Introduction

Dejerine-Sottas Syndrome (DSS), also known as Hereditary Motor and Sensory Neuropathy type III (HMSN III), is an unusual but serious disorder, represented by distinct underlying genetic causes and clinical features.¹

What is dejerine-sottas syndrome?

DSS is characterised by prolonged and progressive neuropathy (damage or dysfunction of one or more nerves) that typically starts in the first year. Later on, neuropathy is accompanied by delayed motor development, muscle weakness in the distal part of the body (hands and feet), loss of sensation, absence of body reflexes (areflexia), and significant hypertonia (increased muscle stiffness) that can be felt by touch. 

Diagnostic factors and frequency 

A classic diagnostic marker for DSS is slow motor conduction in affected nerves (typically less than 12 m/s).² The clinical manifestation of DSS is usually more harsh than Charcot-Marie-Tooth disease type 1 (CMT1), but phenotypical differences (a range of physical characteristics and traits) keep a certain number of patients confined to bed and fully dependent as they age.  

The exact number of patients suffering from DSS is uncertain. However, it makes up a small number of patients suffering from childhood-onset hereditary neuropathies. 

Genetics behind DSS

DSS is a genetically heterogeneous disorder; it can be caused by mutations in various genes, rather than a single genetic source. The primary causative genes are PMP22, MPZ (P0), and EGR2. While EGR2 can demonstrate both dominant and recessive mutations, PRX is labelled as an infrequent cause. DSS can either be inherited (passed on from parents) or de novo (a brand new mutation that was not present in any of the parents) genetic mutation.³ A typical case of DSS can have similar clinical symptoms to CMT1, congenital hypomyelination (born with poorly formed fatty inclusions around nerve axons) and similar deformities. In conclusion, a particular mutation and its resultant impact on the outer layer of the axon can determine the severity and course of the disease.¹ 

How is cranial nerve involvement significant in DSS

While generally affecting nerves in limbs (arms and legs), DSS can have an impact on cranial nerves (nerves that arise directly from the brain instead of the spinal cord) as well. A case study confirms that 15% cases of DSS are associated with cranial nerve involvement. This appears as facial or bulbar weakness when observed through MRI, thus adding further complexity in clinical features and diagnostic criteria of DSS.⁴

This article briefly identifies the cranial nerves that can be influenced in DSS, explains the pathways involved in facial muscle weakness, and reveals 

research-based data on diagnostic approaches, such as clinical assessment, electrophysiology, and imaging. 

Pathophysiology of DSS

The neuropathy observed in DSS is linked to excessive demyelination, segmental remyelination, and the formation of abnormal, onion-bulb structures around axons, rather than healthy Schwann cells. These concentric Schwann cells are formed due to prolonged cycles of cell repair and damage. DSS-related Schwann cell dysfunction imposes a huge impact on the integrity and stability of the myelin sheath. resulting in significantly reduced nerve conduction speed and a gradual loss in sensorimotor abilities. 

Multiple genetic variations are involved in DSS. The most common mutations involved are PMP22 (peripheral myelin protein 22), MPSZ (myelin protein zero), PRX (periaxin), and EGR2 (molecules necessary for normal assembly of myelin and development of Schwann cells). Here, we define how each of these can contribute to DSS symptoms. 

PMP22 and MPZ Mutations 

1. Mutations in PMP22 and MPZ can disturb efficient compaction myelin sheath, which is produced by Schwann cells and then tightly packed in layers around axons. Thus forming a dense, multilayer sheet that insulates the nerve fibre to enhance the speed of neural transmission. A failure to produce this layer can result in reduced nerve stability, structural impairment, and make the nerve more fragile with compromised axonal nerve conduction. Additionally a diminished support from Schwann cells contributes to gradual nerve degeneration^5,6,7,8 
2. Alterations in the EGR2 gene can disrupt transcription the process by which a cell creates RNA from a DNA template. This dysregulation occurs in the genes responsible for the synthesis of myelin (PMP22, MPZ, MAG). Ultimately impairing Schwann cell function and myelin synthesis throughout the body. As EGR2 mutations have widespread effects, they can also impact the myelin sheath of cranial nerves^9,10 
3. PRX (piraxin) is an important protein responsible for connecting the myelin sheath with the Schwann cell cytoskeleton, forming a compact and stabilised myelin sheath structure. A mutation in the PRX gene can result in the loss of myelin sheath integrity and regeneration due to impaired Schwann cells.  Although initial myelination may occur during the developmental phase, these abnormal Schwann cells fail to repair and regenerate the myelin sheath. Prolonged demyelination triggers the unsuccessful remyelination attempts; this pathological, non-functional cycle creates the characteristic onion-bulb structures around the affected axons. These structures are made from layers of mutant Schwann cells^11,12,13  

What is cranial nerve involvement in DSS?

Cranial nerve involvement in Dejerine-Sottas syndrome (DSS) is defined as the extension of neuropathic symptoms beyond limbs and travels to the cranial nerve. Creating functional deficits in the head and neck area. 

Which cranial nerves are involved 

DSS can affect various cranial nerves and manifest unique clinical symptoms. 

Facial nerve (VII): facial weakness or palsy

Demyelination of facial palsy (VII) causes paralysis or weakness in facial muscles. This causes facial asymmetry (facial muscle moved to one side), inability to properly close the eye on the involved side, drooling (unintentional flow of saliva outside of the mouth), and difficulty in producing facial expressions.^9,4,14

Trigeminal nerve (V): sensory loss in the face

Based on case studies and imaging data of DSS patients, an impact on the trigeminal nerve (V) can lead to loss of facial sensation, and appearance symptoms such as numbness or hypoesthesia (reduced sensation to touch, pain or sensation) in the cheek, jaw and forehead areas.²

Oculomotor nerve (III): ptosis and eye movement abnormalities

An effect on the oculomotor nerve can result in ptosis (upper eyelid drop on one or both sides), reduced eye movement (ophthalmoplegia), and abnormal pupillary reaction (an unusual change in the size, shape and movement of the pupil in response to a light stimulus). Researchers document oculomotor dysfunction as part of the cranial nerve spectrum in DSS.²

Auditory nerve (VIII): sensorineural hearing loss

A sensorineural hearing loss (hearing loss due to nerve damage) occurs when the auditory nerve (VIII) is affected by DSS. Evidence from audiometric testing and auditory imaging data highlights a significant hearing loss in patients suffering from DSS. This may present as reduced hearing acuity or tinnitus in DSS. Published patient series and reviews specifically attribute significant hearing loss to DSS, confirmed by audiometric testing and imaging of the auditory pathways.^2,15

Glossopharyngeal (IX), vagus (X), and accessory (XI): less frequent involvement

Demyelination of the glossopharyngeal (IX), vagus (X), and accessory (XI) nerves may appear as dysphagia (difficulty in swallowing), hoarseness (rough and strained voice), impaired gag reflex, or shoulder weakness. While these nerve involvements are rare, case reports have highlighted bulbar symptoms (abnormal functions of swallowing, speaking and breathing) and accessory nerve deficits such as shoulder drooping and weakness, inability to turn the head, and trouble in lifting the arms, in DSS patients.^2,15

Diagnostic approach

Neurological exam: cranial nerves

During the clinical examination of DSS, the doctor may look out for individual signs and symptoms from each cranial nerve that can be involved in DSS. The distinct signs and symptoms described above.²

Electrophysiology (ENG / EMG): facial nerve patterns

Facial nerve studies in DSS typically reveal:

• The compound muscle action potential (CMAP)(which explains how strong the response is when a muscle contracts after nerve stimulation) is reduced
• motor latencies (a measure of the duration it takes for a nerve impulse to travel from the point of nerve stimulation to the muscle that this nerve targets) are prolonged²
• Needle EMG (a test that uses a small needle electrode, inserted in the targeted muscle and helps in recording the electrical activity) shows fewer working nerve signals (neurogenic recruitment patterns), prolonged and high-intensity muscle responses (high-amplitude motor unit potentials), and abnormal muscle twitches at rest (resting fibrillations). All these symptoms indicate long-term nerve damage and loss of nerve insulation (demyelination) 

These findings help to differentiate sensorimotor polyneuropathy from primary muscle disease.

Imaging: MRI & MR neurography

MRI and MR neurography findings in DSS appear as:

• The affected nerves demonstrate significant thickening and appear as clusters instead of individual strands. This indicates significant abnormality and demyelination^16,4
• There is swelling and a build-up of infiltrates (a collection of cells and dead tissue) from nearby tissues. The affected areas exhibit high contrast after injecting gadolinium^17,4
• When cranial nerves are affected, the facial and trigeminal nerves appear enlarged and more visible throughout their bilateral course in imaging scans. A prominent Meckle’s cave may also be observed⁴

These features help in making an accurate diagnosis and ruling out any similar conditions, such as tumours or inflammatory neuropathies.

Genetic testing and nerve biopsy

Genetic analysis is essential to identify specific genetic mutations (PMP22, MPZ, EGR2, PRX, etc.) that might be involved. This can aid in the process of diagnosis and prognosis. Sural nerve biopsy often appears as onion bulb formations, significant demyelination or remyelination, and poor myelinated fibre density. Muscle biopsy may show neurogenic changes and highlight the peripheral origin of nerve impairment.

Summary 

In summary, cranial nerve involvement and its symptoms, like facial muscle weakness, is not a universal feature of Dejerine-Sottas syndrome (DSS); however, their presence has a significant diagnostic and prognostic value. Recognising defects in various cranial nerves, such as facial, trigeminal, and oculomotor nerves, can separate DSS from other congenital neuropathies and facilitate a tailored and prompt patient care plan. Early recognition using multidisciplinary approaches, neurological exam, electrophysiology, imaging, and genetic studies is crucial for streamlining immediate patient support and long-term outcomes.