity SERCA inhibitor derived from turmeric, which has shown promise in improving trafficking and reducing UPR [8]

Challenges and Future Directions

Despite these promising findings, there are still significant challenges to overcome before effective drug treatments can be developed for CMT4J. These include the need for further preclinical studies and clinical trials to demonstrate safety and efficacy.

References:

• [1] Stavrou, M. (2021). Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing.
• [5] Presa, M. (2021). There is currently no treatment for CMT4J. Here, we present the results of preclinical studies testing a gene-therapy approach to restoring FIG4 function.
• [6] There is still no effective drug treatment available for Charcot-Marie-Tooth disease (CMT).
• [7] Elpida Therapeutics has demonstrated the potent beneficial effects of their CMT4J gene therapy (AAV9) in a severe mouse model of CMT4J.
• [8] Administration of curcumin, a low-affinity SERCA inhibitor derived from turmeric, has been shown to improve trafficking and reduce UPR.

Differential Diagnosis of CMT4J

Charcot-Marie-Tooth disease type 4J (CMT4J) is a rare form of demyelinating neuropathy caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene. When diagnosing CMT4J, it's essential to consider other rare hereditary causes of neuropathy that may present similarly.

Other Rare Hereditary Causes of Neuropathy

• Other rare hereditary causes of neuropathy also need to be considered in the differential diagnosis of CMT, but typically these have distinct clinical and genetic features [5].
• These include conditions such as Charcot-Marie-Tooth disease type 2 (CMT2), which is an axonal peripheral neuropathy characterized by distal muscle weakness and atrophy [6].

Key Features to Consider

When differentiating CMT4J from other rare hereditary causes of neuropathy, the following key features should be considered:

• Genetic mutations: CMT4J is caused by recessive mutations in the FIG4 gene. Other conditions may have distinct genetic profiles.
• Clinical presentation: CMT4J typically presents with demyelinating features such as conduction block [3]. Other conditions may have different clinical presentations, such as axonal neuropathy or distal muscle weakness and atrophy.

References

[1] Oct 1, 2018 — Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. [2] by E Cottenie · 2013 · Cited by 53 — Charcot-Marie-Tooth disease type 4J (CMT4J), a rare form of demyelinating CMT, caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene ... [3] by J Li · 2020 · Cited by 2 — Objective:To demonstrate CMT 4J can present electrophysiologically with conduction block. Background: Charcot-Marie Tooth (CMT) disease also ... [4] by LR Peddareddygari · 2022 · Cited by 4 — Charcot Marie Tooth disease type 4J (CMT4J) is an uncommon genetic neuropathy caused by mutations in the FIG4 gene. This gene encodes a ... [5] by JC Hoyle · 2015 · Cited by 93 — Other rare hereditary causes of neuropathy also need to be considered in the differential diagnosis of CMT, but typically these have distinct clinical and genetic features. [6] Charcot-Marie-Tooth disease type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy. Axonal ... [7] by JC Hoyle · 2015 · Cited by 93 — Charcot–Marie–Tooth (CMT) disease is a genetically and phenotypically heterogeneous group of disorders. Classically, CMT includes hereditary disorders ... [8] by TD Bird · 2016 · Cited by 5 — Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity ...