Vein of Galen aneurysm, dilated cardiomyopathy, and slender habitus in a patient with a recurrent pathogenic variant in PACS2.

The PACS2 gene encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation that has been shown to be highly expressed during human prenatal brain development. Pathogenic variants in PACS2 have been recently shown to be implicated in a phenotype with global developmental delay/intellectual disability, seizures, autistic traits, facial dysmorphic features, and cerebellar dysgenesis. Here, we report a 25-year-old male with intellectual disability, epileptic encephalopathy, cerebellar dysgenesis, facial dysmorphism, and a previously reported pathogenic variant in PACS2. To our knowledge, this is the oldest patient reported who, in addition to the known phenotype described in PACS2 patients, presented with a vein of Galen malformation and dilated cardiomyopathy as previously unreported findings.

Genetic diagnosis of basal ganglia disease in childhood.

AIM: To correlate clinical, radiological, and biochemical features with genetic findings in children with bilateral basal ganglia lesions of unknown aetiology, and propose a diagnostic algorithm for early recognition. METHOD: Children with basal ganglia disease were recruited in a 2-year prospective multicentre study for clinical, biomarker, and genetic studies. Radiological pattern recognition was examined by hierarchical clustering analysis. RESULTS: We identified 22 genetic conditions in 30 out of 62 paediatric patients (37 males, 25 females; mean age at onset 2y, SD 3; range 0-10y; mean age at assessment 11y, range 1-25y) through gene panels (n=11), whole-exome sequencing (n=13), and mitochondrial DNA (mtDNA) sequencing (n=6). Genetic aetiologies included mitochondrial diseases (57%), Aicardi-Goutières syndrome (20%), and monogenic causes of dystonia and/or epilepsy (17%) mimicking Leigh syndrome. Radiological abnormalities included T2-hyperintense lesions (n=26) and lesions caused by calcium or manganese mineralization (n=9). Three clusters were identified: the pallidal, neostriatal, and striatal, plus the last including mtDNA defects in the oxidative phosphorylation system with prominent brain atrophy. Mitochondrial biomarkers showed poor sensitivity and specificity in children with mitochondrial disease, whereas interferon signature was observed in all patients with patients with Aicardi-Goutières syndrome. INTERPRETATION: Combined whole-exome and mtDNA sequencing allowed the identification of several genetic conditions affecting basal ganglia metabolism. We propose a diagnostic algorithm which prioritizes early use of next-generation sequencing on the basis of three clusters of basal ganglia lesions.

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

Primary endovascular treatment for acute ischemic stroke in teenage patients: a short case series.

PURPOSE: To analyze the safety and efficacy of primary endovascular treatment (EVT) for acute ischemic stroke (AIS) in patients younger than 18 years of age. METHODS: Review of 4 patients < 18 years of age with AIS, prospectively enrolled in an electronic database registry for acute ischemic stroke patients who underwent thrombectomy at tertiary centers, from January 2011 to February 2017. Clinical and imaging data were analyzed. RESULTS: All patients were female. Patients 1 to 4 were 14, 13, 16, and 13 years old, respectively. Patients 1 and 3 had left middle cerebral artery occlusion, patient 2 basilar occlusion, and patient 4 right tandem occlusion. Mean NIHSS score was 13 (7-19) on arrival and 4 (0-5) at 24 h. Patient 2 had Osler-Weber-Rendu disease and patient 4 a previously surgically repaired complete atrioventricular canal. All patients presented with clinical-radiological mismatch. CT/CTA was used in patients 1 and 4 and MRI/MRA in patients 2 and 3. Stent retriever was used in 3 patients (patients 1, 3, and 4) and direct aspiration first-pass technique in 1 (patient 2). All 4 procedures resulted in successful recanalization and 3-month functional independence. CONCLUSION: Primary EVT is reported in patients 13 to 16 years of age with AIS due to large vessel occlusion and clinical-radiological mismatch. Procedures were safe and effective with prompt recanalization and good clinical outcome.

Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood.

AIM: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations. METHOD: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts. RESULTS: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival. INTERPRETATION: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.

Disease duration and disability in dysfeRlinopathy can be described by muscle imaging using heatmaps and random forests.

INTRODUCTION: The manner in which imaging patterns change over the disease course and with increasing disability in dysferlinopathy is not fully understood. METHODS: Fibroadipose infiltration of 61 muscles was scored based on whole-body MRI of 33 patients with dysferlinopathy and represented in a heatmap. We trained random forests to predict disease duration, Motor Function Measure dimension 1 (MFM-D1), and modified Rankin scale (MRS) score based on muscle scoring and selected the most important muscle for predictions. RESULTS: The heatmap delineated positive and negative fingerprints in dysferlinopathy. Disease duration was related to infiltration of infraspinatus, teres major-minor, and supraspinatus muscles. MFM-D1 decreased with higher infiltration of teres major-minor, triceps, and sartorius. MRS related to infiltration of vastus medialis, gracilis, infraspinatus, and sartorius. DISCUSSION: Dysferlinopathy shows a recognizable muscle MRI pattern. Fibroadipose infiltration in specific muscles of the thigh and the upper limb appears to be an important marker for disease progression. Muscle Nerve 59:436-444, 2019.

Muscle imaging in laminopathies: Synthesis study identifies meaningful muscles for follow-up.

INTRODUCTION: Particular fibroadipose infiltration patterns have been recently described by muscle imaging in congenital and later onset forms of LMNA-related muscular dystrophies (LMNA-RD). METHODS: Scores for fibroadipose infiltration of 23 lower limb muscles in 34 patients with LMNA-RD were collected from heat maps of 2 previous studies. Scoring systems were homogenized. Relationships between muscle infiltration and disease duration and age of onset were modeled with random forests. RESULTS: The pattern of infiltration differs according to disease duration but not to age of disease onset. The muscles whose progression best predicts disease duration were semitendinosus, biceps femoris long head, gluteus medius, and semimembranosus. DISCUSSION: In LMNA-RD, our synthetic analysis of lower limb muscle infiltration did not find major differences between forms with different ages of onset but allowed the identification of muscles with characteristic infiltration during disease progression. Monitoring of these specific muscles by quantitative MRI may provide useful imaging biomarkers in LMNA-RD. Muscle Nerve 58:812-817, 2018.

Imaging abusive head trauma: why use both computed tomography and magnetic resonance imaging?

Abusive head trauma is the leading cause of death in child abuse cases. The majority of victims are infants younger than 1 year old, with the average age between 3 and 8 months, although these injuries can be seen in children up to 5 years old. Many victims have a history of previous abuse and the diagnosis is frequently delayed. Neuroimaging is often crucial for establishing the diagnosis of abusive head trauma as it detects occult injury in 37% of cases. Several imaging patterns are considered to be particularly associated with abusive head trauma. The presence of subdural hematoma, especially in multiple locations, such as the interhemispheric region, over the convexity and in the posterior fossa, is significantly associated with abusive head trauma. Although CT is the recommended first-line imaging modality for suspected abusive head trauma, early MRI is increasingly used alongside CT because it provides a better estimation of shear injuries, hypoxic-ischemic insult and the timing of lesions. This article presents a review of the use and clinical indications of the most pertinent neuroimaging modalities for the diagnosis of abusive head trauma, emphasizing the newer and more sensitive techniques that may be useful to better characterize the nature and evolution of the injury.

At-risk brain tissue identified with arterial spin labeling in neurotuberculosis.

A 13-year-old immunocompromised girl developed neurotuberculosis. Arterial spin labeling technique indicated areas of hypoperfusion in the vascular territories of the left posterior cerebral artery and superior cerebellar artery without restricted diffusion, suggesting early tuberculous arteritis. MR angiography confirmed vascular involvement, so adjunctive anticoagulant therapy was initiated. Complete resolution of arterial spin labeling findings was observed 1 month later. This documents early tuberculous vasculopathy revealed by arterial spin labeling in a child with neurotuberculosis. Since there may be a paucity of clinical symptoms in the evolution of arteritis in neurotuberculosis, arterial spin labeling may help indicate early hypoperfusion and alert for modification of treatment before irreversible vascular damage occurs.

A comprehensive study of skeletal muscle imaging in FHL1-related reducing body myopathy.

OBJECTIVE: FHL1-related reducing body myopathy is an ultra-rare, X-linked dominant myopathy. In this cross-sectional study, we characterize skeletal muscle ultrasound, muscle MRI, and cardiac MRI findings in FHL1-related reducing body myopathy patients. METHODS: Seventeen patients (11 male, mean age 35.4, range 12-76 years) from nine independent families with FHL1-related reducing body myopathy underwent clinical evaluation, muscle ultrasound (n = 11/17), and lower extremity muscle MRI (n = 14/17), including Dixon MRI (n = 6/17). Muscle ultrasound echogenicity was graded using a modified Heckmatt scale. T1 and STIR axial images of the lower extremity muscles were evaluated for pattern and distribution of abnormalities. Quantitative analysis of intramuscular fat fraction was performed using the Dixon MRI images. Cardiac studies included electrocardiogram (n = 15/17), echocardiogram (n = 17/17), and cardiac MRI (n = 6/17). Cardiac muscle function, T1 maps, T2-weighted black blood images, and late gadolinium enhancement patterns were analyzed. RESULTS: Muscle ultrasound showed a distinct pattern of increased echointensity in skeletal muscles with a nonuniform, multifocal, and "geographical" distribution, selectively involving the deeper fascicles of muscles such as biceps and tibialis anterior. Lower extremity muscle MRI showed relative sparing of gluteus maximus, rectus femoris, gracilis, and lateral gastrocnemius muscles and an asymmetric and multifocal, "geographical" pattern of T1 hyperintensity within affected muscles. Cardiac studies revealed mild and nonspecific abnormalities on electrocardiogram and echocardiogram with unremarkable cardiac MRI studies. INTERPRETATION: Skeletal muscle ultrasound and muscle MRI reflect the multifocal aggregate formation in muscle in FHL1-related reducing body myopathy and are practical and informative tools that can aid in diagnosis and monitoring of disease progression.

Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort.

BACKGROUND: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. OBJECTIVE: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). RESULTS: 27 patients (2-62 years, 21-80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A "COL6-like sandwich sign" was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. CONCLUSION: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.

Side effects of oncologic therapies in the pediatric central nervous system: update on neuroimaging findings.

The need for early, accurate diagnosis of central nervous system (CNS) complications occurring during and after pediatric cancer treatment is growing because of the improvement in overall survival rates related to innovative and aggressive oncologic therapies. An elevated degree of suspicion is needed to recognize the radiologic features of these CNS complications. Radiologists need familiarity with the early and late side effects of cancer therapy in the pediatric CNS (eg, toxic effects, infection, endocrine or sensory dysfunction, neuropsychologic impairment, second malignancies), in order to accelerate the imaging diagnosis and minimize as much as possible the associated morbidity. Acquisition of knowledge about these complications will enable the development of more appropriate therapeutic trials and more effective patient surveillance and will lead to an improved quality of life by decreasing the long-term sequelae in survivors.

Leigh syndrome associated with TRMU gene mutations.

tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency causes an early onset potentially reversible acute liver failure, so far reported in less than 30 patients. We describe two new unrelated patients with an acute liver failure and a neuroimaging compatible with Leigh syndrome (LS) due to TRMU deficiency, a combination not previously reported. Our report enlarges the phenotypical spectrum of TRMU disease.

Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect.

FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). METHODS: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. RESULTS: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. CONCLUSION: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.

Measurements of signal intensity of globus pallidus and dentate nucleus suggest different deposition characteristics of macrocyclic GBCAs in children.

INTRODUCTION: The safety of using GBCAs to enhance the visibility of body structures is currently discussed due to possible gadolinium retention in brain structures. The aim of the study was to evaluate the effect of multiple exposures to macrocyclic GBCAs in children. MATERIALS AND METHODS: This retrospective, single-center study included data from 43 patients who had received ≥4 injections of macrocyclic GBCAs during MRI examinations over performed over 8 to 84 months. Signal intensity was measured on unenhanced T1-weighted MRI, and globus pallidus to thalamus (GP/Th) and dentate nucleus to pons (DN/P) ratios were calculated. The differences in ratios were tested with the Student's t-test or the Wilcoxon rank sum test. For categorical data, Pearson's chi-squared test was used. Relationships were analyzed with the Spearman's rank correlation coefficient. RESULTS: Patients with the mean age of 7.5 years (SD = 4.2) received 8.19 (SD = 3.63) injections of GBCAs on average. Differences in GP/Th and DN/P ratios between the first and the last measurement were insignificant. Children before the end of myelination process (≤2 years of age) had the first GP/Th ratio values significantly lower than those >2 years of age (p = 0.0284), which than increased at the final scan and reached the level similar to values obtained in the group of >2 years of age. CONCLUSIONS: Maturation of the brain may affect both signal intensity of brain structures and susceptibility to GBCAs; thus, assessment of signal intensity of the brain structures should be conducted taking into account the age of a child.

Microcephaly with simplified gyral pattern, epilepsy and permanent neonatal diabetes syndrome (MEDS). A new patient and review of the literature.

Microcephaly with simplified gyration, epilepsy and permanent neonatal diabetes syndrome (MEDS) is a recently described, autosomal recessive-inherited syndrome. We report the case of an infant presenting with lethargy at age five weeks and clinical findings of persistent hyperglycaemia and microcephaly with simplified gyration, suggestive of MEDS. The diagnosis was confirmed by the detection of a known c.233 T > C mutation in the IER3IP1 gene. Only eight cases of MEDS have been reported in the literature. We reviewed these with the aim of better delineating their clinical manifestations, which should allow earlier and more accurate diagnosis and genetic counseling.

Cerebral arteriopathy associated with heterozygous Arg179Cys mutation in the ACTA2 gene: Report in 2 newborn siblings.

Mutations in the ACTA2 gene lead to a multisystemic smooth muscle dysfunction syndrome that causes vascular disease, congenital mydriasis, and variable presentation of urinary and gastrointestinal problems. The heterozygous Arg179 mutation is associated with a distinctive cerebrovascular phenotype. We report the cases of two newborn siblings with heterozygous ACTA2 Arg179Cys substitution and provide neuroimaging exams that demonstrate the distinctive cerebrovascular phenotype, also associated with variable degree of hypoplasia of the vertebro-basilar circulation as well as hypoxic-ischemic lesions.

Arthrogryposis as neonatal presentation of Loeys-Dietz syndrome due to a novel TGFBR2 mutation.

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized mainly by cardiovascular, craniofacial and skeletal features. We report on a patient with LDS, whose prenatal examination was compatible with the diagnosis of arthrogryposis multiplex congenita. Neonatal assessment showed craniofacial and cardiovascular findings suggestive of LDS whose diagnosis was confirmed by the detection of a novel mutation (HGVN: NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))) in the TGFBR2 gene. Few prenatal and neonatal cases of LDS have been reported in the literature. We reviewed all cases reported to date with perinatal onset to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome at an early stage to prevent fatal cardiovascular complications. Furthermore we discuss the multidisciplinary follow up required in these patients.