Clinical cases of amyotrophic lateral sclerosis concurrent with hydromyelia.

A comprehensive work-up, clinical correlation, and differential diagnosis are needed to determine if abnormal findings such us hydromyelia in ALS patients are causative or incidental in order to rule out other, more curable conditions that resemble ALS.

Small posterior fossa in Chiari I malformation affected families is significantly linked to 1q43-44 and 12q23-24.11 using whole exome sequencing.

The posterior fossa of the cranium contains the cerebellum and brainstem. Processes that reduce the volume of the posterior fossa squeeze the cerebellum and brainstem caudally, resulting in Chiari I malformation (CM1). CM1 causes neck pain, balance issues, decreased motor skills and headaches in those affected. We have posterior fossa measurements and whole exome sequence data on individuals from 7 extended families from Russia that have a family history of CM1. We performed parametric linkage analyses using an autosomal dominant inheritance model with a disease allele frequency of 0.01 and a penetrance of 0.8 for carriers and 0.0 for non-carriers. Variant-based two-point linkage analysis and gene-based linkage analysis was performed. Our results found a genome-wide significant signal on chromosome 1q43-44 (max HLOD = 3.3) in the variant-based analysis and 12q23 (max HLOD = 4.2) in the gene-based analysis. In both cases, the signal was driven by a single (different) family that contained a long, linked haplotype across the region in question. Using functional annotation, we were able to identify several rare nonsynonymous variants that were enriched in each family. The best candidate genes were rs765865412:G>A in MYBPC1 for the 12q haplotype and rs61749963:A>G in COX20 for the 1q haplotype. Good candidate variants in the 1q haplotype were also identified in CEP170 and AKT. Further laboratory work is planned to verify the causality of these genes.

Epidemiology of Symptomatic Chiari Malformation in Tatarstan: Regional and Ethnic Differences in Prevalence.

BACKGROUND: Epidemiology can assess the effect of Chiari I malformation (CM1) on the neurological health of a population and evaluate factors influencing CM1 development. OBJECTIVE: To analyze the regional and ethnic differences in the prevalence of CM1. METHODS: The population of the Republic of Tatarstan (RT) in the Russian Federation was evaluated for patients with CM1 symptoms over an 11-yr period. Typical symptoms of CM1 were found in 868 patients. Data from neurological examination and magnetic resonance imaging (MRI) measurement of posterior cranial fossa structures were analyzed. RESULTS: MRI evidence of CM1, defined as cerebellar tonsils lying at least 5 mm inferior to the foramen magnum, was found in 67% of symptomatic patients. Another 33% of symptomatic patients had 2 to 4 mm of tonsillar ectopia, which we defined as "borderline Chiari malformation type 1 (bCM1)." The period prevalence in the entire RT for symptomatic CM1 was 20:100 000; for bCM1 was 10:100 000; and for CM1 and bCM1 together was 30:100 000. Prevalence of patients with CM1 symptoms was greater in the northern than southern districts of Tatarstan, due to a high prevalence (413:100 000) of CM1 in the Baltasy region in one of the northern districts. CONCLUSION: One-third of patients with typical symptoms of CM1 had less than 5 mm of tonsillar ectopia (bCM1). Assessments of the health impact of CM1-type symptoms on a patient population should include the bCM1 patient group. A regional disease cluster of patients with Chiari malformation was found in Baltasy district of RT and needs further study.

Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family.

Background: Immune mechanisms recently emerged as important contributors to migraine pathology with cytokines affecting neuronal excitation. Therefore, elucidating the profile of cytokines activated in various forms of migraine, including those with a known genetic cause, can help in diagnostic and therapeutic approaches. Methods: Here we (i) performed exome sequencing to identify the causal gene mutation and (ii) measured, using Bio-Plex technology, 22 cytokines in serum of patients with familial migraine (two with hemiplegic migraine and two with migraine with aura) from a Russian family that ethnically belongs to the Tatar population. MRI scanning was used to assess cerebellar atrophy associated with migraine in mutation carriers. Results: Whole-exome sequencing revealed the R583Q missense mutation in the CACNA1A gene in the two patients with hemiplegic migraine and cerebellar ataxia with atrophy, confirming a FHM1 disorder. Two further patients did not have the mutation and suffered from migraine with aura. Elevated serum levels of pro-inflammatory and pro-nociceptive IL-6 and IL-18 were found in all four patients (compared to a reference panel), whereas pro-apoptotic SCGF-ß and TRAIL were higher only in the patients with the FHM1 mutation. Also, cytokines CXCL1, HGF, LIF, and MIF were found particularly high in the two mutation carriers, suggesting a possible role of vascular impairment and neuroinflammation in disease pathogenesis. Notably, some "algesic" cytokines, such as ß-NGF and TNFß, remained unchanged or even were down-regulated. Conclusion: We present a detailed genetic, neurological, and biochemical characterization of a small Russian FHM1 family and revealed evidence for higher levels of specific cytokines in migraine patients that support migraine-associated neuroinflammation in the pathology of migraine.