Sjögren–Larsson syndrome

Overview

Sjögren–Larsson syndrome (SLS) is a rare inherited neurocutaneous disorder characterized by a triad of symptoms: ichthyosis (a skin condition causing dry, scaly skin), spasticity (particularly affecting the lower limbs), and intellectual disability. The condition typically presents in infancy or early childhood and is progressive in nature. SLS is caused by a defect in fatty alcohol metabolism that leads to the accumulation of toxic substances in the body, affecting the skin, brain, and other organs. It was first described by Swedish physicians Torsten Sjögren and Tage Larsson in 1957.

Causes

Sjögren–Larsson syndrome is caused by mutations in the ALDH3A2 gene, which encodes the enzyme fatty aldehyde dehydrogenase (FALDH). This enzyme plays a critical role in the breakdown of fatty alcohols into fatty acids, which are essential components in cellular membranes and skin barrier function.

When FALDH is deficient or nonfunctional, fatty alcohols and aldehydes accumulate, disrupting normal cell function and leading to the symptoms seen in SLS. The condition is inherited in an autosomal recessive pattern, meaning a child must inherit two copies of the faulty gene (one from each parent) to be affected. Carrier parents do not typically show symptoms but have a 25% chance of passing the condition to each child.

Symptoms

The hallmark features of Sjögren–Larsson syndrome usually manifest within the first year of life. Symptoms can vary in severity but most affected individuals exhibit the classic triad:

1. Ichthyosis:

• Dry, scaly, thickened skin, especially on the trunk and limbs

• Usually present from birth or develops in infancy

• May improve somewhat with age but tends to persist lifelong

2. Spastic Diplegia or Tetraplegia:

• Increased muscle tone and stiffness, mainly in the legs

• Delayed motor milestones such as crawling or walking

• Difficulty walking, often requiring assistive devices in later years

3. Intellectual Disability:

• Mild to moderate developmental delay

• Speech and language delays are common

• Learning difficulties may be present but vary in severity

Additional Features:

• Seizures (in some cases)

• Photophobia (sensitivity to light)

• Retinal crystalline deposits detectable on eye examination

• Dry eyes and decreased tear production

• Pruritus (itching of the skin)

The severity and progression of symptoms can vary significantly, even among affected members of the same family.

Diagnosis

Diagnosis of Sjögren–Larsson syndrome is based on clinical features, biochemical testing, and genetic confirmation. Steps in diagnosis include:

• Clinical evaluation: Identification of the characteristic triad of ichthyosis, spasticity, and intellectual disability

• Skin biopsy: May show abnormalities in the epidermal layer

• MRI of the brain: Often reveals white matter changes (leukoencephalopathy)

• Fundus examination: May detect retinal crystals, a helpful diagnostic clue

• Biochemical assay: Measurement of FALDH enzyme activity in skin fibroblasts or leukocytes shows reduced or absent activity

• Genetic testing: Confirmation of mutations in the ALDH3A2 gene is definitive and allows for carrier testing and prenatal diagnosis

Treatment

There is no cure for Sjögren–Larsson syndrome, and treatment is supportive and symptomatic, focusing on improving quality of life and minimizing complications. A multidisciplinary approach involving dermatology, neurology, rehabilitation, and ophthalmology is essential.

Dermatologic Management:

• Regular use of emollients and moisturizers to hydrate the skin

• Keratolytic agents (e.g., urea, salicylic acid) to reduce scaling

• Topical retinoids in some cases for severe skin symptoms

Neurological and Developmental Support:

• Physical therapy to maintain mobility and reduce spasticity

• Occupational and speech therapy for developmental support

• Antispasticity medications (e.g., baclofen, diazepam) for severe muscle stiffness

Educational and Psychological Support:

• Individualized education plans (IEPs) for learning challenges

• Special education services and early intervention programs

Ophthalmologic and Seizure Management:

• Regular eye exams to monitor for retinal changes and manage photophobia

• Anti-seizure medications if seizures are present

Genetic Counseling:

• Advised for families with a known history of SLS

• Carrier testing and prenatal diagnostic options are available

Prognosis

The prognosis for individuals with Sjögren–Larsson syndrome varies depending on symptom severity and access to supportive care. While there is no cure, many individuals can live into adulthood with appropriate management. Key aspects of prognosis include:

• Motor impairments are usually permanent but may stabilize over time

• Skin symptoms are chronic but manageable with consistent care

• Intellectual development may improve with early intervention and supportive education

With multidisciplinary care and a structured support system, many individuals with SLS can achieve a good quality of life, engage in school and community activities, and reach functional independence in varying degrees.