Abstract Objective DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1 ‐related epilepsy has been reported in small cohorts. We ...dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1 ‐related epilepsy spectrum, and compare the genotype–phenotype correlations observed in our cohort with the literature. Methods Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains. Results DYNC1H1 ‐related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox–Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug‐resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly–pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1 ‐related epilepsy spectrum. Significance We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug‐resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1‐ related epilepsy.
OBJECTIVES To assess the frequency of FUS mutations in 52 probands with familial amyotrophic lateral sclerosis (FALS) and to provide careful documentation of clinical characteristics. DESIGN FUS ...mutation analysis was performed using capillary sequencing on all coding regions of the gene in a cohort of patients with FALS. The clinical characteristics of patients carrying FUS mutations were described in detail. SETTING Three university hospitals in the Netherlands (referral centers for neuromuscular diseases). PATIENTS Fifty-two probands from unrelated pedigrees with FALS. MAIN OUTCOME MEASURE FUS mutations. RESULTS We identified 3 mutations in 4 of 52 probands. We observed 2 previously identified mutations (p.Arg521Cys and p.Arg521His) and 1 novel mutation (p.Ser462Phe). In addition, a p.Gln210His polymorphism was identified in 1 proband and 3 healthy control subjects. Phenotypic analysis demonstrated that patients may lack upper motor neuron signs, which was confirmed at autopsy, and disease survival was short (<36 months for 8 of 10 patients). CONCLUSIONS We discovered FUS mutations in Dutch patients with FALS and the occurrence of benign variations in the gene. Therefore, caution is warranted when interpreting results in a clinical setting. Although the phenotype associated with FUS mutations is variable, most patients predominantly demonstrate loss of lower motor neurons and have short disease survival.Arch Neurol. 2010;67(2):224-230-->
Abstract
The Awaji Commission recently proposed a modification of the electrodiagnostic criteria for ALS. We assessed whether the Awaji recommendations improve the sensitivity of the early diagnosis ...of ALS. In a retrospective study we reviewed clinical and neurophysiological data for 213 patients who visited our motor neuron disease outpatient clinic between October 2006 and December 2008. Using the El Escorial criteria, 51 patients were diagnosed with definite or probable ALS, 14 with probable laboratory-supported ALS, and 28 with possible ALS. An alternative diagnosis was present in 120 patients. Applying the Awaji recommendations, 66 patients were diagnosed with either definite or probable ALS, and 27 with possible ALS. Of the 14 patients diagnosed with probable laboratory-supported ALS, eight switched to probable ALS and six to possible ALS using the Awaji recommendations; none of the patients with an ALS mimic was diagnosed with ALS according to the Awaji recommendations. In conclusion, the new criteria for ALS do not result in a loss of specificity and can potentially improve the sensitivity by 16%. However, this diagnostic improvement appears eliminated if patients with probable laboratory-supported ALS - due to UMN signs in one region - should be categorized as possible ALS.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
BACKGROUND In autosomal dominant cerebellar ataxias (ADCAs), it is unclear whether the associated peripheral nerve involvement is always a typical length-dependent axonopathy rather than primary ...neuronopathy due to neuronal degeneration in the spinal anterior horns and/or dorsal root ganglia. OBJECTIVE To study the nature and extent of peripheral nerve involvement in patients with ADCA. PATIENTS AND METHODS Standardized clinical and electrophysiologic studies of 27 genotyped patients with ADCA were conducted prospectively, with special emphasis on the distinction between primary neuronopathy and dying-back axonopathy. RESULTS Electrophysiologic evidence of involvement of the peripheral nervous system was present in 70% of patients. Findings were compatible with dying-back axonopathy in 30%, while in 40% of patients, neuronopathy was diagnosed. Patients with spinocerebellar ataxia (SCA) 1 and SCA2 mostly displayed features of neuronopathy, while patients with SCA3 and SCA7 displayed both neuronopathy and axonopathy. In SCA6, no significant peripheral nerve involvement was demonstrated. We did not observe an influence of age, disease duration, or ataxia severity on the presence or type of peripheral nerve involvement. CONCLUSIONS Peripheral nerve involvement in ADCA manifests not only as distal axonal neuropathy, but also as primary neuronopathy. Electrodiagnostic studies in this group of patients should be conducted in such a way that primary neuronopathy is detected.Arch Neurol. 2004;61:257-261-->
Progressive muscular atrophy (PMA) is an adult-onset neurodegenerative disease characterized by progressive loss of lower motor neurons (LMNs). Its disease course ranges from slowly progressive in ...many years to rapid progression rates similar to those observed in patients with amyotrophic lateral sclerosis (ALS). Whether PMA is a distinct disease identity separate from ALS remains the question, especially because upper motor neuron signs may develop over time and mutations in the superoxide dismutase 1 gene, which are known causes of ALS, have also been identified in patients with familial PMA. Moreover, mutations in the charged multivesicular protein 2B gene have been reported in 3 patients with sporadic LMN-predominant ALS. Nonsynonymous mutations in the transient receptor potential vanilloid 4 (TRPV4) gene, which encodes a calcium permeable protein channel, have recently been identified in patients with LMN disorders such as congenital distal spinal muscular atrophy, scapuloperoneal spinal muscular atrophy, and Charcot-Marie-Tooth/hereditary motor and sensory neuropathy type 2c. These disorders are characterized by predominant LMN degeneration. The TRPV4 gene is of special interest because mutations may lead to neurotoxicity induced by intracellular hypercalcemia and therefore, pharmacological blockade of TRPV4 channels may offer a target for therapy of TRPV4-associated disorders. We hypothesized that TRPV4 may be a candidate gene for susceptibility to PMA and screened a Dutch cohort of patients with sporadic PMA and control subjects for nonsynonymous mutations. PUBLICATION ABSTRACT
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