Pilar Gómez-Garre

Lafora disease due to EPM2B mutations A clinical and genetic study

Objective: To study EPM2B gene mutations and genotype-phenotype correlations in patients with Lafora disease. Methods: The authors performed a clinical and mutational analysis of 25 patients, from 23 families, diagnosed with Lafora disease who had not shown mutations in the EPM2A gene. Results: The authors identified 18 mutations in EPM2B, including 12 novel mutations: 4 nonsense mutations (R265X, C26X, W219X, and E67X), a 6-base pair (bp) microdeletion resulting in a two amino acid deletion (V294_K295del), a 4-bp insertion resulting in a frameshift mutation (S339fs12), and 6 missense mutations (D308A, I198N, C68Y, E67Q, P264H, and D233A). In our data set of 77 families with Lafora disease, 54 (70.1%) tested probands have mutations in EPM2A, 21 (27.3%) in EPM2B, and 2 (2.6%) have no mutations in either gene. The course of the disease was longer in patients with EPM2B mutations vs patients with EPM2A mutations. Conclusions: Genetic allelic heterogeneity is present in Lafora disease associated with mutations in EPM2B. Patients with mutations in EPM2A and EPM2B express similar clinical manifestation, although patients with EPM2B-associated Lafora disease seem to have a slightly milder clinical course. The lack of mutations in EPM2A and EPM2B in two families could be because of the presence of mutations in noncoding, nontested regions or the existence of an additional gene associated with Lafora disease.

Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12.

Summary:  Background: Familial partial epilepsy with variable foci (FPEVF) is an autosomal dominant syndrome characterized by partial seizures originating from different brain regions in different family members in the absence of detectable structural abnormalities. A gene for FPEVF was mapped to chromosome 22q12 in two distantly related French‐Canadian families.

Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation.

Background: The Ehlers-Danlos syndrome (EDS) comprises a group of hereditary connective tissue disorders. Periventricular nodular heterotopia (PNH) is a human neuronal migration disorder characterised by seizures and conglomerates of neural cells around the lateral ventricles of the brain, caused by FLNA mutations. FLNA encodes filamin A, an actin binding protein involved in cytoskeletal organisation. The amino-terminal actin binding domain (ABD) of filamins contains two tandem calponin homology domains, CHD1 and CHD2. Objective: To report clinical and genetic analyses in a Spanish family affected by a connective tissue disorder suggestive of EDS type III and PNH. Methods: A clinical and molecular study was undertaken in the three affected women. Clinical histories, physical and neurological examinations, brain magnetic resonance imaging studies, and skin biopsies were done. Genetic analysis of the FLNA gene was undertaken by direct sequencing and restriction fragment length polymorphism analysis. Results: Mutation analysis of the FLNA gene resulted in the identification of a novel mutation in exon 3 (c.383C→T) segregating with the combination of both syndromes. This mutation results in a substitution of an alanine residue (A128V) in CHD1. Conclusions: The findings suggest that the Ala128Val mutation causes the dual EDS-PNH phenotype. This association constitutes a new variant within the EDS spectrum. This is the first description of a familial EDS-PNH association with a mutation in FLNA.

Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; MIM 600513) has been associated with mutations in the genes coding for the alfa‐4 (CHRNA4), beta‐2 (CHRNB2), and alpha‐2 (CHRNA2) subunits of the neuronal nicotinic acetylcholine receptor (nAChR) and for the corticotropin‐releasing hormone (CRH). A four‐generation ADNFLE family with six affected members was identified. All affected members presented the clinical characteristics of ADNFLE. Interictal awake and sleep EEG recordings showed no epileptiform abnormalities. Ictal video‐EEG recordings showed focal seizures with frontal lobe semiology. Mutation analysis of the CHRNB2 gene revealed a c.859G>A transition (Val287Met) within the second transmembrane domain, identical to that previously described in a Scottish ADNFLE family. To our knowledge, this is the third family reported presenting a mutation in CHRNB2. The clinical phenotype appears similar to that described with mutations in CHRNA4, suggesting that mutations in these two subunits lead to similar functional alterations of the nAChR.

Genetic Variability Related to Serum Uric Acid Concentration and Risk of Parkinson's Disease

Low serum uric acid (UA) levels have been associated with increased Parkinsons disease (PD) risk and accelerated disease progression. We analyzed the effect of polymorphisms in 9 genes influencing serum UA concentration on the risk of PD.

Prevalence and clinical features of LRRK2 mutations in patients with Parkinson’s disease in southern Spain

Background and purpose: Mutations in leucine‐rich repeat kinase 2 (LRRK2) gene are associated with both familial and idiopathic Parkinson’s disease (PD), whereas mutations in PARK2 (PARKIN) gene result in early onset recessive PD. Here, the objectives were to determine the frequency of LRRK2 G2019S and R1441G mutations in a PD population from southern Spain; to search for LRRK2 mutations in familial PD cases and to study the effect of PARKIN mutations on clinical features of LRRK2‐associated; PD.

Low serum uric acid concentration in Parkinson's disease in southern Spain

Uric acid (UA) is thought to have an antioxidant effect on the central nervous system and may also prevent cerebral damage induced by oxidative stress. Our study aimed to investigate whether patients with Parkinsons disease (PD) had lower serum UA concentrations than controls and whether UA concentration was related to clinical parameters of the disease.

Genome-wide association study in musician's dystonia: A risk variant at the arylsulfatase G locus?

Musicians dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writers dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2‐stage genome‐wide association study in whites. Genotypes at 557,620 single‐nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10−5 and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome‐wide significant SNP (P < 5 × 10−8) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome‐wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 × 10−9; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66‐7.05). rs11655081 was also associated with WD (P = 2.78 × 10−2) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (λ = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.

A PTG variant contributes to a milder phenotype in Lafora disease.

Lafora disease is an autosomal recessive form of progressive myoclonus epilepsy with no effective therapy. Although the outcome is always unfavorable, onset of symptoms and progression of the disease may vary. We aimed to identify modifier genes that may contribute to the clinical course of Lafora disease patients with EPM2A or EPM2B mutations. We established a list of 43 genes coding for proteins related to laforin/malin function and/or glycogen metabolism and tested common polymorphisms for possible associations with phenotypic differences using a collection of Lafora disease families. Genotype and haplotype analysis showed that PPP1R3C may be associated with a slow progression of the disease. The PPP1R3C gene encodes protein targeting to glycogen (PTG). Glycogen targeting subunits play a major role in recruiting type 1 protein phosphatase (PP1) to glycogen-enriched cell compartments and in increasing the specific activity of PP1 toward specific glycogenic substrates (glycogen synthase and glycogen phosphorylase). Here, we report a new mutation (c.746A>G, N249S) in the PPP1R3C gene that results in a decreased capacity to induce glycogen synthesis and a reduced interaction with glycogen phosphorylase and laforin, supporting a key role of this mutation in the glycogenic activity of PTG. This variant was found in one of two affected siblings of a Lafora disease family characterized by a remarkable mild course. Our findings suggest that variations in PTG may condition the course of Lafora disease and establish PTG as a potential target for pharmacogenetic and therapeutic approaches.

Hepatic disease as the first manifestation of progressive myoclonus epilepsy of Lafora

Background: Lafora disease (LD; progressive myoclonus epilepsy type 2; EPM2) is an autosomal recessive disorder caused by mutations in the EPM2A and EPM2B genes. LD is characterized by the presence of strongly PAS-positive intracellular inclusions (Lafora bodies) in several tissues. Glycogen storage disease type IV (GSD-IV; Andersen disease) is an autosomal recessive disorder characterized by cirrhosis leading to severe liver failure. GSD-IV has been associated with mutations in the glycogen branching enzyme gene (GBE). Histopathologic changes of the liver in both diseases show an identical appearance, although cirrhosis has never been described in patients with LD. We report a LD family in which the proband presented severe liver failure at onset of the disease. Methods: Clinical histories, physical and neurologic examination, laboratory tests, EEGs, MRI of the brain, and liver or axillary skin biopsies were performed in the two affected siblings. The diagnosis was confirmed by molecular genetic analysis of the EPM2A, EPM2B, and GBE genes and loci. Results: During the first decade of life, abnormalities in liver function tests were detected in the two affected siblings. The probands liver dysfunction was severe enough to require liver transplantation. Subsequently, both sibs developed LD. Mutation analysis of EPM2A revealed a homozygous Arg241stop mutation in both patients. Conclusions: This is the first description of severe hepatic dysfunction as the initial clinical manifestation of LD. The phenotypic differences between the two affected siblings suggest that modifier genes must condition clinical expression of the disease outside the CNS.