Introduction

Centronuclear myopathy (CNM) is a term that describes a group of hereditary genetic conditions that mainly impact muscle fibres.¹ Also, this condition is associated with congenital myopathies. The structural changes in muscle fibres caused by CNM result in clinical symptoms such as weak muscles, hypotonia, and even respiratory complications.¹ There are three distinct categories of CNM, based upon which gene has been mutated, as well as how the gene is inherited by the offspring. 

Neonatal and infantile-onset CNM is mainly caused by a gene mutation that is linked to the X chromosome.² This is often referred to as myotubular myopathy (MM).¹ As the disease is linked to the X chromosome, cases of MM are higher in male newborns in comparison to female newborns.¹ Data shows that around 1 in 50,000 male newborns are born with MM. Unfortunately, many newborns with this condition die within the first few months; however, some newborns have been able to survive into childhood and adulthood, depending on the severity of the symptoms.² Despite being the main reason behind MM, there have also been other genetic mutations which contribute to its prognosis, such as the RYR1 gene, which is essential in the structural formations of muscles.² 

Diagnosing and managing neonatal and infantile-onset CNM is extremely challenging, with a high number of cases going unresolved.² Diagnoses are hard to come by due to their reliance on biopsies, and even then, a clear picture isn’t always shown. Managing MM is also tricky, as newborns are at a high risk of infections, and alternative treatments are still being researched. 

Pathophysiology and genetics of centronuclear myopathies

CNM are a group of hereditary and spontaneously occurring genetic disorders that affect patients from newborns to adults.¹ However, the onset of CNM is as a result of different genetic mutations underlying the progression of CNM. There are three types of CNM; two types are of autosomal inheritance, meaning that they are not associated with the human sex chromosomes X and Y. One is autosomal dominant, and the other is autosomal recessive. These factors will determine how common CNM progression is, as each inheritance mechanism varies.² 

However, MM is attributed to X-linked inheritance, which means that the condition underlying the mutated MTM1 gene is inherited on the X chromosome from the mother. Since the male child only has one copy of the X chromosome, MM cases are more frequently found. The MTM1 gene encodes for a structure called the myotube, which is essential in the developmental stages of an embryo (the early stages of pregnancy). The MTM1 mutation causes a high number of muscle fibres to have abnormal structure, within the location of the nucleus (the part of the cell that holds the DNA, our body’s genetic information.¹ This disruption to the muscle fibre structure means that patients are unable to contract and relax muscles as normal, leading to the presentation of symptoms such as:^1,2

• Hypotonia 
• Muscle atrophy 
• Weakness after birth
• Respiratory/breathing difficulties
• Difficulty in swallowing and ingesting food
• Difficulty latching on/suckling ³
• Ophthalmoplegia (inability to move eyes)
• Ptosis (droopy eyelids)
• Malformations in the body

In the neonatal onset of CNM, hypotonia, muscle atrophy, and respiratory difficulties are the most common.¹ As the patient develops into infancy, that is where symptoms such as ophthalmoplegia and droopy eyelids become more prevalent; sometimes scoliosis is also present in patients.⁴

With the majority of evidence indicating that X-linked MTM1 gene inheritance correlates with the neonatal onset of CNM, some cases have also shown that autosomally inherited genes also underlie neonatal and infantile-onset MM.³ However, we have cases that also showed that these mutations occurred spontaneously, without inheritance. These patients experienced a less severe onset of symptoms and much later in infancy, as opposed to immediately after birth.³ 

Diagnosis of neonatal and infantile-onset CNM

When diagnosing neonatal and infantile onset CNM, biopsies and histopathological analysis are extremely important. 

• Biopsies include the removal and study of tissues or cells from the patients. However, biopsies come with a lot of risk factors, such as excessive bleeding, which could prove problematic for newborns with MM due to increased vulnerability⁵ 
• Histopathology is the study of cells within tissues using a microscope, which is incredibly useful for diagnosis. Histopathology is particularly important in CNM, as each of the three CNM variants has different structures within the muscle fibres, and this biopsy type helps to differentiate between them.² For example, the histopathological study may not show as much disruption to the muscle fibres as expected, which could mean that the onset of the congenital myopathy would happen later in their life rather than in infancy¹ 

Doctors use histochemical techniques to ascertain the exact structure of the sample, whether using staining or using antibodies to target specific proteins. Once the stains have been removed, specialists can use powerful microscopes to examine the structures within the tissue, potentially revealing its underlying cause. For autosomal dominant-related CNM, one of the characteristic traits is larger type 1 muscle fibres, whereas autosomal recessive-related CNM primarily shows a rounded type 1 muscle fibre instead.² X-linked MM histopathology reveals structures such as large type 1 muscle fibres and a ‘peripheral halo’ surrounding the centralised nuclei, which is characteristic of CNM.² However, the challenge with histology is that each sample is unique and highly variable too 

• Genetic testing is also an essential technique for diagnosing CNM. As the neonatal and infantile onset has a significant genetic component to its progression and severity, a complete genetic screening may be suitable for an accurate diagnosis. Sequencing DNA can pinpoint the location of mutations, leading to a more comprehensive understanding of how mutated genes are expressed³ 
• Imaging techniques, such as MRI or CT scans, can reveal the overall picture of muscle health, possibly indicating which muscle areas are affected more than the others⁶
• Electrophysiology techniques, such as electrocardiograms, can reveal the electrical signalling within the muscles, which is helpful in diagnosis. Electromyographies can be used on patients to understand signalling within the nervous system, and how quickly these signals are able to reach their target³

Management of neonatal and infantile-onset CNM

Managing neonatal and infantile-onset CNM is extremely difficult because its progression, especially for X-linked MM, is severe, and many newborns don’t live past a few months. Ventilation support and feeding tubes are commonly required as they are unable to support these functions on their own.¹ However, those with a less severe progression can progress into childhood, and may even learn to walk normally, where physiotherapy is suggested as a way to improve mobility. 

Gene therapies for the affected mutations are also being trialed, and are a key area of research moving forward for CNM.⁴ Examples include gene silencing, inhibiting specific mechanisms within gene expression or even total gene replacements for X-linked MM.⁴ Overall, having a multidisciplinary and holistic approach to managing neonatal and infantile-onset CNM is important to ensure patients’ quality of life, as recommended by healthcare professionals.

Summary

CNMs are genetic disorders which affect muscle functioning in people of all ages, from newborns to adults.¹ There are three different types of CNM, each with its own characteristics, which are essential to recognise in terms of diagnosis. X-linked MM is considered the most severe form of CNM, as it primarily has a neonatal onset. MM progression is severe, causing premature deaths, and it mainly affects the male child.⁶ 

Symptoms such as muscle weakness and respiratory issues make it hard for newborns to survive on their own, causing the need for feeding tubes and ventilation support. As patients progress into infancy and childhood, the symptoms change to affect the eye muscles and posture. The diagnostic techniques include biopsies, genetic screening, and radiography to understand the underlying cause.¹ Management techniques are also multidisciplinary, so as to improve overall patient health and support them through all the developmental stages.