Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263

Capillary Malformation-Arteriovenous Malformation Syndrome with Spinal Involvement

Capillary malformation-arteriovenous malformation (CM-AVM) is a recently identified autosomal dominant disorder. Arteriovenous lesions have been reported in the brain, limbs, and face. We report a 7-year-old patient with CM-AVM with spinal AVM, which is a rarely reported association

Long-standing fever and Angelman syndrome: Report of two cases

An 8-month-old girl and a 20-month-old boy who presented with motor and developmental delay and long-standing fever are presented. The patients were diagnosed as Angelman syndrome with fluorescence in situ hybridization (FISH) analysis. Despite extensive clinical and laboratory examinations, no inflammatory or infectious origin for the fever was found. It was considered that the long-standing fever observed in these cases was due to hypothalamic dysfunction for thermoregulation

Long-standing fever and Angelman syndrome: Report of two cases

An 8-month-old girl and a 20-month-old boy who presented with motor and developmental delay and long-standing fever are presented. The patients were diagnosed as Angelman syndrome with fluorescence in situ hybridization (FISH) analysis. Despite extensive clinical and laboratory examinations, no inflammatory or infectious origin for the fever was found. It was considered that the long-standing fever observed in these cases was due to hypothalamic dysfunction for thermoregulation

Assessment of Child Neurology Outpatients With Headache, Dizziness, and Fainting -

Neurologic symptoms such as headache, vertigo, dizziness, and fainting can create a diagnostic problem in pediatric neurology practice because they are also the most common presenting symptoms of psychiatric disorders. Children, especially adolescents, who are often admitted with such autonomic symptoms, are frequently misdiagnosed. In this study, we aimed to investigate the psychiatric morbidity and comorbidity rate in children and adolescents presenting with neurologic symptoms such as headache, vertigo, and syncope. We investigated 31 children who presented with these symptoms. All children were evaluated for their medical history and had a physical and neurologic examination. We attempted to rule out a possible organic etiology. All patients received a complete laboratory examination (blood count, electroencephalography), pediatric cardiology and otorhinolaryngology consultations, and a caloric test. All patients were assessed according to Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. The majority of the patients (93.5%) received a psychiatric diagnosis according to the DSM-IV criteria. Most of these patients were adolescents and female. Psychosocial stressors such as academic problems, familial dysfunction, parental psychopathology, and child sexual abuse were associated with somatic symptoms. The results of this study demonstrated the importance of differential diagnosis and psychiatric comorbidity in a pediatric neurologic outpatient population. Treatment should be directed at biopsychosocial integrity, and a multidisciplinary treatment approach should be applied

Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: Less severe mutations predominate in patients with a non-Walker-Warburg phenotype

Six genes including POMT1, POMT2, POMGNTI, FKRP, Fukutin (FKTN) and LARGE encode proteins involved in the glycosylation of alpha-dystroglycan (alpha-DG). Abnormal glycosylation of alpha-DG is a common finding in Walker-Warburg syndrome (WWS), muscle-eye brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD), congenital muscular dystrophy types 1C and ID and some forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2I, LGMD2K, LGMD2M), and is associated with mutations in the above genes. FCMD, caused by mutations in Fukutin (FKTN), is most frequent in Japan, but an increasing number of FKTN mutations are being reported outside of Japan. We describe four new patients with FKTN mutations and phenotypes ranging from: severe WWS in a Greek-Croatian patient, to congenital muscular dystrophy and cobblestone lissencephaly resembling MEB-FCMD in two Turkish patients, and limb-girdle muscular dystrophy and no mental retardation in a German patient. Four of the five different FKTN mutations have not been previously described. (C) 2010 Elsevier B.V. All rights reserved

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients

Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10)