Expanding the Clinical Spectrum of UBTF-Related Neurodevelopmental Disorder

Results

Patient 1 is a 16-year-old boy, born at term after an uneventful pregnancy and spontaneous delivery. No consanguinity nor family history for neurodevelopmental disorders was reported. Psychomotor development was normal up to 5 years of age when he presented with attention deficit, difficulties in relationships with pairs, and coarse movements. At 6 years of age, he had a progressive global regression in cognitive, behavioral, and motor skills. He progressively developed a complex clinical picture characterized by ataxia, nystagmus, oculomotor apraxia, severe cognitive deficit, dysarthria, stuttering, self-injurious episodes, dysmetria, and dysgraphia. A decline in cognitive functions, more prominent in the language and speech skills, and a worsening of the extrapyramidal symptoms' severity were observed during the follow-up. At 15 years of age, he also presented with episodes of obsessive-compulsive behavior. At the last evaluation at 17 years of age, he was still able to walk with support but with an ataxic gait; he had severe sialorrhea but was still able to orally feed himself; he presented with difficulties articulating every single word because of verbal fluency impairment; upper limb movements were functionally impaired by severe dysmetria; he also presented with subacute onset of additional symptoms of movement disorders with dystonia and parkinsonism for which he started treatment with levodopa with a definitive improvement at 4 months of follow-up (Video 1); IQ assessed with Wechsler Intelligence Scale for Children–type IV (WISC-IV) scale confirmed a severe cognitive deficit. Signs or symptoms in other organs/apparatus were not reported. A first brain MRI was performed at 8 years of age showing increased T2 signals in the periventricular supratentorial and deep white matter, thin corpus callosum, and supratentorial atrophy (Figure 1, A and B). A follow-up brain MRI at 16 years of age showed an increase in hyperintensity in T2-weighted white matter with moderate worsening in brain atrophy (Figure 1, C and D). Metabolic analyses of arylsulfatase A, CSF and plasma lactic acid, plasma, and urinary amino acids, acylcarnitine, and urinary organic acid were normal. Histologic and histochemical study of muscle biopsy specimen displayed a few eosinophilic subsarcolemmal accumulations, mild diameter variability of the fibers and isolated vesicular nuclei at hematoxylin-eosin staining (data not shown), a focal increase in oil red O staining (data not shown), and several fibers with a subsarcolemmal increase in cytochrome c oxidase (COX) reaction (Figure 1A). The ultrastructural analysis revealed mitochondrial alterations compatible with the light microscopy findings: accumulation of abnormal large swollen mitochondria, irregularly shaped with hypodense matrix and aberrant residual cristae (eFigure 1, links.lww.com/NXG/A642). Mitochondrial respiratory chain enzyme activities in muscle homogenate were within normal ranges (data not shown).

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Figure 1 Brain MRI Findings in Patient 1 (A–D) and Patient 2 (E–H)

Patient 1: Brain MRI at the first evaluation at 8 years of age showing in mid-sagittal T1-weighted (A) and axial T2-weighted (B) images, increased T2 signals in the periventricular supratentorial and deep white matter, thin corpus callosum, and supratentorial atrophy. Follow-up brain MRI at 16 years of age showing in mid-sagittal T1-weighted (C) and axial T2-weighted (D) images an increase in hyperintensity in T2-weighted white matter with moderate worsening in brain atrophy. Patient 2: Brain MRI at the first evaluation at 4 years of age showing in mid-sagittal T1-weighted (E) and axial T2-weighted (F) images modest cerebral atrophy and hyperintensity in T2-weighted images in the periventricular supratentorial and deep white matter and thin corpus callosum; Follow-up brain MRI at 13 years of age showing in mid-sagittal T1-weighted (G) and axial T2-weighted (H) images progressive cortical and subcortical atrophies, initial signs of cerebellar atrophy, and brainstem atrophy, with further thinning of the corpus callosum and higher hyperintensity of supratentorial white matter signal in T2-weighted images and thalami signal hyperintensity in T2-weighted images.

Patient 2 is a 22-year-old woman, born at term after an uneventful pregnancy and cesarian delivery. No consanguinity nor family history for neurodevelopmental disorders was reported. After nonspecific febrile illness, a global neurodevelopment regression occurred in the second year of life with arrest in motor and language skills, abnormal behavior with irritability, gait unbalance with difficulty climbing stairs, frequent falls, and cranial circumference growth delay. At 6 years of age, the clinical course was complicated by axial asymmetric recurrent dystonic episodes lasting some days compromising the ability to walk and sialorrhea. At 9 years of age, she developed tetraparesis with parkinsonian rigidity and limb dystonia and pseudobulbar syndrome characterized by involuntary and uncontrollable outbursts of laughing lasting several minutes. She lost the ability to walk at 10 years. Dysphagia was progressive and required percutaneous gastrostomy (PEG) tube feeding at 18 years of age. She also presented with nocturnal hypoventilation treated with noninvasive ventilation. Awake and sleep EEG recordings showed no epileptiform or periodic discharges and nerves' conductions were normal. At 22 years of age, she completely lost verbal communication, but she partially reacted to stimuli in the family context (Video 2). A first brain MRI, when she was 4 years of age, showed signs of modest cerebral atrophy and hyperintensity in T2-weighted images in the periventricular supratentorial and deep white matter and thin corpus callosum (Figure 1, E and F). Follow-up brain MRI at the age of 13 years showed signs of progressive cortical and subcortical atrophies, initial signs of cerebellar atrophy, and brainstem atrophy, with further thinning of the corpus callosum and higher hyperintensity of supratentorial white matter and thalami in T2-weighted images (Figure 1, G and H). Clinical and neuroimaging findings were suggestive of metabolic neurodegeneration. Metabolic analyses showed a decrease in biopterin in the CSF and a slight increase in plasma lactic (2.4; n.v. 0.3–1.3 mmol/L) and pyruvic acid (0.11; n.v. 0.03–0.08 mmol/L) levels, while white cell enzymes activities, plasma sialotransferrin and vitamin E, plasma and urinary amino acids and organic acids, urinary purine, pyrimidine, and mucopolysaccharides were in the normal range. Muscle biopsy showed a modest subsarcolemmal increase at Gomori trichrome staining in numerous fibers, observed also with succinate dehydrogenase staining (data not shown), displaying a normal COX activity (Figure 2B). Mitochondrial respiratory chain activity in muscle homogenate detected a partial reduction in complex I activity (10.3; n.v. 13-24).

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Figure 2 Cytochrome Histochemical Activity in Patient 1 (A) and Patient 2 (B) Muscle Specimens Revealing Subsarcolemmal Rims

After inconclusive diagnostic analysis with a next-generation multigene panel, the genetic investigation was expanded to WES, and an in silico panel analysis of genes associated with severe pediatric disorders revealed the presence of a heterozygous missense variant, c.628G>A [p.Glu210Lys], in the UBTF gene (NM_014233.4). According to the American College of Medical Genetics classification, the c.628G>A was classified as pathogenic with the PM2, PP2, PP3, and PP5 (PM = moderate evidence of pathogenicity; PP = supporting evidence of pathogenicity) criteria. Segregation analysis showed that the c.628G>A have arisen de novo in both families, definitely confirming the diagnosis of a UBTF1-related disorder.