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

Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder (OMIM#270200) characterized by spastic di−/quadriplegia, intellectual disability, and generalized ichthyosis [1, 2]. In general, cerebral palsy is the most common cause of motor disability in childhood that usually accompanies limb spasticity [3], and both disorders share similarities of spasticity and a non-progressive nature in their clinical course. An SLS patient initially diagnosed with spastic cerebral palsy as a toddler began to show progressive deterioration in adolescence during over-decade-long follow-up. Dystonia and tremor developed at 12 years of age and precipitated neurological deterioration; she was eventually diagnosed with SLS based on the results of whole-exome sequencing. This report describes progressive neurodegeneration associated with dystonia and tremor in an SLS patient. The results of serial brain imaging, electroencephalography, and evoked potential studies are discussed with the results of a literature review regarding the possible pathomechanisms of neurodegeneration.

The proposita was born at full term with a birth weight of 2900 g and without any perinatal events. Generalized ichthyosis over the torso and extremities was present from birth (Fig. 1a–b), and it was undervalued as being inherited from the father and paternal grandmother, who also had enduring ichthyosis. Although the child experienced febrile convulsion at 10 months, electroencephalography (EEG) at 16 months was normal. A few events of generalized seizures subsided spontaneously, without requiring antiepileptic medications. Brain magnetic resonance imaging (MRI) performed at 2 years of age was normal; however, follow-up MRI at 8 years showed T2-weighted high signal intensities at bilateral parietal deep white matter with mild volume reduction.

Various therapies were applied from the age of 2 years for global developmental delay. Motor delay was remarkable in that she was able to creep by the age of 3 years. Oral anti-spastic medication was started at 4 years of age because of spastic diplegia and was continued for 10 months. At 5 years of age, botulinum toxin was injected twice into her lower limbs which did not show lasting effects. Nonetheless, she was able to walk indoors with ankle-foot orthoses and a walker at 6 years of age. Serial muscle lengthening surgeries on both lower limbs were performed when she was six, 10, and 11 years old; the outcomes were short-term ambulatory improvements only, and contractures remained.

She wore glasses for myopia and photophobia; however, an ophthalmologic evaluation revealed no retinal abnormalities.

Language assessment at 6.3 years of age showed delayed development of receptive language skills compatible with an age of 3.4 years and expressive skills similar to those at an age of 2.4 years. She was able to write her name by the time she was 8 years old. Her intellectual quotient using the Wechsler Intelligence Scale for Children assessed at 13 years of age was a score of 31. At 12 years of age, her independence in activities of daily living scored 57 on the modified Barthel Index.

Genetic analyses

Whole-exome sequencing was conducted in an attempt to find the cause of neurodegeneration. As a result, 85 variants were identified, including 23 that were not previously reported (Fig. 2a, Additional file 2: Table S1). Two of the variants were in the ALDH3A2 gene: a c.1291-1292delAA deletion mutation in exon 9 from the mother and a 798 + 1delG splicing mutation from the father, where deletion of the nucleic acid G hinders splicing of intron 5 and results in premature termination of the protein (Fig. 2b). Each mutation was previously reported in homozygous Japanese patients with typical SLS [4]. The other identified genetic variants do not appear to be directly related to neurological deterioration in this case.

SLS is a rare hereditary neurocutaneous syndrome with a reported prevalence of 0.4 per 100,000 [4]. Mutation in the ALDH3A2 gene encoding fatty aldehyde dehydrogenase (FALDH), a microsomal nicotinamide-adenine-dinucleotide-dependent enzyme, is the pathognomic basis for SLS [1]. As oxidation of long-chain aliphatic aldehydes to fatty acids requires FALDH, the symptoms of FALDH-deficient SLS patients are caused by defective clearance of aldehydes [5]. Neurological disturbances may stem from the accumulation of defective eicosanoid metabolite lipids and aldehyde Schiff base in the brain [6]; reversal of reactive aldehydes produced by oxidative stress-induced lipid peroxidation is also defective without FALDH in SLS [7]. One reactive aldehyde, 4-hydroxynonenal, accumulates in the brain tissues of patients with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis [8]. Accumulated metabolites may have induced neurodegeneration in the present patient, though the exact threshold of reactive aldehyde clearance due to restricted FALDH activity remains unknown.

The proposita in this study exhibited the common features of SLS, such as spastic diplegia and ichthyosis. However, a few manifestations were distinct for the patient, such as neurodegeneration and the occurrence of dystonia with tremor in her early teenage years. Twelve years old, when the patient started to deteriorate, is known as the age of the developmental ceiling for children with SLS [2]. Most patients with SLS are wheelchair-bound due to contractures; however, neuroregression has not been demonstrated with increasing age [9, 10], and the functional level of patients is usually maintained after the developmental plateau [2].

The cause of neurodegeneration and movement abnormalities in our patient was explored with respect to the pathogenesis of SLS and other possible genetic defects through a literature review.

Neurodegeneration has been reported in few children with SLS who required sustained use of anticonvulsants [11] and/or had a history of seizures prior to regression [12]. In those cases, regression occurred at ages of 4 days, 9 months, 4.5 years [11], and 6.5 years [12], much earlier than in our patient. Although apparent seizures were not severe in our patient, neurological deterioration may have been secondary to subclinical seizure activity, as demonstrated with EEG.

Teenage-onset of dystonia with tremor, such as in our proposita, has not been reported previously for SLS. Generalized dystonia was once reported in a Caucasian boy who was diagnosed with SLS at the age of 8 years [13]. The boy’s dystonia was noticeable by the time he was 3 years old, much earlier than in our patient. The boy had two mutations: exon 9 deletion (c.1297-1298 delGA) and exon 6 missense mutation (c.835T > A). Both mutations are known to result in less than 1% residual FALDH activity [14]. The exon 9 deletion in our patient (c.1291-1292 delAA) is in close proximity to the locus in the boy referred to above, with the same 9-bp palindromic sequence [4]. Considering the high prevalence of c.1297-1298 delGA in European SLS families [1], it appears that deletions in exon 9 are less likely to have caused dystonia, despite reduced enzyme activity. Another variant, splicing mutation 798 + 1delG, is also a common mutation reported without dystonia or neurodegeneration. The specific combination of genetic variants in the present patient has not been reported previously and may have resulted in the exceptional clinical course; nonetheless, it is difficult to define a causal relationship. It is known that phenotypic variation is not necessarily related to the type or severity of mutations in SLS patients [15]. A few mechanisms of dystonia may be suggested. White matter disruptions can evoke dystonia due to ephaptic transmission in SLS [13]; disturbed activities, represented as low glucose metabolism, in basal ganglia and thalami may also induce dystonia [16]. Overall, secondary dystonia is a widely noted feature in neurodegenerative conditions and metabolic diseases.

Although the diagnosis of SLS did not fully explain the neurodegeneration in the patient, the results provided better insight to the family. Indeed, the family trait of ichthyosis may have been induced by another ichthyosis-associated gene, as heterozygous carriers of ALDH3A2 mutations are not symptomatic. This apparently coincidental finding nevertheless is worth mentioning because it hindered early diagnosis. Based on the results of genetic analyses, genetic counseling for a younger brother with a normal phenotype was recommended. To our knowledge, this study is the first to report serial electrophysiological changes in correlation with neurologic deterioration in an SLS patient. A lack of longitudinal follow-up reports on SLS patients due to its rarity may have caused disregard of neurodegeneration as a possible prognostic outcome. Further study to identify the pathophysiology of neurodegeneration in SLS using animal models may provide clues for such clinical manifestations.