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BACKGROUND: Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin-mediated endocytosis (CME), as in DNAJC6-related juvenile parkinsonism. OBJECTIVE: To report on a new patient cohort with juvenile-onset DNAJC6 parkinsonism-dystonia and determine the functional consequences on auxilin and dopamine homeostasis. METHODS: Twenty-five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole-exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G-associated kinase and synaptic proteins. RESULTS: We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. (123) I-FP-CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G-associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced. CONCLUSIONS: DNAJC6 is an emerging cause of recessive juvenile parkinsonism-dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G-associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G-associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism-dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Although ribosomes are ubiquitously expressed and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein encoding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100 000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Alexander disease is a rare neurodegenerative leucoencephalopathy caused by de novo mutations in the GFAP gene. Infantile, juvenile, and adult subtypes have been described and the clinical and radiological phenotypes are broad. Here we report on a single case of juvenile-onset Alexander disease associated with a novel frameshift mutation in the GFAP gene. The 8-year-old male patient had a relatively mild clinical phenotype characterized by dystonia, intermittent episodes of raised intracranial pressure, and characteristic radiological changes. He also presented with the additional and to our knowledge previously unreported, neuroimaging finding of periventricular calcification. We postulate that in children with leucoencephalopathy and periventricular calcification of undetermined aetiology, the diagnosis of Alexander disease should be considered. If the magnetic resonance imaging findings are compatible with Alexander disease, then DNA analysis of the GFAP gene should be performed even if the full criteria for a neuroradiological diagnosis are not met.

Botulinum toxin has rapidly gained wide acceptance as a treatment for focal spasticity, and is becoming more readily available. Early studies established its effectiveness, but many issues are still open for discussion. After a brief re view of the historical and scientific development of botulinum toxin as a clinical tool and an outline of previous work in the field, some important questions are discussed in the light of more recent trials.

Objective With the identification of mutations in the conserved telomere maintenance component 1 (CTC1) gene as the cause of Coats plus (CP) disease, it has become evident that leukoencephalopathy with calcifications and cysts (LCC) is a distinct genetic entity. Patients and Methods A total of 15 patients with LCC were identified from our database of patients with intracranial calcification. The clinical and radiological features are described. Results The median age (range) at presentation was 10 months (range, 2 days-54 years). Of the 15 patients, 9 presented with epileptic seizures, 5 with motor abnormalities, and 1 with developmental delay. Motor abnormalities developed in 14 patients and cognitive problems in 13 patients. Dense calcification occurred in the basal ganglia, thalami, dentate nucleus, brain stem, deep gyri, deep white matter, and in a pericystic distribution. Diffuse leukoencephalopathy was present in all patients, and it was usually symmetrical involving periventricular, deep, and sometimes subcortical, regions. Cysts developed in the basal ganglia, thalamus, deep white matter, cerebellum, or brain stem. In unaffected areas, normal myelination was present. No patient demonstrated cerebral atrophy. Conclusion LCC shares the neuroradiological features of CP. However, LCC is a purely neurological disorder distinguished genetically by the absence of mutations in CTC1. The molecular cause(s) of LCC has (have) not yet been determined. ispartof: Neuropediatrics vol:45 issue:3 pages:175-82 ispartof: location:Germany status: published

Alexander disease is a rare neurodegenerative leucoencephalopathy caused by de novo mutations in the GFAP gene. Infantile, juvenile, and adult subtypes have been described and the clinical and radiological phenotypes are broad. Here we report on a single case of juvenile-onset Alexander disease associated with a novel frameshift mutation in the GFAP gene. The 8-year-old male patient had a relatively mild clinical phenotype characterized by dystonia, intermittent episodes of raised intracranial pressure, and characteristic radiological changes. He also presented with the additional and to our knowledge previously unreported, neuroimaging finding of periventricular calcification. We postulate that in children with leucoencephalopathy and periventricular calcification of undetermined aetiology, the diagnosis of Alexander disease should be considered. If the magnetic resonance imaging findings are compatible with Alexander disease, then DNA analysis of the GFAP gene should be performed even if the full criteria for a neuroradiological diagnosis are not met.

Editor,—I read with interest the article “Imaging in scoliosis”. In addition to the radiological techniques described, I would include surface shape measurement as a simple, safe, repeatable, and clinically relevant assessment. Associated with the bony deformity there is a cosmetic problem; indeed, idiopathic scoliosis is primarily a cosmetic disorder. The first sign commonly noticed by the clinician or patient is an asymmetry of backshape, resulting from axial rotation of the spine and rib cage. Treatment is aimed at the reversal or arrest of the progression of this visible deformity as well as …

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γ 3H2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the I ±-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity. © 2012 Nature America, Inc. All rights reserved.