Roth C.,Klinikum Kassel |
Freilinger T.,Ludwig Maximilians University of Munich |
Freilinger T.,University of Tübingen |
Kirovski G.,Klinikum Kassel |
And 4 more authors.
Cephalalgia | Year: 2014
Introduction: Familial hemiplegic migraine (FHM) is a rare subtype of migraine with transient hemiplegic aura. Patients and methods: We describe three unrelated families with familial hemiplegic migraine type II (FHM2). Retrospectively, information on 47 family members could be obtained, 15 by personal examination and 32 by indirect anamnesis from relatives. Genetic analyses were performed in 13 patients. Results: One family had a novel missense mutation in the ATP1A2 gene (c.659CT, p.Ser220Leu) that segregated with the phenotype in three generations. Two further unrelated families with different ethnic backgrounds (one from Germany and one from Russia) had a missense mutation that has not been described as yet in FHM, but occurred in only a single patient with sporadic hemiplegic migraine (c.2723GA, p.Arg908Gln). Clinically the patients had severe attacks lasting up to several weeks as well as epileptic seizures. Three patients with a proven mutation in the ATP1A2 gene clinically presented without hemiparesis. Furthermore, there was a possible relation of FHM2 to mental retardation in another two patients. Conclusion: Clinical symptoms may last for several weeks in some patients. Patients with FHM2 may also present without hemiplegia. Therefore, the full family history has to be taken into account to establish the diagnosis of FHM. © 2013 International Headache Society.
PubMed | Friedrich - Schiller University of Jena, General Hospital of Celle and Medizinisch Genetisches Zentrum
Type: | Journal: Molecular cytogenetics | Year: 2016
Non-progressive cerebellar ataxia with mental retardation (CANPMR, OMIM 614756) and chromosome 1p32-p31 deletion syndrome (OMIM 613735) are two very rare inherited disorders, which are caused by mono-allelic deficiency (haplo-insufficiency) of calmodulin-binding transcription activator 1 (CAMTA1) and, respectively, nuclear factor 1 A (NFIA) genes. The yet reported patients affected by mono-allelic CAMTA1 dysfunction presented with neonatal hypotonia, delayed and ataxic gait, cerebellar atrophy, psychological delay and speech impairment, while individuals carrying a disrupted NFIA allele suffered from agenesis/hypoplasia of the corpus callosum, ventriculomegaly, developmental delay and urinary tract abnormalities. Both disorders were not seen in one patient together before.In this study two related individuals affected by a complex clinical syndrome, characterized by cognitive, neurological and nephrological features were studied for the underlying genetic disorder(s) by molecular cytogenetics. The two individuals present dysmorphic facies, macrocephaly, generalized ataxia, mild tremor, strabismus, mild mental retardation and kidney hypoplasia. Moreover, neuro-radiological studies showed hypoplasia of corpus callosum. Genetic investigations revealed a paracentric inversion in the short arm of one chromosome 1 with breakpoints within CAMTA1 and NFIA coding sequences.To the best of our knowledge, this is the first report of two patients harboring the simultaneous mono-allelic disruptions and consequent haplo-insufficiencies of two genes due to an inversion event. Disruption of CAMTA1 and NFIA genes led to neuro-psychological and nephrological dysfunctions, which comprised clinical features of CANPMR syndrome as well as chromosome 1p32-p31 deletion syndrome.
Finsterer J.,Krankenanstalt Rudolfstiftung |
Stollberger C.,Krankenanstalt Rudolfstiftung |
Holinski-Feder E.,Medizinisch Genetisches Zentrum
Cardiology | Year: 2010
Objectives: So far, a beneficial effect of combined angiotensin-converting enzyme inhibitors (ACEI) and β-blocker therapy for systolic dysfunction in Duchenne muscular dystrophy (DMD) has been reported only in patients in whom DMD was due to deletions in the dystrophin gene. Case Report: In a 24-year-old male with DMD due to the point mutation c.4213C>T (p.Gln1405X) in exon 30 of the dystrophin gene, cardiologic examination at the age of 23 years revealed asymptomatic severely reduced systolic dysfunction with a fractional shortening of 14% in the absence of dilated cardiomyopathy. A combined therapy with enalapril (2.5 mg/day) and bisoprolol (1.25 mg/day) was initiated. After a slow increase in the dosage to 10 mg enalapril/day and 2.5 mg bisoprolol/day, systolic dysfunction resolved to a fractional shortening of 26% already after 7 months. Conclusions: This case shows that asymptomatic reduced systolic function also in patients with DMD due to a point mutation responds favourably to a combination therapy with ACEI and β-blockers. Copyright © 2011 S. Karger AG, Basel.
Freilinger T.,Ludwig Maximilians University of Munich |
Ackl N.,Ludwig Maximilians University of Munich |
Ebert A.,Ludwig Maximilians University of Munich |
Schmidt C.,Ludwig Maximilians University of Munich |
And 3 more authors.
Journal of the Neurological Sciences | Year: 2011
Hemiplegic migraine (HM) is a rare and severe subtype of migraine with aura, characterized by some degree of hemiparesis and other aura symptoms. Mutations in three genes (CACNA1A, ATP1A2 and SCN1A) have been detected in familial and, more rarely, in sporadic cases. The disease can be complicated by permanent neurological deficits, the most frequent one being a cerebellar syndrome; in addition, mental retardation has been recognized as part of the phenotypic spectrum. Here, we report a Caucausian male with a novel CACNA1A mutation and an unusual clinical phenotype: the patient, who had had a history of only two HM attacks, sought medical advice at age 49 primarily because of increasing cognitive decline accompanied by cerebellar dysfunction. While common neurodegenerative causes were excluded, neuropsychological evaluation revealed a distinct profile of deficits of a subcortico-prefrontal type as previously reported in patients with cerebellar dysfunction. This suggests a possible causal link between cerebellar and cognitive disturbances in this patient; in addition to these pathophysiological aspects, we review of the role of the cerebellum in cognition. © 2010 Elsevier B.V.
Velayos-Baeza A.,Oxford Genetics |
Holinski-Feder E.,Medizinisch Genetisches Zentrum |
Neitzel B.,Medizinisch Genetisches Zentrum |
Bader B.,Ludwig Maximilians University of Munich |
And 5 more authors.
Archives of Neurology | Year: 2011
Objective: Todetermine the molecular nature of the neurological disease in the seminal family reported by Critchley et al inthe 1960s, characterized by a hyperkinetic movement disorder and the appearance of acanthocytosis on peripheral blood smear. The eponym Levine-Critchley syndrome, subsequently termed neuroacanthocytosis, has been applied to symptomatically similar, but genetically distinct, disorders, resulting in clinical and diagnostic confusion. Design: DNA analysis. Setting: Molecular biology research laboratories. Participants: First- and second-degree relatives of the original Critchley et al proband from Kentucky. Main Outcome Measures: Mutations in the VPS13A gene. Results: A mutation was identified in the VPS13A gene, responsible for autosomal recessive chorea-acanthocytosis. Haplotype reconstruction suggested that this mutation was homozygous in the proband. Conclusion: These findings strongly support the diagnosis of chorea-acanthocytosis as the disorder described in the original report. ©2011 American Medical Association. All rights reserved.
Schreiber O.,Ludwig Maximilians University of Munich |
Schneiderat P.,Ludwig Maximilians University of Munich |
Kress W.,University of Würzburg |
Rautenstrauss B.,Medizinisch Genetisches Zentrum |
And 3 more authors.
BMC Medical Genetics | Year: 2013
Background: We report on a patient with genetically confirmed overlapping diagnoses of CMT1A and FSHD. This case adds to the increasing number of unique patients presenting with atypical phenotypes, particularly in FSHD. Even if a mutation in one disease gene has been found, further genetic testing might be warranted in cases with unusual clinical presentation. Case presentation: The reported 53 years old male patient suffered from walking difficulties and foot deformities first noticed at age 20. Later on, he developed scapuloperoneal and truncal muscle weakness, along with atrophy of the intrinsic hand and foot muscles, pes cavus, claw toes and a distal symmetric hypoesthesia. Motor nerve conduction velocities were reduced to 20 m/s in the upper extremities, and not educible in the lower extremities, sensory nerve conduction velocities were not attainable. Electromyography showed both, myopathic and neurogenic changes. A muscle biopsy taken from the tibialis anterior muscle showed a mild myopathy with some neurogenic findings and hypertrophic type 1 fibers. Whole-body muscle MRI revealed severe changes in the lower leg muscles, tibialis anterior and gastrocnemius muscles were highly replaced by fatty tissue. Additionally, fatty degeneration of shoulder girdle and straight back muscles, and atrophy of dorsal upper leg muscles were seen. Taken together, the presenting features suggested both, a neuropathy and a myopathy. Patient's family history suggested an autosomal dominant inheritance. Molecular testing revealed both, a hereditary motor and sensory neuropathy type 1A (HMSN1A, also called Charcot-Marie-Tooth neuropathy 1A, CMT1A) due to a PMP22 gene duplication and facioscapulohumeral muscular dystrophy (FSHD) due to a partial deletion of the D4Z4 locus (19 kb). Results: Molecular testing in hereditary neuromuscular disorders has led to the identification of an increasing number of atypical phenotypes. Nevertheless, finding the right diagnosis is crucial for the patient in order to obtain adequate medical care and appropriate genetic counseling, especially in the background of arising curative therapies. © 2013 Schreiber et al.; licensee BioMed Central Ltd.
Neuhann T.,Medizinisch Genetisches Zentrum |
Rautenstrauss B.,Medizinisch Genetisches Zentrum |
Rautenstrauss B.,Ludwig Maximilians University of Munich
Expert Review of Neurotherapeutics | Year: 2013
Hereditary optic neuropathies comprise a group of clinically and genetically heterogeneous disorders. Two subgroups can be formed: isolated hereditary optic atrophies and optic neuropathy as part of complex disorders. In group 1 of hereditary optic neuropathies, optic nerve dysfunction is typically the only manifestation of the disease. This group comprises autosomal dominant, autosomal recessive and X-linked recessive optic atrophy and the maternally inherited Leber's hereditary optic neuropathy. Among the autosomal-dominant forms of optic atrophy, Kjer's disease is most frequently observed. In the second group of complex disorders, various neurologic and other systemic abnormalities are regularly observed. Most frequent in this group are mtDNA mutations, inherited peripheral neuropathies, Charcot-Marie-Tooth disorders (CMT2A2, CMTX5), hereditary sensory neuropathy type 3 (HSAN3), Friedreich's ataxia, leukodystrophies, sphingolipidoses, ceroid-lipofuscinoses and neurodegeneration with brain iron accumulation. We review current knowledge about the underlying genetic predispositions, the most urgent open questions and how this may affect our management of this heterogeneous group of disorders in the future. © 2013 2013 Expert Reviews Ltd.
Kornblum C.,University of Bonn |
Lutterbey G.G.,University of Bonn |
Czermin B.,Medizinisch Genetisches Zentrum |
Reimann J.,University of Bonn |
And 4 more authors.
Acta Neurologica Scandinavica | Year: 2010
Background - Muscle magnetic resonance imaging (MRI) is the most sensitive method in the detection of dystrophic and non-dystrophic abnormalities within striated muscles. We hypothesized that in severe myotonia congenita type Becker muscle stiffness, prolonged transient weakness and muscle hypertrophy might finally result in morphologic skeletal muscle alterations reflected by MRI signal changes. Aim of the study - To assess dystrophic and/or non-dystrophic alterations such as fatty or connective tissue replacement and muscle edema in patients with severe recessive myotonia congenita. Methods - We studied three seriously affected patients with myotonia congenita type Becker using multisequence whole-body high-field MRI. All patients had molecular genetic testing of the muscle chloride channel gene (CLCN1). Results - Molecular genetic analyses demonstrated recessive CLCN1 mutations in all patients. Two related patients were compound heterozygous for two novel CLCN1 mutations, Q160H and L657P. None of the patients showed skeletal muscle signal changes indicative of fatty muscle degeneration or edema. Two patients showed muscle bulk hypertrophy of thighs and calves in line with the clinical appearance. Conclusions - We conclude that (i) chloride channel dysfunction alone does not result in skeletal muscle morphologic changes even in advanced stages of myotonia congenita, and (ii) MRI skeletal muscle alterations in myotonic dystrophy must be clear consequences of the dystrophic disease process. © 2009 Blackwell Munksgaard.
PubMed | Istanbul University, Medizinisch Genetisches Zentrum, University of Gottingen and Baylor College of Medicine
Type: Journal Article | Journal: Genetics in medicine : official journal of the American College of Medical Genetics | Year: 2016
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders of the peripheral nervous system. Copy-number variants (CNVs) contribute significantly to CMT, as duplication of PMP22 underlies the majority of CMT1 cases. We hypothesized that CNVs and/or single-nucleotide variants (SNVs) might exist in patients with CMT with an unknown molecular genetic etiology.Two hundred patients with CMT, negative for both SNV mutations in several CMT genes and for CNVs involving PMP22, were screened for CNVs by high-resolution oligonucleotide array comparative genomic hybridization. Whole-exome sequencing was conducted on individuals with rare, potentially pathogenic CNVs.Putatively causative CNVs were identified in five subjects (~2.5%); four of the five map to known neuropathy genes. Breakpoint sequencing revealed Alu-Alu-mediated junctions as a predominant contributor. Exome sequencing identified MFN2 SNVs in two of the individuals.Neuropathy-associated CNV outside of the PMP22 locus is rare in CMT. Nevertheless, there is potential clinical utility in testing for CNVs and exome sequencing in CMT cases negative for the CMT1A duplication. These findings suggest that complex phenotypes including neuropathy can potentially be caused by a combination of SNVs and CNVs affecting more than one disease-associated locus and contributing to a mutational burden.Genet Med 18 5, 443-451.
PubMed | Charité - Medical University of Berlin and Medizinisch Genetisches Zentrum
Type: Journal Article | Journal: Journal of human genetics | Year: 2016
Gerodermia osteodysplastica is a recessive segmental progeroid disorder mainly characterized by wrinkled skin, generalized connective tissue weakness, infantile onset osteoporosis and normal intelligence. Coding mutations in GORAB, localized on chromosome 1q24.2, are the cause of this disease. 1q24 deletions underlie a spectrum of disorders with intellectual disability and ear abnormalities as phenotypic hallmarks. Here we report on an individual from Azerbaijan originating from a non-consanguineous couple showing short stature, cutis laxa, frequent fractures, facial dysmorphism, cup-shaped ears and intellectual disability. Sanger sequencing of GORAB revealed the seemingly homozygous missense mutation p.Ser175Phe. This mutation was detected in a heterozygous state in the clinically unaffected mother, but was absent in the healthy father. We performed copy-number investigations by high-resolution array-CGH and PCR approaches and found an ~6Mb de novo deletion spanning 1q23.3-q24.2 in the affected boy. This novel combination of genetic defects very well explains the phenotype that goes beyond the usual presentation of gerodermia osteodysplastica. Our data provide new insight into the phenotypic spectrum of 1q23-q25 deletions and shows that the combination with another pathogenic allele can lead to more severe clinical manifestations.