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INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.
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Enfermedad de Alzheimer , Atrofia , Biomarcadores , Encéfalo , Degeneración Lobar Frontotemporal , Imagen por Resonancia Magnética , Proteínas de Neurofilamentos , Progranulinas , Proteínas tau , Humanos , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Degeneración Lobar Frontotemporal/patología , Masculino , Femenino , Atrofia/patología , Anciano , Persona de Mediana Edad , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Proteínas de Neurofilamentos/sangre , Proteínas tau/líquido cefalorraquídeo , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeoRESUMEN
Homozygous VPS50 variants have been previously described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures and neonatal cholestasis. VPS50 encodes a subunit that is unique to the heterotetrameric endosome-associated recycling protein (EARP) complex. The other subunits of the EARP complex, such as VPS51, VPS52 and VPS53, are also shared by the Golgi-associated retrograde protein complex. We report on an 18-month-old female patient with biallelic VPS50 variants. She carried a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant. By long-read genome sequencing, we characterised a structural variant with a 4.3 Mb inversion flanked by deletions at both breakpoints on the maternal allele. The ~428 kb deletion at the telomeric inversion breakpoint encompasses the entire VPS50 gene. We demonstrated a deficiency of VPS50 in patient-derived fibroblasts, confirming the loss-of-function nature of both VPS50 variants. VPS53 and VPS52 protein levels were significantly reduced and absent, respectively, in fibroblasts of the patient. These data show that VPS50 and/or EARP deficiency and the associated functional defects underlie the phenotype in patients with VPS50 pathogenic variants. The VPS50-related core phenotype comprises severe developmental delay, postnatal microcephaly, hypoplastic corpus callosum, neonatal low gamma-glutamyl transpeptidase cholestasis and failure to thrive. The disease is potentially fatal in early childhood.
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PURPOSE: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies. METHODS: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291). RESULTS: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins. CONCLUSION: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.
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Quinasa de Punto de Control 2 , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alelos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa de Punto de Control 2/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Secuenciación del Exoma/métodos , Mutación de Línea Germinal/genética , Neoplasias/genética , Fenotipo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
Biallelic pathogenic variants in the TTC26 gene are known to cause BRENS (biliary, renal, neurological, skeletal) syndrome, an ultra-rare autosomal recessive condition with only few patients published to date. BRENS syndrome is characterized by hexadactyly, severe neonatal cholestasis, and involvement of the brain, heart, and kidney, however the full phenotypic and genotypic spectrum is unknown. Here, we report on a previously undescribed homozygous intronic TTC26 variant (c.1006-5 T > C) in a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy, and congenital heart defect. Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate. The variant is considered to affect correct splicing by the loss of the canonical acceptor splice site and activation of a cryptic acceptor splice site. Hereby, our patient represents one additional patient with BRENS syndrome carrying a previously unreported TTC26 variant. Furthermore, we confirm the involvement of the pituitary gland to be a common clinical feature of the syndrome and broaden the clinical spectrum of TTC26 ciliopathy to include facial clefts and a probable hearing involvement.
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Labio Leporino , Fisura del Paladar , Enfermedades Renales , Polidactilia , Masculino , Humanos , Recién Nacido , Fisura del Paladar/genética , Labio Leporino/genética , Hipófisis/anomalías , Síndrome , FenotipoRESUMEN
OBJECTIVE: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.
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Cefalalgia Histamínica , Trastornos Migrañosos , Masculino , Humanos , Femenino , Cefalalgia Histamínica/epidemiología , Cefalalgia Histamínica/genética , Factores de Riesgo , Estudio de Asociación del Genoma Completo , Fumar/efectos adversos , Fumar/genética , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la Enfermedad/genéticaRESUMEN
BACKGROUND: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). METHODS: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. RESULTS: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. DISCUSSION: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations. HIGHLIGHTS: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL).
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Enfermedad de Alzheimer , Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Humanos , Enfermedad de Alzheimer/patología , Sinucleína beta , Proteínas tau , Degeneración Lobar Frontotemporal/patología , Encéfalo/patología , Biomarcadores , Atrofia/patología , Péptidos beta-AmiloidesRESUMEN
Auditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted owing to genetic or environmental factors. Autosomal-dominant auditory neuropathy type 2 (AUNA2) was linked either to chromosomal bands 12q24 or 13q34 in a large German family in 2017. By whole-genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family. ATP11A encodes a P-type ATPase that translocates phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane. The deletion affects both isoforms of ATP11A and activates a cryptic splice site leading to the formation of an alternative last exon. ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice, and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of AN. By combining whole-genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2.
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Pérdida Auditiva Central , Pérdida Auditiva Sensorineural , Humanos , Ratones , Animales , Pérdida Auditiva Central/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Células Ciliadas Auditivas Internas , Cromosomas , Transportadoras de Casetes de Unión a ATP/genéticaRESUMEN
Purpose: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families. Methods: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis. Results: We identified 2 rare biallelic variants in CAPNS1, encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH. Conclusion: The calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered.
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BACKGROUND: Coding and noncoding repeat expansions are an important cause of neurodegenerative diseases. OBJECTIVE: This study determined the clinical and genetic features of a large German family that has been followed for almost 2 decades with an autosomal dominantly inherited spinocerebellar ataxia (SCA) and independent co-occurrence of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We carried out clinical examinations and telephone interviews, reviewed medical records, and performed magnetic resonance imaging and positron emission tomography scans of all available family members. Comprehensive genetic investigations included linkage analysis, short-read genome sequencing, long-read sequencing, repeat-primed polymerase chain reaction, and Southern blotting. RESULTS: The family comprises 118 members across seven generations, 30 of whom were definitely and five possibly affected. In this family, two different pathogenic mutations were found, a heterozygous repeat expansion in C9ORF72 in four patients with ALS/FTD and a heterozygous repeat expansion in DAB1 in at least nine patients with SCA, leading to a diagnosis of DAB1-related ataxia (ATX-DAB1; SCA37). One patient was affected by ALS and SCA and carried both repeat expansions. The repeat in DAB1 had the same configuration but was larger than those previously described ([ATTTT]≈75 [ATTTC]≈40-100 [ATTTT]≈415 ). Clinical features in patients with SCA included spinocerebellar symptoms, sometimes accompanied by additional ophthalmoplegia, vertical nystagmus, tremor, sensory deficits, and dystonia. After several decades, some of these patients suffered from cognitive decline and one from additional nonprogressive lower motor neuron affection. CONCLUSION: We demonstrate genetic and clinical findings during an 18-year period in a unique family carrying two different pathogenic repeat expansions, providing novel insights into their genotypic and phenotypic spectrums. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Esclerosis Amiotrófica Lateral , Ataxia Cerebelosa , Demencia Frontotemporal , Ataxias Espinocerebelosas , Humanos , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/genética , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Expansión de las Repeticiones de ADN/genética , Ataxia Cerebelosa/genética , Ataxias Espinocerebelosas/genética , Proteínas del Tejido Nervioso/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
OBJECTIVE: Reactive astrogliosis is a hallmark of Alzheimer's disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. Here, we used serum levels of the astroglial marker glial fibrillary acidic protein (GFAP) to investigate differences in patients with AD dementia, mild cognitive impairment (MCI)-AD and behavioural variant FTD (bvFTD). METHODS: This multicentre study included serum samples from patients diagnosed with AD dementia (n=230), MCI-AD (n=111), bvFTD (n=140) and controls (n=129). A subgroup of patients with MCI-AD (n=32) was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, neurofilament light chain (NfL) and pTau181 were measured by Simoa (Quanterix) and Ella (ProteinSimple). RESULTS: In total, samples from 610 individuals from four clinical centres were investigated in this study. Serum GFAP levels in AD dementia were increased (median 375 pg/mL, IQR 276-505 pg/mL) compared with controls (167 pg/mL, IQR 108-234 pg/mL) and bvFTD (190 pg/mL, IQR 134-298 pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300 pg/mL, IQR 232-433 pg/mL, p<0.001) and was higher in patients with MCI-AD who developed dementia during follow-up (360 pg/mL, IQR 253-414 pg/mL vs 215 pg/mL, IQR 111-266 pg/mL, p<0.01, area under the curve (AUC)=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%, likelihood ratio 2.5) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%, likelihood ratio 6.0) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%, likelihood ratio 1.8). CONCLUSIONS: Our data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.
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The detection of a pathogenic variant in the BRCA1 or BRCA2 gene has medical and psychological consequences for both, affected mutation carriers and their relatives. A two-phase study with explanatory sequential mixed methods design examined the psychological impact of genetic testing and associated family communication processes. Analyzing a survey data of 79 carriers of a BRCA1 or BRCA2 mutation, the majority had general psychological distress independent of cancer diagnosis in the patients' history. The point prevalence of depression was 16.9%. Contrary to their subjective perception, the respondents' knowledge about those mutations was moderate. Despite the high rate of information transfer to relatives at risk (100%), their reported uptake of genetic testing was low (45.6%). Communication about the mutation detection was more frequent with female than with male relatives. In-depth focus group interviews revealed significant barriers to accessing genetic counseling including anxiety, uncertainty about the benefits of testing and about the own cancer risk, particularly among males. This study suggests that an adequate knowledge of the genetic background and psychological support is required to reduce emotional distress, to support familial communication and to facilitate genetic testing.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/psicología , Comunicación , Predisposición Genética a la Enfermedad , Pruebas Genéticas/estadística & datos numéricos , Mutación , Adulto , Anciano , Ansiedad/psicología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Femenino , Asesoramiento Genético , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.
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Demencia Frontotemporal , Proteína C9orf72/genética , Demencia Frontotemporal/genética , Genotipo , Humanos , Masculino , Mutación , Estudios Retrospectivos , Secuenciación del Exoma , Proteínas tau/genéticaAsunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , Histonas/genética , Síndrome de Li-Fraumeni/genética , Mutación/genética , Proteína Proto-Oncogénica N-Myc/genética , Adolescente , Neoplasias Encefálicas/patología , Amplificación de Genes , Mutación de Línea Germinal , Glioma/patología , Humanos , MasculinoRESUMEN
Infantile nystagmus syndrome (INS) denominates early-onset, involuntary oscillatory eye movements with different etiologies. Nystagmus is also one of the symptoms in oculocutaneus albinism (OCA), a heterogeneous disease mainly caused by defects in melanin synthesis or melanosome biogenesis. Dopachrome tautomerase (DCT, also called TYRP2) together with tyrosinase (TYR) and tyrosin-related protein 1 (TYRP1) is one of the key enzymes in melanin synthesis. Although DCT´s role in pigmentation has been proven in different species, until now only mutations in TYR and TYRP1 have been found in patients with OCA. Detailed ophthalmological and orthoptic investigations identified a consanguineous family with two individuals with isolated infantile nystagmus and one family member with subtle signs of albinism. By whole-exome sequencing and segregation analysis, we identified the missense mutation c.176G > T (p.Gly59Val) in DCT in a homozygous state in all three affected family members. We show that this mutation results in incomplete protein maturation and targeting in vitro compatible with a partial or total loss of function. Subsequent screening of a cohort of patients with OCA (n = 85) and INS (n = 25) revealed two heterozygous truncating mutations, namely c.876C > A (p.Tyr292*) and c.1407G > A (p.Trp469*), in an independent patient with OCA. Taken together, our data suggest that mutations in DCT can cause a phenotypic spectrum ranging from isolated infantile nystagmus to oculocutaneous albinism.
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Albinismo Oculocutáneo/genética , Oxidorreductasas Intramoleculares/genética , Melaninas/biosíntesis , Mutación Missense , Nistagmo Congénito/genética , Adolescente , Albinismo Oculocutáneo/diagnóstico , Albinismo Oculocutáneo/enzimología , Albinismo Oculocutáneo/patología , Secuencia de Bases , Calnexina/genética , Calnexina/metabolismo , Niño , Estudios de Cohortes , Consanguinidad , Femenino , Regulación de la Expresión Génica , Células HEK293 , Homocigoto , Humanos , Oxidorreductasas Intramoleculares/deficiencia , Masculino , Melaninas/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Monofenol Monooxigenasa/genética , Monofenol Monooxigenasa/metabolismo , Nistagmo Congénito/diagnóstico , Nistagmo Congénito/enzimología , Nistagmo Congénito/patología , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Linaje , Secuenciación del Exoma , Adulto JovenRESUMEN
Fibrillin-2, encoded by FBN2, plays an important role in the early process of elastic fiber assembly. To date, heterozygous pathogenic variants in FBN2 have been shown to cause congenital contractural arachnodactyly (CCA; Beals-Hecht syndrome). Classical CCA is characterized by long and slender fingers and toes, ear deformities, joint contractures at birth, clubfeet, muscular hypoplasia and often tall stature. In individuals with a severe CCA form, different cardiovascular or gastrointestinal anomalies have been described. Here, we report on a 15-year-old girl with a severe form of CCA and novel biallelic variants in FBN2. The girl inherited the missense variant c.3563G > T/p.(Gly1188Val) from her unaffected father and the nonsense variant c.6831C > A/p.(Cys2277*) from her healthy mother. We could detect only a small amount of FBN2 transcripts harboring the nonsense variant in leukocyte-derived mRNA from the patient and mother suggesting nonsense-mediated mRNA decay. As the father did not show any clinical signs of CCA we hypothesize the missense variant c.3563G > T to be a hypomorphic allele. Taken together, our data suggests that severe CCA can be inherited in an autosomal-recessive manner by compound heterozygosity of a hypomorphic and a null allele of the FBN2 gene.
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Aracnodactilia/genética , Contractura/genética , Fibrilina-2/genética , Adolescente , Alelos , Aracnodactilia/patología , Contractura/patología , Femenino , Humanos , MutaciónRESUMEN
Objective: Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. Methods: Overall, 275 patients from 8 European neurological centers were examined. We included ALS with <6 and >6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients (N = 65). Results: Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 (p = 0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients' progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. Conclusions: CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.
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Esclerosis Amiotrófica Lateral , Hexosaminidasas , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/genética , Biomarcadores , Progresión de la Enfermedad , Hexosaminidasas/genética , Humanos , Proteínas de Neurofilamentos , PronósticoRESUMEN
INTRODUCTION: The behavioral variant of frontotemporal dementia (bvFTD) is a rare neurodegenerative disease. Reliable predictors of disease progression have not been sufficiently identified. We investigated multivariate magnetic resonance imaging (MRI) biomarker profiles for their predictive value of individual decline. METHODS: One hundred five bvFTD patients were recruited from the German frontotemporal lobar degeneration (FTLD) consortium study. After defining two groups ("fast progressors" vs. "slow progressors"), we investigated the predictive value of MR brain volumes for disease progression rates performing exhaustive screenings with multivariate classification models. RESULTS: We identified areas that predict disease progression rate within 1 year. Prediction measures revealed an overall accuracy of 80% across our 50 top classification models. Especially the pallidum, middle temporal gyrus, inferior frontal gyrus, cingulate gyrus, middle orbitofrontal gyrus, and insula occurred in these models. DISCUSSION: Based on the revealed marker combinations an individual prognosis seems to be feasible. This might be used in clinical studies on an individualized progression model.
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Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5'-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.
Asunto(s)
Fosfatasa Alcalina , Hipofosfatasia , Adulto , Anciano , Fosfatasa Alcalina/genética , Huesos/patología , Femenino , Estudios de Asociación Genética , Humanos , Hipofosfatasia/genética , Hipofosfatasia/patología , Masculino , Persona de Mediana Edad , Músculos/fisiología , MutaciónRESUMEN
BACKGROUND: Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2. METHODS: A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided. RESULTS: Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26). CONCLUSIONS: PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.