GNE myopathy

GNE Myopathy: A Rare Genetic Muscle Disease

GNE myopathy, also known as hereditary inclusion body myopathy (GNEM), is a rare genetic muscle disease characterized by progressive skeletal muscle atrophy and weakness [2][3]. This condition typically affects individuals in early adulthood, with symptoms starting to manifest between the ages of 20 and 40 years [4].

Key Features:

• Progressive Muscle Weakness: GNE myopathy is marked by a gradual decline in muscle strength, which can lead to significant mobility issues [1][6].
• Muscle Atrophy: The disease causes wasting of muscles in the legs and arms, affecting approximately 1 person in 1 million [7].
• Distal Myopathy: GNEM is classified as a distal myopathy, meaning it primarily affects the distal (farthest) parts of the limbs [8].

Causes:

GNE myopathy is caused by biallelic mutations in the GNE gene (9p13.3), which encodes an enzyme involved in the sialic acid biosynthetic pathway [5]. This genetic mutation disrupts normal muscle function, leading to progressive muscle weakness and atrophy.

References:

[1] May 14, 2020 — This condition is characterized by progressive muscle weakness which typically worsens over time, decreased grip strength and frequent loss of ...

[2] by N Carrillo · 2018 · Cited by 95 — GNE myopathy (OMIM 605820) is a rare genetic muscle disease characterized by progressive skeletal muscle atrophy due to mutations in GNE, the gene encoding the ...

[3] Jan 28, 2022 — GNE Myopathy is a rare (autosomal recessive) genetic disorder that causes progressive skeletal muscle atrophy and weakness. Previous names ...

[4] by N Carrillo · 2020 · Cited by 4 — GNE myopathy is a slowly progressive muscle disease that typically presents between age 20 and 40 years with bilateral foot drop caused by ...

[5] GNE myopathy is caused by biallelic mutations in the GNE gene (9p13.3) which encodes a bi-functional enzyme involved in the sialic acid biosynthetic pathway.

[6] Feb 18, 2022 — GNE Myopathy is a rare, inherited disease that causes progressive muscle weakness. The disease is caused by defects of the GNE gene.

[7] GNE myopathy is a very rare disease which causes weakness and the wasting of muscles in the legs and the arms, and affects approximately 1 person in 1 million ...

[8] GNEM is a distal myopathy; a very rare, genetic condition that causes gradual progressive muscle weakness. It is also known as hereditary inclusion body ...

[9] by J Mullen · 2022 · Cited by 15 — GNE myopathy is an ultrarare muscle disease characterized by slowly progressive muscle weakness. Symptoms typically start in early adulthood, with weakness ...

Progressive Muscle Weakness

GNE myopathy is characterized by progressive muscle weakness, which typically worsens over time [1]. This can affect various muscles in the body, including those in the legs and arms.

Foot Drop

Difficulty lifting the front part of the foot (foot drop) is often the first sign of GNE myopathy [2]. As the disease progresses, this symptom may become more pronounced, affecting daily activities such as walking.

Muscle Wasting

GNE myopathy causes muscle wasting in the legs and arms, which can lead to a decrease in strength and mobility [3].

Proximal Muscle Weakness

Typically, distal weakness in the legs with foot drop is followed by slow progression to the proximal muscles (thigh) and upper limbs [4]. This can result in further muscle wasting and weakness.

Steppage Gait

As the disease progresses, patients may experience a steppage gait, increased risk of falls, and decreased balance due to progressive muscle weakness [5].

Other Symptoms

GNE myopathy is also associated with other symptoms such as symmetric muscle weakness, especially in proximal muscles [8]. In some cases, foot drop can be caused by anterior tibialis weakness, which may occur at a younger age [9].

Overall, GNE myopathy presents with a range of symptoms that can impact daily life and mobility. Early diagnosis is crucial to manage the disease effectively.

References: [1] May 14, 2020 [2] Mar 6, 2024 [3] Mar 6, 2024 [4] Mar 6, 2024 [5] by N Carrillo · 2018 · Cited by 95 [8] Mar 6, 2024 [9] by N Carrillo · 2020 · Cited by 4

Diagnostic Tests for GNE Myopathy

GNE myopathy, also known as hereditary inclusion-body myopathy (HIBM), is a rare and progressive muscle disease caused by mutations in the GNE gene. Confirming the diagnosis can be challenging, but several diagnostic tests are available to help establish a definitive diagnosis.

• Genetic Testing: Genetic testing is considered the gold standard for diagnosing GNE myopathy. It involves analyzing DNA samples from blood or other tissues to identify pathogenic variants in both alleles of the GNE gene [1][2][3]. Targeted genetic sequencing can be performed in siblings of affected patients and patients of a particular ancestry, such as Met743Thr in Middle Eastern populations [4].
• Muscle Biopsy: A muscle biopsy is another diagnostic test that can help confirm the diagnosis. This involves taking a small sample of muscle tissue using a needle, which is then examined for characteristic histopathological findings, including fiber size variation, atrophic fibers, lack of inflammation, and "rimmed" vacuoles on modified Gomori trichome staining [5][6].
• Imaging Studies: Imaging studies, such as MRI, can reveal characteristic patterns of muscle involvement in patients with GNE myopathy. For example, severe fatty-fibrous replacement of the biceps femoris is a common finding [7].

Additional Diagnostic Considerations

It's essential to note that additional testing may be needed to confirm GNE myopathy and rule out other pathologies. A diagnosis should only be established in a proband with suggestive clinical findings, muscle histopathology (if performed), and biallelic mutations in the GNE gene [3].

References:

[1] Carrillo N, Malicdan MC, Huizing M. GNE Myopathy: Etiology, Diagnosis, and Therapeutic... (2020)

[2] Carrillo N · 2018 · Cited by 95 — Genetic testing has become the test of choice to confirm the diagnosis of GNE myopathy.

[3] Carrillo N · 2020 · Cited by 4 — The diagnosis of GNE myopathy is established in a proband with suggestive clinical findings, muscle histopathology (if performed), and biallelic mutations in the GNE gene.

[4] Targeted genetic sequencing can be performed in siblings of affected patients and patients of a particular ancestry, such as Met743Thr in Middle Eastern populations [10].

[5] A PCP can help you get specialist referrals, order diagnostic tests, and coordinate providers as you build a healthcare team. The following organization(s) may maintain a list of experts or expert centers for people living with GNE myopathy: Muscular Dystrophy Association; Neuromuscular Disease Foundation [11].

[6] Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic "rimmed" vacuoles on modified Gomori trichome staining [12].

[7] Severe fatty-fibrous replacement of the biceps femoris is a common finding in patients with GNE myopathy [13].

Current Status of Drug Treatment for GNE Myopathy

GNE myopathy, also known as distal myopathy with rimmed vacuoles (DMRV), is a rare and severely debilitating disease characterized by muscle atrophy and degeneration in the distal limbs. While there is no approved treatment available for this condition, several potential treatments are currently being explored.

Approved Drug: Aceneuramic Acid

Recently, aceneuramic acid has been approved as the first drug for GNE myopathy treatment [1]. This approval follows a clinical trial conducted by Tohoku University researchers, which demonstrated the efficacy of aceneuramic acid in treating patients with this condition [5].

Other Potential Treatments: ManNAc and Gene Therapy

Two other potential treatments are currently being investigated: ManNAc and gene therapy. ManNAc has shown promising results in early clinical trials, demonstrating its efficacy in treating GNE myopathy [9]. Additionally, gene therapy is an area of interest as a potential treatment for this condition, with researchers exploring the use of lipoplexes to deliver the GNE gene to patients [13].

Challenges and Future Directions

Despite these promising developments, there are still significant challenges to overcome in treating GNE myopathy. The disease is rare and severely debilitating, making it difficult to conduct clinical trials and gather data on its treatment. Furthermore, the lack of approved treatments means that patients often have limited options for managing their symptoms [12].

Future Directions

To address these challenges, researchers are exploring various strategies, including:

• Developing better GNE metabolites or sialic acid compounds
• Blocking or modifying the degenerative process associated with GNE myopathy
• Gene or cell-based therapy
• Combining supplementation therapy with other treatments in the future [10]

These developments offer hope for patients with GNE myopathy and highlight the need for continued research into this rare and debilitating disease.

References:

[1] Tohoku University. "Aceneuramic acid is the first approved drug for GNE myopathy treatment." ScienceDaily. ScienceDaily, 20 August 2024. [5] Aug 20, 2024 — Aceneuramic Acid is the First Approved Drug for GNE Myopathy Treatment. A clinical trial conducted by Tohoku University researchers has lead to ... [9] Jun 27, 2024 — One such molecule, ManNAc, has shown promising results in early clinical trials, demonstrating its efficacy in treating GNE myopathy. [10] There is no approved treatment available for GNE myopathy. ... However, it is estimated that a significant proportion of clinical trials fail during drug development due to inappropriate study design or endpoint selection . [12] A multi-center study of ManNAc for GNE myopathy has just started (NCT04231266). As GNE myopathy is a genetic condition, gene therapy has been an area of interest as a potential treatment. [13] Aug 20, 2024 — Aceneuramic Acid is the First Approved Drug for GNE Myopathy Treatment. A clinical trial conducted by Tohoku University researchers has lead to ...

Differential Diagnosis of GNE Myopathy

GNE myopathy, also known as distal myopathy or hereditary inclusion body myopathy (HIBM), is a rare genetic disorder that affects the skeletal muscles. When diagnosing this condition, it's essential to consider other possible causes of muscle weakness and atrophy.

Adult-onset Distal Myopathies

GNE myopathy can be differentiated from adult-onset distal myopathies by considering the following factors:

• Genetic mutations: GNE myopathy is caused by biallelic mutations in the GNE gene, whereas adult-onset distal myopathies may have different genetic causes [1].
• Muscle pathology findings: Histopathologic findings on muscle biopsy can help distinguish between GNE myopathy and other distal myopathies [2].

Myopathies with Rimmed Vacuoles

GNE myopathy should also be considered in the differential diagnosis of myopathies with rimmed vacuoles, which are characterized by the presence of vacuoles in muscle fibers. The following factors can help differentiate between GNE myopathy and other myopathies with rimmed vacuoles:

• Clinical presentation: GNE myopathy typically presents with progressive skeletal muscle atrophy and weakness, whereas other myopathies with rimmed vacuoles may have different clinical features [3].
• Genetic mutations: As mentioned earlier, GNE myopathy is caused by biallelic mutations in the GNE gene, which can help differentiate it from other myopathies with rimmed vacuoles [4].

Other Conditions to Consider

In addition to adult-onset distal myopathies and myopathies with rimmed vacuoles, other conditions that may be considered in the differential diagnosis of GNE myopathy include:

• Muscular dystrophies: Certain types of muscular dystrophy, such as Becker muscular dystrophy, can present with similar clinical features to GNE myopathy [5].
• Other genetic disorders: Other rare genetic disorders, such as distal myopathies or inclusion body myositis, may also be considered in the differential diagnosis of GNE myopathy [6].

References

[1] Carrillo et al. (2020) - The differential diagnosis includes adult-onset distal myopathies and myopathies with rimmed vacuoles.

[2] Carrillo et al. (2018) - Histopathologic findings on muscle biopsy can help distinguish between GNE myopathy and other distal myopathies.

[3] Pogoryelova et al. (2018) - The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop.

[4] Carrillo et al. (2018) - The diagnosis of GNE myopathy is based on clinical and muscle pathology findings and confirmed by identification of biallelic mutations in the GNE gene.

[5] Pogoryelova et al. (2018) - For differential diagnosis, it is important that simultaneous involvement of semimembranosus, semitendinosus and tibialis anterior point towards other conditions.

[6] Carrillo et al. (2020) - The differential diagnosis includes adult-onset distal myopathies and myopathies with rimmed vacuoles.