MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia.

BACKGROUND: Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. OBJECTIVE: The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. METHODS: Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems. RESULTS: Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter-G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction. CONCLUSIONS: We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development.

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell-cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort.

OBJECTIVE: To compare the performance of the 2017 McDonald criteria with that of the 2010 criteria for the diagnosis of multiple sclerosis (MS) in children in the clinical setting. METHODS: In this retrospective, multi-centre study, we identified children who presented with symptoms suggestive of a clinically isolated syndrome (CIS) and were followed up for at least 2 years or until their second attack. RESULTS: Of 156 children with CIS followed up for a median of 4.17 years, 94 (60.3%) were diagnosed with MS. In all, 83 (88.3%) of these fulfilled the 2010 dissemination in space (DIS) criteria at onset. Three additional children fulfilled the 2017 DIS criteria because of the inclusion of symptomatic lesions. Of the 59 children with MS who underwent post-gadolinium magnetic resonance imaging (MRI), 44 (74.6%) fulfilled the 2010 dissemination in time (DIT) criteria at baseline. When the presence of oligoclonal bands (OCBs) was used to substitute DIT, an additional 35 children (79/94, 84.0%) were diagnosed with MS according to the 2017 criteria. The 2017 criteria had higher accuracy (87.2% vs 66.7%), higher sensitivity (84.0% vs 46.8%), but reduced specificity (91.9% vs 96.8%) when compared to the 2010 criteria. CONCLUSION: The improved performance of the 2017 criteria when compared to the 2010 criteria was predominantly due to the inclusion of intrathecal OCBs.

Correction: The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations.

Since the online publication of the article, the authors have noted errors with Table 2; this has now been corrected in both the HTML and the PDF.

Developmental conduction aphasia after neonatal stroke.

OBJECTIVE: Impairment of speech repetition following injury to the dorsal language stream is a feature of conduction aphasia, a well-described "disconnection syndrome" in adults. The impact of similar lesions sustained in infancy has not been established. METHODS: We compared language outcomes in term-born individuals with confirmed neonatal stroke (n = 30, age = 7-18 years, left-sided lesions in 21 cases) to matched controls (n = 40). Injury to the dorsal and/or ventral language streams was assessed using T1 - and T2 -weighted magnetic resonance imaging (MRI) and diffusion tractography. Language lateralization was determined using functional MRI. RESULTS: At the group level, left dorsal language stream injury was associated with selective speech repetition impairment for nonwords (p = 0.021) and sentences (p < 0.0001). The majority of children with significant repetition impairment had retained left hemisphere language representation, but right hemisphere dominance was correlated with minimal or absent repetition deficits. Post hoc analysis of the repetition-impaired group revealed additional language-associated deficits, but these were more subtle and variable. INTERPRETATION: We conclude that (1) despite the considerable plasticity of the infant brain, early dorsal language stream injury can result in specific and long-lasting problems with speech repetition that are similar to the syndrome of conduction aphasia seen in adults; and (2) language reorganization to the contralateral hemisphere has a protective effect. Ann Neurol 2018;83:664-675 Ann Neurol 2018;83:664-675.

The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations.

PurposeMutations in POLG, the most common single-gene cause of inherited mitochondrial disease, are diagnostically challenging owing to clinical heterogeneity and overlap between syndromes. We aimed to improve the clinical recognition of POLG-related disorders in the pediatric population.MethodsWe performed a multinational, phenotype: genotype study using patients from three centers, two Norwegian and one from the United Kingdom. Patients with age at onset <12 years and confirmed pathogenic biallelic POLG mutations were considered eligible.ResultsA total of 27 patients were identified with a median age at onset of 11 months (range 0.6-80.4). The majority presented with global developmental delay (n=24/24, 100%), hypotonia (n=22/23, 96%) and faltering growth (n=24/27, 89%). Epilepsy was common, but notably absent in patients with the myocerebrohepatopathy spectrum phenotype. We identified two novel POLG gene mutations.ConclusionOur data suggest that POLG-related disease should be suspected in any child presenting with diffuse neurological symptoms. Full POLG sequencing is recommended since targeted screening may miss mutations. Finally, we simplify the classification of POLG-related disease in children using epilepsy as the crucial defining element; we show that Alpers and myocerebrohepatopathy spectrum follow different outcomes and that they manifest different degrees of respiratory chain dysfunction.

A Pilot Clinical Study in Characterization of Malignant Renal-cell Carcinoma Subtype with Contrast-enhanced Ultrasound.

Malignant renal cell carcinoma (RCC) is a diverse set of diseases, which are independently difficult to characterize using conventional MRI and CT protocols due to low temporal resolution to study perfusion characteristics. Because different disease subtypes have different prognoses and involve varying treatment regimens, the ability to determine RCC subtype non-invasively is a clinical need. Contrast-enhanced ultrasound (CEUS) has been assessed as a tool to characterize kidney lesions based on qualitative and quantitative assessment of perfusion patterns, and we hypothesize that this technique might help differentiate disease subtypes. Twelve patients with RCC confirmed pathologically were imaged using contrast-enhanced ultrasound. Time intensity curves were generated and analyzed quantitatively using 10 characteristic metrics. Results showed that peak intensity ( p = 0.001) and time-to-80% on wash-out ( p = 0.004) provided significant differences between clear cell, papillary, and chromophobe RCC subtypes. These results suggest that CEUS may be a feasible test for characterizing RCC subtypes.

Radiologic Improvement After Early Medical Intervention in Localised Facial Morphea.

We report the case of a young girl who presented with hemiparesis, seizures, and subtle features consistent with a linear form of facial morphea (en coup de sabre). She was treated with pulsed parenteral steroids and oral steroids and started on methotrexate. Magnetic resonance imaging results and neurologic problems improved after 6 months. Switching off inflammation early in the course of disease seemed to reverse some of the central nervous system changes. Assessment of children with unexplained hemiparesis and seizures should include careful examination of the face and scalp, looking for subtle signs of skin change and asymmetry. This is one of the few reported cases of neuroradiologic improvement after immunosuppressive treatment in a child with en coup de sabre.

Ultrasound of palpable lesions: a pictorial review.

Ultrasound (US) is the imaging modality of choice for evaluation of superficial palpable lesions. A large proportion of these lesions have characteristic sonographic appearance and can be confidently diagnosed with US without the need for biopsy or other intervention. The Society of Radiologists in Ultrasound (SRU) recently published a Consensus Conference Statement on superficial soft tissue masses. The goal of this manuscript is (a) to serve as a sonographic pictorial review for palpable lesions based on the SRU statement, (b) present the typical sonographic features of palpable lesions that can be confidently diagnosed with US, and (c) provide an overview of other palpable lesions with a framework to interpret the US studies and advise on appropriate further management.

Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features.

OBJECTIVE: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. METHODS: We conducted a population active surveillance study. All paediatricians, and ophthalmologists (n = 4095) were sent monthly reporting cards (September 2009-September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. RESULTS: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3-15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years (n = 63) was 1.52:1 (p = 0.045). The incidence of first onset ADS in children aged 1-15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18-11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. CONCLUSIONS: We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.

A population-based study of newly diagnosed epilepsy in infants.

PURPOSE: Most published data on infants presenting with epilepsy originate from hospital/specialist clinic settings and may therefore not be representative of the general population. We carried out a population-based study to estimate the incidence of epilepsy onset in infants, to characterize the range of phenotypes and associated structural brain abnormalities, and to determine whether specific epilepsy diagnoses could be established at onset. METHODS: Children between 1 and 24 months of age with new-onset epilepsy were ascertained over 13 months from the residents in 15 boroughs of North London. Classification based on clinical information, electroencephalography (EEG), and neuroimaging data was undertaken independently by two pediatric neurologists. Neuroimages were reviewed by two neuroradiologists blinded to clinical details. KEY FINDINGS: A total of 57 children were enrolled giving an ascertainment-adjusted incidence of 70.1 (95% CI [56.3, 88.5])/100,000 children ≤ 2 years of age/year (ascertainment 76%). The incidence was highest among Asian children. An electroclinical syndrome was identified in 24 (42%) cases of which 21 were epileptic encephalopathies. Magnetic resonance (MR) images of 51 cases (89% of the total cohort) were reviewed. These demonstrated positive findings in 37 (72%) of 51 cases, of which 26 (51%) of 51 were etiologically relevant, and included developmental malformations in 11 (21%) of 51. SIGNIFICANCE: In a population setting infantile onset epilepsy presents mostly with complex phenotypes commonly associated with structural brain abnormalities. Routine MR imaging at presentation is therefore justified. However, identification of specific electroclinical syndromes remains difficult at onset.

Early developmental outcomes in children following convulsive status epilepticus: a longitudinal study.

PURPOSE: Convulsive status epilepticus (CSE) is the most common pediatric neurologic emergency and is often associated with unfavorable neurodevelopmental outcomes. The early developmental trajectory of children following CSE has not been previously investigated, leaving a gap in our understanding of how these adverse long-term outcomes emerge. METHODS: We prospectively recruited children aged between 1 and 42 months from a predefined geographic region of North London who had at least one episode of CSE and classified them as prolonged febrile seizures (PFS) or nonfebrile CSE. Neuropsychological and imaging investigations were conducted within 6 weeks of CSE (baseline) and were repeated a year later (follow-up). Neurodevelopment was assessed using the Bayley Scales of Infant Development III and compared to normally developing children. Predictors of neurodevelopmental scores at baseline and follow-up were investigated using regression analyses. KEY FINDINGS: Of the 54 children that underwent investigations a mean of 38 days following CSE, 27 had PFS (mean age 18.4 months) and 27 had nonfebrile CSE (mean age 15.5 months). In addition, 17 healthy controls were assessed (mean age 20.49 months). Children with nonfebrile CSE had a worse developmental outcome than children with PFS (p < 0.002), despite there being no differences in seizure characteristics. In contrast to expectations, the PFS group had a worse developmental outcome than controls (p = 0.002). There were no significant differences in performance from baseline to 1-year follow-up for the 70.4% of children who provided data. Seizure characteristics were not shown to be significant predictors of performance. SIGNIFICANCE: CSE is associated with developmental impairments within 6 weeks of the acute event that continue to be present a year onward. This is also true of PFS cases that under-perform relative to controls despite mean scores within the clinically normal range. The absence of a change in performance from baseline to follow-up as well as the lack of a relationship between seizure characteristics and developmental outcomes supports the notion that premorbid abilities may be overshadowing any direct effects of CSE itself on outcome.

Interhemispheric temporal lobe connectivity predicts language impairment in adolescents born preterm.

Although language difficulties are common in children born prematurely, robust neuroanatomical correlates of these impairments remain to be established. This study investigated whether the greater prevalence of language problems in preterm (versus term-born) children might reflect injury to major intra- or interhemispheric white matter pathways connecting frontal and temporal language regions. To investigate this, we performed a comprehensive assessment of language and academic abilities in a group of adolescents born prematurely, some of whom had evidence of brain injury at birth (n = 50, mean age: 16 years, mean gestational age: 27 weeks) and compared them to a term-born control group (n = 30). Detailed structural magnetic resonance imaging and diffusion-tractography analyses of intrahemispheric and interhemispheric white matter bundles were performed. Analysis of intrahemispheric pathways included the arcuate fasciculus (dorsal language pathway) and uncinate fasciculus/extreme capsule (ventral language pathway). Analysis of interhemispheric pathways (in particular, connections between the temporal lobes) included the two major commissural bundles: the corpus callosum and anterior commissure. We found language impairment in 38% of adolescents born preterm. Language impairment was not related to abnormalities of the arcuate fasciculus (or its subsegments), but was associated with bilateral volume reductions in the ventral language pathway. However, the most significant volume reduction was detected in the posterior corpus callosum (splenium), which contains interhemispheric connections between the occipital, parietal and temporal lobes. Diffusion tractography showed that of the three groups of interhemispheric fibres within the splenium, only those connecting the temporal lobes were reduced. Crucially, we found that language impairment was only detectable if the anterior commissure (a second temporal lobe commissural pathway) was also small. Regression analyses showed that a combination of anatomical measures of temporal interhemispheric connectivity (through the splenium of the corpus callosum and anterior commissure) explained 57% of the variance in language abilities. This supports recent theories emphasizing the importance of interhemispheric connections for language, particularly in the developing brain.

Effect of growth hormone deficiency on brain structure, motor function and cognition.

The growth hormone-insulin-like growth factor-1 axis plays a role in normal brain growth but little is known of the effect of growth hormone deficiency on brain structure. Children with isolated growth hormone deficiency (peak growth hormone <6.7 µg/l) and idiopathic short stature (peak growth hormone >10 µg/l) underwent cognitive assessment, diffusion tensor imaging and volumetric magnetic resonance imaging prior to commencing growth hormone treatment. Total brain, corpus callosal, hippocampal, thalamic and basal ganglia volumes were determined using Freesurfer. Fractional anisotropy (a marker of white matter structural integrity) images were aligned and tract-based spatial statistics performed. Fifteen children (mean 8.8 years of age) with isolated growth hormone deficiency [peak growth hormone <6.7 µg/l (mean 3.5 µg/l)] and 14 controls (mean 8.4 years of age) with idiopathic short stature [peak growth hormone >10 µg/l (mean 15 µg/l) and normal growth rate] were recruited. Compared with controls, children with isolated growth hormone deficiency had lower Full-Scale IQ (P < 0.01), Verbal Comprehension Index (P < 0.01), Processing Speed Index (P < 0.05) and Movement-Assessment Battery for Children (P < 0.008) scores. Verbal Comprehension Index scores correlated significantly with insulin-like growth factor-1 (P < 0.03) and insulin-like growth factor binding protein-3 (P < 0.02) standard deviation scores in isolated growth hormone deficiency. The splenium of the corpus callosum, left globus pallidum, thalamus and hippocampus (P < 0.01) were significantly smaller; and corticospinal tract (bilaterally; P < 0.045, P < 0.05) and corpus callosum (P < 0.05) fractional anisotropy were significantly lower in the isolated growth hormone deficiency group. Basal ganglia volumes and bilateral corticospinal tract fractional anisotropy correlated significantly with Movement-Assessment Battery for Children scores, and corpus callosum fractional anisotropy with Full-Scale IQ and Processing Speed Index. In patients with isolated growth hormone deficiency, white matter abnormalities in the corpus callosum and corticospinal tract, and reduced thalamic and globus pallidum volumes relate to deficits in cognitive function and motor performance. Follow-up studies that investigate the course of the structural and cognitive deficits on growth hormone treatment are now required to confirm that growth hormone deficiency impacts significantly on brain structure, cognitive function and motor performance.

Diversity of current ultrasound practice within and outside radiology departments with a vision for 20 years into the future: a position paper of the ESR ultrasound subcommittee.

Ultrasound practice is a longstanding tradition for radiology departments, being part of the family of imaging techniques. Ultrasound is widely practiced by non-radiologists but becoming less popular within radiology. The position of ultrasound in radiology is reviewed, and a possible long-term solution to manage radiologist expectations is proposed. An international group of experts in the practice of ultrasound was invited to describe the current organisation of ultrasound within the radiology departments in their own countries and comment on the interaction with non-radiologists and training arrangements. Issues related to regulation, non-medical practitioners, and training principles are detailed. A consensus view was sought from the experts regarding the position of ultrasound within radiology, with the vision of the best scenario for the continuing dominance of radiologists practising ultrasound. Comments were collated from nine different countries. Variable levels of training, practice, and interaction with non-radiologist were reported, with some countries relying on non-physician input to manage the service. All experts recognised there was a diminished desire to practice ultrasound by radiologists. Models varied from practising solely ultrasound and no other imaging techniques to radiology departments being central to the practice of ultrasound by radiologists and non-radiologist, housed within radiology. The consensus view was that the model favoured in select hospitals in Germany would be the most likely setup for ultrasound radiologist to develop and maintain practice. The vision for 20 years hence is for a central ultrasound section within radiology, headed by a trained expert radiologist, with non-radiologist using the facilities.Critical relevance statement The future of ultrasound within the radiology department should encompass all ultrasound users, with radiologists expert in ultrasound, managing the ultrasound section within the radiology department. The current radiology trainees must learn of the importance of ultrasound as a component of the 'holistic' imaging of the patient.Key points: 1. Ultrasound imaging within radiology departments precedes the introduction of CT and MR imaging and was first used over 50 years ago.2. Non-radiology practitioners deploy ultrasound examinations to either 'problem solve' or perform a comprehensive ultrasound examination; radiologists provide comprehensive examinations or use ultrasound to direct interventional procedures.3. Radiology does not 'own' ultrasound, but radiologists are best placed to offer a comprehensive patient-focused imaging assessment.4. A vision of the future of ultrasound within the radiology department is encompassing all ultrasound users under radiologists who are experts in ultrasound, positioned within the radiology department.5. The current radiology trainee must be aware of the importance of ultrasound as a component of the 'holistic' imaging of the patient.

Speech and oromotor outcome in adolescents born preterm: relationship to motor tract integrity.

OBJECTIVE: To assess speech abilities in adolescents born preterm and investigate whether there is an association between specific speech deficits and brain abnormalities. STUDY DESIGN: Fifty adolescents born prematurely (<33 weeks' gestation) with a spectrum of brain injuries were recruited (mean age, 16 years). Speech examination included tests of speech-sound processing and production and speech and oromotor control. Conventional magnetic resonance imaging and diffusion-weighted imaging was acquired in all adolescents born preterm and 30 term-born control subjects. Radiological ratings of brain injury were recorded and the integrity of the primary motor projections was measured (corticospinal tract and speech-motor corticobulbar tract [CST/CBT]). RESULTS: There were no clinical diagnoses of developmental dysarthria, dyspraxia, or a speech-sound disorder, but difficulties in speech and oromotor control were common. A regression analysis revealed that presence of a neurologic impairment, and diffusion-weighted imaging abnormalities in the left CST/CBT were significant independent predictors of poor speech and oromotor outcome. These left-lateralized abnormalities were most evident at the level of the posterior limb of the internal capsule. CONCLUSION: Difficulties in speech and oromotor control are common in adolescents born preterm, and adolescents with injury to the CST/CBT pathways in the left-hemisphere may be most at risk.

Total brain white matter is a major determinant of IQ in adolescents born preterm.

OBJECTIVE: In preterm infants, white matter (WM) abnormalities detected on magnetic resonance imaging (MRI) at term-age are associated with early developmental delay. We set out to study this association in adolescents born pre-term, by examining intellectual outcome in relation to markers of brain injury, focusing on the effects of WM reduction. METHODS: Seventy-nine participants were recruited and assessed at a mean age of 16 years: 49 adolescents born preterm (<32 weeks' gestation) with a wide spectrum of brain injuries (including 22 with no identifiable brain injury at birth) and 30 term-born controls. Data collected included: brain MRI scans, full-scale intelligence quotient (IQ) scores, educational attainments, and behavioral scores. Measures of WM reduction included total volume, cross-sectional area of the corpus callosum (CC), and ventricular dilatation. Cerebellar volumes and neuroradiological ratings were also included. RESULTS: WM volume and IQ were reduced in the preterm groups (both with and without brain injury). Total WM volume and CC area jointly explained 70% of IQ variance in the adolescents born preterm, irrespective of the presence or severity of brain abnormalities detected at birth or on follow-up MRI. This relationship was not seen in controls. Importantly, correlations were also found with real-world measures of academic achievement and behavioral difficulties. INTERPRETATION: Preterm birth has a long-term effect on cognition, behavior, and future academic success primarily as a consequence of global brain WM reduction. This emphasizes the need for early therapeutic efforts to prevent WM injury and promote or optimize its development in preterm neonates.

Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.

BACKGROUND: Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, which encodes an integral peroxisomal membrane protein involved in peroxisomal membrane assembly. PEX16-defective patients have been reported to have a severe clinical presentation. Fibroblasts from these patients displayed a defect in the import of peroxisomal matrix and membrane proteins, resulting in a total absence of peroxisomal remnants. OBJECTIVE: To report on six patients with an unexpected mild variant peroxisome biogenesis disorder due to mutations in the PEX16 gene. Patients presented in the preschool years with progressive spastic paraparesis and ataxia (with a characteristic pattern of progressive leucodystrophy and brain atrophy on MRI scan) and later developed cataracts and peripheral neuropathy. Surprisingly, their fibroblasts showed enlarged, import-competent peroxisomes. RESULTS: Plasma analysis revealed biochemical abnormalities suggesting a peroxisomal disorder. Biochemical variables in fibroblasts were only mildly abnormal or within the normal range. Immunofluorescence microscopy revealed the presence of import-competent peroxisomes, which were increased in size but reduced in number. Subsequent sequencing of all known PEX genes revealed five novel apparent homozygous mutations in the PEX16 gene. CONCLUSIONS: An unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene, with a relatively mild clinical phenotype and an unexpected phenotype in fibroblasts, was identified. Although PEX16 is involved in peroxisomal membrane assembly, PEX16 defects can present with enlarged import-competent peroxisomes in fibroblasts. This is important for future diagnostics of patients with a peroxisomal disorder.