Kshitij Mankad

Zellweger syndrome and secondary mitochondrial myopathy.

Defects in peroxisomes such as those associated with Zellweger syndrome (ZS) can influence diverse intracellular metabolic pathways, including mitochondrial functioning. We report on an 8-month-old female infant and a 6-month-old female infant with typical clinical, radiological and laboratory features of Zellweger syndrome; light microscopic and ultrastructural evidence of mitochondrial pathology in their muscle biopsies; and homozygous pathogenic mutations of the PEX16 gene (c.460 + 5G > A) and the PEX 12 gene (c.888_889 del p.Leu297Thrfs*12), respectively. Additionally, mitochondrial respiratory chain enzymology analysis in the first girl showed a mildly low activity in complexes II–III and IV. We also review five children previously reported in the literature with a presumptive diagnosis of ZS and additional mitochondrial findings in their muscle biopsies. In conclusion, this is the first study of patients with a molecularly confirmed peroxisomal disorder with features of a concomitant mitochondrial myopathy and underscores the role of secondary mitochondrial dysfunction in Zellweger syndrome, potentially contributing to the clinical phenotype.

Pontocerebellar hypoplasia type 2D and optic nerve atrophy further expand the spectrum associated with selenoprotein biosynthesis deficiency

BACKGROUND The term Pontocerebellar hypoplasias collectively refers to a group of rare, heterogeneous and progressive disorders, which are frequently inherited in an autosomal recessive manner and usually have a prenatal onset. Mutations in the SEPSECS gene, leading to deficiency in selenoprotein biosynthesis, have been identified in recent times as the molecular etiology of different pre/perinatal onset neurological phenotypes, including cerebello-cerebral atrophy, Pontocerebellar hypoplasia type 2D and progressive encephalopathy with elevated lactate. These disorders share a similar spectrum of central (e.g., brain neurodegeneration with grey and white matter both involved) and peripheral (e.g., spasticity due to axonal neuropathy) nervous system impairment. CASE PRESENTATION We hereby describe a 9-year-old boy with (i) a typical Pontocerebellar hypoplasia type 2D phenotype (e.g. profound mental retardation, spastic quadriplegia, ponto-cerebellar hypoplasia and progressive cerebral atrophy); (ii) optic nerve atrophy and (iii) mild secondary mitochondrial myopathy detected by muscle biopsy and respiratory chain enzyme analysis. We performed whole exome sequencing which identified a homozygous mutation of the SEPSECS gene (c.1001T > C), confirming the clinical suspect of Pontocerebellar hypoplasia type 2D. CONCLUSION This report further corroborates the notion of a potential secondary mitochondrial dysfunction in the context of selenoprotein biosynthesis deficiency and also adds optic nerve atrophy as a new potential clinical feature within the SEPSECS-associated clinical spectrum. These findings suggest the presence of a possible shared genetic etiology among similar clinical entities characterized by the combination of progressive cerebello-cerebral and optic nerve atrophy and also stress the biological importance of selenoproteins in the regulation of neuronal and metabolic homeostasis.

RARS2 mutations in a sibship with infantile spasms

Pontocerebellar hypoplasia is a group of heterogeneous neurodevelopmental disorders characterized by reduced volume of the brainstem and cerebellum. We report two male siblings who presented with early infantile clonic seizures, and then developed infantile spasms associated with prominent isolated cerebellar hypoplasia/atrophy on magnetic resonance imaging (MRI). Using whole exome sequencing techniques, both were found to be compound heterozygotes for one previously reported and one novel mutation in the gene encoding mitochondrial arginyl‐tRNA synthetase 2 (RARS2). Mutations in this gene have been classically described in pontocerebellar hypoplasia type six (PCH6), a phenotype characterized by early (often intractable) seizures, profound developmental delay, and progressive pontocerebellar atrophy. The electroclinical spectrum of PCH6 is broad and includes a number of seizure types: myoclonic, generalized tonic–clonic, and focal clonic seizures. Our report expands the characterization of the PCH6 disease spectrum and presents infantile spasms as an associated electroclinical phenotype.

MRI abnormalities in children following sequential chemotherapy, hyperfractionated accelerated radiotherapy and high-dose thiotepa for high-risk primitive neuroectodermal tumours of the central nervous system.

Intensive postsurgical therapies have improved survival in children with primitive neuroectodermal tumour, but there is concern that the combination of chemotherapy and radiotherapy may result in a compound injury to normal brain. The purposes of this analysis were to characterise what types of imaging abnormalities occur, identify risk factors and explore how treatment‐related changes may be distinguished from tumour.

A de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity

Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. We report a on 6‐year‐old girl with a de novo 0.63 Mb deletion on chromosome 6q25.1 who demonstrated multiple congenital anomalies including a ventricular septal defect and an underdeveloped cerebellar vermis. She presented with severe pre‐ and post‐natal growth failure, hyperextensible small joints (Beighton scores = 8/9; with normal parental scores), and an abnormally elastic, redundant skin. Abnormally high upper/lower segment ratio (i.e., 1.34 = > 3SD), mild dysmorphic facial features and developmental delay were also present. The girls phenotype was compared with: (i) two girls, each previously reported by Bisgaard et al. and Caselli et al. with similar albeit larger (2.6–7.21 Mb) deletions; (ii) seven additional individuals (6 M; 1 F) harboring deletions within the 6q25.1 region reported in the literature; and (iii) ten further patients (5 M; 4 F; 1 unrecorded sex) recorded in the DECIPHER 6.0 database. We reported on the present girl as her findings could contribute to advance the phenotype of 6q deletions. In addition, the present deletion is the smallest so far recorded in the 6q25 region encompassing eight known genes [vs. 41 of Bisgaard et al., and 23 of Caselli et al.,], including the TAB2 (likely responsible for the girls congenital heart defect), LATS1 gene, and the UST gene (a regulator of the homeostasis of proteoglycans, which could have played a role in the abnormal dermal and cartilage elasticity).

Melanotic neuroectodermal tumour of infancy: A case report and differential diagnosis

Melanotic neuroectodermal tumour of infancy is an uncommon pigmented neoplasm of neural crest origin. It was first described in 1918 by Krompecher, known as congenital melanocarcinoma at that time. Although it is generally agreed upon that it is a benign entity, it is locally aggressive and has a significant recurrent risk, reported to be between 10–15%. There have also been prior reports of malignant behaviour in these tumours, although extremely rare. The majority of cases of this tumour (about 70%) arise from the maxilla and its occurrence in the cranial vault represents approximately 15.6% of cases. We describe a rare case of melanotic neuroectodermal tumour of infancy, with simultaneous involvement of the cranial vault and petrous temporal bone, in a four-month-old child, complicated by post-surgical pseudo-meningocele. This case illustrates the diagnostic dilemma in differentiating reactive osseous sclerosis from direct tumour infiltration, both of which can occur in the context of melanotic neuroectodermal tumour of infancy. The discussion places emphasis on differential diagnoses and useful radiological features to assist in clinching the diagnosis of melanotic neuroectodermal tumour of infancy.

Current concepts and challenges in the radiologic assessment of brain tumors in children: part 2

Assessing tumor response is a large part of everyday clinical work in neuroradiology. However in the setting of tumor treatment, distinguishing tumor progression from treatment-related changes is difficult on conventional MRI sequences. This is made even more challenging in children where mainstay advanced imaging techniques that are often used to decipher progression versus treatment-related changes have technical limitations. In this review, we highlight the challenges in pediatric neuro-oncologic tumor assessment with discussion of pseudophenomenon including pseudoresponse and pseudoprogression. Additionally, we discuss the advanced imaging techniques often employed in neuroradiology to distinguish between pseudophenomenon and true progressive disease.

Impact of induction chemotherapy, hyperfractionated accelerated radiotherapy and high-dose thiotepa on brain volume loss and functional status of children with primitive neuroectodermal tumour

The introduction of aggressive chemo‐radiotherapy regimens has improved overall survival in children with primitive neuroectodermal tumours (PNET). However, these combinations may result in neurotoxicity. Previously reported magnetic resonance imaging abnormalities in children receiving intensive sequential chemotherapy, hyperfractionated accelerated radiotherapy (HART) and high‐dose thiotepa prompted us to investigate the degree of brain volume loss and patients’ functional status after therapy.

A novel PLP1 mutation associated with optic nerve enlargement in two siblings with Pelizaeus–Merzbacher disease: A new MRI finding

Pelizaeus-Merzbacher disease (PMD) is a rare, X-linked disorder characterized by hypomyelination of the Central Nervous System due to mutations in the PLP1 gene. Certain mutations of the PLP1 gene correlate with specific clinical phenotypes and neuroimaging findings. We herein report a novel mutation of the PLP1 gene in two siblings with PMD associated with a rare and protean neuroimaging finding of optic nerve enlargement. To the best of our knowledge this is the first time that this novel mutation H133P of PLP1 gene is identified and clinically associated with optic nerve enlargement in PMD patients.

Genetic heterogeneity for SMARCB1, H3F3A and BRAF in a malignant childhood brain tumour: genetic-pathological correlation.

Intra-tumour heterogeneity is an important diagnostic, therapeutic and prognostic challenge. Its extent and mechanism in brain tumours is incompletely understood[1]. We describe a malignant tumour with unique pathological and genetic features. Most notably the tumour contained mutations in the SMARCB1 gene (typically associated with Atypical Teratoid/Rhabdoid Tumours[2]), the H3F3A gene (typically associated with high grade glioma in children[3]) and the BRAF gene. Furthermore, there was marked heterogeneity in mutation load between different parts of the tumour. This heterogeneity has implications both for the evolution of the tumour and for its diagnosis.