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Lysosomal storage diseases are a heterogeneous group of disorders caused by lysosomal enzyme dysfunction. Individually they are very rare, but this group as a whole has a prevalence of more than 1:8,000 live births. While severe phenotypes are easily diagnosed this can be a real challenge with attenuated forms. Because musculoskeletal complaints are frequently the first reason for the patient to seek medical advice, the rheumatologist plays a key role for the early recognition of these diseases. Since several of these can be treated very effectively by enzyme replacement, a timely diagnosis and start of therapy are essential to avoid irreversible organ damage and poor quality of life. Therefore, each clinical rheumatologist should be aware of the cardinal symptoms of lysosomal storage diseases.

Most skeletal dysplasias are characterized by small stature. Less well known is the fact that most skeletal dysplasias are also associated with specific spinal problems or deformities. This article summarizes the various aspects of spinal problems in this patient population as well as the diagnostic strategies and current and new treatment options.

Children complaining of hip pain most likely suffer from Perthes' disease. Similar morphological changes are seen in the hereditary diseases of the epiphyseal dysplasias which have a prevalence of about 40 of 100 000 inhabitants. We now show the differentiation between bilateral Perthes' disease, epiphyseal dysplasia and skeletal disorders like mucopolysaccharidosis and pseudoachondroplasia.We describe the diseases of multiple epiphyseal dysplasia and spondyloepiphyseal dysplasia on the basis of two case reports. Furthermore, we discuss differential diagnostic aspects, therapeutic options and prognosis.Epiphyseal dysplasias are classified as osteochondral dysplasia. The characteristic feature of these heredopathies is short statue due to skeletal dysplasias at various sites. Multiple epiphyseal dysplasia is caused by an abnormality of enchondral ossification. A distinction is made between the severe Fairbank form, the milder Ribbing form and a mild but rather localised Meyer form. In addition to the femoral head, the spinal bodies can also be affected by the same enchondral ossification disorders and this is defined as spondyloepiphyseal dysplasia.The diagnosis of a Perthes' disease can be made from an X-ray of the hip, showing either an advanced necrosis of the femoral head or early signs of it. Typical radiological findings allow the differentiation to other skeletal dysplasias like epiphyseal dysplasia and metabolic disorders.

The mucopolysaccharidoses, first described at the beginning of this century, are still subject of research. The accumulation of pathological metabolites and the underlying enzyme defects are now correlated to specific gene mutations. A comparison of genotype and phenotype of the individual forms of the mucopolysaccharidoses is the subject of ongoing studies. In many cases, symptomatic treatment was not able to increase the quality of life of patients suffering from mucopolysaccharidosis to a satisfactory degree. International working groups are, thus, currently trying to improve and standardize symptomatic therapies. A causal therapeutic approach was attempted by implanting different cells and tissues that are able to produce the missing enzymes. Bone-marrow transplantations were also performed, but both treatment approaches were not very effective and in some cases even proved fatal for the patients. An intensive international research effort focuses on enzyme-replacement therapy and gene therapy. Mucopolysaccharidoses are rare diseases, affecting only about one hundred patients in Austria. Nevertheless, Austria plays an active role in researching these metabolic disorders.

In recent years, several clinical and biochemical studies have been published contributing to better understanding of mucopolysaccharide storage diseases. Our purpose, therefore, is, to give an updated survey of this group of lysosomal diseases for diagnostic orientation to the pathologist. The present classification of mucopolysaccharidoses is based on a mixture of clinical symptoms, demonstration of enzyme defects, analysis of urinary excretion of glycosaminoglycans (mucopolysaccharides) and historical eponyms. A broad heterogeneity has been revealed: identical enzyme defects may lead to severe mental and physical deterioration and death during childhood or to mild forms with normal adult height, intelligence, and life expectancy. Conversely, identical phenotypes may result from mutations of different genes. Various types of mucopolysaccharidoses are mostly characterized by quantitative differences of main symptoms (coarse facial features, various skeletal abnormalities, hepatosplenomegaly, corneal clouding, mental retardation, and cardiac failure). Morphologically, storage material can be observed practically in all tissues by light and/or electron microscopy. Until recently, no more than palliative treatment could be offered. In the last decade, bone marrow transplantation has become available and may have beneficial effects in selected cases. The genes of several lysosomal enzymes have been identified, and comprehensive studies to introduce the gene into defective cells are currently undertaken. However, substantial efforts are still necessary until gene transfer will become available for patients with mucopolysaccharidoses.

The mucopolysaccharidoses represent a group of lysosomal storage disorders characterized by coarse facies, skeletal deformities, and often mental deterioration. Recent clinical and biochemical studies have revealed a broad genetic heterogeneity of these metabolic diseases: An identical enzyme defect may lead to a mild form with normal adult height and normal life expectancy or to a severe hydrops fetalis that does not survive the first days of life. Conversely, Sanfilippo disease is an example that identical phenotypes may result from mutations of different genes. From clinical observations it became clear, that not only the skin, brain and skeletal system are involved in the storage process, but also the lungs and the cardiovascular system. Until recently, no more than palliative treatment could be offered. This consists of corneal transplantation, cervical fusion to prevent atlantoaxial subluxation, especially in Morquio's disease, and shunt operation to relieve hydrocephalus. In the last decade bone marrow transplantation became available; this may have beneficial effects in selected cases, especially in mucopolysaccharidosis I. Since the genes of several lysosomal enzymes have been identified, many efforts to introduce the normal gene into the affected cells were done. This method was successfully applied in an animal model. But many efforts in several laboratories are still necessary until this therapeutic regimen will become available for patients with mucopolysaccharidosis.

Mucopolysaccharidoses are autosomal recessive or X-linked hereditary lysosomal storage diseases occurring to one in 10,000 to 16,000 births. The definitive diagnosis is based on the biochemical verification of the enzyme defect in cultured fibroblasts of amniotic fluid cells, in amniotic fluid, in chorionic biopsies and by determination of the urinary excretion of glycosaminoglycans. Morphological studies are of utmost importance both for genetic counselling and enlightenment of the pathogenesis. In recent years, numerous reports appeared dealing with morphological changes in different types of mucopolysaccharidoses. Based on own studies in pre- and postnatal cases, the present paper gives an update review on light and electron microscopic peculiarities of the different types and subtypes of mucopolysaccharidoses according to the classification of MCKUSICK and NEUFELD (1983). Lysosomal storage is found in practically all organs. However, there are quantitative and qualitative differences which are responsible for variations in clinical symptomatology. The purpose of this paper is to describe these differences with particular emphasis on changes in various tissues, on the pathogenetic mechanism of the storage as well as on pre- and postnatal morphological diagnostics.

The authors describe two brothers with pseudo-achondroplasia. The literature is reviewed and the clinical and radiological features and differential diagnosis are discussed.

The basic defects of a number of genetic disorders affecting the connective tissue have been elucidiated during the last few years. A similar progress in understanding the pathobiochemistry of other dermatological diseases is expected. The present review summarizes our knowledge about structure, synthesis, degradation, macromolecular organization and possible function of glycosaminoglycans, which are an important constitutent of the ground substance in the skin. The difficulties of relating the clinical symptoms of diseases with the basic defects are examplified for the mucopolysaccharidoses.

The syndrome of pyknodysostosis is described in a male patient 42 years of age. Pyknodysostosis is characterized by short stature, delayed closure of fontanels, persistence of open cranial sutures and bone fractures. Pyknodysostosis is a hereditary disorder with a prevalence to offsprings of consanguineous intermarriages.

The autopsy of the 27-year-old patient suffering from a severe form of mucopolysaccharidosis type VI-A (Maroteaux-Lamy) described in the article by Rampini et al. revealed the compressive cervical myelopathy (C1) to be due to a severe, slit-like deformity of the vertebral canal which was due to a massive thickening of the ligaments, dislocation of the posterior arch of the atlas and broadening of the dura. The massive, generalized disorder of the enchondral ossification involving mainly tubular bones and spine, led to short stature, arthrosis of large joints, and to an angular thoraco-lumbar kyphoscoliosis. Our patient had a massive V-shaped stenosis of the upper third of the trachea. The atrio-ventricular valves of the heart were thickened, and there was fibrosis of the endocardium. The cardiac conduction system displayed fibrosis and foam cell transformation of the fibroblasts in the bundle of His, a lesion not previously reported. Light and electron microscopic investigation showed a massive increase of mucopolysaccharides mainly in the matrix of the fibrous tissue and of the cartilage. Furthermore, the fibroblasts and chondrocytes as well as the hepatocytes and the ganglion cells of the central nervous system contained increased amounts of glycosaminoglycans.

About 40 of the genetically induced metabolic defects in humans which are known today can be diagnosed prenatally. The diagnosis of some diseases is possible from the amnionic liquor itself or from uncultivated amnion cells. But in many cases it is necessary to perform the tests for prenatal diagnosis of a biochemical defect with cultivated amnion cells. Of the numerous test procedures, 4 methods, different in principle, will be described here. They all permit a reliable prenatal diagnosis with a minimum of time and cell material.

Sphingolipidoses and heteroglycanoses are inborn errors of the carbohydrate metabolism. Biochemically and clinically hetero-glycanoses are sub-divided into mucopolysaccharidoses, oligosaccharidoses and mucolipidoses. These disorders of complex carbohydrate metabolism are due to the inborn defect of one or more lysosomal enzymes which in turn cause an intracellular accumulation of not-degraded complex carbohydrates corresponding to a wide pattern of clinical expression and symptomatology ranging from psychomotor retardation without any dysmorphic signs to severe features of a storage disease with dwarfism, peculiar facial appearance, organomegaly and skeletal changes. Investigations of recent years revealed that there is tremendous phenotypic variation even within diseases caused by a deficiency of the same enzyme. On the other hand, clinically indistinguishable phenotypes may be caused by the defect of different enzymes.

Mucopolysaccharidosis I-S in two encygotic twin sisters. The disease is characterised by opacification of the cornea, hepatospenomegaly, carpal tunnel syndrome, flexion contractures of the fingers and toes, valvar heart disease, normal intelligence and essentially normal behaviour. The biochemical defect consists of deficiency of the lysosomal hydrolase alpha-L-iduronidase. Urinary dermatan-sulphate excretion is raised. The muscles are also involved:the electron microscopic revelas interstitial storage of glycosaminoglycan-like substance. There is no specific treatment.

Numerous control systems are involved in the growth and differentiation of chondro-osseous tissue. Theoretically, the failure of each single step will result in a peculiar skeletal dysplasia. The resulting disorders are caused by errors in the metabolism of collagen, minerals, complex carbohydrates and the protein of the ground substance. Skeletal dysplasias with a known or probable metabolic base include osteogenesis imperfecta, osteoectasia with macrocranium, Menkes syndrome, the mucopolysaccharidoses and hypophosphatasia.

We have observed and operated on 5 children at the age of 15 months to 6 years for carpal tunnel syndrome. 4 children, all belonging to the same family had bilateral median nerve compression syndrome. These 4 children also suffered from bilateral tenosynovitis, and a mild form of mucopoolysaccharidosis (M. Scheie) was diagnosed. The symptoms in all 5 children were uncharacteristic and initially difficult to associate with nerve compression at first. Numbness and dysaesthesia in the thumb, index and middle finger, the most frequent signs in adult patients, were missing. In these children, the observation of general manual clumsiness, unusual patterns of grasping, sudden change in playing habits with avoidance of manual activity led to the suspicion of a median nerve compression syndrome. In all children decompression of the median nerve resulted in normalization or marked improvement of hand function.

In lymphocytes, monocytes and basophil granulocytes of patients with mucopolysaccharidosis specific fluorescence of acid mucopolysaccharides exists after fixation of blood smears with 9-aminoacridin-hydrochloride and subsequent staining with pseudoisocyanine at pH 4.2. A total of eleven children with various types of mucopolysaccharidosis were investigated. Specificaly stained granula were demonstrated in 5 to 49 percent of all lymphocytes and monocytes. Acid mucopolysaccharides were for the first time also shown in red-cell precursors of the bone marrow of children with mucopolysaccharidosis.