Search

Scientific letter

BackgroundMitochondrial progressive external ophthalmoplegia (PEO) encompasses a broad spectrum of clinical and genetic disorders. We describe the phenotypic subtypes of PEO and its correlation with molecular defects and propose a diagnostic algorithm.MethodsRetrospective analysis of the clinical, pathological and genetic features of 89 cases.ResultsThree main phenotypes were found: ‘pure PEO’ (42%), consisting of isolated palpebral ptosis with ophthalmoparesis; Kearns-Sayre syndrome (10%); and ‘PEO plus’, which associates extraocular symptoms, distinguishing the following subtypes: : myopathic (33%), bulbar (12%) and others (3%). Muscle biopsy was the most accurate test, showing mitochondrial changes in 95%. Genetic diagnosis was achieved in 96% of the patients. Single large-scale mitochondrial DNA (mtDNA) deletion was the most frequent finding (63%), followed by multiple mtDNA deletions (26%) due to mutations in TWNK (n=8), POLG (n=7), TK2 (n=6) or RRM2B (n=2) genes, and point mtDNA mutations (7%). Three new likely pathogenic mutations were identified in the TWNK and MT-TN genes.ConclusionsPhenotype–genotype correlations cannot be brought in mitochondrial PEO. Muscle biopsy should be the first step in the diagnostic flow of PEO when mitochondrial aetiology is suspected since it also enables the study of mtDNA rearrangements. If no mtDNA deletions are identified, whole mtDNA sequencing should be performed.

Gerstmann-Sträussler-Scheinker disease (GSS) is a rare neurodegenerative illness that belongs to the group of hereditary or familial Transmissible Spongiform Encephalopathies (TSE). Due to the presence of different pathogenic alterations in the prion protein (PrP) coding gene, it shows an enhanced proneness to misfolding into its pathogenic isoform, leading to prion formation and propagation. This aberrantly folded protein is able to induce its conformation to the native counterparts forming amyloid fibrils and plaques partially resistant to protease degradation and showing neurotoxic properties. PrP with A117V pathogenic variant is the second most common genetic alteration leading to GSS and despite common phenotypic and neuropathological traits can be defined for each specific variant, strikingly heterogeneous manifestations have been reported for inter-familial cases bearing the same pathogenic variant or even within the same family. Given the scarcity of cases and their clinical, neuropathological, and biochemical variability, it is important to characterize thoroughly each reported case to establish potential correlations between clinical, neuropathological and biochemical hallmarks that could help to define disease subtypes. With that purpose in mind, this manuscript aims to provide a detailed report of the first Spanish GSS case associated with A117V variant including clinical, genetic, neuropathological and biochemical data, which could help define in the future potential disease subtypes and thus, explain the high heterogeneity observed in patients suffering from these maladies.

Scientific letter

Fabry disease is a rare X-linked disorder affecting α-galactosidase A, a rate-limiting enzyme in lysosomal catabolism of glycosphingolipids. Current treatments present important limitations, such as low half-life and limited distribution, which gene therapy can overcome. The aim of this work was to test a novel adeno-associated viral vector, serotype 9 (AAV9), ubiquitously expressing human α-galactosidase A to treat Fabry disease (scAAV9-PGK-GLA). The vector was preliminary tested in newborns of a Fabry disease mouse model. 5 months after treatment, α-galactosidase A activity was detectable in the analyzed tissues, including the central nervous system. Moreover, we tested the vector in adult animals of both sexes at two doses and disease stages (presymptomatic and symptomatic) by single intravenous injection. We found that the exogenous α-galactosidase A was active in peripheral tissues as well as the central nervous system and prevented glycosphingolipid accumulation in treated animals up to 5 months following injection. Antibodies against α-galactosidase A were produced in 9 out of 32 treated animals, although enzyme activity in tissues was not significantly affected. These results demonstrate that scAAV9-PGK-GLA can drive widespread and sustained expression of α-galactosidase A, cross the blood brain barrier after systemic delivery, and reduce pathological signs of the Fabry disease mouse model., Graphical Abstract, This study focuses on the development of a novel gene therapy vector for Fabry disease (FD). The approach is based on the systemic delivery of an AAV9, which crosses the blood brain barrier and drives sustained expression of α-galactosidase A, reducing pathological signs in multiple organs of a FD mouse model, including the central nervous system.

Background: Restless legs syndrome (RLS) is a common complication of uremia that may improve after transplantation. Its frequency might not be as low as expected, as some uremic disturbances may continue even after a successful graft. Our aim was to investigate the prevalence and related conditions for RLS in renal transplant patients. Methods: We carried out a cross-sectional, observational study. A self-administered questionnaire following the International Restless Legs Syndrome Study Group diagnostic criteria was administered to 129 patients (82 men and 47 women) aged 57 ± 12.8 years followed up for at least 1 year, with stable renal function (Cr 1.5 ± 0.54 mg/dL). Patients with probable RLS according to the screening questionnaire underwent comprehensive neurological examination to exclude RLS mimics. Results: The frequency of RLS according to questionnaires was 29.5% (18 men/20 women). After neurological exam, RLS was confirmed in 19 patients providing an overall frequency of 14.8% (higher than the prevalence in the general population). A definitive diagnosis of RLS was established for 6 men (7.3%) and 13 women (27.7%), indicating a positive predictive value for the screening questionnaire of 65% for women and 33% for men. There were fewer patients under renin-angiotensin aldosterone system (RAAS) blocking treatment in the RLS group (21.1 vs. 47.3%). Women with RLS had poorer renal function (52 ± 17.5 vs. 42 ± 13.9 mL/min) and phosphate-reabsorption rate (75 ± 10.5 vs. 65 ± 9.2). There was no difference in age, comorbidities, anticalcineurin therapy, renal function, anemia and time since transplantation between transplant patients with and without RLS. Conclusion: The prevalence of RLS after transplantation remains high (14.8%). This condition is twice more prevalent for females. Contribution of RAAS, graft function and phosphate overload requires further investigation.

Resumen Introduccion La puncion-aspiracion con aguja fina (PAAF) es la tecnica de referencia en la evaluacion de los pacientes con nodulos tiroideos. Su mayor limitacion son las muestras inadecuadas, que deberian ser menos del 20% de los casos. Objetivo Analizar la curva de aprendizaje de dicha tecnica de un endocrinologo sin experiencia (endocrinologo 2), comparando sus resultados con los obtenidos en los mismos nodulos por un colega experimentado (endocrinologo 1). Material y metodos Se realizaron 60 PAAF entre los meses de febrero y junio de 2016. Cada endocrinologo realizo 2 punciones de cada nodulo en un orden establecido aleatorizadamente. El orden de las punciones y el endocrinologo que las realizaba eran datos desconocidos para la patologa que analizo las muestras. Resultados En el total de las PAAF, el endocrinologo 1 tuvo un porcentaje de diagnosticos significativamente superior al endocrinologo 2 (82 vs. 72%; p = 0,015). En las primeras 20 PAAF la diferencia entre ambos fue notable y estadisticamente significativa (80 vs. 50%; p = 0,047). En las siguientes 20 PAAF la diferencia se redujo y ya no tenia significacion estadistica (90 vs. 65%; p = 0,058). Y en las ultimas 20 la diferencia fue minima y sin significacion estadistica (75 vs. 70%; p = 0,723). Conclusiones La curva de aprendizaje de la eco-PAAF puede completarse en un entorno adecuado haciendola un minimo de 60 veces. Aunque las guias recomiendan al menos 3 punciones por nodulo, 2 son suficientes para conseguir un porcentaje adecuado de diagnosticos.

There are few reports on axonal CMT due to dominant GDAP1 mutations. We describe two unrelated Spanish families with a dominant axonal CMT. A novel in frame GAA deletion in exon 5 of the GDAP1 gene (c.677_679del; p.R226del) was identified in both families. Disease onset varied from early childhood to adulthood. Affected family members complained of distal lower limb weakness, cramps and foot deformities with variable CMTNS score in both families. Several individuals were asymptomatic or had paraesthesia only, however neurological examination and nerve conduction studies demonstrated neuropathic signs. Transfection of HeLa cells with the p.R226del mutation led to an increased mitochondrial aggregation. We report an AD-CMT2K with large phenotypic variability due to a novel dominant GDAP1 variant. This is the second founder GDAP1 pathogenic variant reported in Spain.

Se presenta el caso de una paciente que consulta por debilidad y dolor muscular de años de evolución junto con elevación persistente de la creatinina cinasa. Los análisis realizados (que incluyeron hormonas, autoinmunidad y serologías), la resonancia magnética y el electromiograma no mostraron resultados concluyentes. Tras la práctica de una biopsia muscular se diagnostica de glucogenosis tipo V (enfermedad de McArdle). Las glucogenosis son un conjunto de enfermedades metabólicas de base genética caracterizadas por un trastorno en el catabolismo del glucógeno. La enfermedad de McArdle se define por la ausencia de la miofosforilasa, una enzima que cataliza la transformación de glucógeno en glucosa-1-fosfato en las fibras musculares esqueléticas, representando una forma de miopatía pura.

A G(4)C(2) hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG(3)C(2) repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G(4)C(2) repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.

GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.

Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.

Background Fabry disease is a multisystemic lysosomal storage disorder caused by the impairment of α-galactosidase A. The incidence of this rare disease is underestimated due to delayed diagnosis. Moreover, the management of the identified subjects is often complicated by the detection of variants of unclear diagnostic interpretation, usually identified in screening studies. We performed an observational study based on biochemical and genetic analysis of 805 dried blood spot samples from patients with clinical symptoms or family history of this pathology, which were collected from 109 Spanish hospitals, all over the country. Results We identified 77 new diagnosed patients with mutations related to classical Fabry disease, as well as 2 subjects with c.374A > T; p.His125Leu, a possible new mutation that need to be confirmed. Additionally, we detected 8 subjects carrying genetic variants possibly linked to late onset Fabry disease (p.Arg118Cys and p.Ala143Thr), 4 cases with polymorphism p.Asp313Tyr and 36 individuals with single nucleotide polymorphisms in intronic regions of GLA. Five of the identified mutations (c.431delG; c.1182delA; c.374A > T; c.932 T > C; c.125 T > A; c.778G > A), which were associated with a classical phenotype have not been previously described. Moreover 3 subjects presenting complex haplotypes made up by the association of intronic variants presented impaired levels of GLA transcripts and Gb3 deposits in skin biopsy. Conclusions Enzymatic screening for Fabry Disease in risk population (2 or more clinical manifestations or family history of the disease) helped to identify undiagnosed patients and unravel the impairment of GLA expression in some subjects with complex haplotypes. Electronic supplementary material The online version of this article (10.1186/s13023-018-0792-8) contains supplementary material, which is available to authorized users.

Deficient sleep quality (SQ) has been linked with a higher hospitalization rate and mortality in dialysis patients, however the prevalence of sleep disorders and their influence on prognosis in non-dialysis chronic kidney disease (CKD) has been poorly investigated. The aim of this study was to assess factors related with SQ in CKD patients (stages I-IV) followed in a nephrology outpatient clinic as well as the long-term impact of SQ on patient’s outcome. Between January and May 2008, Pittsburgh Sleep Quality Index (PSQI) was self-administered by 122 patients (68 males and 54 females) with a mean age of 65 years. Patients were classified as “good” (global PSQI < 6) and “poor” sleepers (global PSQI ≥ 6). We identified 66 (54%) poor sleepers (PS), characterized by an older age (66 ± 14.2 vs 57 ± 17.0, p < 0.01), female predominance (59% vs 26%, p < 0.01) and worse renal function (49 ± 19.1 vs 57 ± 23.2 ml/min, p < 0.05). There was a significant correlation between phosphate and PSQI score (r = 0.234, p = 0.01), however no correlation with calcium or PTH. Vitamin D was also lower in PS (17 ± 7.2 vs 23 ± 15.1 ng/ml, p < 0.05). Until June 2015, hospitalization rate was higher among PS (64% vs 44%, p < 0.05). In this period, there was also a trend towards higher mortality for PS (18% vs 16%). In summary, over 50% of CKD patients have poor SQ, which was associated with older age, female gender, worse renal function, lower vitamin D and higher phosphate levels. Deficient sleep was associated with a greater probability of hospitalization and might be a prognostic marker in CKD.

Background: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cause of stroke and vascular dementia in adults. Objective: to report the histopathological and ultrastructural findings in a patient with CADASIL at the time of diagnosis and in the post mortem study of the central nervous system, 10 years later. Patients and methods: we studied a patient with migraine with aura and a family history of migraine, stroke and dementia. Imaging tests, skin and muscle biopsies and molecular studies of Notch 3 were performed. In the post mortem examination, representative regions of the brain, muscle and skin samples were studied. Results: striking leukoaraiosis was found on MRI. Electrondense granular deposits characteristic of CADASIL were identified in the vascular walls in the biopsy samples. A mutation was detected in Notch 3 gene. Post mortem examination showed multiple brain infarcts, demyelination and vascular wall thickening, with striking granular deposits. Conclusions: neuropathological examination showed the characteristic findings of evolved CADASIL in the brain, skin and skeletal muscle vessels. The presence of early strokes in patients with family history should suggest the diagnosis of CADASIL (Alzheimer. Real Invest Demenc. 2011;48:5-12)

A high serum level of creatine kinase (CK) is a common reason for referring to medical specialities. Myopathies are one of the causes of elevated levels of CK. McArdle disease is the most common disorder of skeletal muscle carbohydrate metabolism. The cases are presented on 2 patients who were referred to our medical consultation to study the cause of their increased CK levels: a 72 year old asymptomatic man with high levels of CK detected by chance in a routine analysis, and a 30 year old woman with very few symptoms, apart from slight muscle pain and tiredness. Electromyography was normal in both patients. There was null activity of myophosphorylase in muscle biopsy of both cases, so a diagnosis of McArdle disease was made.

A high serum level of creatine kinase (CK) is a common reason for referring to medical specialities. Myopathies are one of the causes of elevated levels of CK. McArdle disease is the most common disorder of skeletal muscle carbohydrate metabolism. The cases are presented on 2 patients who were referred to our medical consultation to study the cause of their increased CK levels: a 72 year old asymptomatic man with high levels of CK detected by chance in a routine analysis, and a 30 year old woman with very few symptoms, apart from slight muscle pain and tiredness. Electromyography was normal in both patients. There was null activity of myophosphorylase in muscle biopsy of both cases, so a diagnosis of McArdle disease was made.

BACKGROUND Advanced glycation end products (AGEs) accumulation, a measure of cumulative metabolic stress, constitute a novel pathogenic mechanism involved in aging, diabetes, cardiovascular (CVD) and chronic kidney disease (CKD). Despite removal of uremic toxins and AGEs after a successful renal transplant (RT), CVD remains the leading cause of mortality. We hypothesized that AGEs measurement by Skin Autofluorescence (SAF) might be useful even after a successful RT and thus reflect the high cardiovascular risk burden of these patients. METHODS 189 stable RT (61% men, aged 56±13.0 years), CKD stages 1-4 and >12 months since RT were enrolled. Variables collected comprised comorbid history, medication use, smoking habit, routine biochemistry, subclinical atheromatosis by ankle-brachial-index (ABI) and allograft resistivity index (RI), 24-h ABPM, anthropometry and handgrip strength. AGEs were measured by SAF and expressed in arbitrary units (AU). Vascular age was estimated by Koetsier´s formula (SAF-0.83/0.024) and expected 10-years cardiovascular death risk was calculated with the REGICOR score. RESULTS Mean SAF was 3.00±0.83 AU and estimated vascular age 90±34.7 years (30 years above biological age). SAF was higher among men (3.10±0.91 vs 2.81±0.66), diabetic nephropathy (3.49±0.75 vs 2.96±0.83) and steroid users (3.14±0.86 vs 2.71±0.69). We observed a positive correlation of SAF with night-systolic blood pressure (r = 0.25, p = 0.001), parathormone (r = 0.20, p

Background Fine-needle aspiration biopsy (FNAB) is the reference procedure for thyroid nodule evaluation. Its main limitations are inadequate samples, which should be less than 20%. Objective To analyze the learning curve of the procedure by comparing the results of a non-experienced endocrinologist (endocrinologist 2) to those of an experienced one (endocrinologist 1). Material and methods Sixty FNABs were analyzed from February to June 2016. Each endocrinologist made 2 punctures of every nodule in a random order. This order and the professional making every puncture were unknown to the pathologist who examined the samples. Results Endocrinologist 1 had a higher percentage of diagnoses than endocrinologist 2 (82% vs. 72%, p = 0.015). In the first 20 FNABs, the difference between both physicians was remarkable and statistically significant (80% vs. 50%, p = 0.047). In the following 20 FNABs, the difference narrowed and was not statistically significant (90% vs. 65%, p = 0.058). In the final 20 FNABs, the difference was minimal and not statistically significant (75% vs. 70%, p = 0.723). Conclusions The learning curve of ultrasound-guided FNAB may be completed in a suitable environment by performing it at least 60 times. Although the guidelines recommend at least 3 punctures per nodule, 2 are enough to achieve an accurate percentage of diagnoses.

Fabry disease (FD) is treated by enzyme replacement therapy (ERT) or pharmacological chaperons (in UE). However, ERT has a short half-life and cannot cross the blood brain barrier (BBB), while pharmacological chaperons are not indicated for all diagnosed patients. We aim to test the efficacy of a gene therapy vector for FD, based on Adeno-Associated-Virus9 (scAAV9). The vector (pAAV9_PGK_GLA) expresses human α-GalactosidaseA (rh-α-GalA) under the promoter phosphoglycerate-kinase1. This vector can potentially achieve systemic expression of rh-α-GalA and cross the BBB. Similar therapies that are being developed are excluded from the CNS, therefore our vector could complement their effects. Although FD is not prevalently a neurological disorder, α-GalA is expressed in neurons, astrocytes and microglia and its defect maybe related to stroke in FD patients. scAAV9_PGK_GLA was injected in hemizygous B6;129-Glatm1Kul/J newborns (P1, No12) and the animals were sacrificed 3 or 5 months post-injection. rh-α-GalA activity was measured in brain, spinal cord, liver, heart and kidney and glycosphynsolipid deposits were detected by immunohistochemistry. rh-α-GalA is functional in all the analyzed tissues including the CNS and remains stable after 5 months. Gb3 deposit are less abundant in treated animals compared with not injected knock outs. Currently we are analyzing tissues from adult injected animals of both sexes, which were treated at two doses (15-50x1010vg/Kg) and ages (1 month or 3 months). Preliminary results indicate that rh-α-GalA is expressed and functional in all the analyzed tissues (brain, heart, kidney, liver) of the adult mice. These results confirmed that the vector lead the expression of rh-α-GalA when it is injected at early stages (P1) and possibly when injected in presymtomatic (1 month) or symptomatic (3 months) adults. We will analyze Lyso-Gb3 (Mass_Spec), viral genome distribution and antibody production (by Feb19). This project is sponsored by the French patients association Vaincre les Maladie Lisosomales.

McArdle's disease is the most common muscle glycogenosis. It is caused by the deficiency of myophosphorylase, encoded by the PYGM gene. We studied 123 patients previously diagnosed with McArdle's disease and we identified 20 novel mutations (10 missense and 3 nonsense mutations, 3 small deletions, 2 gross deletions and 2 small insertions). Most patients of this cohort belong to Spanish and French populations. This allowed us to determine the differences between the allelic frequencies of the common mutations R50X and G205S of these populations. The R50X has an allelic frequency in this cohort of about 61.7%, being 68.5% in French and 53.7% in Spanish patients. The G205S had a higher allelic frequency in the Spanish (10.2%) than in the French population (3.2%). Moreover, a clinical study of 91 patients was performed to establish both genotype-phenotype correlation and gender influence in the severity of the disease. We conclude that no genotype-phenotype correlation is evident and that no gender effect is related to the phenotype.

To perform the ultrastructural examination of a chorionic villi biopsy as a predictor of foetal involvement in the infantile form of glycogenosis type II (Pompe disease).Ultrastructural, biochemical and genetic analyses were performed on chorionic villi biopsies of three consecutive pregnancies in a woman with a previous child affected by Pompe disease.In the only affected foetus, glycogen storage was observed in fibrocytes and endothelial cells of a chorionic villi sample at 11 week's gestation. Severe multi-organ involvement was demonstrated in the tissues of the aborted foetus. No abnormal material was found in the chorionic samples of two subsequent pregnancies, and a healthy boy and girl were born at term and remain unaffected. Both exhibited a partial reduction in acid maltase and were carriers of the maternal mutation.Ultrastructural findings correlated with biochemical and genetic results, providing a clear and early indicator of the definite diagnosis for future pregnancy management or an early therapeutic approach.

In the Acknowledgments of our report we unintentionally omitted to include a sentence stating that J.G. holds a postdoctoral fellowship (JAE-Doc) from the Program “Junta para la Ampliacion de Estudios” co-funded by the Fondo Social Europeo (FSE). The authors regret this omission.

Criado-García, Olga et al., Lafora disease (LD), a fatal neurodegenerative disorder characterized by the presence of intracellular inclusions called Lafora bodies (LBs), is caused by loss-of-function mutations in laforin or malin. Previous studies suggested a role of these proteins in the regulation of glycogen biosynthesis, in glycogen dephosphorylation and in the modulation of the intracellular proteolytic systems. However, the contribution of each of these processes to LD pathogenesis is unclear. We have generated a malin-deficient (Epm2b-/-) mouse with a phenotype similar to that of LD patients. By 3-6 months of age, Epm2b-/- mice present neurological and behavioral abnormalities that correlate with a massive presence of LBs in the cortex, hippocampus and cerebellum. Sixteen-day-old Epm2b-/- mice, without detectable LBs, show an impairment of macroautophagy (hereafter called autophagy), which remains compromised in adult animals. These data demonstrate similarities between the Epm2a-/- and Epm2b-/- mice that provide further insights into LD pathogenesis. They illustrate that the dysfunction of autophagy is a consequence of the lack of laforin-malin complexes and a common feature of both mouse models of LD. Because this dysfunction precedes other pathological manifestations, we propose that decreased autophagy plays a primary role in the formation of LBs and it is critical in LD pathogenesis. © The Author 2011. Published by Oxford University Press. All rights reserved., This work was funded by the Spanish Ministerio de Ciencia eInnovacio ́ n (SAF2008-00226 to S.R.C.; BFU2007-61774 andBFU2010-16031toP.B.;BFU2008-00186toE.K.;SAF2008-01907 to P.S.; and SAF2010-18586 to J.M.S.), theRed de Biobancos del FIS (RD09/0076/00011 to C.N.), theFondo de Investigacio ́ n Sanitaria (PI10/02628 to C.N.;PI070023 to M.S.), the Fundacio ́ n Marato TV3 (Ref. 100130to P.S., E.K. and S.R.C.) and the Centro de Investigacio ́ n Bio-me ́dica en Red de Enfermedades Raras (CIBERER).A.M.G.-C. holds a fellowship from the Fundacio ́ n ConchitaRa ́bago

Knecht, Erwin et al., Lafora disease (LD), a fatal neurodegenerative disorder characterized by intracellular inclusions called Lafora bodies (LBs), is caused by recessive loss-of-function mutations in the genes encoding either laforin or malin. Previous studies suggested a role of these proteins in regulating glycogen biosynthesis, in glycogen dephosphorylation and in the modulation of intracellular proteolytic systems. However, the contribution of each of these processes to LD pathogenesis is unclear. Here we review our recent finding that dysfunction of autophagy is a common feature of both laforin- and malin-deficient mice, preceding other pathological manifestations. We propose that autophagy plays a primary role in LD pathogenesis and is a potential target for its treatment. © 2012 Landes Bioscience., Spanish Ministry of Science and Innovation (SAF2008-00226 to SRdeC, BFU2010-16031 to PB; BFU2008-00186, SAF2008-01907, SAF2010-18586); the Red de Biobancos del FIS (RD09/0076/00011); the Fondo de Investigación Sanitaria (PI10/02628, PI070023); the Fundación Marato TV3 (Ref.100130); the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Fundación Conchita Rábago

This study aimed to identify the genetic defect in a multigenerational family presenting an autosomal dominant myopathy with histological features of congenital fiber type disproportion. Linkage analysis and genetic sequencing identified, in all affected members of the family, the c.5807A>G heterozygous mutation in MYH7, which encodes the slow/β-cardiac myosin heavy chain. This mutation causes skeletal but not cardiac involvement. Myosin heavy chain expression pattern was also characterized by immunohistochemistry, western blot and q-PCR in muscle biopsies from two patients aged 25 and 62, respectively. While only congenital fiber type disproportion was observed in the younger patient, older patient's biopsy presented aggregates of slow myosin heavy chains, in fiber sub-sarcolemmal region. These clinico-pathologic findings suggest a novel phenotype within the emerging group of hereditary myosin myopathies, which in this family presents typical characteristics of congenital fiber type disproportion in early stages and later evolves to myosin storage myopathy.

Limb girdle muscular dystrophies are a heterogeneous group of muscle disorders predominantly affecting the pelvic and shoulder girdles. They have been classified into autosomal recessive and dominant forms, the former being by far the commonest. Genetic analyses have led to the description of 14 recessive forms and 7 dominant. In four of the dominant forms the chromosomal loci have been localised but the gene and the protein have not been yet identified. The genes and proteins in these subgroups are localised over a wide range across the muscle fiber and at the extracellular matrix. Immunohistochemistry and Western blotting analyses of the proteins involved in the various forms of muscular dystrophies, have permitted a refined pathological approach, necessary to conduct genetic studies and to offer an appropriate genetic counseling. The application of molecular medicine in genetic muscular dystrophies also brings great expectations to the therapeutic management of these patients.

Fabry disease (FD) is a lysosomal storage disorder (LSD) with multisystem manifestations among which skin lesions are common and well-recognized. They may appear early in childhood in both hemizygous males and heterozygous females, their frequency increasing with age. In addition to dermatological lesions, normal-looking skin, as occurs with other tissues, accumulates unmetabolized products in multiple cells of different embryonic origin with variable distribution, biochemical and staining properties and morphological features, according to the type of stored material and the physiopathology of the disease. Globotryaosil-ceramide (Gb3), the most abundant glycosphyngolipid accumulated in FD, can be specifically documented with immunocytochemical methods using a particular monoclonal antibody. On the other hand, ultrastructural characteristics of Gb3 and its distribution in dermal cells are well-defined. Furthermore, the study of unmyelinated and small myelinated fibers in epidermal nerve endings is a reflection of the impaired sensory innervation and the characteristic painful neuropathy present in FD. Therefore, a combination of different technologies in tissues obtained with noninvasive techniques, such as skin biopsy, is advisable and should be considered in order to obtain better insights into FD. This is essential in the case of heterozygous women in whom biochemical diagnosis is often controversial.

Limb girdle muscular dystrophies are a heterogeneous group of muscle disorders predominantly affecting the pelvic and shoulder girdles. They have been classified into autosomal recessive and dominant forms, the former being by far the commonest. Genetic analyses have led to the description of 14 recessive forms and 7 dominant. In four of the dominant forms the chromosomal loci have been localised but the gene and the protein have not been yet identified. The genes and proteins in these subgroups are localised over a wide range across the muscle fiber and at the extracellular matrix.

Acute necrotizing encephalopathy of childhood is a rare disease with a broad clinical, radiologic, and biochemical spectrum. In the few postmortem studies published to date, the neuropathologic findings involved symmetric, necrotic brain lesions as the hallmark. Here we report on the clinical and neuropathologic findings of a Spanish child with the most severe form of the disease.