Bernd Ringelstein

Clinical features and molecular genetics of hereditary peripheral neuropathies.

Abstract. Hereditary peripheral neuropathies are the most common monogenetically inherited diseases of the nervous system. The prevalence of the Hereditary Motor and Sensory Neuropathy Type 1A (HMSN 1A or Charcot-Marie-Tooth Neuropathy 1A, CMT1A) alone is estimated to be as high as 1/5000. In 1991, a duplication on chromosome 17p11.2 was identified as the causative genetic defect of CMT1A. Since then causative mutations in 17 genes have been identified. This review summarises the clinical and molecular genetic features of primary inherited neuropathies. It is aimed primarily at clinicians and geneticists. Therefore less emphasis is placed on the pathology and the (often unknown) underlying biological disease mechanisms.

CCSVI and MS: a statement from the European Society of neurosonology and cerebral hemodynamics.

To systematically review the ultrasonographic criteria proposed for the diagnosis of chronic cerebrospinal venous insufficiency (CCSVI). The authors analyzed the five ultrasonographic criteria, four extracranial and one intracranial, suggested for the diagnosis of CCSVI in multiple sclerosis (MS), together with the references from which these criteria were derived and the main studies that explored the physiology of cerebrospinal drainage. The proposed CCSVI criteria are questionable due to both methodological and technical errors: criteria 1 and 3 are based on a scientifically incorrect application of data obtained in a different setting; criteria 2 and 4 have never been validated before; criterion 2 is technically incorrect; criteria 3 and 5 are susceptible to so many external factors that it is difficult to state whether the data collected are pathological or a variation from the normal. It is also unclear how it was decided that two or more of these five ultrasound criteria may be used to diagnose CCSVI, since no validation of these criteria was performed by different and independent observers nor were they blindly compared with a validated gold-standard investigation. The European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) has considerable concerns regarding the accuracy of the proposed criteria for CCSVI in MS. Therefore, any potentially harmful interventional treatment such as transluminal angioplasty and/or stenting should be strongly discouraged.

Genotype-phenotype analysis in patients with giant axonal neuropathy (GAN)

Giant axonal neuropathy (GAN, MIM: 256850) is a devastating autosomal recessive disorder characterized by an early onset severe peripheral neuropathy, varying central nervous system involvement and strikingly frizzly hair. Giant axonal neuropathy is usually caused by mutations in the gigaxonin gene (GAN) but genetic heterogeneity has been demonstrated for a milder variant of this disease. Here, we report ten patients referred to us for molecular genetic diagnosis. All patients had typical clinical signs suggestive of giant axonal neuropathy. In seven affected individuals, we found disease causing mutations in the gigaxonin gene affecting both alleles: two splice-site and four missense mutations, not reported previously. Gigaxonin binds N-terminally to ubiquitin activating enzyme E1 and C-terminally to various microtubule associated proteins causing their ubiquitin mediated degradation. It was shown for a number of gigaxonin mutations that they impede this process leading to accumulation of microtubule associated proteins and there by impairing cellular functions.

Heart rate monitoring on the stroke unit. What does heart beat tell about prognosis? An observational study

BackgroundGuidelines recommend maintaining the heart rate (HR) of acute stroke patients within physiological limits; data on the frequency and predictors of significant deviations from these limits are scarce.MethodsDemographical data, stroke risk factors, NIH stroke scale score, lesion size and location, and ECG parameters were prospectively assessed in 256 patients with ischemic stroke. Patients were continuously monitored for at least 24 hours on a certified stroke unit. Tachycardia (HR ≥120 bpm) and bradycardia (HR <45 bpm) and cardiac rhythm (sinus rhythm or atrial fibrillation) were documented. We investigated the influence of risk factors on HR disturbances and their respective influence on dependence (modified Rankin Scale ≥ 3 after three months) and mortality.ResultsHR ≥120 bpm occurred in 39 patients (15%). Stroke severity (larger lesion size/higher NIHSS-score on admission), atrial fibrillation and HR on admission predicted its occurrence. HR <45 bpm occurred in 12 patients (5%) and was predicted by lower HR on admission. Neither HR ≥120 nor HR <45 bpm independently predicted poor outcome at three moths. Stroke location had no effect on the occurrence of HR violations. Clinical severity and age remained the only consistent predictors of poor outcome.ConclusionsSignificant tachycardia and bradycardia are frequent phenomena in acute stroke; however they do not independently predict clinical course or outcome. Continuous monitoring allows detecting rhythm disturbances in stroke patients and allows deciding whether urgent medical treatment is necessary.

Four frequently observed polymorphisms in the 3‘-UTR of human peripheral myelin protein 22 (PMP22): identification of different haplotypes

Candidate gene for: PMP22 is a candidate gene for several types of inherited peripheral neuropathies (Ballabio & Zoghbi 1995). Large insertions and deletions at the PMP22 gene locus have been demonstrated to cause inherited motor and sensory neuropathies. Charcot-Marie-Tooth disease type 1A (CMTlA) has been associated with a duplication of a 1.5-megabase DNA segment harboring PMP22 (Lupski et al. 1991, Patel et al. 1992, Pentao et al. 1992). A deletion of the same or a similar segment has previously been found in patients with hereditary neuropathy with liability to pressure palsies (HNPP) (Chance et’al. 1993, Chance et al. 1994). A minority of non-duplicated CMTlA cases and nondeleted HNPP cases show point mutations in PMP22 (Roa et al. 1993a, Nicholson et al. 1994). Furthermore, point mutations are also found associated with Dejerine-Sottas syndrome (DSS; Roa et al. 1993b). The clinical diagnosis of the disorders is primarily based on nerve conduction studies and histological examinations of sural nerve biopsies. As an aid to genetic analyses polymorphic markers of varying information content have been identified throughout the duplicated segment. We identified four biallelic polymorphisms in the PMP22 3’-UTR and determined eight haplotypes in a subgroup of 27 out of 50 individuals. The identified intragenic markers should prove to be useful in indirect genetic diagnostics of inherited peripheral neuropathies.

Absence of mutations in the prion-protein gene in a large cohort of HMSN patients

Cellular prion-protein is expressed in axons and Schwann cells of peripheral nerves. Some patients with prion diseases show peripheral nerve involvement and prion-protein deficient mice develop age dependent demyelination of peripheral nerves. Therefore we tested the hypothesis that mutations in the prion-protein gene might also cause hereditary motor and sensory neuropathies. We screened 108 patients with a diagnosis of hereditary motor and sensory neuropathies in whom the common genetic defects causing hereditary motor and sensory neuropathies had previously been excluded for mutations in the protein-coding region of the PRNP gene. Mutations in the coding region of the prion-protein gene were not found. We conclude that mutations in the protein coding region of the prion-protein gene are not a common cause of HMSN (95% CI 0-0.034).

Genomic organization and mutation analysis of three candidate genes for hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy (HNA) is an autosomal‐dominant inherited recurrent focal neuropathy affecting mainly the brachial plexus. In this study we report the genomic structure and mutation analysis of three candidate genes: sphingosine kinase 1 (SPHK1); tissue inhibitor of metalloproteinase 2 (TIMP2); and cytoglobin (CYGB). We did not find any disease‐associated mutations, indicating that HNA is not caused by point mutations in these genes. However, we identified several sequencing errors in the cDNA of SPHK1 as well as seven novel single‐nucleotide polymorphisms. Muscle Nerve 29: 601–604, 2004

Obituary to Prof. Klaus Poeck, MD, FRSM, FRCP

With great sadness, we must announce that our teacher and colleague Professor Klaus Poeck, aged 80 years, passed away at the University Hospital of Aachen secondary to complications from a fall. He was a great and inspiring man who made lasting contributions to the fields of neurology and neuropsychology. Klaus Poeck studied medicine in Berlin and Heidelberg, where he received his MD degree under the supervision of Paul Vogel in 1953. He continued his clinical and research training in Düsseldorf with Eberhard Bay, the leading German aphasiologist of the time, and in Pisa with Guiseppe Moruzzi, the eminent Italian physiologist. For his training in psychiatry, he went to Waldau/Berne, Switzerland, where he studied the psychopathology of the frontal and limbic system together with Georg Pilleri. In 1961 he became Assistant Professor in Neurology at the University Hospital in Freiburg. There he worked on phantom phenomena in children with amputated limbs and conducted a developmental study on the supramodal representation of the body scheme. In 1967, he was appointed Professor of Neurology at the newly founded Medical Faculty of the Rheinisch-Westfälische Technische Hochschule (RWTH) in Aachen, the ancient capital of Charlemagne. Aachen remained Poeck’s hometown; here he made a life-long impact on the development of clinical neurology, neuropsychology, and aphasiology in Germany and soon became a well-known and appreciated researcher worldwide. Klaus Poeck was fluent in Italian, French, and English and had numerous cultural interests. He was a man of art, music, literature, and the cinema. Because of his interdisciplinary approach to clinical science, he was highly respected by his peers in Europe, North America, and other parts of the world. As the director of a steadily growing department, Klaus Poeck focused his research interests on classical neuropsychological topics such as the Gerstmann syndrome and taxonomy of apraxia. He aimed to resolve traditional controversies with new and sound empirical evidence. An interdisciplinary research group was established with Max Kerschensteiner, a neurologist, and Wolfgang Hartje, a psychologist. Starting in the early 1970s, Poeck’s main interest shifted to aphasia. He attracted junior scientists from linguistics and psychometrics to join his attempts to study both the psycholinguistic underpinnings of language disorders and their consequences for clinical diagnosis and treatment. His collaborators were Franz-Josef Stachowiak, Walter Huber, Dorothea Weniger, Klaus Willmes, and Ria De Bleser, Walter Sturm. Poeck and his aphasia research group were eager to study the effectiveness of their approach and to learn about the recovery potential after language damage. The Aachen Aphasia Test (AAT) was developed and standardized. This turned out to be a useful tool to Werner Hacke Walter Huber Bernd Ringelstein Wolfgang Hartje Hermann Zeumer Klaus Willmes Obituary to Prof. Klaus Poeck, MD, FRSM, FRCP OBITUARY J Neurol (2006) 253 : 1379–1380 DOI 10.1007/s00415-006-0342-5