Introduction

Dejerine–Sottas Syndrome (DSS) is a rare, inherited neurological disorder. Historically, diagnosis relied on observing clinical symptoms and performing nerve studies. Today, advances in genetic testing allow clinicians to examine a person’s DNA to identify mutations responsible for DSS, offering clarity for families and improving early diagnosis. This article explores:

• The disease mechanism of DSS
• The clinical features of DSS
• Genes associated with DSS
• The role and importance of genetic testing

What is Dejerine–Sottas Syndrome?

Dejerine–Sottas Syndrome (DSS) is a genetic disorder that affects the peripheral nervous system, causing progressive motor and sensory impairments, particularly in the arms and legs. It is considered a subtype of Charcot–Marie–Tooth disease (CMT) and usually presents in infancy or early childhood, with symptoms worsening over time.^1–3

Symptoms of DSS

DSS can present with a range of signs:

• Delayed motor development, such as late sitting, crawling, or walking
• Progressive muscle weakness, starting in the legs and extending to the arms
• Loss of reflexes (areflexia), particularly deep tendon reflexes
• Sensory deficits, including reduced ability to sense vibration, pain, or temperature
• Foot deformities, such as high arches (pes cavus)
• Scoliosis, or abnormal spinal curvature
• Mood or behavioural changes

Peripheral nerves and DSS

The nervous system is divided into the central (CNS) and peripheral (PNS) nervous systems. Peripheral nerves, which extend into the limbs, carry sensory information to the brain and control movement. In DSS, the myelin sheath, the protective layer around peripheral nerves, becomes damaged or “demyelinated,” impairing signal transmission. This demyelination is responsible for the motor and sensory symptoms seen in DSS.^1–3

Genetic basis of DSS

Genes are the body’s instruction manuals, guiding the production of proteins and overall cellular function. Mutations in specific genes can disrupt these instructions, leading to disorders such as DSS. As a hereditary disease, DSS can be passed from parent to child, making early genetic testing vital.⁴

Genes linked to DSS

Several genes are associated with DSS, categorised by inheritance pattern:

Autosomal dominant genes (one copy of the mutated gene is enough for disease):

• PMP22 (17p12): Encodes a protein crucial for myelin formation. Mutations disrupt myelin stability, contributing to demyelination⁶
• MPZ (1q22): Encodes myelin protein zero (P0), the most abundant myelin protein in the PNS. Mutations impair myelin compaction and nerve function⁷
• EGR2 (10q21.1): Produces a transcription factor that regulates other myelin-related genes. Mutations hinder myelin production⁸

Autosomal recessive genes (both copies must be mutated):

• PRX: Produces periaxin, which maintains myelin stability. Mutations in both copies result in defective myelin maintenance⁹

De novo mutations

Not all DSS cases are inherited. Sometimes, spontaneous “de novo” mutations occur during egg, sperm, or early embryonic development10. This highlights the importance of genetic testing even when there is no family history of DSS.

What is genetic testing?

Genetic testing involves examining DNA, chromosomes, or proteins to detect abnormal changes that may cause disease.¹¹

Testing can:

• Confirm a diagnosis
• Assess risk for developing the disease
• Guide personalised treatment plans
• Support family planning decisions

Types of genetic testing

Different tests are available, ranging from targeted to comprehensive approaches:

• Single-gene tests: Examine a specific mutation known to cause a disorder
• Gene panels: Look at multiple genes simultaneously
• Whole exome sequencing: Examines all coding regions in the genome
• Whole genome sequencing: Analyses the patient’s entire DNA sequence^11–12

Pros and cons of genetic testing
Pros:

• Early detection and risk assessment
• Personalised treatment planning
• Informed reproductive decisions
• Motivation for lifestyle and health interventions^13–14

Cons:

• Results may be uncertain or incomplete
• Emotional and psychological impacts
• High cost and limited accessibility for some techniques^13–14

Genetic testing for DSS

Hundreds of tests are now available for DSS, targeting genes such as PMP22, MPZ, EGR2, and PRX1. Techniques include:

• Multiplex Ligation-dependent Probe Amplification (MLPA) for detecting PMP22 deletions or duplications¹⁵
• DNA sequencing for point mutations in genes like MPZ¹⁶
• Whole exome or genome sequencing if single or panel testing is inconclusive¹⁷

Genetic testing alone cannot confirm DSS. It must be combined with clinical assessments and neurological tests to establish a definitive diagnosis.

Clinical testing for neurological function

Since DSS is a demyelinating neuropathy, clinicians may use:

• Nerve conduction studies: Measure the speed of electrical signals through nerves; DSS patients show slower velocities¹⁸
• Electromyography (EMG): Records nerve-to-muscle electrical activity, often reduced in DSS¹⁹
• Nerve biopsy: Examines nerve tissue under a microscope, revealing Schwann cell dysfunction and myelin abnormalities²⁰

Differential diagnosis

Many inherited neuropathies resemble DSS, including Charcot–Marie–Tooth disease. Genetic testing helps differentiate these conditions:

• PMP22 duplication suggests CMT
• Rare MPZ or PRX mutations strongly support DSS^6,7,9

Combining genetic results with clinical and electrophysiological findings improves diagnostic accuracy.

FAQs

What are the treatment options for DSS?

Treatment focuses on managing symptoms and improving quality of life, including physical therapy, pain management, mobility aids, and surgical correction of foot deformities. Genetic therapies and symptom-specific medications are being researched1.

At what age is DSS usually diagnosed?

Symptoms often appear in infancy or early childhood, with diagnosis typically around age two.¹

If genetic testing is negative, can someone still have DSS?

Yes. Not all DSS-related genes have been discovered, and some mutations may be undetectable. Clinical assessment remains essential.¹

Is DSS the same as Charcot–Marie–Tooth disease?

DSS is a subtype of CMT but is usually more severe, presents earlier in childhood, and involves some distinct genes such as EGR2 and PRX1. Genetic overlap explains similarities with CMT.¹

Is prenatal testing available for DSS?

Yes. If a disease-causing mutation is known in the family, prenatal or preconception testing can be offered.¹

Summary 

Dejerine–Sottas Syndrome is a rare, early-onset demyelinating disorder affecting motor and sensory function. Key genes include PMP22, MPZ, EGR2, and PRX, and mutations may be inherited or arise de novo. Genetic testing, including gene panels and sequencing, is critical in diagnosis, while clinical tests like nerve conduction studies, EMG, and biopsy confirm nerve involvement. Early detection allows for improved symptom management, personalised care, and informed family planning.