Hello
The pattern you describe is concerning for a progressive neuromuscular disorder, and the muscle biopsy finding of neurogenic atrophy with mild myopathy is a particularly important clue. Unfortunately, it is not possible to determine the exact diagnosis from the information provided, but several possibilities deserve consideration.
Features that stand out include:
* Slowly progressive weakness over several years * Predominantly proximal weakness (difficulty rising from a squat, chair, climbing stairs, lifting arms) * Facial involvement (persistent upper lip weakness) * Neck, trunk, abdominal, jaw, arm, and leg involvement * No sensory symptoms * Permanent loss of function once weakness develops * Biopsy showing neurogenic atrophy * Lack of response to prednisone
This combination raises concern for disorders affecting the motor neurons, peripheral nerves, neuromuscular junction, or certain genetic muscle diseases. Possibilities that would warrant further evaluation include:
* Adult-onset spinal muscular atrophy (SMA) * Hereditary motor neuropathies * Facioscapulohumeral muscular dystrophy (FSHD) * Limb-girdle muscular dystrophies * Inclusion body myopathy variants (less typical at your age) * Rare genetic neuromuscular syndromes * Less commonly, atypical motor neuron diseases
The fact that prednisone, huperzine A, and D-ribose were ineffective makes an inflammatory muscle disease or classic myasthenia gravis less likely, though not completely excluded.
At this stage, the most valuable next steps would be:
1. Comprehensive EMG and nerve conduction studies, preferably at a specialized neuromuscular center. 2. Genetic testing, ideally a broad neuromuscular gene panel or whole-exome/genome sequencing if not already performed. 3. Review of the muscle biopsy by a neuromuscular pathology expert if this has not been done. 4. Measurement of CK (creatine kinase), respiratory muscle function, and cardiac evaluation if not already completed. 5. Assessment at a tertiary neuromuscular referral center with expertise in rare neuromuscular diseases.
The facial weakness following dental anesthesia is particularly unusual. The return of sensation but persistent inability to elevate the lip suggests either nerve injury with incomplete recovery or an underlying vulnerability of the motor system. The neurologist’s observation of failed reinnervation makes this an important clue rather than something that should automatically be attributed solely to the dental procedure.
Because your weakness is progressive and affecting multiple muscle groups, I would encourage seeking evaluation at a major neuromuscular center rather than continuing isolated local consultations. The biopsy result showing neurogenic atrophy indicates that further investigation of the motor neuron and peripheral motor nerve systems is especially important.
Feel free to talk Take care
Thank you for your response! My CK have always been consistently normal. The biopsy did not show any ragged-red fibers nor was there any histological evidence of myositis. However few targetoid fibers were detectable, alongside the findings of neurogenic atrophy. I have been tested multiple times for both myasthenia gravis and Lambert-Eaton myasthenic syndrome antibodies and the results were consistently negative.
Hello
The additional information makes inflammatory myopathy, mitochondrial myopathy, myasthenia gravis, and Lambert-Eaton syndrome less likely.
The combination of:
* Progressive proximal and trunk weakness * Normal CK * Neurogenic atrophy with targetoid fibers on biopsy * No sensory symptoms * Facial involvement * Poor recovery of lost function
raises greater concern for a motor neuron disorder, hereditary motor neuropathy, or a genetic neuromuscular disease rather than a primary muscle inflammation.
If not already done, the most important next steps would be comprehensive genetic testing and expert review by a specialized neuromuscular center, especially with detailed EMG/nerve conduction studies. The biopsy findings point more toward a problem affecting the motor nerve-muscle unit than classic muscle disease.
Hello It sounds like you’re dealing with a complex and challenging situation, especially with the neurogenic atrophy findings from your muscle biopsy. I can understand how frustrating it must be to experience weakness and loss of function without relief from treatments. Here’s a friendly approach to consider as you navigate this:
### Next Steps to Consider
1. Seek a Specialist: - If local neurologists are overwhelmed, consider seeking a referral to a neuromuscular specialist or a neurorehabilitation center. They often have more experience with complex cases and can provide tailored treatment plans.
2. Comprehensive Evaluation: - A thorough evaluation by a specialist may include advanced imaging (like MRI) and additional tests to assess nerve function and muscle health. This can help pinpoint the underlying cause of your symptoms.
3. Physical Therapy: - Continue with physical therapy, but ensure it’s tailored to your specific needs. A physical therapist with experience in neuromuscular conditions can help design a program that focuses on maintaining mobility and strength without exacerbating weakness.
4. Occupational Therapy: - An occupational therapist can assist with daily activities and suggest adaptive strategies or tools to help you manage your symptoms better.
5. Nutritional Support: - Consider consulting a nutritionist who specializes in neuromuscular disorders. Proper nutrition can play a role in muscle health and overall well-being.
6. Explore Alternative Therapies: - Some patients find relief through complementary therapies like acupuncture, massage, or yoga. While these should not replace conventional treatment, they may help improve quality of life.
7. Support Groups: - Connecting with others who have similar conditions can provide emotional support and practical advice. Look for local or online support groups for individuals with neuromuscular disorders.
8. Regular Follow-Ups: - Keep regular follow-up appointments with your healthcare team to monitor your condition and adjust treatment plans as necessary.
### Summary Navigating a complex condition like yours can be daunting, but seeking specialized care and a comprehensive approach can make a difference. Don’t hesitate to advocate for yourself and explore all available options.
Thank you
Hello dear See as per clinical history it seems presence of Nerve degeneration Differential diagnosis include Nerve irritation Bmr impact Body weakness Thyroid dysfunction may be but rare Iam suggesting some medication and precautions for improvement Please follow them for atleast a week Zincovit multivitamin therapy onca a day for 3 months Hot fomentation application twice a day for 5 days Crave bandage application twice a day for 5 days In addition please get following tests done for confirmation of exact diagnosis and best treatment Please share the result with orthopedic surgeon for better clarity CBC Esr Serum tsh Hla b 27 Crp Ct scan if recommended by orthopedic surgeon Hopefully you recover soon Regards
Hello, This is a very unusual and concerning pattern of weakness, and based on the history you provided, I would be cautious about attributing it to a simple muscle disease alone.
Several features stand out: Progressive weakness over nearly 5 years Predominantly proximal muscles (neck, shoulders, thighs, trunk, jaw) No sensory symptoms (no numbness, tingling, pain) Weakness is asymmetric (right > left) Function, once lost, never returns Muscle biopsy showing neurogenic atrophy plus mild myopathic changes Development of a facial weakness that failed to recover normally Lack of response to prednisolone No clear benefit from therapies aimed at neuromuscular junction disorders
Taken together, this pattern raises concern for a disorder affecting the motor unit (motor neuron, peripheral motor nerve, neuromuscular junction, or muscle), but the biopsy finding of neurogenic atrophy is particularly important.
Conditions I would want excluded 1. Motor neuron disease spectrum I am not saying this is definitely ALS, especially given your young age and long course, but a chronic motor neuron disorder should be considered. There are hereditary and juvenile forms that can progress much more slowly than classical ALS. Questions: Have EMG/NCS studies shown active denervation? Any fasciculations (muscle twitching)? Any brisk reflexes or Babinski signs? 2. Hereditary motor neuropathy / distal or proximal spinal muscular atrophy Some genetic motor neuron disorders can present in young adults with slowly progressive weakness, asymmetry, and neurogenic biopsy findings. Examples include: SMA variants Hereditary motor neuropathies Rare motor neuron syndromes 3. Multisystem proteinopathies and genetic myopathies The combination of: Neurogenic atrophy Mild myopathy Facial involvement Truncal weakness can occasionally be seen in genetic neuromuscular disorders. Genes that may be considered depending on previous testing include: VCP LMNA FHL1 DES MYOT FLNC BAG3 Titin-related disorders 4. Facioscapulohumeral muscular dystrophy (FSHD) The facial weakness and asymmetric involvement are interesting. Although your presentation is not classic, FSHD can cause: Facial weakness Shoulder girdle weakness Truncal weakness Asymmetry and may occasionally be overlooked. 5. Mitochondrial or metabolic myopathies The early complaint of fatigue under load raises this possibility, although the later fixed weakness and neurogenic biopsy make this less straightforward. The upper lip weakness is particularly informative A permanently weakened upper lip after dental anesthesia is unusual. The anesthetic itself may not have caused the problem. Rather, it may have unmasked an underlying vulnerability of the facial nerve or motor unit. The neurologist’s description of failed reinnervation suggests that the motor nerve supplying that muscle may have had difficulty regenerating. That finding would push me toward a neurogenic process rather than a purely muscular one.
What I would ask next 1. What exactly did the EMG show? This is arguably the most important missing piece. 2. Was CK (creatine kinase) elevated? 3. Have genetic panels been performed? Neuromuscular panel Motor neuron disease panel Muscular dystrophy panel 4. Was whole-exome or whole-genome sequencing done? 5. What did MRI of the thigh muscles show? Fatty replacement pattern can be highly diagnostic. 6. Were reflexes normal, reduced, or brisk?
Why the diagnosis remains difficult The biopsy result of both neurogenic atrophy and mild myopathy can occur because long-standing denervation eventually causes secondary muscle changes. Therefore, the mild myopathy may not be the primary disease. The major question is whether the primary problem is: Motor neuron Motor nerve Genetic neuromuscular disease Less likely muscle alone
My recommendation Given the complexity and progression, I would strongly consider evaluation at a specialized neuromuscular center rather than general neurology alone, ideally one with expertise in:
Neuromuscular genetics EMG interpretation Muscle pathology
If you can provide: EMG/NCS results,
Feel free to reach out again.
Regards, Dr. Nirav Jain MBBS, D.Fam.Medicine
Thank you so much for your incredible detailed and honest answer!My CK have always been normal. In muscle biopsy metabolic or mitochondrial myopathies-including myoadenylate deaminase (AMPD1) deficiency were not detectable.The only genetic evaluation i’ve had so far was a specific molecular genetic test in March 2025. This was done because, due to my muscle fatigue under load, doctors initially suspected a metabolic myopathy. However, that test officially ruled out myoadenylate deaminase (AMPD1) deficiency and all myasthenia related antibodies are also negative. Regarding my current daily symptoms, i experience a combination of these things: the permanent clinical weakness and i still suffer from muscle fatigue under load. I really appreciate your perspective!
Hello again, Thank you for sharing the biopsy details. While a muscle biopsy can rarely identify the exact diagnosis on its own, I do think it gives some clues about where the primary problem may be located.
What stands out most to me is that the biopsy appears much more neurogenic than myopathic: • Angular atrophic fibers are a classic feature of denervation. • Targetoid fibers also tend to support a neurogenic process. • There is no significant necrosis, no major regenerative response, and no strong inflammatory pattern. • Normal enzyme stains and absence of ragged-red fibers make a primary metabolic or mitochondrial myopathy less likely. • The isolated inflammatory cells do not strike me as sufficient evidence for an inflammatory myositis.
If I were looking only at the biopsy report, I would be inclined to place the “primary location” of the problem somewhere along the motor unit rather than within the muscle fiber itself.
That still leaves several possibilities: • Anterior horn cell / motor neuron disorders • Motor-predominant hereditary neuropathies • Distal hereditary motor neuropathy (dHMN) spectrum • Certain genetic neuromuscular disorders affecting motor axons • Less commonly, chronic disorders of neuromuscular transmission
What I find particularly interesting is your description of stepwise deterioration. Many neuromuscular disorders progress gradually, but patients sometimes experience sudden functional losses when they cross a compensatory threshold. In other words, the underlying disease may be progressing slowly for months, but once enough motor units are lost, a task that was possible one week may suddenly become impossible the next. That does not necessarily mean there was a new injury or a sudden acceleration of disease activity. Sometimes it reflects loss of physiologic reserve.
The specific example you describe, being able to lift the leg but collapsing when weight is transferred onto it, is something I would want correlated with a detailed neurological examination and repeat EMG/NCS. The fact that the last EMG was 3 years ago is important, because the disease has clearly evolved since then. Based on everything you have described so far, I personally remain more suspicious of a chronic neurogenic disorder than a primary muscle disease.
Advice: • Consider a repeat EMG/NCS, as a 3-year-old study may no longer reflect the current disease process. • If not already done, discuss comprehensive neuromuscular genetic testing (whole-exome sequencing or a broad neuromuscular gene panel) with your neurologist. • Continue physiotherapy, but avoid repeatedly pushing muscles into prolonged post-exertional worsening. • Keep a written timeline of functional losses, as the pattern of progression may provide diagnostic clues. • Seek urgent evaluation if breathing, swallowing, or speech difficulties begin to progress.
Unfortunately I don’t have the reports from EMG/MRI or other examinations. The last EMG was 3 years ago. But i do have the muscle biopsy report:The biopsy shows groups of atrophic/hypotrophic angular muscle fibers, which appear predominantly angularly atrophic. This is interpreted in the context of a neurogenic atrophy. There are focal, isolated inflammatory infiltrates and occasional basophilic regenerative fibers. Necrotic fibers are completely absent. ATPase stains show neither fiber type grouping nor any fiber-specific atrophy. AMPDA, NADH, and phosphorylase stains show no pathological enzyme activities. Ragged red fibers are not detectable. Occasional targetoid fibers are present. There is no distinct membranous upregulation of MHC-I. There are no deposits of the complement component C5b-9, specifically not on endomysial capillaries. Immunohistochemistry reveals only isolated CD3- and CD8-positive lymphocytes.
I wonder how this disease progresses. While the process overall seems chronic and slow, there are moments where functions suddenly drop and never recover. Like in Dec 2023 or in February 2025, it got worse quickly. On February 5, 2025, I was still able to climb higher steps with both legs without any problems, not even muscle fatigue. By February 14, 2025, it was suddenly impossible with both legs. Since then, my left leg can only manage low steps without problems, and my right leg can’t climb steps at all anymore. I can lift my right leg onto a stair without a problem, but at the moment I put weight on it to step up, I fall instantly. To my final question: Based on the details of the biopsy where exactly do you see the primary „location“ of the issue? Thank you for your detailed answers!
Hello again, Thank you for providing those additional details. The fact that CK has remained normal, metabolic/mitochondrial myopathies were not identified on muscle biopsy, AMPD1 deficiency has been ruled out genetically, and myasthenia antibodies are negative makes the picture even more interesting.
What stands out to me is that you seem to have two overlapping features:
1. A fixed, progressive weakness that has accumulated over time. 2. Significant muscle fatigability during exertion.
The neurogenic atrophy reported on muscle biopsy remains an important clue. In general, neurogenic atrophy suggests that the muscle may be losing normal nerve input rather than being affected by a primary muscle disease alone.
Given your history, I would personally want to ensure that the evaluation has thoroughly considered:
• Distal hereditary motor neuropathies (dHMN) • Charcot-Marie-Tooth spectrum disorders and related hereditary neuropathies • Spinal muscular atrophy variants and other motor neuron disorders • Congenital myasthenic syndromes (which can occur despite negative myasthenia gravis antibodies) • Rare genetic neuromuscular disorders that may not be detected by targeted testing
If not already performed, a comprehensive neuromuscular genetic panel or whole-exome sequencing (WES) would be a logical next step, particularly because many rare hereditary neuromuscular conditions can present with normal CK levels and may not be obvious on routine investigations.
I would also be interested in the exact findings from: • EMG/NCS reports • Muscle biopsy report (full pathology wording) • MRI of affected muscles • Any family history of gait abnormalities, foot deformities, unexplained weakness, or exercise intolerance
One observation is that the progression over several years without respiratory failure, severe swallowing difficulties, or marked systemic involvement may be somewhat reassuring against some of the more aggressive neuromuscular disorders, although a precise diagnosis is still important.
Prescription/Advice: • Continue physiotherapy, but avoid overexertion that worsens symptoms for days afterward. • Follow up with a neuromuscular specialist if available. • Discuss comprehensive neuromuscular genetic testing (WES or a large neuromuscular gene panel). • Keep copies of all EMG/NCS, biopsy, MRI, and genetic reports together, as pattern recognition often becomes clearer when all data are reviewed collectively. • Seek urgent evaluation if you develop breathing difficulty, choking while swallowing, or rapidly progressive weakness.
Your symptoms and the progressive nature of your muscle weakness suggest a complex underlying neuromuscular disorder. The findings of neurogenic atrophy with mild myopathy on the muscle biopsy point toward a condition affecting both nerves and muscles. Given the combination of motor weakness, failed reinnervation, and asymmetrical involvement, several conditions could be considered in your differential diagnosis. Amyotrophic lateral sclerosis (ALS) or other motor neuron diseases could be possibilities, though usually they present with upper and lower motor neuron findings, and sensory loss is rare. Although some patterns don’t fit perfectly, consider specialized testing for rarer disorders like multifocal motor neuropathy or even rare metabolic or mitochondrial disorders given the systemic involvement. It’s imperative to consult a neuromuscular specialist or even a center specializing in rare neurological diseases for targeted investigations, such as electrophysiological studies (EMG/NCS), genetic testing, and possibly advanced imaging like MRI of the spine or brain if not already done.
Immunological causes might include inflammatory conditions such as inclusion body myositis or steroid-resistant autoimmune neuropathies, despite your non-response to prednisone. Further, the involvement of the right thigh and significant changes post-surgery for a desmoid tumor may indicate a separate localized complication which should not be dismissed. Given these complexities, a thorough re-evaluation at a highly specialized neurology center is advisable. The management plan should be multi-disciplinary, involving neurologists, physiotherapists skilled in neurological rehabilitation, and perhaps occupational therapists to help with functional adaptability in daily activities. While the failed treatments can be disheartening, exploring newer immunotherapies, or even trials may benefit if an autoimmune component is identified. Consider lifestyle adaptations to reduce strain on affected muscles, like using assistive devices for mobility, customizing diet with a nutritionist to ensure optimal muscle health, and continuing physio and occupational therapy for maintaining as much function as possible. Persistence and a holistic approach are key, given the complexity and uniqueness of your symptoms.
