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Aim: Mutations in the genes encoding the riboflavin transporters RFVT2 and RFVT3 have been identified in Brown-Vialetto-Van Laere syndrome, a neurodegenerative disorder characterized by hearing loss and pontobulbar palsy. Treatment with riboflavin has been shown to benefit individuals with the phenotype of RFVT2 deficiency. Understanding the characteristics of hearing loss in riboflavin transporter deficiency would enable early diagnosis and therapy.Method: We performed hearing assessments in seven children (from four families) with RFVT2 deficiency and reviewed results from previous assessments. Assessments were repeated after 12 months and 24 months of riboflavin therapy and after cochlear implantation in one individual.Results: Hearing loss in these individuals was due to auditory neuropathy spectrum disorder (ANSD). Hearing loss was identified between 3 years and 8 years of age and progressed rapidly. Hearing aids were not beneficial. Riboflavin therapy resulted in improvement of hearing thresholds during the first year of treatment in those with recent-onset hearing loss. Cochlear implantation resulted in a significant improvement in speech perception in one individual.Interpretation: Riboflavin transporter deficiency should be considered in all children presenting with an auditory neuropathy. Speech perception in children with ANSD due to RFVT2 deficiency may be significantly improved by cochlear implantation. [ABSTRACT FROM AUTHOR]

Aim: The alpha-1 isoform of the calcium channel gene is expressed abundantly in neuronal tissue, especially within the cerebellum. Mutations in this gene may manifest with hemiplegic migraine, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) in adults. There are reports of children with CACAN1A mutations presenting with paroxysmal tonic upgaze, abnormal saccades and congenital nystagmus as well as severe forms of hemiplegic migraine. The aim of this study was to review the clinical presentation and subsequent course of all children with a CACNA1A mutation who presented to a tertiary children's hospital.Method: We reviewed retrospectively nine children with a proven CACNA1A mutation who presented to the Children's Hospital at Westmead between 2005-2015. The initial and subsequent clinical presentation, radiological features and molecular genetic profile of each child was reviewed.Results: Nine children presented to out institute over a 10 year period; six were female and three male. The median age of presentation was 1.2 years. Eye movement disorders were the presenting feature in eight children. Three of these children later presented with severe hemiplegic migraine episodes often requiring ICU care. Affected children also had developmental delay and developed classical hemiplegic migraine, episodic ataxia and seizures. Calcium channel blockers were used with some efficacy in preventing severe HM episodes.Interpretation: Eye movement disorders are an early manifestation of CACNA1A mutations in children. Improved recognition of the CACNA1A phenotype in childhood is important for early diagnosis, counselling and appropriate emergency management. There is some early evidence that calcium channel blockers may be an effective prophylactic agent for the severe hemiplegic migraine episodes. [ABSTRACT FROM AUTHOR]

Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions. [ABSTRACT FROM AUTHOR]

Mitofusin 2, a large transmembrane GTPase located in the outer mitochondrial membrane, promotes membrane fusion and is involved in the maintenance of the morphology of axonal mitochondria. Mutations of the gene encoding mitofusin 2 ( MFN2) have recently been identified as the cause of approximately one-third of dominantly inherited cases of the axonal degenerative forms of Charcot–Marie–Tooth disease (CMT type 2A) and of rarer variants. The latter include a severe, early-onset axonal neuropathy, which may occur in autosomal dominant or recessive forms, as well as some instances associated with pyramidal tract involvement (CMT type 5), with optic atrophy (CMT type 6), and, occasionally, with alterations of cerebral white matter. All individuals with a dominantly or recessively inherited or otherwise unexplained, chronic progressive axonal degenerative polyneuropathy should be tested for mutations of MFN2. [ABSTRACT FROM AUTHOR]

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin pbinding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals. [ABSTRACT FROM AUTHOR]

Objective: Brown-Vialetto-Van Laere (BVVL) syndrome is a progressive motor and sensory neuronopathy secondary to mutations in SLC52A2 encoding the riboflavin transporter type 2 (RFVT2). The phenotype is characterized by early childhood onset hearing loss and sensory ataxia followed by progressive upper limb weakness, optic atrophy, bulbar weakness and respiratory failure. To gain further insight into disease pathophysiology and response to riboflavin supplementation, the present study investigated whether axonal ion channel or membrane abnormalities were a feature of BVVL. Methods: Axonal excitability studies and clinical assessments were prospectively undertaken on six patients with BVVL secondary to riboflavin transporter deficiency type 2 (age range 10-21 years) at baseline and after 12 months of riboflavin (1000 mg daily) therapy. Results: At baseline, depolarizing and hyperpolarizing threshold electrotonus was 'fanned out' and superexcitability was increased, while the resting current-threshold gradient and refractoriness were significantly reduced in BVVL patients when compared to controls. Mathematical modeling suggested that functional alterations of myelin underlay these findings with an increase in myelin permeability. Riboflavin therapy resulted in partial normalization of the axonal excitability findings, paralleled by maintenance of muscle strength. Conclusions: The present study established that abnormalities in myelin permeability at the paranode was a feature of BVVL and were partially normalized with riboflavin therapy. [ABSTRACT FROM AUTHOR]

Abstract: Benign hereditary chorea caused by mutations in the NK2 homeobox 1 gene (NKX2-1), shares clinical features with ataxic and dyskinetic cerebral palsy (CP), resulting in the possibility of misdiagnosis. A father and his two children were considered to have ataxic CP until a possible diagnosis of benign familial chorea was made in the children in early teenage. The father's neurological condition had not been appreciated prior to examination of the affected son. Whole exome sequencing of blood derived DNA and bioinformatics analysis were performed. A 7 bp deletion in exon 1 of NKX2-1, resulting in a frame shift and creation of a premature termination codon, was identified in all affected individuals. Screening of 60 unrelated individuals with a diagnosis of dyskinetic or ataxic CP did not identify NKX2-1 mutations. BHC can be confused with ataxic and dyskinetic CP. Occasionally these children have a mutation in NKX2-1. [Copyright &y& Elsevier]

Curcumin is the newest therapeutic agent for ameliorating the clinical and neuropathologic phenotype of a mouse model of Déjérine-Sottas disease. We undertook a 12-month dose-escalation safety trial of oral curcumin in a 15-year-old Caucasian girl with Déjérine-Sottas disease (point mutation, Ser72Leu) complicated by severe weakness, scoliosis, and respiratory impairment. The patient received 50mg/kg/day oral curcumin for the first 4 months and 75mg/kg/day thereafter, to complete a 12-month trial. Outcome measures included muscle strength, pulmonary function, upper/lower extremity disability, neurophysiologic studies, and health-related quality of life. After 12 months, the patient experienced no adverse events, and reported good compliance. There was little improvement in objective outcome measures. Knee flexion and foot strength increased slightly, but hand and elbow strength decreased. Pulmonary function, hand function, and measures of upper/lower extremity disability were stable or reduced. Her neurophysiologic findings were unchanged. Parent-reported quality of life improved for most domains, especially self-esteem, during the 12 months of treatment. Child-reported quality of life, assessed at the final visit, mirrored these results, with overall feelings of happiness and contentment. Further studies are required to explore the efficacy and safety of curcumin for severe demyelinating neuropathies of infancy and early childhood. [Copyright &y& Elsevier]

Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Linkage analysis in a Dutch family and an Australian family suggested that the candidate gene maps to Xq22.1-q24. Oligonucleotide microarray expression profiling of fibroblasts from two probands of the Dutch family revealed reduced expression levels of the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1). Subsequent sequencing of PRPS1 led to the identification of two different missense mutations, c.455T→C (p.L152P) in the Dutch family and c.398A→C (p.Q133P) in the Australian family. Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients. This is in contrast to the gain-of-function mutations in PRPS1 that were identified previously in PRPS-related gout. The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. To replenish low levels of purines, treatment with S-adenosylmethionine theoretically could have therapeutic efficacy, and a clinical trial involving the two affected Australian brothers is currently underway. [ABSTRACT FROM AUTHOR]

A patient with triosephosphate isomerase deficiency resulting from compound heterozygote mutation is described. Chronic axonal neuropathy was identified on clinical and neurophysiologic grounds and confirmed by sural nerve biopsy. This report describes the first biopsy-proven case confirming that peripheral neuropathy can occur with triosephosphate isomerase deficiency. [Copyright &y& Elsevier]