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Spastic paraplegia type 7 (SPG7) is one of the most common hereditary spastic paraplegias. SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), frequently with mixed phenotypes. We sought to clinically and genetically characterize a Spanish cohort of SPG7 patients. Patients were recruited from our HCA and HSP cohorts. We identified twenty-one patients with biallelic pathogenic SPG7 mutations. Mean age at onset was 37.4 years (SD ± 14.3). The most frequent phenotype was spastic ataxia (57%), followed by pure spastic paraplegia (19%) and complex phenotypes (19%). Isolated patients presented with focal or multifocal dystonia, subclinical myopathy or ophthalmoplegia. p.Ala510Val was the most frequent pathogenic variant encountered. Compound heterozygous for p.Ala510Val displayed younger onset (p

Objective: To perform phenotype and genotype characterization in myoclonus-dystonia patients and to validate clinical rating tools. Method: Two movement disorders experts rated patients with the Burke-Fahn-Marsden and Unified-Myoclonus rating scales using a video-recording protocol. Clinimetric analysis was performed. SGCE mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification. Results: 48 patients were included and 43/48 rated. Mean age at assessment was 12.9±10.5 years (range 3–51) and 88% were ≤18 years of age. Myoclonus was a universal sign with a rostro-caudal severity-gradient. Myoclonus increased in severity and spread to lower limbs during action tests. Stimulus-evoked myoclonus was observed in 86.8% cases. Dystonia was common but mild. It had a focal distribution and was action-induced, causing writer's cramp (69%) and gait dystonia (34%). The severity of both myoclonus and dystonia had a strong impact on hand writing and walking difficulties. The Unified Myoclonus Rating scale showed the best clinimetric properties for the questionnaire, action myoclonus and functional subscales, and exceeded the Burke-Fahn-Marsden scale in its utility in assessing functional impairment in MDS patients. Twenty-one different SGCE mutations were identified in 45/48 patients, eleven being novel (most prevalent p. Val187*, founder mutation in Canary Islands). Conclusion: This study quantifies the severity of the motor phenotype in SGCE-myoclonus dystonia syndrome, with a special focus on children, and identifies disabilities in gross and fine motor tasks that are essential for childhood development. Our results contribute to the knowledge of SGCE-related MDS in the early stage of evolution, where disease-modifying therapies could be initiated in order to prevent long-term social and physical burdens. © 2020 Elsevier Ltd

The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2 , PLA2G6 , WDR45 , C19ORF12 , FA2H , ATP13A2 , COASY , FTL1 , CP , and DCAF17 . Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.

Background: Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration. Methods: In this international cross-sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment. The scale included 34 items (maximal score, 135) encompassing 6 subscales for cognition, behavior, disability, parkinsonism, dystonia, and other neurological signs. Results: Forty-seven genetically confirmed patients (30 ± 17 years; range, 6-77 years) were examined with the scale (mean score, 62 ± 21; range, 20-106). Dystonia with prominent cranial involvement and atypical parkinsonian features were present in all patients. Other common signs were cognitive impairment, psychiatric features, and slow and hypometric saccades. Dystonia, parkinsonism, and other neurological features had a moderate to strong correlation with disability. The scale showed good internal consistency for the total scale (Cronbach's α = 0.87). On interrater analysis, weighted kappa values (0.30-0.93) showed substantial or excellent agreement in 85% of the items. The scale also discriminated a subgroup of homozygous c.1583C>T patients with lower scores, supporting construct validity for the scale. Conclusions: The proposed scale seems to be a reliable and valid instrument for the assessment of pediatric and adult patients with pantothenate kinase-associated neurodegeneration. Additional validation studies with a larger sample size will be required to confirm the present results and to complete the scale validation testing. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society

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.

Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p. R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p. R190W mutation and another patient that harboured a MORC2 p. S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.

Distal hereditary motor neuropathies (dHMN) are a group of rare hereditary neuromuscular disorders characterized by an atrophy that affects peroneal muscles in the absence of sensory symptoms. To date, 23 genes are thought to be responsible for dHMN, four of which encode chaperones: DNAJB2, which encodes a member of the HSP40/DNAJ co-chaperone family; and HSPB1, HSPB3, and HSPB8, encoding three members of the small heat shock protein family. While around 30 different mutations in HSPB1 have been identified, the remaining three genes are altered in many fewer cases. Indeed, a mutation of HSPB3 has only been described in one case, whereas a few cases have been reported carrying mutations in DNAJB2 and HSPB8, most of them caused by a founder c.352+1G>A mutation in DNAJB2 and by mutations affecting the K141 residue in the HSPB8 chaperone. Hence, their rare occurrence makes it difficult to understand the pathological mechanisms driven by such mutations in this neuropathy. Chaperones can assemble into multi-chaperone complexes that form an integrated chaperone network within the cell. Such complexes fulfill relevant roles in a variety of processes, such as the correct folding of newly synthesized proteins, in which chaperones escort them to precise cellular locations, and as a response to protein misfolding, which includes the degradation of proteins that fail to refold properly. Despite this range of functions, mutations in some of these chaperones lead to diseases with a similar clinical profile, suggesting common pathways. This review provides an overview of the genetics of those dHMNs that share a common disease mechanism and that are caused by mutations in four genes encoding chaperones: DNAJB2, HSPB1, HSPB3, and HSPB8.

Coenzyme Q(10) (CoQ) deficiency syndromes comprise a growing number of neurological and extraneurological disorders. Primary-genetic but also secondary CoQ deficiencies have been reported. The biochemical determination of CoQ is a good tool for the rapid identification of CoQ deficiencies but does not allow the selection of candidate genes for molecular diagnosis. Moreover, the metabolic pathway for CoQ synthesis is an intricate and not well-understood process, where a large number of genes are implicated. Thus, only next-generation sequencing techniques (either genetic panels of whole-exome and -genome sequencing) are at present appropriate for a rapid and realistic molecular diagnosis of these syndromes. The potential treatability of CoQ deficiency strongly supports the necessity of a rapid molecular characterization of patients, since primary CoQ deficiencies may respond well to CoQ treatment.

Charcot-Marie-Tooth disease type 4C (CMT4C) is a hereditary neuropathy with prominent unsteadiness. The objective of the current study is to determine whether the imbalance in CMT4C is caused only by reduced proprioceptive input or if vestibular nerve involvement is an additional factor. We selected 10 CMT4C patients and 10 age-matched and sex-matched controls. We performed a comprehensive evaluation of the vestibular system, including video Head Impulse Test, bithermal caloric test, galvanic stimulation test and skull vibration-induced nystagmus test. None of the patients experienced dizziness, spontaneous or gaze-evoked nystagmus, but all had significant vestibular impairment when tested when compared to controls. Seven had completely unexcitable vestibular systems and abnormal vestibuloocular reflex. There was no correlation between the degree of vestibulopathy and age or clinical severity. Significant vestibular impairment is a consistent finding in CMT4C and is present early in disease evolution. The profound imbalance that is so disabling in these patients may result from a combination of proprioceptive loss and vestibular neuropathy, and this would modify the recommended rehabilitation strategies.

Four private mutations responsible for three forms demyelinating of Charcot-Marie-Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom); p.C737_P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN-Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN-Russe (25%) and HMSN-Lom (17.86%). The relevant frequency of HMSN-Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN-Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN-Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range.

Introduction: carcinoid tumors (CTs) represent the most common type of neuroendocrine tumors (NETs). Digestive CTs in the gastroduodenal and colorectal tracts may be assessed using endoscopy and echoendoscopy or endoscopic ultrasonography (EUS) with the goal of attempting local resection with curative intent without having recourse to surgery. Objective: endpoints in this study included: - Assessing the usefulness of EUS for selecting CTs as candidates to endoscopic excision. - Assessing the effectiveness of local resection (complete carcinoid resection) and the safety (complications) of the technique involved. Patients and methods: our series included 18 patients (12 males and 6 females) with 23 tumors. Sixteen patients (10 males and 6 females) were selected, with age ranging from 40 to 81 years (mean: 57 years), biopsied, endoscopically treated digestive carcinoid tumors, and a previous negative extension study. Twenty-one 2-to-20-mm (mean size 8 mm) tumors were resected in 23 procedures. After endoscopy plus biopsy and echoendoscopy (EUS), excision was carried out with conventional polypectomy snare mucosectomy and submucosal injection with saline and/or adrenaline in most cases (15), and mucosectomy technique following lesion ligation with elastic bands for six cases. Two cases underwent transanal endoscopic surgery (TEM), one of them following non-curative polypectomy. A total of 23 local procedures were performed with the key goal of assessing efficacy (complete resection: CR) and safety (complications). Results: there were no severe complications except for the last gastric mucosectomy for a 6-mm carcinoid, where a miniperforation occurred that was solved by using 3 clips (1/23: 4.3%). EUS sensitivity was 94%. Complete resection was 90.5% (19/21). Conclusions: the endoscopic mucosal resection of selected carcinoid tumors is a safe, effective technique. EUS is the technique of choice to select patients eligible for endoscopic resection (carcinoids smaller than 20 mm in superficial layers, with an unscathed muscularis propria and negative extension study). Introducción: los tumores carcinoides (TC) son los tumores neuroendocrinos (TNEs) más frecuentes. Los TC digestivos localizados en el tracto gastroduodenal y rectocolónico pueden ser evaluados por endoscopia y por ecoendoscopia o ultrasonografía endoscópica (USE), con el objetivo de efectuar una resección local como tratamiento curativo sin recurrir a la cirugía. Objetivo: los objetivos finales de este estudio fueron: - Analizar si es útil la USE en la selección de TC como candidatos a una extirpación endoscópica. - La evaluación de la eficacia de la resección local (resección completa del carcinoide) y la seguridad (complicaciones) de la técnica efectuada. Pacientes y métodos: la serie consta de 18 pacientes (12 varones y 6 mujeres) con 23 tumores. Se han seleccionado 16 pacientes (10 varones y 6 mujeres) con un rango de 40 a 81 años (media: 57 años), con tumores carcinoides digestivos biopsiados y tratados endoscópicamente, con estudio previo de extensión negativo. Se resecaron 21 tumores de 2 a 20 mm (tamaño medio: 8 mm), en 23 procedimientos. Después de endoscopia más biopsia y ecoendoscopia (USE), se llevó a cabo la extirpación mediante mucosectomía con asa de polipectomía convencional e inyección submucosa con suero salino y/o adrenalina en la mayoría de casos (15) y en seis con técnica de mucosectomía tras ligar la lesión con bandas elásticas. En dos casos con cirugía endoscópica transanal (TEM) (uno después de haber efectuado polipectomía no curativa). Se efectuaron en total 23 tratamientos localizados con el objetivo fundamental de evaluar la eficacia (resección completa: RC) y seguridad (complicaciones). Resultados: no hubo complicaciones muy importantes, excepto en la última mucosectomía gástrica por un carcinoide de 6 mm, en la que se produjo una miniperforación (1/23: 4,3%) que se resolvió con la colocación de 3 clips. La sensibilidad de la USE fue del 94%. La resección completa fue del 90,5% (19/21). Conclusiones: la resección mucosa endoscópica de tumores carcinoides seleccionados es una técnica segura y eficaz. La USE es la técnica de elección para seleccionar los pacientes candidatos a resección endoscópica (carcinoides menores de 20 mm situados en las primeras capas, con muscular propia indemne y con estudio de extensión negativo).

Mutations in the ganglioside-induced-differentiation-associated protein 1 gene (GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A) or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive inheritance, but few autosomal dominant GDAP1 mutations have also been reported. We performed a GDAP1 gene screening in a clinically well-characterized series of 81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to 4 unrelated families in whom the heterozygous p.R120W was found to be the only disease-causing mutation. The main objective was to fully characterize the neuropathy caused by this mutation. The clinical picture included a mild-moderate phenotype with onset around adolescence, but great variability. Consistently, ankle dorsiflexion and plantar flexion were impaired to a similar degree. Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic resonance imaging studies demonstrated selective involvement of intrinsic foot muscles in all patients and a uniform pattern of fatty infiltration in the calf, with distal and superficial posterior predominance. Pathological abnormalities included depletion of myelinated fibers, regenerative clusters and features of axonal degeneration with mitochondrial aggregates. Our findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene mutations which can cause an axonal CMT with a wide clinical profile.

Introduction: carcinoid tumors (CTs) represent the most common type of neuroendocrine tumors (NETs). Digestive CTs in the gastroduodenal and colorectal tracts may be assessed using endoscopy and echoendoscopy or endoscopic ultrasonography (EUS) with the goal of attempting local resection with curative intent without having recourse to surgery. Objective: endpoints in this study included: - Assessing the usefulness of EUS for selecting CTs as candidates to endoscopic excision. - Assessing the effectiveness of local resection (complete carcinoid resection) and the safety (complications) of the technique involved. Patients and methods: our series included 18 patients (12 males and 6 females) with 23 tumors. Sixteen patients (10 males and 6 females) were selected, with age ranging from 40 to 81 years (mean: 57 years), biopsied, endoscopically treated digestive carcinoid tumors, and a previous negative extension study. Twenty-one 2-to-20-mm (mean size 8 mm) tumors were resected in 23 procedures. After endoscopy plus biopsy and echoendoscopy (EUS), excision was carried out with conventional polypectomy snare mucosectomy and submucosal injection with saline and/or adrenaline in most cases (15), and mucosectomy technique following lesion ligation with elastic bands for six cases. Two cases underwent transanal endoscopic surgery (TEM), one of them following non-curative polypectomy. A total of 23 local procedures were performed with the key goal of assessing efficacy (complete resection: CR) and safety (complications). Results: there were no severe complications except for the last gastric mucosectomy for a 6-mm carcinoid, where a miniperforation occurred that was solved by using 3 clips (1/23: 4.3%). EUS sensitivity was 94%. Complete resection was 90.5% (19/21). Conclusions: the endoscopic mucosal resection of selected carcinoid tumors is a safe, effective technique. EUS is the technique of choice to select patients eligible for endoscopic resection (carcinoids smaller than 20 mm in superficial layers, with an unscathed muscularis propria and negative extension study).

Mutations in SH3TC2 (KIAA1985) cause Charcot-Marie-Tooth disease (CMT) type 4C, a demyelinating inherited neuropathy characterized by early-onset and scoliosis. Here we demonstrate that the SH3TC2 protein is present in several components of the endocytic pathway including early endosomes, late endosomes and clathrin-coated vesicles close to the trans-Golgi network and in the plasma membrane. Myristoylation of SH3TC2 in glycine 2 is necessary but not sufficient for the proper location of the protein in the cell membranes. In addition to myristoylation, correct anchoring also needs the presence of SH3 and TPR domains. Mutations that cause a stop codon and produce premature truncations that remove most of the TPR domains are expressed as the wild-type protein. In contrast, missense mutations in or around the region of the first-TPR domain are absent from early endosomes, reduced in plasma membrane and late endosomes and are variably present in clathrin-coated vesicles. Our findings suggest that the endocytic and membrane trafficking pathway is involved in the pathogenesis of CMT4C disease. We postulate that missense mutations of SH3TC2 could impair communication between the Schwann cell and the axon causing an abnormal myelin formation.

Cranial nerve involvement in Charcot-Marie-Tooth disease (CMT) is rare, though there are a number of CMT syndromes in which vocal cord paralysis is a characteristic feature. CMT disease due to mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) has been reported to be associated with vocal cord and diaphragmatic palsy. In order to address the prevalence of these complications in patients with GDAP1 mutations we evaluated vocal cord and respiratory function in nine patients from eight unrelated families with this disorder. Hoarseness of the voice and inability to speak loudly were reported by eight patients and one had associated symptoms of respiratory insufficiency. Patients were investigated by means of peripheral and phrenic nerve conduction studies, flexible laryngoscopy, pulmonary function studies and polysomnography. Nerve conduction velocities and pathological studies were compatible with axonal CMT (CMT2). Flexible laryngoscopy showed left vocal cord palsy in four cases, bilateral cord palsies in four cases and was normal in one case. Restrictive respiratory dysfunction was seen in the eight patients with vocal cord paresis who were all chair-bound. These eight had confirmed phrenic nerve dysfunction on neurophysiology evaluation. The patient with normal vocal cord and pulmonary function had a less severe clinical course.This study shows that CMT patients with GDAP1 mutations develop severe disability due to weakness of limb muscles and that laryngeal and respiratory muscle involvement occurs late in the disease process when significant proximal upper limb weakness has developed. The early and predominant involvement of the left vocal cord innervated by the longer left recurrent laryngeal nerve suggests a length dependent pattern of nerve degeneration. In GDAP1 neuropathy, respiratory function should be thoroughly investigated because life expectancy can be compromised due to respiratory failure.

Hemophilia A is an X-linked recessive disorder caused by a lack or decrease of factor VIII activity. Its socio-economic impact is high given its high bleeding expression and treatment cost. Our aim was to establish the mutation of each patient to improve family management. A total of 116 unrelated families with severe and moderate hemophilia A were involved. Non-carriers of intron 22 and intron 1 rearrangements were included in F8 gene screening. Intron 1 and 22 inversion frequencies were 3% and 52.5% respectively. Putative mutations were identified in all the families; 38 were new. The cumulative inhibitor incidence was 22%. Approximately half the families carry non-recurrent mutations, which were unique in around one third. Harmful effects for mutations predicting null alleles are expected. Missense mutation consequences are not easily predictable, despite the help of some bio-informatics tools.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized clinically by progressive motor impairment, cognitive decline, and emotional deterioration. The disease is caused by the abnormal expansion of a CAG trinucleotide repeat in the first exon of the huntingtin gene in chromosome 4p16.3. HD is spread worldwide and it is generally accepted that few mutational events account for the origin of the pathogenic CAG expansion in most populations. We have investigated the genetic history of HD mutation in 83 family probands from the Land of Valencia, in Eastern Spain. An analysis of the HD/CCG repeat in informative families suggested that at least two main chromosomes were associated in the Valencian population, one associated with allele 7 (77 mutant chromosomes) and one associated with allele 10 (two mutant chromosomes). Haplotype A-7-A (H1) was observed in 47 out of 48 phase-known mutant chromosomes, obtained by segregation analysis, through the haplotype analysis of rs1313770-HD/CCG-rs82334, as it also was in 120 out of 166 chromosomes constructed by means of the PHASE program. The genetic history and geographical distribution of the main haplotype H1 were both studied by constructing extended haplotypes with flanking short tandem repeats (STRs) D4S106 and D4S3034. We found that we were able to determine the age of the CAG expansion associated with the haplotype H1 as being between 4,700 and 10,000 years ago. Furthermore, we observed a nonhomogenous distribution in the different regions associated with the different extended haplotypes of the ancestral haplotype H1, suggesting that local founder effects have occurred.

Hemophilia B (factor IX deficiency) is an X-linked recessive disorder with a prevalence of 1:30,000 male births, which rarely affects females. A missense mutation T38R (6488C>G) of the factor IX (FIX) gene was characterized in a young female with moderate-to-severe hemophilia B. She is heterozygous for this mutation, which she inherited from her carrier mother. Analysis of the methyl-sensitive HpaII sites in the first exon of the human androgen-receptor locus indicated a de novo skewed X-chromosomal inactivation. This indicates that the paternal X-chromosome carrying her normal FIX gene is the inactive one, which has led to the phenotypic expression of hemophilia B in this patient.