Metabolic Stroke as a Clinical Manifestation of Zhu-Tokita-Takenouchi-Kim Syndrome

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare condition caused by a loss-of-function alteration in SON (SON DNA and RNA binding protein) which is located on chromosome region 21q22.¹ SON encodes a protein involved in multiple cellular processes, including transcription, premessenger RNA splicing, and cell cycle regulation, but much is still unknown about its function.² Global developmental delay has been seen in all cases.¹ Manifestations also include dysmorphic facial features, musculoskeletal abnormalities, abnormal brain MRI findings, hypotonia, eye anomalies, seizures, and short stature in more than 50% of cases.¹ Less common manifestations include cardiac, gastrointestinal, and genitourinary abnormalities.¹ Management of these conditions remains supportive. With only 60 known cases of ZTTK syndrome,¹ reports which expand the clinical phenotype will help inform clinicians of previous findings, diagnoses, and management strategies. In this study, we report 2 unrelated individuals who presented to our institution with a metabolic stroke. Although not widely described, we have identified one report of another individual with ZTTK syndrome who experienced a metabolic stroke.³ Metabolic stroke is classically known as a rapid-onset central neurologic deficit in the absence of a vessel occlusion, with brain MRI confirming ischemia not confined to a vascular territory.⁴ Metabolic stroke has not been commonly reported as a clinical manifestation of ZTTK syndrome, but mitochondrial dysfunction seen within SON may be implicated.^5,6

Case 1

A 12-year-old adolescent girl presented to our institution with sudden-onset left hemiplegia. She carried a diagnosis of ZTTK syndrome since 6 years given her clinical characteristics of global developmental delay, dysmorphic facial features, musculoskeletal abnormalities, abnormal brain MRI, hypotonia, seizures, and short stature. Along with a whole-genome single nucleotide-polymorphism (SNP) microarray revealing a homozygous 589 KB interstitial deletion of arr[hg19] 21q22.11(34,841,458-35,430,729), which includes SON, TMEM50B, GART, DONSON, CRYZL1, ITSN1, and ATP50. After discharge, subsequent testing for combined mitochondrial genome, mitochondrial focused nuclear gene panel/sequencing and deletion/duplication testing returned negative for mitochondrial disease. On admission, her examination was notable for severe encephalopathy; fixed right gaze preference; and left lower face, arm, and leg paralysis. Extensive workup was significant for MRI obtained on the sixth day of symptomology and revealed diffusion restriction throughout the entire right hemisphere that is not confined to a single vascular territory, which is most likely consistent with a metabolic stroke (Figure 1). MRI scans obtained on the first and fourth days of symptomology also revealed subtle diffusion restriction that progressively worsened. EEG tracings showed initial severe right hemispheric attenuation, slowly giving way to periodic lateralized epileptiform discharges from the ipsilateral region days after her admission. Two days before presentation, she experienced her typical seizure involving staring and left-sided weakness, but without her typical recovery in 10–12 hours, therefore prompting the family to seek medical attention. One clinical seizure occurred on the sixth day of symptomology and was described as abnormal movements of her left face, tongue, drooling, and left gaze preference with nystagmus. During her symptomatic period, her plasma lactate was between 0.8 and 3.0 mmol/L (0.5–2.2 mmol/L) and her pyruvate level was measured as 0.3 mmol/L (0.3–0.7 mmol/L). Her CSF lactate and pyruvate levels were not checked. She was treated with arginine, carnitine, and ubiquinone similarly to how some metabolic strokes are treated in individuals with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. She recovered close to her previous functional baseline before the metabolic stroke by 2 weeks after the onset of symptoms.

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Figure 1 Case 1

MRI of the brain (Aa-Ab axial diffusion weighted images [DWI]; Ba-Bb axial apparent diffusion coefficient [ADC] images) demonstrating diffusion restriction throughout the entire right hemisphere that is not confined to a single vascular territory, which is most likely consistent with a metabolic stroke.

Case 2

An 11-year-old adolescent girl presented to our institution with sudden-onset left hemiplegia. At that time, she had the clinical characteristics of ZTTK syndrome, global developmental delay, dysmorphic facial features, musculoskeletal abnormalities, abnormal brain MRI, hypotonia, seizures, cardiac abnormalities, gastrointestinal abnormalities, eye anomalies, and hearing loss. Whole-exome sequencing revealed a heterozygous p.R10X or C.27dupT leading to a de novo nonsense sequence variation in SON, a pathogenic variant. Later, she was diagnosed with ZTTK syndrome when the association was found between her clinical characteristics and genetic abnormality. On admission, her examination was notable for severe encephalopathy; fixed right gaze preference; and left lower face, arm, and leg paralysis. Extensive workup was significant for brain MRI findings demonstrating diffusion restriction in the right parietal and occipital areas, which is not confined to a single vascular territory, which is most likely consistent with a metabolic stroke (Figure 2). EEG tracings showed right central parietal sharp waves superimposed on right hemispheric slowing and disorganization. During her symptomatic period, her laboratory test results revealed a CSF lactate level of 1.3 mmol/L and a plasma pyruvate level of 0.13 mmol/L (0.08–0.16 mmol/L). Her CSF pyruvate and plasma lactate levels were not checked. She recovered close to her previous functional baseline before the metabolic stroke by 1 week after the onset of symptoms.

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Figure 2 Case 2

MRI of the brain (Aa-Ab axial diffusion weighted images [DWI]; Ba-Bb axial apparent diffusion coefficient [ADC] images) demonstrating diffusion restriction in the right parietal and occipital areas that is not confined to a single vascular territory, which is most likely consistent with a metabolic stroke.

Appendix Authors

• Received November 14, 2022.
• Accepted in final form February 27, 2023.

• Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.