Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.

Heterozygous mutations in REEP1 (MIM #609139) encoding the receptor expression-enhancing protein 1 (REEP1) are a well-recognized and relatively frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), SPG31.1 REEP1 localizes in the mitochondria and endoplasmic reticulum (ER) and facilitates ER-mitochondria interactions.2 In addition to the HSP phenotype, REEP1 has been associated with an autosomal dominant spinal type of Charcot-Marie-Tooth disease in 2 families.3 More recently, a patient with homozygous REEP1 mutation with a much more severe phenotype akin to spinal muscular atrophy with respiratory distress type 1 (SMARD1) was reported.4 In this report, we present a patient with a homozygous mutation in REEP1 manifesting a severe congenital distal spinal muscular atrophy (SMA) with diaphragmatic paralysis, expanding the phenotype from mild autosomal dominant HSP through to severe recessive distal SMA pattern

Late-onset Lafora disease with prominent parkinsonism due to a rare mutation in EPM2A

Lafora disease (LD) is an autosomal recessive form of progressive myoclonic epilepsy that is caused by mutations in EPM2A, encoding laforin, and NHLRC1 (EPM2B), encoding malin.(1) LD is classically described with onset in early teenage years. Patients develop myoclonus, epilepsy, visual hallucinations, and psychosis. Dementia is a prominent feature and often occurs in the late teenage years. LD typically progresses quickly, and patients become bedridden and dependent within 10 years of symptom onset, with life expectancy in the early 20s.(2,3) Only a small number of late-onset cases of LD have been described. Even then, these so-called late-onset cases have typically presented in the 20s, with dementia occurring in the early 30s. We describe a patient with extremely late onset and extended survival with prominent parkinsonism due to a novel EPM2A variant

Whole-genome sequencing

The costs of whole-genome sequencing have rapidly decreased, and it is being increasingly deployed in large-scale clinical research projects and introduced into routine clinical care. This will lead to rapid diagnoses for patients with genetic disease but also introduces uncertainty because of the diversity of human genomes and the potential difficulties in annotating new genetic variants for individual patients and families. Here we outline the steps in organising whole-genome sequencing for patients in the neurology clinic and emphasise that close liaison between the clinician and the laboratory is essential

Novel fluid biomarkers to differentiate frontotemporal dementia and dementia with Lewy bodies from Alzheimer's disease: A systematic review

RATIONALE: Frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) are two common forms of neurodegenerative dementia, subsequent to Alzheimer's disease (AD). AD is the only dementia that includes clinically validated cerebrospinal fluid (CSF) biomarkers in the diagnostic criteria. FTD and DLB often overlap with AD in their clinical and pathological features, making it challenging to differentiate between these conditions. AIM: This systematic review aimed to identify if novel fluid biomarkers are useful in differentiating FTD and DLB from AD. Increasing the certainty of the differentiation between dementia subtypes would be advantageous clinically and in research. METHODS: PubMed and Scopus were searched for studies that quantified and assessed diagnostic accuracy of novel fluid biomarkers in clinically diagnosed patients with FTD or DLB, in comparison to patients with AD. Meta-analyses were performed on biomarkers that were quantified in 3 studies or more. RESULTS: The search strategy yielded 614 results, from which, 27 studies were included. When comparing bio-fluid levels in AD and FTD patients, neurofilament light chain (NfL) level was often higher in FTD, whilst brain soluble amyloid precursor protein β (sAPPβ) was higher in patients with AD. When comparing bio-fluid levels in AD and DLB patients, α-synuclein ensued heterogeneous findings, while the noradrenaline metabolite (MHPG) was found to be lower in DLB. Ratios of Aβ42/Aβ38 and Aβ42/Aβ40 were lower in AD than FTD and DLB and offered better diagnostic accuracy than raw amyloid-β (Aβ) concentrations. CONCLUSIONS: Several promising novel biomarkers were highlighted in this review. Combinations of fluid biomarkers were more often useful than individual biomarkers in distinguishing subtypes of dementia. Considering the heterogeneity in methods and results between the studies, further validation, ideally with longitudinal prospective designs with large sample sizes and unified protocols, are fundamental before conclusions can be finalised

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome: genetic and clinical insights

Purpose of review: This review aims to summarise the present cerebellar ataxia, neuropathy, vestibular ataxia syndrome (CANVAS) literature, providing both clinical and genetic insights that might facilitate the timely clinical and genetic diagnosis of this disease. // Recent findings: Recent advancements in the range of the clinical features of CANVAS have aided the development of a broader, more well-defined clinical diagnostic criteria. Additionally, the identification of a biallelic repeat expansion in RFC1 as the cause of CANVAS and a common cause of late-onset ataxia has opened the door to the potential discovery of a pathogenic mechanism, which in turn, may lead to therapeutic advancements and improved patient care. // Summary: The developments in the clinical and genetic understanding of CANVAS will aid the correct and timely diagnosis of CANVAS, which continues to prove challenging within the clinic. The insights detailed within this review will raise the awareness of the phenotypic spectrum and currently known genetics. We also speculate on the future directions of research into CANVAS

PRUNE1: a disease-causing gene for secondary microcephaly

In their Letter to the Editor, Karakaya et al. (2017) present an interesting case report describing the clinical course involving secondary microcephaly of a 3-year-old Turkish boy found to be homozygous for a frameshift mutation in PRUNE1 identified through whole exome sequencing. The child presented with congenital hypotonia, contractures and global developmental delay with respiratory insufficiency and seizures developing in the first year of life. The authors note that the affected child’s head circumference plotted on the 75th centile at birth, and that by 38 months of age he had developed microcephaly. Neuroimaging at 14 months revealed cerebral and cerebellar atrophy consistent with other patients described with Prune syndrome (Karaca et al., 2015; Costain et al., 2017; Zollo et al., 2017). Although the child had abnormal neurology from birth, there was a period of early developmental regression. Peripheral spasticity in the lower extremities and optic atrophy were not documented until 38 months. In addition to the PRUNE1 variant, Karakaya et al. also identified a second homozygous variant in the CCDC14 gene in the Turkish child’s whole exome sequencing data that, while listed to have an allele count of 108 in the current Genome Aggregation Database (gnomAD) release, is notably absent in homozygous fashion (Lek et al., 2016). CCDC14 is known to be expressed in human brain, reported to negatively regulate centriole duplication and interact with proteins previously associated with primary microcephaly (Firat-Karalar et al., 2014). Thus, while it seems likely that the homozygous PRUNE1 variant is primarily responsible for the clinical presentation in the Turkish child, it is impossible to determine whether there may be any phenotypical contribution from this additional homozygous sequence variant. Recently, Costain et al. (2017) described a homozygous consensus splice site variant in PRUNE1 (c.521-2A4G; NM_021222.1) in a 2-year-old Oji-Cre male who presented with congenital hypotonia and talipes, whose head circumference was large at birth ( +3 standard deviations), but by 2 years and 2 months plotted on the 50th centile, with a weight and height on the 95th and 75th centiles, respectively. However, it should be noted that the child’s father is macrocephalic ( +4 standard deviations), the published clinical photographs at 2 years 5 months of age illustrate bitemporal narrowing, a sloping forehead and large ears, consistent with a developing microcephaly, and neuroimaging revealed cortical and cerebellar atrophy. He developed respiratory insufficiency shortly after birth, and infantile spasms in the first year of life (Costain et al., 2017). It remains to be determined how the phenotypical outcomes stemming from proposed loss-of-function mutations defined by Karakaya et al. and Costain et al., relate to missense mutations published by Karaca et al. and also Zollo et al., which are likely to involve at least partial gain-of-function outcomes in PRUNE1 activity. However, as more cases are investigated and published, the phenotype associated with autosomal recessive Prune neurodevelopmental disorder, and the functional outcomes of PRUNE1 mutation, are becoming clearer. It is now apparent that while some patients have a small head at birth and others a head circumference in the normal range, the key component of the microcephaly is that it is progressive, and associated with characteristic neuroimaging findings with a thin or hypoplastic corpus callosum and cortical and cerebellar atrophy developing in early childhood. Although all patients with Prune syndrome described to date are neurologically impaired from birth, there also appears to be a neurodegenerative component with progression of the disorder. In our manuscript, we described clinical overlap of Prune syndrome with the neurodegenerative condition associated with homozygous mutations in TBCD (Zollo et al., 2017). TBCD encodes one of the five tubulin-specific chaperones that are required for a/b-tubulin de novo heterodimer formation and the disorder is characterized by developmental regression, seizures, optic atrophy and secondary microcephaly, cortical atrophy with delayed myelination, cerebellar atrophy and thinned corpus callosum (Edvardson et al., 2016; Flex et al., 2016; Miyake et al., 2016; Pode-Shakked et al., 2017). The neurodegenerative phenotype documented in the Turkish child by Karakaya et al. further demonstrates the similarities with the TBCD disorder and Prune syndrome, and confirms optic atrophy to be a feature of Prune syndrome. Interestingly, it is also becoming clear that respiratory insufficiency is a common feature of Prune syndrome, having been documented by Karakaya et al. and in the Oji-Cre child, as well as the youngest affected Omani child described in our manuscript

DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder

Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion. There are currently no disease-modifying treatments available. The broad development of therapies for DRPLA, as well as other similar rare diseases, has hit a roadblock due to the rarity of the condition and the wide global distribution of patients and families, consequently inhibiting biomarker development and therapeutic research. Considering the shifting focus towards diverse populations, widespread genetic testing, rapid advancements in the development of clinical and wet biomarkers for Huntington’s disease (HD), and the ongoing clinical trials for antisense oligonucleotide (ASO) therapies, the prospect of developing effective treatments in rare disorders has completely changed. The awareness of the HD ASO program has prompted global collaboration for rare disorders in natural history studies and the development of biomarkers, with the eventual goal of undergoing treatment trials. Here, we discuss DRPLA, which shares similarities with HD, and how in this and other repeat expansion disorders, neurogenetics groups like ours at UCL are gearing up for forthcoming natural history studies to accelerate future ASO treatment trials to hopefully emulate the progress seen in HD