Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2.

Objective: To describe the clinical and neurophysiologic phenotype of a family with hereditary sensory and autonomic neuropathy type 1 (HSANI) due to a novel mutation in SPTLC2 and to characterize the biochemical properties of this mutation.

Methods: We screened 107 patients with HSAN who were negative for other genetic causes for mutations in SPTLC2. The biochemical properties of a new mutation were characterized in cell-free and cell-based activity assays.

Genetic analysis of inherited leukodystrophies: genotype-phenotype correlations in the CSF1R gene.

Importance: The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis.

Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels.

Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%-2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.

Rapidly progressive asymmetrical weakness in Charcot-Marie-Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy.

Charcot-Marie-Tooth disease type 4J (CMT4J), a rare form of demyelinating CMT, caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene, is characterised by progressive proximal and distal weakness and evidence of chronic denervation in both proximal and distal muscles. We describe a patient with a previous diagnosis of CMT1 who presented with a two year history of rapidly progressive weakness in a single limb, resembling an acquired inflammatory neuropathy. Nerve conduction studies showed an asymmetrical demyelinating neuropathy with conduction block and temporal dispersion.

SPG11 Presenting with Tremor.

Background: Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurological diseases, which typically present with progressive lower extremity weakness and spasticity causing progressive walking difficulties. Complicating neurological or extraneurological features may be present.

Case Report: We describe a 19-year-old male who was referred because of an action tremor of the hands; he later developed walking difficulties.

Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.

Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.

A novel α-synuclein missense mutation in Parkinson disease.

Alpha-synuclein (SNCA) is central to the pathogenesis of Parkinson disease (PD), with 3 missense mutations reported to date. We report a novel mutation (p.H50Q) in a pathologically proven case.

Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia.

Dystonia type 4 (DYT4) was first described in a large family from Heacham in Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and a characteristic hobby horse ataxic gait. We carried out a genetic linkage analysis in the extended DYT4 family that spanned 7 generations from England and Australia, revealing a single LOD score peak of 6.33 on chromosome 19p13.

α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy?

We report a British family with young-onset Parkinson's disease (PD) and a G51D SNCA mutation that segregates with the disease. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive parkinsonism with onset in their late thirties. Clinical features show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation.

Clinical features of childhood-onset paroxysmal kinesigenic dyskinesia with PRRT2 gene mutations.

Aim: To define better the phenotype and genotype of familial and sporadic cases of paroxysmal kinesigenic dyskinesia (PKD) caused by mutations in the PRRT2 gene presenting in the paediatric age group.

Method: We report the detailed clinical and molecular genetic features of 11 patients (six females, five males) with childhood-onset PRRT2-mutation-positive PKD.

Results: Mean age at disease onset was 8 years 7.

Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity.

Autosomal-recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders with more than 20 different forms currently recognized, many of which are also associated with increased tone and some of which have limb spasticity. Gaucher disease is a lysosomal storage disease resulting from a defect in the enzyme acid β-glucosidase 1. β-glucosidase 2 is an enzyme with similar glucosylceramidase activity but to date has not been associated with a monogenic disorder.

Novel mutations mapping to the fourth sodium channel domain of Nav1.7 result in variable clinical manifestations of primary erythromelalgia.

We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration.

Characterisation and validation of insertions and deletions in 173 patient exomes.

Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in complex diseases remains so far elusive. Despite rapid advances of next-generation sequencing, both the technology and the analysis of the data it produces are in its infancy.

The glucocerobrosidase E326K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease.

Background: Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher's disease (GD), are the strongest known risk factor for Parkinson's disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD.

Methods: One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing.

Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.

Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype.

The frequency of spinocerebellar ataxia type 23 in a UK population.

Spinocerebellar ataxias (SCA) are a genetically heterogeneous group of neurodegenerative diseases characterised by progressive cerebellar ataxia, dysarthria and oculomotor abnormalities. Recently the prodynorphin (PDYN) gene was identified as the cause of SCA23 in four Dutch families displaying progressive gait and limb ataxia. In this study we aimed to assess the frequency of PDYN gene defects and extend the phenotype of SCA23 patients in a UK ataxia series and also in patients from Greece, Egypt and India.

Kohlschütter-Tönz syndrome: mutations in ROGDI and evidence of genetic heterogeneity.

Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschütter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in five likely related Druze families.

PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine.

Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM).

Creation of an open-access, mutation-defined fibroblast resource for neurological disease research.

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia.

Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease.

Objective: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.

THAP1 mutations and dystonia phenotypes: genotype phenotype correlations.

THAP1 mutations have been shown to be the cause of DYT6. A number of different mutation types and locations in the THAP1 gene have been associated with a range of severity and dystonia phenotypes, but, as yet, it has been difficult to identify clear genotype phenotype patterns. Here, we screened the THAP1 gene in a further series of dystonia cases and evaluated the mutation pathogenicity in this series as well as previously reported mutations to investigate possible phenotype-genotype correlations.

Review: genetics and neuropathology of primary pure dystonia.

Neuropathology has been the key to understanding the aetiology of many neurological disorders such as Alzheimer's disease, Parkinson's disease, frontotemporal degeneration and cerebellar ataxias. Dystonia shares many clinical features with these conditions but research in general, has been unrewarding in providing information on disease processes. Neuropathological studies are few in number and only limited morphological abnormalities have been described.