Thomas T. Warner

Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome

Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12–q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration.

Genetic and environmental factors in the cause of Parkinson's disease

Despite being the subject of intense study, the pathogenesis of Parkinsons disease still remains unclear. In recent years, however, there has been increasing evidence to support a role for genetic factors in its cause. This has come from twin and family studies, the mapping and cloning of PARK genes that are associated with the development of PD, and analysis of potential susceptibility genes. There is also evidence indicating that environmental factors may play a role in the disease process. It is likely that for most cases, there is a complex interplay between these genetic and environmental influences in the causation of Parkinsons disease. This article reviews the evidence in support of genetic and environmental factors in the cause of PD. Ann Neurol 2003;53 (suppl 3):S16–S25

A prevalence study of primary dystonia in eight European countries

There have been few epidemiological studies of dystonia. Most previous studies have provided estimates based on few cases. A European prevalence study was undertaken to provide more precise rates of dystonia by pooling data from eight European countries. Diagnosed cases were ascertained by adult neurologists with specialist movement disorders (and botulinum toxin) clinics. The crude annual period prevalence rate (1996–1997) for primary dystonia was 152 per million (95% confidence interval 142–162), with focal dystonia having the highest rate of 117 per million (108–126). Prevalence rates for cervical dystonia, blepharospasm and writers cramp were as follows: 57 (95% confidence interval 51–63), 36 (31–41), and 14 (11–17). The age-adjusted relative rates were significantly higher in women than in men for segmental and focus dystonias with the exception of writers cramp. Comparing rates between centres demonstrated significant variations for cervical dystonia, blepharospasm and writers cramp, probably due to methodological differences. Our results provide the first data on the prevalence of primary dystonia and its subtypes across several European countries. Due to under-ascertainment of cases, our rates should be seen as conservative and an under-estimate of the true prevalence of dystonia.Abstract There have been few epidemiological studies of dystonia. Most previous studies have provided estimates based on few cases. A European prevalence study was undertaken to provide more precise rates of dystonia by pooling data from eight European countries. Diagnosed cases were ascertained by adult neurologists with specialist movement disorders (and botulinum toxin) clinics. The crude annual period prevalence rate (1996–1997) for primary dystonia was 152 per million (95% confidence interval 142–162), with focal dystonia having the highest rate of 117 per million (108–126). Prevalence rates for cervical dystonia, blepharospasm and writers cramp were as follows: 57 (95% confidence interval 51–63), 36 (31–41), and 14 (11–17). The age-adjusted relative rates were significantly higher in women than in men for segmental and focus dystonias with the exception of writers cramp. Comparing rates between centres demonstrated significant variations for cervical dystonia, blepharospasm and writers cramp, probably due to methodological differences. Our results provide the first data on the prevalence of primary dystonia and its subtypes across several European countries. Due to under-ascertainment of cases, our rates should be seen as conservative and an under-estimate of the true prevalence of dystonia.

What are the determinants of quality of life in people with cervical dystonia

Background: Little is known about the quality of life in patients with cervical dystonia, although pain and depression are relatively common. Objective: To test the hypothesis that an individuals ability to cope with the disease will modify the association of intrinsic, extrinsic, and disease related factors with quality of life. Methods: Patients with cervical dystonia diagnosed by a movement disorder specialist were recruited from seven European countries. Data on quality of life (SF-36), measures of coping, and intrinsic, extrinsic, and disease related factors were collected by a self completed postal questionnaire. Results: 289 patients (101 men and 188 women), mean age 55 years, completed the questionnaire. Both physical and mental quality of life scores were predicted by self esteem and self deprecation, educational level, employment status, social support, response to botulinum toxin, disease severity, social participation, stigma, acceptance of illness, anxiety, and depression. In multivariable analyses, the strongest predictors were anxiety and depression. Severe depression was associated with a 19.1 point decrement in the physical summary score (95% confidence interval, −31.7 to −6.6; p = 0.003); however, disease duration and severity remained predictors. Conclusions: Care for patients with cervical dystonia must not only focus on reducing the severity of the dystonia but also on the psychological wellbeing of the patient. Interventions aimed at treating depression or anxiety, especially of a cognitive nature, may have a large impact on improving quality of life.

PRRT2 gene mutations From paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine

ABSTRACT 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). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.

A novel RAB7 mutation associated with ulcero-mutilating neuropathy

There are two known autosomal dominant genes for the hereditary ulcero‐mutilating neuropathies: SPTLC1 (hereditary sensory neuropathy type 1) and RAB7 (Charcot–Marie–Tooth disease type 2B). We report a family with autosomal dominant ulcero‐mutilating neuropathy, developing in the teens and characterized by ulcers, amputations, sensory involvement in the feet but no motor features. Sequencing the RAB7 gene showed a novel heterozygous A to C mutation, changing asparagine to threonine at codon 161. The mutation is situated adjacent to a previously identified valine to methionine mutation at codon 162, implying a hotspot for mutations in the highly conserved C terminus of RAB7. Ann Neurol 2004;56:586–590

Creatine therapy for Huntington's disease: Clinical and MRS findings in a 1-year pilot study

Human and transgenic animal studies have implicated defective energy metabolism and oxidative stress in Huntington’s disease (HD), with evidence for deficiencies of respiratory chain activity and defective adenosine triphosphate (ATP) synthesis in brain and skeletal muscle.1,2⇓ Correlation of the muscle bioenergetic defect and CAG repeat length provides a link between this biochemical abnormality and the HD molecular defect.1 The role of calcium-mediated excitotoxicity and mitochondrial dysfunction is also supported by recent findings of a mitochondrial calcium handling defect.3 In the R6/2 HD transgenic mouse, 2% dietary creatine supplementation significantly improved survival, delayed motor progression, and slowed development of brain atrophy.4 Creatine has several potential neuroprotective effects, including buffering intracellular mitochondrial energy reserves, stabilizing intracellular calcium, and inhibiting activation of the mitochondrial permeability transition pore, which have all been linked to apoptotic and oxidative cell death. Two trials have been reported where patients with HD were given 5 g for 12 months5 and 3g for 2 months followed by 5 g for 2 months. …

High-dose creatine therapy for Huntington disease: A 2-year clinical and MRS study

Calcium-mediated excitotoxicity and defective energy metabolism have been implicated in the pathogenesis of Huntington disease (HD).1 In R6/2 HD transgenic mice, administration of 2% dietary creatine presymptomatically at 6 and 8 weeks improved survival, delayed motor progression, and reduced weight loss and brain atrophy.2,3 Creatine buffers intracellular energy reserves and has several neuroprotective effects demonstrated both in vivo and in vitro.4 A placebo-controlled pilot trial of 5 g/day of creatine for 1 year appeared ineffective in 26 patients with HD,5 although this dose was lower than the equivalent dose given to R6/2 HD mice. We previously reported clinical and MR spectroscopy (MRS) findings in a 1-year open-label pilot study of high-dose creatine (10 g/day) supplementation in 13 patients with HD.6 Serial 31P-MRS of muscle monitored changes in energy metabolism in vivo, and 1H-MRS was used to determine creatine levels in brain tissue. High-dose creatine was well tolerated, and total motor score (TMS), functional capacity, and neuropsychology testing remained stable at 12 months. We now report …

Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease.

Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, homozygosity mapping, and exome sequencing in three families, we identified mutations in CLPP as the likely cause of this phenotype. In each family, affected individuals were homozygous for a different pathogenic CLPP allele: c.433A>C (p.Thr145Pro), c.440G>C (p.Cys147Ser), or an experimentally demonstrated splice-donor-site mutation, c.270+4A>G. CLPP, a component of a mitochondrial ATP-dependent proteolytic complex, is a highly conserved endopeptidase encoded by CLPP and forms an element of the evolutionarily ancient mitochondrial unfolded-protein response (UPR(mt)) stress signaling pathway. Crystal-structure modeling suggests that both substitutions would alter the structure of the CLPP barrel chamber that captures unfolded proteins and exposes them to proteolysis. Together with the previous identification of mutations in HARS2, encoding mitochondrial histidyl-tRNA synthetase, mutations in CLPP expose dysfunction of mitochondrial protein homeostasis as a cause of Perrault syndrome.

Impact of cervical dystonia on quality of life.

We studied the effect of cervical dystonia on quality of life in a cohort of 289 patients by using a generic health status measurement scale (SF36). Cervical dystonia had a significant negative impact on quality of life compared with age‐matched general population data. This negative impact was comparable to that seen in multiple sclerosis, Parkinsons disease, and stroke.