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Sjögren-Larsson syndrome is a rare inherited autosomal recessive neurocutaneous syndrome and leukodystrophy characterized by the clinical triad of ichthyosis, intellectual disability, and spastic diplegia or tetraplegia.
Although considered very rare, the exact prevalence is not known.
The typical clinical features include the triad of:
- ichthyosis 1-3
- characterized by generalized yellow-brown thickened hyperkeratosis 1-3
- often very pruritic, resulting in excoriations 1
- often the first clinical feature, becoming apparent in early childhood 1-3
- intellectual disability 1-3
- moderate in severity and apparent during early childhood 1
- in one study, patients reached a developmental age of 5-6 years 1
- spastic di- or tetraplegia 1-3
- lower limbs are more frequently and severely involved than upper limbs 1-3
- progressive course, often leading to the necessary use of gait aids by adolescence 1
Additionally, other common clinical features include a crystalline macular dystrophy resulting in vision loss, pseudobulbar palsy resulting in dysarthria or anarthria, and prematurity of birth 1,2. Epilepsy may also be encountered but is considered uncommon 1.
Sjögren-Larsson syndrome is caused by mutations in the FALDH gene, also known as the ALDH3A2 gene, located on chromosome 17p11.2 1,3. These mutations have an autosomal recessive mode of inheritance 1,2.
The FALDH gene encodes for fatty aldehyde dehydrogenase (FALDH) 1-3. In normal circumstances, FALDH plays a key role in the oxidation of fatty aldehydes, which are primarily derived from fatty alcohols, into fatty acids 1-3. In Sjögren-Larsson syndrome, there is a deficiency of FALDH, resulting in an accumulation of fatty aldehydes and fatty alcohols within the body, especially within the skin and white matter, which is thought to result in the clinical syndrome 1-3.
MRI is the modality of choice in evaluating the central nervous system features of Sjögren-Larsson syndrome, where there are often striking cerebral white matter changes, with sparing of grey matter structures and the cerebellum 1-5. Interestingly, one study found that the severity of white matter signal changes did not correlate with the severity of the clinical phenotype 2.
Characteristically, there are confluent T2/FLAIR hyperintensities of the white matter, typically involving the periventricular white matter and centrum semiovale, often with a posterior or occipital predominance 1-5. On T1 sequences, affected regions may have a normal or slightly hypointense signal 2. These white matter changes may be appreciated in patients younger than 1 year, and tend to not significantly progress temporally 2.
Similarly to other leukodystrophies, subcortical U-fibers are generally spared 1-5. In Sjögren-Larsson syndrome, this sparing is noted even in older affected patients, possibly indicative of arrest of myelination at a young age 2.
Additionally, cerebral atrophy is also common, becoming apparent as patients reach adolescence 1,2. Even in older affected patients, cerebral atrophy is generally mild 2.
The almost pathognomonic characteristic seen in Sjögren-Larsson syndrome is an abnormal resonance at 1.3 ppm, only in cerebral white matter, indicative of accumulation of lipids such as fatty aldehydes and fatty alcohols 1-3. A similar smaller abnormal resonance is also seen in cerebral white matter, at 0.8-0.9 ppm, likely indicative of methyl groups which are frequently present in lipids 1,2. Similar to cerebral white matter changes, these peaks may be appreciated very early in the disease process, with one study noting them in a patient younger than 1 year 2.
Treatment and prognosis
Currently (as of February 2019), there is no disease-modified treatment available for Sjögren-Larsson syndrome, thus management is generally supportive with physiotherapy and other allied health input, with pharmacotherapy only useful for complications, such as epilepsy 1. Notably, dietary restriction of fatty alcohols has not been shown to be beneficial 1.
History and etymology
It was first described by Swedish physicians Torsten Sjögren (1896-1974) and Tage Larsson (1905-1998) in their 1957 seminal case series 6.