Frontotemporal dementia: the post-tau era.
Explore the source record for details and available documents.
Adenosine Triphosphatases↗
Biomedical subjects
Hans H Goebel
Publications and source records attributed to Hans H Goebel.
Diagnosis of the neuronal ceroid lipofuscinoses: an update.
For the majority of families affected by one of the neuronal ceroid lipofuscinoses (NCLs), a biochemical and/or genetic diagnosis can be achieved. In an individual case this information not only increases understanding of the condition but also may influence treatment choices and options. The presenting clinical features prompt initial investigation and also guide clinical care. The clinical labels "infantile NCL", "late infantile NCL" and "juvenile NCL", therefore remain useful in practice. In unusual or atypical cases ultra-structural analysis of white blood cells or other tissue samples enables planning and prioritisation of biochemical and genetic tests. This review describes current methods available to achieve clinical, pathological, biochemical and genetic diagnosis in children presenting with symptoms suggestive of one of the NCLs.
Age Factors↗
Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred.
Myosin storage myopathy (OMIM 608358), a congenital myopathy characterised by subsarcolemmal, hyaline-like accumulations of myosin in Type I muscle fibres, was first described by Cancilla and Colleagues in 1971 [Neurology 1971;21:579-585] in two siblings as 'familial myopathy with probable lysis of myofibrils in type I muscle fibres'. Two mutations in the slow skeletal myosin heavy chain gene (MYH7) have recently been associated with the disease in other families. We have identified a novel heterozygous Leu1793Pro mutation in MYH7 in DNA from paraffin sections of one of the original siblings. This historical molecular analysis confirms the original cases had myosin storage myopathy.
Cardiac Myosins↗
Images in cardiovascular medicine. Giant right atrium in the setting of desmin-related restrictive cardiomyopathy.
Explore the source record for details and available documents.
Cardiomyopathy, Restrictive↗
Camptocormia associated with focal myositis in multiple-system atrophy.
Camptocormia (CC) or pronounced forward flexion of the trunk is a common symptom of Parkinson's disease. We describe 2 patients with probable, respectively possible multiple-system atrophy and CC. Magnetic resonance imaging of the erector trunci showed focal patchy hyperintensities with gadolinium enhancement and muscle biopsy was indicative of variably pronounced focal myositis. CC was progressive and the major handicap for both patients after 1 and 1.5 years of follow-up, respectively. The therapeutic response was poor. Similarities with the dropped-head syndrome suggest that the muscle pathology may be either the primary cause of CC, a focal reaction to the CC posture, or a coincident syndrome of old age.
Aged↗
Protein aggregate myopathies.
Protein aggregate myopathies (PAMs) based on the morphologic phenomenon of aggregation of proteins within muscle fibers may occur in children (selenoproteinopathies, actinopathies, and myosinopathies) or adults (certain myofibrillar myopathies and myosinopathies). They may be mutation related, which includes virtually all childhood forms but certain other forms as well, or sporadic, which are largely seen in adults. Their classification as myofibrillar or desmin-related myopathies, actinopathies, or myosinopathies is based on the identification of respective mutant proteins, most of them components of the sarcomeres. Recognition of PAM requires muscle biopsy and an extensive immunohistochemical and electron microscopic workup of the biopsied muscle tissue after which molecular analysis of morphologically ascertained proteins should ensue to permit recognition of individual entities and genetic counseling of patients and families. Because pathogenetic principles in PAMs are still incompletely known, causative therapy, at this time, is not available.
Animals↗
Patient with actin aggregate myopathy and not formerly identified ACTA1 mutation is heterozygous for the Gly15Arg mutation of ACTA1, which has previously been associated with actinopathy.
Explore the source record for details and available documents.
Actins↗
Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses.
The neuronal ceroid lipofuscinoses (NCLs) are a group of severe neurodegenerative diseases with onset usually in childhood and characterised by the intracellular accumulation of autofluorescent storage material. Within the last decade, mutations that cause NCL have been found in six human genes (CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8). Mutations in two additional genes cause disease in animal models that share features with NCL-CTSD in sheep and mice and PPT2 in mice. Approximately 160 NCL disease-causing mutations have now been described (listed and fully cited in the NCL Mutation Database, http://www.ucl.ac.uk/ncl/ ). Most mutations result in a classic morphology and disease phenotype, but some mutations are associated with disease that is of later onset, less severe or protracted in its course, or with atypical morphology. Seven common mutations exist, some having a worldwide distribution and others associated with families originating from specific geographical regions. This review attempts to correlate the gene, disease-causing mutation, morphology and clinical phenotype for each type of NCL.
Aminopeptidases↗
Delayed or late-onset type II glycogenosis with globular inclusions.
Three unrelated patients, one girl, one boy, and an adult female, aged 14, 11 and 41 years, respectively, at the time of biopsy, revealed lysosomal glycogen storage, autophagic vacuoles and peculiar globular inclusions of distinct ultrastructure, which were reducing but did not appear like true "reducing bodies" as described in the congenital myopathy "reducing body myopathy". All three patients had residual activity of acid alpha-glucosidase in their muscle biopsy samples. Leukocytes in the girl showed normal acid alpha-glucosidase activity, but in the boy activity was reduced. Molecular genetic analysis of the GAA gene revealed disease-causing mutations in each patient: H568L/R672W, IVS1-13T>G/G615F, and IVS1-13T>G/IVS1-13T>G. Although only one patient with such globular inclusions has been reported up to now, the three patients described here indicate that in the late-onset type of GSD II such inclusions may not be rare.
Adult↗
The enlarging spectrum of desminopathies: new morphological findings, eastward geographic spread, novel exon 3 desmin mutation.
A 52-year-old man, who had developed distal muscle weakness in legs and arms, was found to have distal muscle atrophy as well as cardiac arrhythmia. His 10-year younger brother developed restrictive cardiomyopathy at the age of 20 years, which required cardiac transplantation at the age of 41 years. Skeletal muscle biopsy specimens of the older brother revealed granulofilamentous material and plaques containing numerous proteins, foremost desmin, as did cardiac biopsy tissue. The explanted heart of the younger brother showed similar protein-rich plaques and granulofilamentous material within cardiac myocytes. A novel heterozygous Glu245Asp (E245D) missense mutation in exon 3 of the desmin gene (DES) at 2q35 was found in the older brother. While clinical data and muscle biopsy pathology of the older brother conform to the nosological spectrum of desminopathies, the early-onset cardiomyopathy, a similar cardiac pathology as in skeletal muscle tissues and a novel missense mutation in the DES gene, enlarge the nosological spectrum of desminopathies.
Adult↗
Congenital myopathies in the new millennium.
Few medical disciplines have benefited so enormously from the molecular revolution as myology. Whereas the congenital myopathies have flourished from enzyme histochemistry and electron microscopy, defining individual congenital myopathies by structural abnormalities, genetic research has only recently focused on congenital myopathies. However, a number of congenital myopathies have been molecularly elucidated: central and multiminicore diseases, nemaline myopathy, myotubular myopathy, and congenital myopathy marked by aggregation of proteins, giving rise to the concept of protein aggregate myopathies, to which now desminopathies, alpha-B crystallinopathies, selenoproteinopathy, myotilinopathy, actinopathies, and myosinopathies belong. Based on recent identification of mutations in respective genes, the principle "from morphology, that is, immunohistochemistry, to molecular analysis" through recognition of certain accrued proteins within muscle fibers and subsequent analysis of their respective genes has resulted in a wealth of genetic data and in reconsidering classification and nosologic interpretation of certain congenital myopathies. This heuristic principle needs to be further applied to other genetically still obscure congenital myopathies.
Humans↗
Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene.
Desmin-related myopathies (DRMs) are a heterogeneous group of muscle disorders, morphologically defined by intrasarcoplasmic aggregates of desmin. Mutations in the desmin and the alpha-B crystallin genes account for approximately one third of the DRM cases. The genetic basis of the other forms remain unknown, including the early-onset, recessive form with Mallory body-like inclusions (MB-DRMs), first described in five related German patients. Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of classical multiminicore disease. The finding of Mallory body-like inclusions in two cases of genetically documented SEPN-RM led us to suspect a relationship between MB-DRM and SEPN1. In the original MB-DRM German family, we demonstrated a linkage of the disease to the SEPN1 locus (1p36), and subsequently a homozygous SEPN1 deletion (del 92 nucleotide -19/+73) in the affected patients. A comparative reevaluation showed that MB-DRM and SEPN-RM share identical clinical features. Therefore, we propose that MB-DRM should be categorized as SEPN-RM. These findings substantiate the molecular heterogeneity of DRM, expand the morphological spectrum of SEPN-RM, and implicate a necessary reassessment of the nosological boundaries in early-onset myopathies.
Adult↗
A series of West European patients with severe cardiac and skeletal myopathy associated with a de novo R406W mutation in desmin.
Desminopathy is a familial or sporadic cardiac and skeletal muscular dystrophy associated with mutations in desmin. We have previously characterized a de novo desmin R406W mutation in a patient of European origin with early onset muscle weakness in the lower extremities and atrioventricular conduction block requiring a permanent pacemaker. The disease relentlessly progressed resulting in severe incapacity within 5 years after onset. We have now identified three other patients with early onset rapidly progressive cardiac and skeletal myopathy caused by this same desmin R406W mutation. The mutation was present in each studied patient, but not in their parents or other unaffected family members, indicating that the mutation in all four cases was generated de novo. The patients' mutation-carrying chromosomes showed no similarity, suggesting that the R406W mutation has occurred independently. These observations strongly confirm that the de novo R406W desmin mutation is the genetic basis for early-onset cardiac and skeletal myopathy in patients with sporadic disease and indicate that desmin position 406 is a hot spot for spontaneous mutations. The high pathogenic potential of this mutation can be explained by its location in the highly conserved YRKLLEGEE motif at the C-terminal end of the 2B helix that has a critical role in the process of desmin filament assembly.
Adolescent↗
Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin.
We present comparisons of the clinical pictures in a series of 60 patients with nemaline myopathy in whom mutations had been identified in the genes for nebulin or skeletal muscle alpha-actin. In the patients with nebulin mutations, the typical form of nemaline myopathy predominated, while severe, mild or intermediate forms were less frequent. Autosomal recessive inheritance had been verified or appeared likely in all nebulin cases. In the patients with actin mutations, the severe form of nemaline myopathy was the most common, but some had the mild or typical form, and a few showed other associated features such as intranuclear rods or actin accumulation. Most cases were sporadic, but in addition there were instances of both autosomal dominant and autosomal recessive inheritance, while two families showed mosaicism for dominant mutations. Although no specific phenotype was found to be associated with mutations in either gene, clinical and histological features together with pedigree data may be used in guiding mutation detection. Finding the causative mutation(s) determines the mode of inheritance and permits prenatal diagnosis if requested, but will not as such permit prognostication.
Actins↗
The Eighth Meryon Society Lecture read at Worcester College, Oxford on 2 July, 2004.
Explore the source record for details and available documents.
Female↗
Prophylactic implantable cardioverter defibrillator placement in a sporadic desmin related myopathy and cardiomyopathy.
Desminopathy is a neuromuscular disorder associated with the accumulation of the protein desmin. This article reports a case of a man with a mutation in the desmin gene suffering from cardiomyopathy and skeletal myopathy. This patient underwent implantable cardioverter defibrillator (ICD) implantation for prognostic considerations and subsequently developed a sustained ventricular tachycardia (SVT). While nonsustained VTs (NSVT) have previously been reported, this is the first time that a SVT could be seen in a patient with this disease.
Adolescent↗
Current state of clinical and morphological features in human NCL.
The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathological (C-P) findings described 4 forms, classified as infantile (INCL) (2), late-infantile (LINCL) (5), juvenile (JNCL) (6), and adult (ANCL) (12). Most patients with NCL have progressive ocular and cerebral dysfunction, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 520 patients with NCL, we found that about 104 (20%) did not fit this classification of NCL. With further research, 4 additional forms have been recognized: Finnish (13), Gypsy/Indian (14), Turkish (15)--variants of LINCL, and Northern epilepsy (16), also known as progressive epilepsy with mental retardation. These eight NCL forms resulted from 151 different mutations in genes CLN1 to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1. The diagnosis of NCL is based on clinicopathological (C-P) findings, enzymatic assay, and molecular genetic testing. Ultrastructural studies must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles, or granular osmiophilic deposits) before doing biochemical testing. Pheno/genotypic correlation studies are discussed.
Adult↗
July 2003: 62-year-old female with progressive muscular weakness.
The July 2003 Case of the Month (COM). A 62-year-old female patient experienced progressive muscular weakness over the last ten years, involving shoulder and pelvic girdle muscles, paraspinal and facial muscles. A biopsy was taken from the left deltoid muscle where hepatitis vaccination had taken place 4 weeks previously. The specimen revealed macrophagic myofasciitis due to the injection of aluminium-bound vaccines. The finding can be reproduced experimentally by injecting vaccines in rats. The pathomechanism is supposed to involve immune stimulation due to long term persistence of the adjuvant. Macrophagic myofasciitis has been suggested to occasionally cause myopathy but is supposed to be unrelated to the underlying myopathy in our patient.
Aluminum Hydroxide↗