Neurodegeneration in an adolescent with Sjogren-Larsson syndrome: a decade-long follow-up case report

Abstract

BackgroundSjogren-Larsson syndrome is a hereditary neurocutaneous syndrome that is non-progressive in nature. Although neuroregression has been reported in seizure-prone preschool children requiring anti-epileptic treatment, teenage-onset dystonia precipitating neurodegeneration without any immediate causal events has yet to be reported.Case presentationWe describe a young woman with spastic diplegia and intellectual disability who began to show progressive neurological deterioration from 12 years of age, with the onset of dystonia and tremor. She was initially diagnosed with spastic cerebral palsy and periventricular leukomalacia based on brain magnetic resonance imaging. Follow-up brain imaging from 13 years of age did not reveal apparent changes, though abnormal electroencephalographic findings occurred in parallel with her decline in motor function. By 19 years of age, she had developed dysphagia and became completely dependent on others for most activities of daily living. Ultimately, whole-exome sequencing revealed a heterozygous compound mutation in the ALDH3A2 gene that corresponds to Sjogren-Larsson syndrome: an exon 9 deletion (1291-1292delAA) from the mother and an exon 5 splicing mutation (798 + 1delG) from the father. Neuroregression has been reported in preschool children after seizures requiring treatment, though our patient did not experience any immediate causal events. This report summarizes the clinical, radiologic, and electrophysiological findings observed over a decade concurrent with neurological deterioration after the onset of dystonia and tremor at the age of developmental ceiling in Sjogren-Larsson syndrome.ConclusionsIn addition to the influence of additive variants or other environmental factors, accumulation of metabolites due to defective fatty aldehyde dehydrogenase is a potential pathomechanism of neurodegeneration in this patient. Neurological deterioration may be a presentation that is unnoticed in Sjogren-Larsson syndrome due to the rarity of the disease. This report highlights a unique clinical feature of Sjogren-Larsson syndrome with progressive neurodegeneration associated with dystonia and tremor.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0663-0) contains supplementary material, which is available to authorized users.

A Neurodegenerative Phenotype Associated With Sjögren-Larsson Syndrome

“…We 8 -10 and others 11,12 have described 7 additional patients with Sjögren-Larsson syndrome with a neurodegenerative clinical course (see Table 1). All were genetically confirmed with pathologic variants in ALDH3A2 , or in 1 case (P7) 12 was genetically related to the original Swedish Sjögren-Larsson syndrome cohort patients who carry a common c.943C>T pathologic variant.…”

“…13,14 Regressive changes ranged from the temporary loss of motor and verbal skills (P5) 10 to a permanent loss of verbal, cognitive, and motor abilities 8,9 and/or progressive tremor, dystonia, and decreased upper limb function. 11 All of the patients with a neurodegenerative phenotype were children. The age of onset of regression ranged from 6-7 months to 12 years.…”

“…However, progression of neurologic disease in childhood has recently been identified, usually attributed to uncontrolled seizures. 8 -12 We now report a young patient with Sjögren-Larsson syndrome who developed a striking neurodegenerative course that was apparently triggered by an infectious illness. We further review additional published cases of Sjögren-Larsson syndrome associated with loss of neurologic function beyond that expected from slowly progressive spastic contractures.…”

End-stage crystalline maculopathy with retinal atrophy in Sjögren-Larsson syndrome: a case report and review of the literature

“…In the central nervous system, deficiency in the function of ALDH3A2 interferes with the production and integrity of myelin, including in the brain and spinal cord of patients with SLS. 2 , 4 , 23 This may contribute to the neurologic features of the disease, including abnormalities in visual evoked potentials. 4 Magnetic resonance imaging (MRI) of the brain often reveals a gradual development of abnormalities starting as soon as the first year of life manifesting as white matter changes, along with mild ventricular enlargement, diffuse brain atrophy, and hypoplastic corpus callosum.…”

“…24 Interestingly, in one case report, F18-fluorodeoxyglucose positron emission tomography showed low glucose metabolism in the basal ganglia and thalami of a 13-year-old young woman with SLS who had as of yet an unremarkable MRI. 23 Cerebral proton magnetic resonance spectroscopy ( 1 H-MRS) of patients with SLS typically show lipid accumulation in the cerebral white matter beginning in the first year of life. 25 Yet there is little to no correlation between white matter findings on MRI, patient age, or clinical symptoms, 24 suggesting changes in gray matter and spinal cord contribute to the neurologic phenotype.…”