DFNA6/14/38 (low-frequency, WFS1)

Overview

DFNA6/14/38 refers to a specific type of inherited hearing loss known as autosomal dominant non-syndromic sensorineural hearing loss. 'Non-syndromic' means that the hearing loss occurs without other associated medical problems affecting different parts of the body. The 'low-frequency' aspect indicates that individuals with this condition typically have more difficulty hearing sounds with lower pitches, while their ability to hear high-pitched sounds might be better preserved [PMID:12488812].

This condition usually progresses slowly over time, often starting in childhood or young adulthood. The impact on daily life can vary, with some individuals experiencing mild difficulties and others facing more significant challenges in understanding speech, particularly in noisy environments. Because it is a genetic condition, family history of similar hearing loss may be observed.

Symptoms & clinical features

The primary symptom of DFNA6/14/38 is sensorineural hearing loss, which means there is damage to the inner ear or the nerve pathways from the inner ear to the brain. Unlike some other forms of hearing loss, DFNA6/14/38 specifically targets the lower sound frequencies. This can make it challenging to hear deeper voices, certain musical notes, or background hums, while sounds like birdsong or alarms might still be perceived easily [PMID:23709210].

Individual experiences can differ; some people may notice hearing loss from a young age, while for others, symptoms may become apparent later in life. The hearing loss is typically bilateral, affecting both ears, and can be slowly progressive, meaning it may worsen over many years. Regular audiology assessments are important to monitor changes in hearing thresholds.

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Affected organs

The main organ affected in DFNA6/14/38 is the inner ear, specifically the cochlea. The cochlea is a spiral-shaped cavity responsible for converting sound vibrations into nerve impulses that the brain interprets as sound. In this condition, the specialised hair cells within the cochlea, or the nerve fibres connected to them, are primarily impacted, especially those responsible for detecting low-frequency sounds. There are no other major organs typically affected by DFNA6/14/38, as it is a non-syndromic form of hearing loss.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of hearing loss in DFNA6/14/38 can vary significantly among affected individuals, even within the same family. It typically ranges from mild to moderate and is often progressive, meaning it can gradually worsen over time. The onset of hearing loss usually occurs in childhood or early adulthood, although some may notice it later. Due to the low-frequency nature, individuals may struggle with certain aspects of communication or appreciating music.

Since this is a non-syndromic condition, there are generally no increased risks of other health problems. However, it is important for individuals to have regular audiological evaluations to monitor hearing changes and explore appropriate interventions. The exact prevalence of DFNA6/14/38 is not well established, but it is considered a rare form of genetic hearing loss.

Genetic causes

DFNA6/14/38 is caused by pathogenic variants in the WFS1 gene [PMID:12488812]. The WFS1 gene provides instructions for making a protein called wolframin. This protein is found in several tissues, including the inner ear, and plays a role in cellular stress responses, particularly within the endoplasmic reticulum (ER). The ER is a network of membranes within cells that helps with protein folding and transport.

Pathogenic variants in WFS1 can disrupt the normal function of wolframin. In the inner ear, this disruption is thought to particularly affect the survival and function of the hair cells in the cochlea that are tuned to low-frequency sounds. When the wolframin protein is not working correctly, it can lead to problems with cell signalling and energy balance within these delicate cells, ultimately resulting in the characteristic progressive low-frequency hearing loss.

• WFS1
  wolframin ER transmembrane glycoprotein

Inheritance pattern

DFNA6/14/38 is inherited in an autosomal dominant (AD) pattern. This means that a person only needs to inherit one copy of the altered WFS1 gene from one parent to develop the condition. If a parent has DFNA6/14/38, there is a 50% chance with each pregnancy that their child will inherit the pathogenic variant and therefore also develop the condition, regardless of the child's sex.

Autosomal dominant inheritance patterns mean the condition can affect males and females equally. It can also appear in every generation of a family. Genetic counselling can provide more detailed information about inheritance risks and family planning for individuals and families affected by DFNA6/14/38.

Diagnosis & testing

Diagnosing DFNA6/14/38 typically begins with clinical assessment, including a detailed medical history, family history of hearing loss, and a comprehensive audiological evaluation to identify the specific pattern of hearing loss, particularly the low-frequency involvement. If a low-frequency sensorineural hearing loss is identified and a genetic cause is suspected, particularly with a family history, genetic testing may be offered.

Genetic testing for DFNA6/14/38 involves analysing the WFS1 gene to identify specific pathogenic variants. In the UK, genetic testing for hearing loss often falls under the NHS Genomic Medicine Service (GMS) framework. Referrals for genetic testing are typically made by clinical genetics services or specialist audiology clinics. The appropriate GMS 'R' code for testing hearing loss, including WFS1, would be used for molecular genetic analysis as part of a broader hearing loss panel.

Management & lifestyle

While there is no cure for DFNA6/14/38, management focuses on optimising hearing and communication. This typically involves regular audiological monitoring to track the progression of hearing loss. Hearing aids are a common intervention, specifically programmed to amplify the lower frequencies that are most affected, to improve sound perception and speech understanding. In some cases, other assistive listening devices may also be beneficial.

Individuals with DFNA6/14/38 may benefit from communication strategies, such as lip-reading or using visual cues, and may find support from audiology professionals or charities specialising in hearing loss. The goal of management is to maintain the best possible quality of life and communication ability. Management plans are individualised and depend on the degree and progression of hearing loss, and decisions are made in consultation with audiology and medical professionals.

UK care pathway

In the UK, suspected cases of genetic hearing loss like DFNA6/14/38 are typically managed through the NHS Genomic Medicine Service (GMS). This pathway involves referral to a clinical genetics service or a specialist audiology team. These specialists can offer genetic counselling, discuss the possibility of genetic testing (which uses specific NHS 'R' codes for hearing loss panels) and help families understand the inheritance pattern and potential implications. Genetic counsellors play a vital role in providing information and support to individuals and families throughout the diagnostic process and beyond.

Related conditions

While DFNA6/14/38 is a non-syndromic condition, meaning hearing loss is the sole feature, WFS1 pathogenic variants can also cause Wolfram syndrome, which is a syndromic condition involving diabetes mellitus and optic atrophy, among other features. It's important to note that the specific types of WFS1 pathogenic variants and their inheritance patterns differ significantly between these conditions; Wolfram syndrome is typically inherited in an autosomal recessive manner. DFNA6/14/38 is a distinct condition where only the hearing is affected, but awareness of Wolfram syndrome can be important for differential diagnosis to ensure accurate patient care.

Frequently asked questions