Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia.

SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here, we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants, which were submitted to 'matching' platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of cerebrospinal fluid studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in Saccharomyces cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition.

Congenital Cranial Dysinnervation Disorder: An Unusual Phenotype With Multiple Cranial Neuropathies and Novel Neuroimaging Findings.

Congenital cranial dysinnervation disorders result from a maldevelopment of brainstem nuclei and/or cranial nerves. In some cases, specific genetic abnormalities have been identified. We expand the clinical phenotype of these disorders with the report of a 28-month-old girl who was initially evaluated for seizures and was found to have right sixth nerve palsy, small optic discs with reduced vision in her right eye. Her development was delayed. Brain MRI showed multiple abnormalities involving other cranial nerves, the optic chiasm and brainstem. Her developmental delay and seizure disorder suggest additional cortical involvement.

Neuropsychiatric Features in Primary Mitochondrial Disease.

Mitochondrial diseases are a clinically heterogeneous group of disorders that ultimately result from dysfunction of the mitochondrial respiratory chain. There is some evidence to suggest that mitochondrial dysfunction plays a role in neuropsychiatric illness; however, the data are inconclusive. This article summarizes the available literature published in the area of neuropsychiatric manifestations in both children and adults with primary mitochondrial disease, with a focus on autism spectrum disorder in children and mood disorders and schizophrenia in adults.

The magnetic resonance imaging appearance of monophasic acute disseminated encephalomyelitis: an update post application of the 2007 consensus criteria.

Acute disseminated encephalomyelitis (ADEM) is an immunologically mediated inflammatory disease of the central nervous system that typically occurs after a viral infection or recent vaccination, and is most commonly seen in the pediatric population. In 2007 the International Pediatric Multiple Sclerosis Study Group proposed a consensus definition for ADEM for application in research and clinical settings. This article gives an overview of ADEM in children, focusing on differences that have emerged since the consensus definition was established. Although the focus is on neuroimaging in these patients, a synopsis of the clinical features, immunopathogenesis, treatment, and prognosis of ADEM is provided.

Cognitive trajectories in 4 patients with pediatric-onset multiple sclerosis: serial evaluation over a decade.

Cognitive dysfunction is common in pediatric-onset multiple sclerosis, but long-term data on cognitive maturation in these patients are sparse. We report the clinical features and cognitive trajectories in 4 pediatric-onset multiple sclerosis patients who were 10 years or younger at first attack and were followed between 1998 and 2010. Relapses in all 4 patients were frequent early in the disease and became infrequent or absent over time. Declines on neuropsychological testing were most pronounced on measures of processing speed, specifically visuomotor speed, and executive control requiring mental sequencing and set shifting, whereas global intellectual ability and phonemic fluency remained stable or improved over time. These case studies demonstrate a negative impact of multiple sclerosis on cognitive development in the long term and suggest that continued observation into adulthood is required to appreciate the vocational consequences of pediatric-onset multiple sclerosis.

Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2.

Leigh syndrome (LS) is a progressive neurodegenerative disease caused by either mitochondrial or nuclear DNA mutations resulting in dysfunctional mitochondrial energy metabolism. Mutations in genes encoding for subunits of the respiratory chain or assembly factors of respiratory chain complexes are often documented in LS cases. Nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) enzyme deficiencies account for a significant proportion of mitochondrial disorders, including LS. In an attempt to expand the repertoire of known mutations accounting for LS, we describe the clinical, radiological, biochemical and molecular data of six patients with LS found to have novel mutations in two complex I subunits (NDUFV1 and NDUFS2). Two siblings were homozygous for the previously undescribed R386C mutation in NDUFV1, one patient was a compound heterozygote for the R386C mutation in NDUFV1 and a frameshift mutation in the same gene, one patient was a compound heterozygote for the R88G and R199P mutations in NDUFV1, and two siblings were compound heterozygotes for an undescribed E104A mutation in NDUFS2. After the novel mutations were identified, we employed prediction models using protein conservation analysis (SIFT, PolyPhen and UCSC genome browser) to determine pathogenicity. The R386C, R88G, R199P, and E104A mutations were found to be likely pathogenic, and thus presumably account for the LS phenotype. This case series broadens our understanding of the etiology of LS by identifying new molecular defects that can result in complex I deficiency and may assist in targeted diagnostics and/or prenatal diagnosis of LS in the future.