Introduction 

What is nemaline myopathy (NM)?

Nemaline myopathy is a group of genetic muscle disorders. These disorders can be inherited through either dominant or recessive genes.¹ This means that if an individual has a recessive disorder, they need two copies of the gene (one from each parent) to exhibit signs and symptoms of the disease. Meanwhile, in dominant disorders, they only need one copy of the gene to show signs and symptoms. Nemaline myopathy is caused by changes in at least one of twelve genes, and it is diagnosed by a muscle biopsy, which would show nemaline (rod-shaped) structures in the muscle.⁴ Common signs and symptoms of nemaline myopathy include stiffness, weakness, and muscle hypotonia, which is a decreased muscle tone causing floppiness in movement and the inability to resist force. Other less common symptoms include ophthalmoplegia, which is paralysis of the eye, as well as difficulty breathing and cardiac issues.³

What is genetic counselling, and why is it important?

Genetic counselling became a recognised profession around fifty-five years ago, although the act of genetic counselling has been around for much longer. In 2018, it was estimated that there were around 7000 genetic counsellors globally.⁵ The National Society of Genetic Counselors defined genetic counselling as “the process of helping people to understand and adapt to the medical, psychological, and familial implications of genetic contributions to diseases”. The counselling includes topics on the family's medical history, the chance of disease recurrence, and education surrounding disease inheritance testing, management, and prevention. Having this information from counselling allows families to make informed decisions.⁶

Overview of nemaline myopathy

Diagnosing nemaline myopathy

Nemaline myopathy can be diagnosed through a series of tests. One of the first of these diagnostic methods is taking a family history, which essentially asks the patient about any known conditions that run in the family and the causes of death in other family members. The clinician may also ask about any other conditions or symptoms the patient is dealing with to make sure they have the right diagnosis. They will also do a physical exam to check nerve function. A muscle biopsy will also be performed, and if there are small rod inclusions in the muscle fibres, then this is a positive diagnosis of nemaline myopathy.⁸ Other tests that may be performed include a genetic test, which can help to check if other family members carry the same defective gene. The patient may also have to visit a neurologist, a medical doctor specialising in conditions that affect the nervous system.⁹ 

The expected lifespan of people with nemaline myopathy can vary depending on the severity of the condition. Commonly, in less severe cases, patients have the typical muscle weakness and reduced tone in their muscles; these symptoms can get worse over time and can lead to paralysis if they have reduced tone in leg muscles. In the more severe cases, people suffering from this condition may not be able to make it past the early stages of life, as they might struggle with breathing, sucking, and swallowing. Some people may show signs whilst still in the womb, as the foetus has reduced or no movement at all.¹

Different types of nemaline myopathy 

Nemaline myopathy can begin at different stages in life, depending on the type. Severe nemaline, also known as neonatal nemaline, affects children since they are born. It can cause the baby to struggle with basic tasks, such as eating and breathing.¹³

There is also recessive TNNT1 nemaline, previously called “Amish nemaline myopathy”. This is because it was more prevalent amongst the Amish community, but now, it is also found outside this community. The onset of this type of myopathy is usually within one year of birth. This type of myopathy is progressive, which means it gets worse with time.¹³

The most common type of nemaline myopathy is called typical nemaline myopathy, which is responsible for about 50% of all types of nemaline myopathy. Individuals suffering from this type of nemaline myopathy usually begin showing symptoms before one year of age.⁷ While people with this type of nemaline myopathy do show symptoms early, they are capable of reaching milestones after a while, as this type of nemaline myopathy is typically non-progressive, meaning it does not get worse over time.¹³

Genetic basis and inheritance patterns

Genetic heterogeneity and the genes involved 

Genetic heterogeneity occurs due to changes to one or more genes (mutations) that result in the same condition; in this case, the condition is nemaline myopathy. Gene heterogeneity means that changes in any number of different genes can result in the same condition. There are 12 genes whose mutations can potentially cause nemaline myopathy. Among these, the genes that are frequently mutated and are therefore responsible for nemaline myopathy are ACTA1 and NEB.¹

Autosomal and recessive nemaline myopathy

Nemaline myopathy can be inherited in two patterns, which are dominant and recessive gene inheritance. When we inherit genes, we inherit one from each parent, meaning that we have two versions of every gene. The manifestation of a certain gene into a trait is dependent on whether the gene is dominant or recessive. For a recessive gene to manifest, two copies are required (one from each parent), whereas a dominant gene only needs one copy of itself (from either parent) to present itself as a characteristic.¹⁴

In nemaline myopathy, genes can be either dominant or recessive. In recessive nemaline myopathy, both parents carry one of the genes, but in recessive conditions, people carrying only one copy of the gene may not show any symptoms. However, in dominant conditions, even with only one copy of the gene, the individual will show signs. In dominant nemaline myopathy, there is a 50% chance of passing on the condition to the children, whereas in the recessive type, there is a 25% chance of the child developing the condition and a 50% chance of the child being a carrier of the disorder.

Role of genetic counselling

Goals of genetic counselling in nemaline myopathy

The role of genetic counselling is not about diagnosing the disease; instead, it is about preparing for a positive diagnosis and how to move forward if there is a positive diagnosis. Its purpose is not only to help families learn about the new diagnosis but also to help them learn how to adapt to it and navigate the future with the condition.

Other goals of genetic counselling are to deal with the human feelings that come with a diagnosis of genetic conditions, such as the risk of recurrence. The genetic counsellor will inform the patient and their family about the medical diagnosis and the treatment or management of the diagnosis. Alongside this, they will also explain the hereditary contributions to the disorder and the chance of recurrence in different family members. Your genetic counsellor will also explain options in dealing with the chance of recurrence. They will also help you choose your next course of action, tailored to your views, ethics, religion, and goals.¹⁰ 

Carrier screening in nemaline myopathy helps to check if an individual has one of the genes for nemaline myopathy but isn't showing symptoms. This can be beneficial if the individual is thinking of having a child and wants to know the chances of the child having nemaline myopathy.

Family planning options

Several family planning options are available for individuals with nemaline myopathy. Testing for nemaline myopathy before the child is born is called prenatal testing. There are several ways prenatal testing can be done. One of the first ways this may be done is via ultrasound, in which the technician may see reduced or absent movements of the baby's limbs. 

There is also a test that can be carried out on the umbilical cord, which is known as whole-exome sequencing. Through this method, we can find out the genes present in the infant without removing the baby from the womb.¹¹

Preimplantation Genetic Diagnosis (PGD) is an implantation method that aims to diagnose babies before they are born. In PGD, several embryos are fertilised in vitro, meaning that they are fertilised outside the womb. Once the embryos are up to 10 cells, their DNA is checked for mutations, and if no mutations are detected, they are implanted into the mother's womb.¹⁶

In contrast to PGD, in prenatal testing, the baby is conceived naturally, and once conceived, there is a range of testing done to help assess the health of the baby while they are growing.¹⁷

Summary

Genetic counselling plays a critical role by educating families about the nature of NM, its modes of inheritance, and the likelihood of recurrence in future children. Counsellors also guide families through emotional, ethical, and medical considerations, offering options such as carrier screening, prenatal testing, and preimplantation genetic diagnosis. These tools empower individuals to make reproductive decisions that align with their values and help manage the impact of NM on current and future family members.