Introduction

Nemaline myopathy (NM) is a rare genetic disorder which causes muscle weakness and impaired muscle function. This condition is generally congenital (present at birth), however the clinical onset of NM can occur during childhood, and, in rare circumstances, in adulthood. Whilst congenital cases of NM are typically caused by a mutation in one of over 12 genes which control muscle formation, some adult cases of NM have been found to be caused by autoimmune disorders.¹

The main symptom of NM is muscle weakness, which predominantly occurs in the face and neck but also in the limbs. More severely, muscle weakness in the respiratory system (the muscles we use to breathe) can lead to issues with breathing and potentially respiratory failure.¹ 

NM can be further categorised into several different types depending on its severity and the age of onset, hence, the prognosis of NM can vary greatly.¹ Whilst there is currently not a cure for this disorder, there are several therapies available to manage NM which can improve the patient's quality of life. In this article we will cover the symptoms, diagnosis and treatment options of NM, and dive into the cutting edge research into the cause of NM. 

Causes and genetics

Nemaline Myopathy can arise from a multitude of genetic mutations, with over 12 genes already identified with the disorder. All of the genes associated with NM encode proteins, which contribute to the structure and regulation of the sarcomere, muscle fibres of the skeletal muscle, which are essential to muscle contraction.¹ The most common gene, which causes NM is in the NEB gene, which encodes nebulin, a large protein found in the sarcomere, and is associated with all forms of NM.² Other genes associated with NM, include: ACTA1, TPM3, TPM2, MYPN, TNNT1, TNNT3, KLHL40, KLHL41, and KBTBD13.¹ Whilst these genes look very complicated, it is important for both the patient and health care professional to know which gene is the cause of NM as that can narrow down the type of NM and help guide which treatment options are best for the patient.

NM is a disorder which is estimated to affect 1 in every 50,000 newborns. It is currently unknown if factors such as sex or race affect its prevalence. Research into the pattern of inheritance of NM has shown that it depends on the mutated gene. NM can be passed from parent to child in a ‘dominant’ manner, meaning only one parent has to have the mutated gene, or a ‘recessive’ manner, meaning both parents need to have the specific gene. Fortunately, just because one or both parents suffer from NM, doesn’t mean the child will definitely inherit the disease. 

Pathophysiology

Nemaline myopathy originates from the disruption in the structure and function of the muscle fibres in the skeletal muscle (the muscle attached to the skeleton). The condition primarily involves mutations in the genes coding for the muscle proteins, which leads to the formation of abnormal rod-shaped structures in the muscle cells.³ These rods disrupt the normal 'checquer-board' structure of slow and fast muscle fibres, often showing a predominance of slow fibres, which impairs the muscles’ ability to contract. 

Healthcare professionals can analyse the form and composition of these structures to better understand the mutations in the affected gene and the underlying mechanism of the disorder, which in turn allows for better treatments for patients.

Symptoms and clinical features

Nemaline myopathy manifests with a spectrum of symptoms and clinical features, and is primarily characterised by muscle weakness and impaired muscle function. The muscle weakness is generally symmetrical in both sides of the body, and particularly affects the neck and face muscles.¹ This can result in motor developmental delays, and children with the disorder having difficulties achieving milestones; which is a tell-tale sign in undiagnosed children. The loss of muscle function can vary greatly in severity and can manifest in many different ways ranging from a smaller range of motion, to the loss of facial expression or, in extremely rare and severe cases, the inability to move altogether.

Another major symptom of NM is the weakness of the muscles in the respiratory system, which can often exhibit greater weakness than the other affected muscle groups in the body. This can result in a condition called hypoxia, where the body is not able to take in enough oxygen to function properly, which can affect patients even with mild NM.³ In more severe cases of NM respiratory failure can occur, and even serve as the initial presenting symptom. Hence regular monitoring of the respiratory system is important for proper patient care.³

The diversity in the manifestations of NM can make it difficult to diagnose. Congenital onset of the disease can vary from mild to severe whilst childhood and adult onset are generally less severe, even though the disorder is still likely to have been present at birth. The wide range of symptoms and potential for respiratory complications demonstrates the need for a comprehensive approach to the diagnosis, management and ongoing care for individuals affected by NM.

Diagnosis

If you or your child show symptoms of nemaline myopathy, it is imperative that you seek out professional healthcare advice. To start the process of diagnosing NM the healthcare practitioner will look at the patient's medical history, specifically focusing on any motor developmental delays, muscle weakness or respiratory symptoms. A detailed look into family history for signs of the disease will also aid in diagnosis due to the hereditary nature of NM.

A definitive diagnosis will require a muscle biopsy, where a small amount of muscle tissue is examined under a microscope. This process used a Gomori trichrome stain (a liquid which changes the colour of certain cellular structures) to identify rod-like structures in the muscle.

The specific gene mutation leading to NM can sometimes be diagnosed through molecular testing. This involves the sequencing of the patient’s DNA, which can be an expensive and intricate process.³ This is made harder due to the high number of genes associated with NM, however, due to the recent advancement in technology, this is steadily becoming more accessible. Knowing the gene causing the disorder can be a powerful piece of information that can help guide treatment, as each mutation causes slightly different symptoms.

Treatment and management

There is currently no cure for nemaline myopathy, so treatment focuses on the management of symptoms to improve the patient’s quality of life. The treatment options will depend on the type of NM the patient has, however, both typical congenital nemaline myopathy, other intermediate NMs, and severe congenital NM all have similar base treatments, with more severe NM having additional treatments.

• Low-impact exercise to increase muscular strength and maintain function
• Massage to maintain muscle function
• Stretching techniques to increase the muscles’ range of motion
• Mechanical ventilation to ensure the patient breathes enough oxygen during sleep
• Feeding tubes for patients who struggle with eating
• L-Tyrosine supplementation, which has been observed to increase energy levels and strength in patients (why this is the case is still unknown)⁴

Prognosis and life expectancy

The prognosis for nemaline myopathy varies greatly, depending on the severity of the disease. Patients with milder cases, including adult-onset NM, can exhibit less impact on daily life, especially when accompanied by a range of treatments. NM will always remain a lifelong condition for the patient, however, with ongoing research and advancements in technology, the prognosis and life expectancy of this disorder will hopefully improve with time.

For those with severe NM, and even those with intermediate and mild cases, respiratory muscle weakness is a significant issue which can greatly lower life expectancy among patients. Additionally, patients may not have the ability to walk, eat or communicate. Severe congenital nemaline myopathy is a very serious and scary disorder to live with, and it is paramount that the patient and the patient's family receive the necessary support.

Support and resources

Support and resources for Nemaline Myopathy (NM) encompass a network of patient advocacy groups (such as A Foundation Building Strength for Nemaline Myopathy), providing information, community forums, and emotional support for individuals and families affected by NM. Medical centres specialising in neuromuscular disorders offer expertise and comprehensive care. Genetic counselling services aid families in understanding the condition and making informed decisions. Ongoing research initiatives contribute to advancing knowledge and potential treatments. These collective efforts create a supportive ecosystem, enhancing the quality of life for those living with NM and fostering a sense of community among individuals facing similar challenges.

Summary

In conclusion, Nemaline Myopathy (NM) presents a complex spectrum of symptoms and challenges. As a rare genetic disorder, NM's onset varies from congenital to adult cases, impacting muscle function, particularly in the face, neck, and respiratory system. Genetic mutations in over 12 identified genes contribute to NM, emphasising the importance of molecular diagnostics for tailored treatment approaches. Despite lacking a cure, therapeutic interventions like low-impact exercise and respiratory support enhance patients' quality of life. Prognosis depends on disease severity, with severe cases having a significantly reduced life expectancy. Ongoing research, coupled with supportive resources from advocacy groups and medical centres, offers hope for improved diagnostics, treatments, and ultimately a brighter outlook for individuals and families affected by NM.