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.
Neurodegenerative features
Functional deterioration began when she was 12 years old with the appearance of dystonia and tremor, which were exacerbated with head rotation and forearm pronation, and decline of gait ability. At 15 years of age, with aggravation of dystonia and tremor in the face and upper limbs, dysarthria and upper limb dysfunction became remarkable. Thus, oral medications, pramipexole and baclofen were started; however, only her dystonia was alleviated. Neurological deterioration became apparent when she was 19 years old (Additional file 1: Video S1). A video fluoroscopic swallow test, which was previously normal at 13 years of age, revealed a definite oral and pharyngeal phase delay that required diet modification. Due to aggravated dysarthria, she could only produce vowel sounds. Furthermore, she could not express the desire to defecate or urinate. As a result, her dependence on others for daily living increased, and her modified Barthel Index score was 19 (Fig. 1c).
Additional file 1: Video S1. Dystonia and tremor aggravated by age. The video shows dystonic features of the patient at ages 13 and 19 years. As she grew older, the dystonia and tremor aggravated and precipitated the neurological deterioration. (AVI 983 kb)
Brain imaging studies
To assess the unexplained dystonia and tremor, brain MRI was performed again at 13 years of age, and the results were similar to the previous exam at 8 years old. The last brain MRI for dysphagia at the age of 19 also did not show any change (Fig. 1d). Her 18F-fluorodeoxyglucose positron emission tomography scan at 13 years old showed low glucose metabolism in basal ganglia and thalami. In contrast, no abnormal findings were detected by brain MRI in basal ganglia and thalami.
Electrodiagnostic studies
At 13 years of age, her motor and sensory evoked potentials were all within normal ranges. However, the follow-up study when she was 19 years old revealed delayed motor evoked potentials in all extremities and delayed somatosensory evoked potentials in right side extremities.
Although the initial EEG conducted at 16 months was normal, on serial follow-up, abnormal EEG findings appeared to propagate from intermittent high-amplitude slow discharges in the posterior cerebral region at 8 years of age to sharp discharges from the left parieto-occipital area at 13 years old and then to diffuse cerebral dysfunction compatible with a partial seizure wave at 19 years old. Clinically, she did not have any seizure events after 13 years of age and never required antiepileptic drugs.
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.