Novel imaging finding and novel mutation in an infant with molybdenum cofactor deficiency: a mimicker of hypoxic ischaemic encephalopathy

Molybdenum cofactor deficiency is a rare metabolic disorder with neonatal onset seizures, developmental delay, microcephaly and spasticity. In this report, we describe a three-month-old infant presented with neonatal onset, poorly controlled seizures, developmental delay, microcephaly, spastic quadriparesis and visual insufficiency. Magnetic resonance imaging of brain had shown cystic encephalomalacia involving bilateral parieto-occipital lobe, and elevated lactate in magnetic resonance spectroscopy.  Restricted diffusion noted along the corticospinal tract in our case is a novel imaging finding in molybdenum cofactor deficiency.  Low serum uric acid and elevated urine sulphite excretion were observed. A novel homozygous mutation was detected in exon 4 of MOCS2 gene.Early infantile or neonatal onset seizures, developmental delay, microcephaly and cystic encephalomalacia in neuroimaging mimicking hypoxic ischaemic encephalopathy should raise the suspect for molybdenum cofactor deficiency. Screening of all neonates for urinary sulphite metabolites helps in early diagnosis and management. Early diagnosis and treatment with cyclic pyranopterin monophosphate could arrest the progression of this disease. More research is needed to explore further treatment options in this otherwise lethal disorder

Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder

BACKGROUND: MAPK-activated protein kinase 5 (MAPKAPK5) is an essential enzyme for diverse cellular processes. Dysregulation of the pathways regulated by MAPKAPK enzymes can lead to the development of variable diseases. Recently, homozygous loss-of-function variants in MAPKAPK5 were reported in four patients from three families presenting with a recognisable neurodevelopmental disorder, so-called 'neurocardiofaciodigital' syndrome. OBJECTIVE AND METHODS: In order to improve characterisation of the clinical features associated with biallelic MAPKAPK5 variants, we employed a genotype-first approach combined with reverse deep-phenotyping of three affected individuals. RESULTS: In the present study, we identified biallelic loss-of-function and missense MAPKAPK5 variants in three unrelated individuals from consanguineous families. All affected individuals exhibited a syndromic neurodevelopmental disorder characterised by severe global developmental delay, intellectual disability, characteristic facial morphology, brachycephaly, digital anomalies, hair and nail defects and neuroradiological findings, including cerebellar hypoplasia and hypomyelination, as well as variable vision and hearing impairment. Additional features include failure to thrive, hypotonia, microcephaly and genitourinary anomalies without any reported congenital heart disease. CONCLUSION: In this study, we consolidate the causality of loss of MAPKAPK5 function and further delineate the molecular and phenotypic spectrum associated with this new ultra-rare neurodevelopmental syndrome

Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder

[Background]: MAPK-activated protein kinase 5 (MAPKAPK5) is an essential enzyme for diverse cellular processes. Dysregulation of the pathways regulated by MAPKAPK enzymes can lead to the development of variable diseases. Recently, homozygous loss-of-function variants in MAPKAPK5 were reported in four patients from three families presenting with a recognisable neurodevelopmental disorder, so-called ‘neurocardiofaciodigital’ syndrome. [Objective and methods]: In order to improve characterisation of the clinical features associated with biallelic MAPKAPK5 variants, we employed a genotype-first approach combined with reverse deep-phenotyping of three affected individuals. [Results]: In the present study, we identified biallelic loss-of-function and missense MAPKAPK5 variants in three unrelated individuals from consanguineous families. All affected individuals exhibited a syndromic neurodevelopmental disorder characterised by severe global developmental delay, intellectual disability, characteristic facial morphology, brachycephaly, digital anomalies, hair and nail defects and neuroradiological findings, including cerebellar hypoplasia and hypomyelination, as well as variable vision and hearing impairment. Additional features include failure to thrive, hypotonia, microcephaly and genitourinary anomalies without any reported congenital heart disease. [Conclusion]: In this study, we consolidate the causality of loss of MAPKAPK5 function and further delineate the molecular and phenotypic spectrum associated with this new ultra-rare neurodevelopmental syndrome.HH is funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). SE is supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1’

Loss-of-Function Variants in DRD1 in Infantile Parkinsonism-Dystonia

The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with clinical features of dopamine deficiency: severe infantile parkinsonism-dystonia, characterised by frequent oculogyric crises, dysautonomia and global neurodevelopmental impairment. CSF neurotransmitter analysis was unexpectedly normal. Triome whole-genome sequencing revealed a homozygous variant (c.110C>A, (p.T37K)) in DRD1, encoding the most abundant dopamine receptor (D1) in the central nervous system, most highly expressed in the striatum. This variant was absent from gnomAD, with a CADD score of 27.5. Using an in vitro heterologous expression system, we determined that DRD1-T37K results in loss of protein function. Structure-function modelling studies predicted reduced substrate binding, which was confirmed in vitro. Exposure of mutant protein to the selective D1 agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D1 agonists failed to rescue the cellular defect, reflected clinically in the patient, who had no benefit from dopaminergic therapy. Our study identifies DRD1 as a new disease-associated gene, suggesting a crucial role for the D1 receptor in motor control

Intraosseus and extraosseus juxtaarticular calcification: Osteopoikilosis with synovial osteochondromatosis - an association

Osteopoikilosis presents as round or ovoid sclerotic lesions with an appearance like enostosis on pathology. Synovial osteochondromatosis occurs due to cartilaginous metaplasia with synovial villous proliferation with calcified nodules in proximity to joints. A case of osteopoikilosis associated with synovial osteochondromatosis is described. Intraosseus and juxta osseus sclerotic bone lesions were identified on radiographs and computed tomography in a patient with knee pain. The association of osteopoikilosis with synovial osteochondromatosis is rare and to our knowledge has received little attention in the literature

Clinical, imaging and histopathological features of isolated CNS lymphomatoid granulomatosis

Lymphomatoid granulomatosis is a rare systemic angiocentric/angiodestructive, B cell lymphoproliferative disorder. Central nervous system involvement occurs as part of systemic disease. Isolated central nervous system disease is rare with only few case reports. A 53-year-old male presented with progressive cognitive decline, extrapyramidal features, and altered sensorium with seizures over the last 4 years. His magnetic resonance imaging (MRI) of brain showed multiple small enhancing nodules in subependymal/ependymal regions and along the vessels. Brain biopsy showed atypical lymphohistiocytic infiltrate suggestive of lymphomatoid granulomatosis. There was no evidence of systemic disease; thus, isolated central nervous system lymphomatoid granulomatosis was diagnosed

Imaging features of rhinocerebral mucormycosis: A study of 43 patients

Background: Rhinocerebral mucormycosis is a life-threatening infection caused by saprophytic fungi seen almost exclusively in immunocompromised patients.The objective of this study was to describe the imaging findings in patients with rhinocerebral mucormycosis. Materials and methods: The case records of patients with biopsy/culture proven invasive rhinocerebral mucormycosis were reviewed. Computed Tomography (CT) and/or Magnetic Resonance Imaging (MRI) images were retrieved from the Picture Archiving and Communication System (PACS) and analyzed. Statistical analysis was performed using descriptive statistics. Results: CT and MR imaging of 43 patients showed predominant involvement of the ethmoid (37, 86%) and maxillary (34, 79%) sinuses. Extension to the orbit (32, 76%) and face (24, 57%) preceded involvement of the deep skull base (5, 12%) and brain (13, 31%). CT showed minimally enhancing hypodense soft tissue thickening as the predominant finding in involved areas, while MRI showed T2 isointense to mildly hypointense soft tissue thickening and heterogeneous post contrast enhancement as the main finding. Bone erosion was seen less often (17, 40%), with rest (26, 60%) of the patients showing extrasinus extension across grossly intact appearing bones on imaging. Conclusion: CT and MRI shows a spectrum of findings in rhinocerebral mucormycosis. Imaging plays a major role in assessing the extent of involvement and complications

A case of Erdheim Chester disease with central nervous system involvement

Erdheim Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, commonly involving the musculoskeletal system. Other tissue can also be involved, including the central nervous system with wide spectrum of clinical features, at times being nonspecific. This can cause diagnostic dilemmas with delay in diagnosis and initiation of therapy. Here we describe a 63-year-old man who had presented with ataxia and behavioral changes, bony pains, weight loss, and fatigue. His computed tomography (CT), 99Tc scintigraphy and histopathological features on bone biopsy were consistent with ECD. Thus, ECD should be considered as a differential diagnosis in patients presenting with bony pain and nonspecific features of multiorgan involvement