Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms

Phenotypic insights into ADCY5-associated disease

Background Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal‐dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations. Methods In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole‐exome sequencing. Results Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile‐onset action‐induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement. Conclusion We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5‐associated dyskinesia may be under‐recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications

Systems: a screening test of higher mental function in childhood

Children with deficits of higher mental function are often referred to paediatricians and child neurologists. The referrals may occur for the specific evaluation of a child’s school difficulties or because of a symptom, such as school refusal, headache or deterioration in behaviour. It is generally accepted that examination of the higher mental abilities could be a routine part of a complete neurological examination in any child presenting with such problems. Despite this, there is very little information concerning normal values for screening tests of higher mental function at different ages in childhood

The SYSTEMS - School-Years Screening Test for the Evaluation of Mental Status

This paper introduces the School-Years Screening Test for Evaluation of Mental Status (SYSTEMS). It was designed to be used by neurologists, pediatricians, and other health professionals assessing children with suspected cognitive problems or changes. SYSTEMS was initially based on the adult Mini-Mental State Examination developed by Folstein, Folstein, and McHugh in 1975. SYSTEMS is a 7- to 12-minute, one-on-one interview test containing 46 items for use in children between 5 and 12 years of age. Although a full diagnosis cannot be made, the results do provide an indication of whether to send a child for further detailed cognitive assessment. The development of SYSTEMS comprised seven studies with a total of 1207 children involved from Sydney primary schools and neurology clinics of the New Children's Hospital, Westmead, New South Wales, Australia. All children were administered the SYSTEMS. Some of the children also were administered the Stanford-Binet Intelligence Test, 4th edition, or the Differential Ability Scales. Results showed that the SYSTEMS was internally consistent, unbiased by sex, socioeconomic indicators, or language groups; discriminated well by age; and strongly correlated (r = 0.88) with mental age. No significant differences in results obtained by two trained administrators were evident and no indication of apparent practice effect was found. The SYSTEMS was found to have desirable levels of sensitivity (83% and 92%), specificity (76% and 95%), and likelihood ratio for cognitive impairment (3.63 and 17.5) when compared with neurologic judgments and the Differential Ability Scales, respectively. This paper presents and evaluates the School-Years Screening Test for the Evaluation of Mental Status (SYSTEMS). The test was designed to assess the cognitive state of a child when he or she first presents to a neurologist or pediatrician. Low scores on the SYSTEMS would suggest cognitive impairment or cognitive deterioration and would indicate the need for a more detailed cognitive assessment

Development and validation of a novel rating system for scoring standing foot posture : the Foot Posture Index

Introduction. The limitations of clinical methods for appraising foot posture are well documented. A new measure, the Foot Posture Index is proposed, and its development and validation described. Methods. A four-phase development process was used: (i) to derive a series of candidate measures, (ii) to define an appropriate scoring system, (iii) to evaluate the validity of components and modify the instrument as appropriate, and (iv) to investigate the predictive validity of the finalised instrument relative to static and dynamic kinematic models. Methods included initial concurrent validation using Rose's Valgus Index, determination of inter-item reliability, factor analysis, and benchmarking against three dimensional kinematic models derived from electromagnetic motion tracking of the lower limb. Results. Thirty-six candidate components were reduced to six in the final instrument. The draft version of the instrument predicted 59% of the variance in concurrent Valgus Index scores and demonstrated good inter item reliability (Cronbach's α = 0.83). The relevant variables from the motion tracking lower limb model predicted 58-80% of the variance in the six components retained in the final instrument. The finalised instrument predicted 64% of the variance in static standing posture, and 41% of the variance in midstance posture during normal walking. Conclusion. The Foot Posture Index has been subjected to thorough evaluation in the course of its development and a final version is proposed comprising six component measures that performed satisfactorily during the validation process. The Foot Posture Index assessment is quick and simple to perform and allows a multiple segment, multiple plane evaluation that offers some advantages over existing clinical measures of foot posture

Pressure characteristics in painful pes cavus feet resulting from Charcot-Marie-Tooth disease

Charcot–Marie–Tooth (CMT) disease often presents with peripheral muscle imbalance associated with a painful cavus (medial higharched) foot deformity which becomes increasingly severe and rigid as the disease progresses. The purpose of this study was to investigate the effect of pes cavus on foot pain and dynamic plantar pressure in CMT, and to explore the relationships between plantar pressure and pain. Sixteen participants diagnosed with CMTand painful pes cavus were assessed for foot posture, ankle dorsiflexion range of motion, levels of foot pain, functional impairment, health-related quality of life and plantar pressure distribution while walking. Plantar pressure parameters (mean pressure, peak pressure, pressure–time integral) and contact duration were measured using the Novel Pedar1 in-shoe capacitance transducer system and the foot was divided into rearfoot, midfoot and forefoot regions for analysis. Increasing cavus foot deformity was associated with more widespread foot pain and increased pressure under the forefoot and midfoot regions. In contrast, peak pressure decreased under the rearfoot. Neither relationship was found between foot pain intensity and any of the pressure variables, nor was ankle dorsiflexion range of motion correlated with pain location, intensity or degree of pes cavus. Although pes cavus in CMT is associated with substantial pain and dysfunction, there is no clear link between foot pain and plantar pressure. The more severe the degree of pes cavus, however, the more pressure develops under the lateral margin of the foot; probably as a result of the changed foot-ground contact seen during gait

Factors that influence health-related quality of life in Australian adults with Charcot-Marie-Tooth disease

Health-related, quality of life (HRQoL) is an important outcome in clinical trials of patients with Charcot–Marie–Tooth disease (CMT). In a cross-sectional survey of 295 Australian adults with CMT, HRQoL was measured using the Short Form-36 (SF-36) and predictors of reduced HRQoL were identified with a CMT-specific health status questionnaire. People with CMT demonstrated lower HRQoL scores than the general Australian population in all SF-36 dimensions. The disparity between people with CMT and normative data was greater for physical dimensions than for mental health dimensions. SF-36 scores were generally lower in older vs younger people, but not between men and women, or between CMT types. HRQoL in CMT was predicted strongly by lower limb weakness and to a lessor extent by leg cramps, suggesting clinical trials targeting weakness and cramps may improve HRQoL in patients with CMT