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H H Goebel

Publications and source records attributed to H H Goebel.

At least 19 recordsLinked to original sources
PubMed2002

A G468-T AMPD1 mutant allele contributes to the high incidence of myoadenylate deaminase deficiency in the Caucasian population.

Myoadenylate deaminase deficiency is the most common metabolic disorder of skeletal muscle in the Caucasian population, affecting approximately 2% of all individuals. Although most deficient subjects are asymptomatic, some suffer from exercise-induced myalgia suggesting a causal relationship between a lack of enzyme activity and muscle function. In addition, carriers of this derangement in purine nucleotide catabolism may have an adaptive advantage related to clinical outcome in heart disease. The molecular basis of myoadenylate deaminase deficiency in Caucasians has been attributed to a single mutant allele characterized by double C to T transitions at nucleotides +34 and +143 in mRNA encoded by the AMPD1 gene. Polymerase chain reaction-based strategies have been developed to specifically identify this common mutant allele and are considered highly sensitive. Consequently, some laboratories preferentially use this technique over other available diagnostic tests for myoadenylate deaminase deficiency. We previously identified a G468-T mutation in one symptomatic patient who was only heterozygous for the common AMPD1 mutant allele. In this report, nine additional individuals with this compound heterozygous genotype are revealed in a survey of 48 patients with documented deficiency of skeletal muscle adenosine monophosphate deaminase and exercise-induced myalgia. Western blot analysis of leftover biopsy material from one of these individuals does not detect any immunoreactive myoadenylate deaminase polypeptide. Baculoviral expression of the G468-T mutant allele produces a Q156H substitution enzyme exhibiting labile catalytic activity. These combined results demonstrate that the G468-T transversion is dysfunctional and further indicate that AMPD1 alleles harboring this mutation contribute to the high incidence of partial and complete myoadenylate deaminase deficiency in the Caucasian population. Consequently, genetic tests for abnormal AMPD1 expression designed to diagnose patients with metabolic myopathy, and to evaluate genetic markers for clinical outcome in heart disease should not be based solely on the detection of a single mutant allele.

AMP Deaminase↗
PubMed2002

Mucolipidosis IV: novel mutation and diverse ultrastructural spectrum in the skin.

Mucolipidosis IV, a severe neurologic and ophthalmologic progressive disorder has a clinical range of onset between early childhood and adolescence entailing clinically severe, moderate, and mild forms, all of them majorly affecting Ashkenazi Jewish patients in an autosomal-recessive fashion owing to mutations in the MCOLN1 gene which encodes a transmembrane protein called mucolipin 1. We report on one of two affected siblings, the older brother having died of ML IV at the age of 33 years, the younger recently at the age of 37 years. Biopsied skin disclosed several types of lysosomal residual bodies, membrane-bound vacuoles, avacuolar lamellar bodies resembling membraneous cytoplasmic bodies, and a diverse spectrum of lipopigments which include curvilinear and fingerprint profiles. Contrary to earlier reports, disease-specific lysosomal residual bodies could not be identified in circulating lymphocytes of our patient. Mutation analysis revealed a homozygous novel mutation of a 34 bp deletion and 3 bp insertion in exon 2 of the MCOLN1 gene, perhaps the reason for this unusual clinical and morphological phenotype.

Adult↗
PubMed2001

A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation.

OBJECTIVE: To determine the cause of sporadic rippling muscle disease (RMD) in a 24-year-old patient. BACKGROUND: RMD is a rare myopathy characterized by percussion-induced rapid muscle contractions (PIRC), muscle mounding, and rippling waves. We have recently found that autosomal dominant RMD is caused by mutations in the caveolin-3 gene (CAV3) on chromosome 3p25. Possibly, increased activity of neuronal nitric oxide synthase (nNOS) contributes to the clinical characteristics of increased mechanical muscle hyperexcitability. METHODS: Clinical examination, mutational analysis, and immunohistochemistry of muscle tissue were performed in a patient with sporadic RMD. RESULTS: The authors observed a de novo CAV3 missense mutation Arg26Gln. Immunohistochemistry showed reduced caveolin-3 surface expression in a muscle biopsy. In addition, the authors found normal sarcolemmal nNOS expression and a reduced expression of alpha-dystroglycan in muscle fibers. CONCLUSIONS: These data confirm that RMD is caused by CAV3 mutations. Moreover, there is evidence that CAV3 mutations may also be found in patients without a positive family history of RMD.

Adult↗
PubMed2001

[Keratopathy as a sign of multifocal congenital sensory polyneuropathy. A case report].

PATIENT: A 63-year-old female with bilateral recurrent corneal ulcerations for 10 years, suffered from vascularisation of the cornea and absence of corneal sensitivity. Other symptoms were multifocal hypoaesthesia with hypalgesia of hands and legs, generalised lack of deep tendon reflexes, absence of somato-sensory evoked potentials (SSEP) and of sensory nerve action potentials (SNAP) in these regions. A sural biopsy demonstrated extreme lack of myelinated fibres. Acquired causes for polyneuropathy were excluded. THERAPY: Subsequent to local ocular treatment we carried out a perforating corneal transplantation of the left eye because of corneal scars. This had to be repeated 2 years later because of vascularisation of the transplant. The visual function of the left eye could be stabilised at values between 0.2 and 1/50. CONCLUSION: Anamnesis and clinical symptoms of the patient are compatible with the diagnosis of hereditary sensory neuropathy type II (HSN II) affecting the trigeminal nerves. In patients with neuropathy and impaired corneal sensitivity, a favourable prognosis may be achieved by a corneal transplant.

Cornea↗
PubMed2001

Neuronal ceroid lipofuscinosis: late infantile or Jansky Bielschowsky type--re-revisited.

Among the now eight genetic types of neuronal ceroid-lipofuscinoses (NCL), CLN1 to CLN8, CLN2 is considered classic late-infantile NCL. It was originally described by Jansky in a family of eight children with four of them affected [Jansky J (1908) Sborn Lék 13:165-196] and, subsequently, by Bielschowsky in a family of three children each of whom was affected, and, hence, termed Jansky-Bielschowsky type of NCL. Earlier, archival studies of Bielschowsky's original post-mortem tissue blocks had documented accumulation of autofluorescent lipopigments with a curvilinear ultrastructure. In a subsequent study, described here, immunohistochemical absence of the CLN2-related lysosomal enzyme tripeptidyl peptidase-I and two heterozygous mutations in the CLN2 gene could be demonstrated in these archival tissues, further corroborating the identity of Bielschowsky's familial disorder and CLN2 described by M. Bielschowsky at the beginning of the last century. Furthermore, these immunohistochemical and mutational investigations underscore the value of archival tissue studies.

Aminopeptidases↗
PubMed2001

Surplus protein myopathies.

Certain muscular dystrophies are marked by absence or reduction of mutant proteins, foremost dystrophinopathies and sarcoglycanopathies. Conversely, other sporadic and familial neuromuscular conditions are marked by a surplus of proteins present in a granular or filamentous form, such as desmin-related myopathies, actinopathy and, perhaps, hyaline body myopathy. This emerging group of congenital myopathies is clinically, immunohistochemically, and genetically diverse. Clinically, early- and late-onset diseases with variable courses are described. Immunohistochemically, mutant gene-related and other proteins have been identified by immunohistochemistry. Mutations in the desmin and alpha-B crystallin genes have been discovered in desminopathies. Mutations in the actin gene, but in no other genes have been revealed in actinopathy. Surplus sarcoplasmic and/or intranuclear nemaline bodies have been related to mutant tropomyosin-3, actin and nebulin genes. This emerging concept of surplus protein myopathies will require substantial investigation to further interpret the results of present and future studies.

Humans↗
PubMed2001

Morphological studies on CLN2.

Electron microscopic, fluorescence microscopic, and immunohistochemical studies earlier performed on archival cerebral tissue from Max Bielchowsky's original three patients revealed curvilinear bodies rich in subunit C of mitochondrial ATP synthase (SCMAS). Recent progress in the elucidation of CLN2, i.e. identification of the defective lysosomal enzyme tripeptidyl-peptidase I (TPP-I) and mutations in the CLN2 gene have further corroborated earlier data. Immunohistochemically the absence of the TPP-I protein could be confirmed in the archival tissues using pathological controls. Unlike biochemistry, immunohistochemistry enables examination of these archival tissues elucidating the causative defect. Complementary molecular studies identified mutations in the CLN2 gene in the archival tissues and thereby convincingly demonstrated that these three children truly had classic late infantile neuronal ceroid lipofuscinosis (LINCL), now called CLN2. This archival study documents the possibilities to revalidate disease-specific original nosologic reports. Chloroquine is toxic to lysosomal enzymes and results in lysosomal storage. The material is autofluorescent and gives the ultrastructural pattern of curvilinear profiles, thus resembling classic late infantile NCL, representing a good experimental model. In humans chloroquine therapy may cause a myopathy (and retinopathy) and, as recently suggested, an encephalopathy marked by lysosomal accretion in several cell types including neurons. Immunohistochemically, SCMAS also accumulates, further strengthening morphologic similarity between LINCL and human chloroquine intoxication.

Aminopeptidases↗
PubMed2001

Fulminant course in a case of diffuse myelinoclastic encephalitis-- a case report.

We report on a 10-year old previously healthy boy who exhibited a fulminant and nearly monophasic clinical course of demyelinating encephalitis with relapsing intracranial hypertension syndrome. Histologic examination of a diagnostic brain biopsy revealed an inflammatory demyelinating process with perivascular T lymphocytic infiltration and axonal damage reminiscent of multiple sclerosis-like lesions. In the brain, the DNA of human Herpes virus 6 (HHV6) was detectable. Eleven months after the initial symptoms and on maintainance with oral steroids, MRI showed demyelination of both hemispheres as well as demyelination of the brain stem and Wallerian degeneration. The boy exhibited a severe neurologic defect syndrome. The clinical and radiological course is unusual because of the asymmetric progression of the encephalitis and the extensive confluent lesions without demarcated border or enhancement of the rim after injection of gadolinium. The clinical course showed no definite steroid response. The pathogenetic relevance of HHV6 remains elusive. Although single patients with HHV6-associated encephalomyelitis have been reported, HHV6 DNA is occasionally detected in brains of healthy individuals.

Biopsy↗
PubMed2001

Reducing body myopathy with cytoplasmic bodies and rigid spine syndrome: a mixed congenital myopathy.

At the age of five years a male child started to develop a progressive rigid spine, torsion scoliosis, and flexion contractures of his elbows, knees, hips, and ankles owing to severe proximal and distal muscle weakness. He had three muscle biopsies from three different muscles at ages 7, 11, and 14 years, respectively. Myopathologically, these muscle tissues contained numerous inclusions which, at the ultrastructural level, turned out to be reducing bodies and cytoplasmic bodies, often in close spatial proximity. Similar histological inclusions, although not further identified by histochemistry and electron microscopy, were seen in his maternal grandmother's biopsied muscle tissue who had developed weakness of the legs and hands after the age of 50 years. The patient's parents were healthy, but the mother's quadriceps muscle showed an increased spectrum of muscle fibre diameters. Our patient, thus, had a neuromuscular disorder, perhaps familial, presenting as a mixed congenital myopathy, i.e., reducing body myopathy with cytoplasmic bodies, of which the morphological lesions could be consistently documented over several years in his different limb muscles. While other mixed congenital myopathies had shown cores and rods, both related to sarcomeres and thus possibly morphogenetically related, cytoplasmic bodies thought to be related to Z-bands and reducing bodies dissimilar to any muscle fibre constituent do not share any common denominator. Therefore, we suggest that this neuromuscular disorder may be a unique mixed congenital myopathy, either sporadic or genetic. In the latter case, the transmission pattern suggested X-linked recessive inheritance, but an autosomal-dominant transmission with variable penetrance could not be ruled out.

Adult↗
PubMed2001

Congenital myopathies.

Most congenital myopathies have been defined on account of the morphological findings in enzyme histochemical preparations. In effect, the diagnosis of this group of diseases continues to be made on the histological pattern of muscle biopsies. However, progress has been made in elucidating the molecular genetic background of several of the congenital myopathies. In this updated review we address those congenital myopathies for which gene defects and mutant proteins have been found (central core disease, nemaline myopathies, desminopathy, actinopathy, certain vacuolar myopathies, and myotubular myopathy) and the other disease with central nuclei (centronuclear myopathy).

Actins↗
PubMed2001

Neurodegenerative diseases.

This article briefly discusses and illustrates the major important neurodegenerative diseases of adulthood and neurometabolic (neurodegenerative in a broader sense) diseases of childhood and their gross neuropathology. Macroscopic views of the brain including the cerebellum and the brain stem and the spinal cord are given by external inspection as well as gross sections after brain cutting. Histologic details and photographs are supplied to explain and corroborate certain gross findings. This article attempts to correlate nosologic and neuropathologic features as the basis for interpreting neuroimaging data.

Adult↗
PubMed2000

Morphological aspects of the neuronal ceroid lipofuscinoses.

Morphological aspects of the neuronal ceroid lipofuscinoses (NCL) encompass two main features: loss of nerve cells and accumulation of autofluorescent lipopigments within cellular compartments. The former requires histology and morphometry for assessment, while the latter necessitates fluorescence microscopy, electron microscopy, and immunohistochemistry. Accumulation of lipopigments is widespread throughout the central nervous system and extracerebrally. The latter feature enables diagnosis of NCL and its clinical subtype. Loss of neurons is most pronounced in cerebral and cerebellar cortices, in early childhood forms. In subcortical grey matter and in later-onset forms, juvenile and adult NCL, reduction in neurons and possible preceding dendritic pathology may only correctly be ascertained by age-matched, controlled morphometric investigations which, to date, have not yet completely assessed subcortical neuronal damage. Presently, clinical and morphological evaluations are mandatory for genetic analysis, genetic counselling, and prenatal diagnosis, the latter often being based on combined genetic and morphological studies.

Brain↗
PubMed2000

Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dysferlinopathies).

Dysferlin is the protein product of the gene (DYSF) that is defective in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Calpain 3 is the muscle-specific member of the calcium activated neutral protease family and primary mutations in the CAPN3 gene cause limb girdle muscular dystrophy type 2A. The functions of both proteins remain speculative. Here we report a secondary reduction in calpain 3 expression in eight out of 16 patients with a primary dysferlinopathy and clinical features characteristic of limb girdle muscular dystrophy type 2B or Miyoshi myopathy. Previously CAPN3 analysis had been undertaken in three of these patients and two showed seemingly innocuous missense mutations, changing calpain 3 amino acids to those present in the sequences of calpains 1 and 2. These results suggest that there may be an association between dysferlin and calpain 3, and further analysis of both genes may elucidate a novel functional interaction. In addition, an association was found between prominent expression of smaller forms of the 80 kDa fragment of laminin alpha 2 chain (merosin) and dysferlin-deficiency.

Calpain↗
PubMed2000

Desmin splice variants causing cardiac and skeletal myopathy.

Desmin myopathy is a hereditary or sporadic cardiac and skeletal myopathy characterised by intracytoplasmic accumulation of desmin reactive deposits in muscle cells. We have characterised novel splice site mutations in the gene desmin resulting in deletion of the entire exon 3 during the pre-mRNA splicing. Sequencing of cDNA and genomic DNA identified a heterozygous de novo A to G change at the +3 position of the splice donor site of intron 3 (IVS3+3A-->G) in a patient with sporadic skeletal and cardiac myopathy. A G to A transition at the highly conserved -1 nucleotide position of intron 2 affecting the splice acceptor site (IVS2-1G-->A) was found in an unrelated patient with a similar phenotype. Expression of genomic DNA fragments carrying the IVS3+3A-->G and IVS2-1G-->A mutations confirmed that these mutations cause exon 3 deletion. Aberrant splicing leads to an in frame deletion of 32 complete codons and is predicted to result in mutant desmin lacking 32 amino acids from the 1B segment of the alpha helical rod. Functional analysis of the mutant desmin in SW13 (vim-) cells showed aggregation of abnormal coarse clumps of desmin positive material dispersed throughout the cytoplasm. This is the first report on the pathogenic potentials of splice site mutations in the desmin gene.

Adult↗
PubMed2000

Progress in desmin-related myopathies.

Desmin-related myopathies are sporadic and familial neuromuscular conditions of considerable clinical heterogeneity uniformly marked by the pathologic accretion of desmin, often in a filamentous fashion. A large variety of other proteins, some of them cytoskeletal, also accrue. Morphologically, two types may be distinguished, one characterized by inclusions such as cytoplasmic and spheroid bodies or desmin-dystrophin plaques and another marked by granulofilamentous material. The genetic spectrum of desmin-related myopathies is quite diverse in that missense mutations and deletions in the desmin gene and a missense mutation in the alpha-B crystallin gene have been detected and several genes on other chromosomes have been mapped; the encoded protein products of these genes, however, are unknown. Accumulation of desmin and other proteins appears to be due to impaired nonlysosomal proteolysis. Mutant desmin that appears to be hyperphosphorylated seems to act as a seed protein for filament aggregation, inducing formation of inclusions and granulofilamentous material in these conditions. This condition is part of the group of disorders known as "surplus protein myopathies."

Crystallins↗