J.-J. Martin

Pompe's Disease: An Inborn Lysosomal Disorder with Storage of Glycogen

SummaryAnatomopathological studies are reported in a new case of Pompes disease (glycogenosis type II). The topography of the selective neuronal involvement is again stressed and more accurately localized regarding the thalamus. The accumulation of glycogen-filled vacuoles in astroglia, Schwann cells and myenteric plexus is demonstrated by light or electron microscopy or both.The histochemical features of the basophilic material coexisting with glycogen in striated muscle are described. Our results indicate a close relationship between glycogen and the basophilic material; they indicate that phosphate groups may be responsible for the alcianophilia and metachromasia at low pH.Ultrastructural studies of biopsy and autopsy specimens of striated muscle show that much of the glycogen is in vacuoles which are most probably of lysosomal nature.

Patient homozygous for a recessive POLG mutation presents with features of MERRF.

Both dominant and recessive missense mutations were recently reported in the gene encoding the mitochondrial DNA polymerase gamma (POLG) in patients with progressive external ophthalmoplegia (PEO). The authors report on a patient homozygous for a recessive missense mutation in POLG who presented with a multisystem disorder without PEO. The most prominent features were myoclonus, seizure, and sensory ataxic neuropathy, so the clinical picture overlapped with the syndrome of myoclonus, epilepsy, and ragged red fibers (MERRF).

SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I

Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G→C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.

Acid maltase deficiency in non-identical adult twins

SummaryAcid maltase deficiency is described in non-identical adult twins. The onset of the disease can be traced into late infancy; the clinical picture is one of severe muscular dystrophy; respiratory insuficiency was the cause of death in one case. The autopsy showed the central nervous system, heart and liver to be spared. Glycogen filled vacuoles are found in skin, mesenchymal cells, small nerves and skeletal muscles. The light microscopic study of 9 different muscles showed extremely variable involvement ranging from normal appearance to overt vacuolization. A 6–20% residual acid α-glucosidase activity was found in visceral organs, cultured fibroblasts and in some skeletal muscles. No satisfactory explanation can be given why this generalized acid α-glucosidase deficiency produces a selective involvement of skeletal muscles. If compared with infantile AMD (Pompes disease) our cases have a much higher residual acid α-glucosidase activity and show the presence of an antigenically detectable protein.From our study and from a similar report in the literature (de Barsy et al., 1975), it appears that a combined approach of light microscopy, electron microscopy and biochemical analysis (determination of acid α-glucosidase) is necessary to make a diagnosis of AMD in adults.ZusammenfassungIn einem Paar nicht identischer Zwillinge wird der Säuremaltasemangel beschrieben. Beginn der Erkrankung im späten Kleinkindesalter mit Symptomen wie bei einer schweren Muskeldystrophie. In einem Fall Tod durch Ateminsuffizienz. Bei der Autopsie erwiesen sich das zentrale Nervensystem, Herz und Leber als ausgespart. In der Haut, in mesenchymalen Zellen, in kleinen Nerven und in Skeletmuskeln fanden sich Glykogen-gefüllte Vacuolen. Die lichtmikroskopische Untersuchung von 9 verschiedenen Muskeln zeigte extrem unterschiedlichen Befall, der von einem normalen Aspekt bis zu eindrücklicher Vacuolisation reichte. In der Viscera fand sich eine residuale Aktivität von saurer α-Glucosidase in der Größenordnung von 6–20% der Norm, ebenso in kultivierten Fibroblasten und in einzelnen Skeletmuskeln. Es kann nicht befriedigend erklärt werden, warum dieser generalisierte Mangel an α-Glucosidase einen so selektiven Befall des Skeletmuskels ergibt. Verglichen mit der infantilen Form des Säuremaltasemangels (Pompesche Erkrankung) haben unsere Fälle eine viel höhere Restaktivität von saurer α-Glucosidase und zeigen das Vorhandensein eines antigenetisch nachweisbaren Proteins. Aus unserer Untersuchung und aus ähnlichen Berichten in der Literatur ergibt sich, daß eine kombinierte lichtmikroskopische, elektronenmikroskopische und biochemische Untersuchung (mit Bestimmung der sauren α-Glucosidase) für die Diagnosestellung des Mangels an saurer Maltase notwendig ist.

Acid maltase deficiency (type II glycogenosis). Morphological and biochemical study of a childhood phenotype.

Pathological and biochemical data are reported on a 4(4)/12-year-old male patient with a severe myopathic disorder, hepatomegaly, recurrent pulmonary infections ending fatally. Combined morphological and enzymatic studies on muscle biopsy led to the diagnosis of acid maltase deficiency (Type II glycogenosis). On post mortem examination, lysosomal glycogen storage is found in skeletal muscles and liver, while heart and central nervous sytem are spared. Both hydrolytic and transferase activities of acid maltase are absent in cultured fibroblasts, heart, liver and postmortem skeletal muscles. That in the biopsied skeletal muscle only, the transferase activity alone is deficient while the hydrolytic function is maintained at low normal levels correlates well with the abnormal structure of the glycogen stored in that muscle. However, these findings on biopsied muscle cannot be reconciled with the absence of both functions and the presence of normal glycogen in other biopsied tissues or in postmortem specimens from the same patient.

Distal Hereditary Motor Neuropathy Type II (Distal HMN Type II): Phenotype and Molecular Genetics

ABSTRACT: The distal hereditary motor neuropathies (distal HMN) are clinically and genetically heterogeneous and are subdivided in seven subtypes according to the mode of inheritance, age at onset and clinical evolution. We studied a multigenerational Belgian pedigree with autosomal dominant distal HMN type II. The clinical phenotype closely resembles classical Charcot‐Marie‐Tooth (CMT) disease with an age at onset between 15 and 25 years. Linkage studies have shown that distal HMN II is not linked to the known CMT1 and CMT2 loci. A genome‐wide search was performed and significant linkage was obtained between markers D12S86 and D12S340, suggesting that a gene causing distal HMN II is located on chromosome 12q24.3. The gene encoding the human pancreatic phospholipase A2 (PLA2A), which is expressed in peripheral nerves during degeneration, is a positional candidate gene. Because no disease‐specific mutations were detected in the coding region, however, PLA2A is most likely not the disease causing gene. A yeast artificial chromosome (YAC) contig map spanning the candidate region has been constructed to isolate the gene responsible for distal HMN II. Positional and functional candidate genes are currently being screened for the presence of mutations in distal HMN II patients.

Whole-body MR screening of muscles in the evaluation of neuromuscular diseases

This work was presented at the ECR-2003 as “Scientific Paper” B-0580. O. Ozsarlak (✉) · P. M. Parizel A. M. De Schepper Department of Radiology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium e-mail: ozkan.ozsarlak@uza.be Tel.: +32-3-8214585 Fax: +32-3-8252026 P. De Jonghe · J. J. Martin Department of Neurology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium Eur Radiol (2004) 14:1489–1493 DOI 10.1007/s00330-004-2270-z N E U R O

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and early-onset liver cirrhosis in two siblings

Abstract We present the clinical, pathological, biochemical, and molecular results on an infant girl with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and data on her deceased elder brother for whom this condition was retrospectively diagnosed. Clinical signs were liver enlargement and elevated liver enzymes, failure to thrive, and neurological disease (coma, seizures) triggered by an infectious stress. In the second child hepatic failure and status epilepticus developed during the onset of a rotavirus gastroenteritis. A barbituric coma was induced, but hypotonia and lack of eye pursuit persisted after suppression of antiepileptic drugs. She ultimately died of heart failure. Unlike previously reported cases, both of these patients had early-onset cirrhosis, and severe neurological disease was observed in the second child. Conclusion Liver cirrhosis and brain damage may be underestimated in cases of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and may occur early in life.

Genetic Linkage Analysis in Early-Onset Familial Alzheimer’s Dementia

At least 50% of all patients with senile dementia are clinically diagnosed having Alzheimer’s disease (AD; Terry and Katzman 1983). At autopsy, AD is confirmed by the large abundance of senile plaques and neurofibrillary tangles in the brain, particularly in the hippocampus and cerebral cortex (Brun 1983). In as many as 40% of these AD patients there is strong evidence of a previous family history of the disease, indicating that a genetic predisposing factor is involved in this neurodegenerative disorder (Davies 1986; Fitch et al. 1988). In some families the disease segregates according to a clear autosomal dominant inheritance pattern (Davies 1986; Bird et al. 1988). Although there are large variations in age at onset of disease symptoms, duration of the illness, and clinical manifestation of the disease among these families, genetic linkage analysis of the pedigrees with polymorphic DNA markers may be helpful to localize the primary defect responsible for the disease in the families (Davies 1986; Botstein et al. 1980).

Alzheimer’s Disease and Hemorrhagic Stroke: Their Relationship to βA4 Amyloid Deposition

Distinct mutations have been reported in approximately 5% of early-onset Alzheimer disease (AD) families in the gene coding for the amyloid precursor protein (APP) located at chromosome 21q21.2. Mutations in APP have also been found in families segregating hemorrhagic stroke due to congophilic βA4 amyloid angiopathy (CAA) both in the presence and absence of AD. These mutations are located close to known proteolytic cleavage sites in APP, either at the N-terminal or C-terminal site or within the sequence of βA4 amyloid, the proteolytic product found in AD and CAA brain lesions. cDNA transfection experiments have indicated that these APP mutations interfere with the normal processing of APP, causing either an overproduction of βA4 amyloid or a longer βA4 amyloid that is more prone to aggregation. We have initiated cDNA transfection experiments in COS-1 cells and have studied the production of βA4 amyloid. Our results confirm previous observations in other cell types, i.e., overproduction of βA4 amyloid is not a consistent finding in all known APP mutations.