Brain dopamine-serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder.

Two male siblings from a consanguineous union presented in early infancy with marked truncal hypotonia, a general paucity of movement, extrapyramidal signs and cognitive delay. By mid-childhood they had made little developmental progress and remained severely hypotonic and bradykinetic. They developed epilepsy and had problems with autonomic dysfunction and oculogyric crises. They had a number of orthopaedic problems secondary to their hypotonia. Cerebrospinal fluid (CSF) neurotransmitters were initially normal, apart from mildly elevated 5-hydroxyindolacetic acid, and the children did not respond favourably to a trial of levodopa-carbidopa. The youngest died from respiratory complications at 10 years of age. Repeat CSF neurotransmitters in the older sibling at eight years of age showed slightly low homovanillic acid and 5-hydroxyindoleacetic acid levels. Whole-exome sequencing revealed a novel mutation homozygous in both children in the monoamine transporter gene SLC18A2 (p.Pro237His), resulting in brain dopamine-serotonin vesicular transport disease. This is the second family to be described with a mutation in this gene. Treatment with the dopamine agonist pramipexole in the surviving child resulted in mild improvements in alertness, communication, and eye movements. This case supports the identification of the causal mutation in the original case, expands the clinical phenotype of brain dopamine-serotonin vesicular transport disease and confirms that pramipexole treatment may lead to symptomatic improvement in affected individuals.

Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair.

Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ10, and the siblings were subsequently established on a therapeutic dose of CoQ10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.

Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease.

Mutations in the gene SLC19A3 result in thiamine metabolism dysfunction syndrome 2, also known as biotin-thiamine-responsive basal ganglia disease (BTBGD). This neurometabolic disease typically presents in early childhood with progressive neurodegeneration, including confusion, seizures, and dysphagia, advancing to coma and death. Treatment is possible via supplement of biotin and/or thiamine, with early treatment resulting in significant lifelong improvements. Here we report two siblings who received a refined diagnosis of BTBGD following whole-genome sequencing. Both children inherited compound heterozygous mutations from unaffected parents; a missense single-nucleotide variant (p.G23V) in the first transmembrane domain of the protein, and a 4808-bp deletion in exon 1 encompassing the 5' UTR and minimal promoter region. This deletion is the smallest promoter deletion reported to date, further defining the minimal promoter region of SLC19A3 Unfortunately, one of the siblings died prior to diagnosis, but the other is showing significant improvement after commencement of therapy. This case demonstrates the power of whole-genome sequencing for the identification of structural variants and subsequent diagnosis of rare neurodevelopmental disorders.

A Comparison of Cognitive Function in Former Rugby Union Players Compared with Former Non-Contact-Sport Players and the Impact of Concussion History.

AIM: This study investigated differences in cognitive function between former rugby and non-contact-sport players, and assessed the association between concussion history and cognitive function. METHODS: Overall, 366 former players (mean ± standard deviation [SD] age 43.3 ± 8.2 years) were recruited from October 2012 to April 2014. Engagement in sport, general health, sports injuries and concussion history, and demographic information were obtained from an online self-report questionnaire. Cognitive functioning was assessed using the online CNS Vital Signs neuropsychological test battery. Cohen's d effect size statistics were calculated for comparisons across player groups, concussion groups (one or more self-reported concussions versus no concussions) and between those groups with CNS Vital Signs age-matched norms (US norms). Individual differences within groups were represented as SDs. RESULTS: The elite-rugby group (n = 103) performed worse on tests of complex attention, processing speed, executive functioning, and cognitive flexibility than the non-contact-sport group (n = 65), and worse than the community-rugby group (n = 193) on complex attention. The community-rugby group performed worse than the non-contact group on executive functioning and cognitive flexibility. Compared with US norms, all three former player groups performed worse on verbal memory and reaction time; rugby groups performed worse on processing speed, cognitive flexibility and executive functioning; and the community-rugby group performed worse on composite memory. The community-rugby group and non-contact-sport group performed slightly better than US norms on complex attention, as did the elite-rugby group for motor speed. All three player groups had greater individual differences than US norms on composite memory, verbal memory and reaction time. The elite-rugby group had greater individual differences on processing speed and complex attention, and the community-rugby group had greater individual differences on psychomotor speed and motor speed. The average number of concussions recalled per player was greater for elite rugby and community rugby than non-contact sport. Former players who recalled one or more concussions (elite rugby, 85 %; community rugby, 77 %; non-contact sport, 23 %) had worse scores on cognitive flexibility, executive functioning, and complex attention than players who did not recall experiencing a concussion. CONCLUSIONS: Past participation in rugby or a history of concussion were associated with small to moderate neurocognitive deficits (as indicated by worse CNS Vital Signs scores) in athletes post retirement from competitive sport.

Whole Exome Sequencing Reveals Compound Heterozygosity for Ethnically Distinct PEX7 Mutations Responsible for Rhizomelic Chondrodysplasia Punctata, Type 1.

We describe two brothers who presented at birth with bone growth abnormalities, followed by development of increasingly severe intellectual and physical disability, growth restriction, epilepsy, and cerebellar and brain stem atrophy, but normal ocular phenotypes. Case 1 died at 19 years of age due to chronic respiratory illnesses without a unifying diagnosis. The brother remains alive but severely disabled at 19 years of age. Whole exome sequencing identified compound heterozygous stop mutations in the peroxisome biogenesis factor 7 gene in both individuals. Mutations in this gene cause rhizomelic chondrodysplasia punctata, type 1 (RCDP1). One mutation, p.Arg232 (∗) , has only been documented once before in a Japanese family, which is of interest given these two boys are of European descent. The other mutation, p.Leu292 (∗) , is found in approximately 50% of RCDP1 patients. These are the first cases of RCDP1 that describe the coinheritance of the p.Arg232 (∗) and p.Leu292 (∗) mutations and demonstrate the utility of WES in cases with unclear diagnoses.