LSD - An Overview
The Scorpion
Fabry Disease
Fabry Disease is an X-chromosomal inherited lysosomal storage disorder based on the deficiency of the enzyme alpha-galactosidase A. This leads to accumulation of globotriaosyl-ceramide (Gb3) in the cells of various organs. The clinical picture of M. Fabry is very heterogeneous and ranges from mild phenotypes rather in heterozygous women to severe clinical course in classically affected men. Characteristic symptoms include acroparesthesia, cardiac symptoms associated with cardiomyopathy and arrhythmias, progressive renal failure and cerebro-vascular complications (strokes). A typical eye manifestation is the cornea verticillata. Therapeutically, 3 drugs are currently available: enzyme replacement therapies with agalsidase alfa or agalsidase beta or chaperone therapy with migalastat.
The Octopus
ASMD
ASMD (= Acid Sphingomyelinase Deficiency, Niemann-Pick Disease Type A/B) is based on the deficiency of the enzyme acid sphingomyelinase, which is caused by a defect in the SMPD1 gene. The lack of acid sphingomelinase leads to an accumulation of sphingomyelin in the cells of various organs (e.g. spleen and liver). Three clinical phenotypes are distinguished: infantile neurovisceral ASMD (Niemann-Pick disease type A), chronic neurovisceral ASMD (Niemann-Pick disease type A/B) and chronic visceral ASMD (Niemann-Pick disease type B). Infantile neurovisceral ASMD is characterized by hepatosplenomegaly, failure to thrive, psychomotor developmental retardation and progressive neurodegeneration. Life expectancy is significantly limited. Clinical signs of chronic neurovisceral ASMD include hepatosplenomegaly, interstitial lung disease and variable neurological symptoms (including ataxia, peripheral neuropathy, cognitive impairment). Visceral symptoms, such as hepatosplenomegaly and interstitial lung disease, are typical for chronic visceral ASMD. Enzyme replacement therapy with recombinant acid sphingomyelinase is currently in clinical trials.
The Chameleon
Niemann-Pick Type C disease
In Niemann-Pick disease type C, a defect in the NPC1 gene (approximately 95% of cases) or in the NPC2 gene (approx. 5% of cases) leads to impaired intracellular cholesterol trafficking and consecutive to accumulation of unesterified cholesterol in the cells of various organs. The age of manifestation extends from the perinatal period to late adulthood. Clinical symptoms are very heterogeneous. In addition to visceral signs – consisting of a splenomegaly or hepatosplenomegaly – neurological symptoms, such as progressive cerebellar ataxia, dysarthria, vertical supranuclear gaze palsy, epilepsy, cataplexy and progressive dementia are characteristic. For the treatment of progressive neurological symptoms, substrate reduction therapy with miglustat is currently available.
The Hyena
Gaucher Disease
Gaucher Disease is an autosomal recessively inherited lysosomal storage disorder caused by the deficiency of the lysosomal enzyme beta-glucocerebrosidase. This leads to intracellular storage of glycosylceramide in the cells of various organs, especially in the liver, spleen and bone marrow. Three phenotypes are distinguished: Gaucher disease type I, type II and type III. Gaucher disease type I, the most common phenotype, describes the chronic non-neurological form and is characterized by hepatosplenomegaly, bone symptoms (pain, bone infarction osteonecrosis), thrombocytopenia and anemia. Gaucher disease type II is the rarest form and is distinguished by manifestation in infancy with severe rapidly progressive neurological symptoms (bulbar and pyramidal signs, myoclonic epilepsy). In addition to the clinical signs of Gaucher disease type I, Gaucher disease type III combines progressive neurological symptoms (oculomotor apraxia, ataxia, epilepsy). Therapeutically, 4 approved drugs are available (enzyme replacement therapies with imiglucerase or velaglucerase alfa for Gaucher disease type I and type III, substrate reduction therapies with miglustat or eliglustat for Gaucher disease type I).
The Crocodile
GM1-Gangliosidosis
GM1-gangliosidosis caused by lack of ß-galactosidase has characteristics of mucopolysacharidosis and sphingolipidosis. ß-galactosidase plays a role in both metabolic pathways and is deficient in this disease. Macrocephalus and dysostosis multiplex are findings whose cause can be found in the defect of the mucopolysaccharide metabolism. In contrast, neurological findings - motor developmental disorder, pyramidal tract signs, cherry-red spot, epilepsy and mental retardation - are to be interpreted in terms of sphingolipidosis. In the course of the disease, pronounced spastic cerebral palsy dominates the clinical picture. In attenuated forms coarse facial features, macrocephalus organomegaly and cherry-red spots can be absent.
The Piranha
Mucolipidosis Type II and Type III
Mucolipidosis type II (ML II) and mucolipidosis type III (ML III) are caused by a defect of the GlcNAc-1-phosphotransferase complex, which is composed of three subunits, alpha, beta und gamma. Mutations of the gene GNPTAB encoding the alpha/beta subunits result in Mucolipidosis II (ML II, also called I-cell disease) or the clinically milder condition mucolipidosis (ML III) alpha/beta. ML III gamma (or ML IIIC) arises from mutations of the gene GNPTG encoding the gamma-subunit. The GlcNAc-1-phosphotransferase complex is responsible for the formation of the mannose-6-phosphate recognition marker required for correct targeting of lysosomal hydrolases to the lysosomes. A defect of this complex leads to missorting of multiple lysosomal enzymes ending in the accumulation of different non-degraded macromolecultes in several tissues and organs. In ML II (I-cell disease) clinical signs are present already in newborns, these include dysmorphic features with striking gingival hypertrophy, developmental disturbance, skeletal abnormalities, hepatosplenomgaly and cardiomyopathy; the patients often die in early childhood. The mucolipidosis III (ML III alpha/beta and ML III gamma) are slowly progressive disorders that mainly affect the skeletal, joint and connective tissue, but spare the central nervous system. The life expectany is hardly reduced.
The Boa Constrictor
Pompe Disease
Pompe disease (also referred to as glycogenosis type II or acid maltase deficiency) is a rare, inherited metabolic disease caused by a deficiency of the enzyme acid glucosidase. This deficiency results in a progressive accumulation of glycogen in the lysosomes. Complete deficiency of this enzyme causes a pronounced cardiomyopathy, muscle weakness and feeding problems already during the first months of life. Without treatment, the children die in the first year of life. With residual enzyme activity a milder course of the disease is seen, characterized by increasing muscle weakness and/or breathing problems during adolescence and adulthood. Examination of blood samples shows increased activity of creatinine kinase (CK) and of liver enzymes.
The Koala
Alpha-Mannosidosis
Alpha-mannosidosis, a glycoproteinosis, is due to a genetic defect of the lysosomal enzyme alpha-mannosidase that is responsible for the hydrolysis of glycoprotein carbohydrate moieties. The decreased activity of this enzyme leads to accumulation of oligosaccharides in several cells and organs. Alpha-mannosidosis is a slowly progressive disorder that shows a broad phenotypic variability. Clinical features include hearing impairment, skeletal abnormalities, impairment of mental function, sometimes periods of psychosis. In addition, muscular weakness and ataxia are observed. In the first decade of life recurrent infections occur due to an immune defect.
The Dwarf Pony
Mucopolysaccharidosis Type I
Mucopolysaccharidosis type I (defect of the enzyme alpha-iduronidase) is characterized by a broad phenotypic spectrum, ranging from the severe infantile form, called Hurler disease (MPS IH), to the adult form, called Scheie disease (MPS IS), that is associated with an almost normal life expectancy. Typical symptoms in patients with Hurler disease are disproportionate short stature, hepatosplenomegaly, corneal clouding and coarse facial features. Motor and mental development are delayed, without treatment the patients die at the age of around ten years. Patients with Scheie disease have an almost normal stature and no mental retardation, they may have, however, dysmorphic facial features, corneal clouding and joint contractures. Patients whith a clinical phenotype between Hurler and Scheie disease are called Hurler-Scheie-phenotype (MPS IHS). For Hurler patients the treatment of choice is bone marrow transplantation, for MPS IS- and MPS HIS-patients enzyme replacement therapy is available.
The Dwarf Pony
Mucopolysaccharidosis Type II
Mucopolysaccharidosis type II (MPS II, Hunter disease, defect of the enzyme iduronate-sulfatase) is an X-linked storage disorder; therefore almost solely male patients are affected. The clinical signs and symptoms are comparable with those of mucopolysaccharidosis type I, corneal clouding, however, is absent. Characteristic striking features in Hunter disease are pronounced joint contractures. The phenotypic spectrum ranges from a severe (neurological) form with a profound visceral and skeletal manifestation and intellectual disability to a very mild form with only a few somatic features and normal intelligence.
The Dwarf Pony
Mucopolysaccharidosis Type III
The subtypes of mucopolysaccharidosis III (MPS III) A,B,C and D are caused by lysosomal enzymes that are responsible for the degradation of heparan sulfate, an essential component of nerve cell membranes. This explains why in this mucopolysaccharidosis predominantly the central nervous system is affected and the patients have only slight dysmorphic features. First symptoms such as agitated behaviour and learning difficulties, mainly regarding speech development, appear at the age of 3-5 years. Later on epileptic seizures occur, at the end the patients get tetraspastic, most die at the age of around 20 years. The subtypes A.B,C and D do not show any difference in clinical phenotype.
The Dwarf Pony
Mucopolysaccharidosis Type IVA
In mucopolysaccharidosis type IVA (MPS IVA, Morquio disease A, deficiency of the enzyme Acetylgalactosamine-6-Sulfatase) predominantly the skeletal system is affected: Severe deformities of the spine, thorax and extremities result in disproportionate short stature, in severe cases the final height is about 120 cm. However, patients with a normal height have been described, too. Further characteristic features include joint laxity, instability of the cranio-cervical junction, leading to paraplegia, corneal clouding and hearing problems. The intelligence is normal.
The Dwarf Pony
Mucopolysaccharidosis Type IVB
In mucopolysaccharidosis type IVB (MPS IVB, Morquio disease B, deficiency of beta-Galactosidase) predominantly the skeletal system is affected: Deformities of the spine, thorax and extremities result in disproportionate short stature with a final height of 130 - 150 cm. In general, the symptoms are milder than in MPS IVA. Instability of the cranio-cervical junction, that may lead to paraplegia, represents a severe complication. Further symptoms include corneal clouding and hearing impairment. Patients with MPS IVB often suffer also from cardiac involvement such as cardiomyopathy or valve insufficiency. The intelligence is normal.
The Dwarf Pony
Mucopolysaccharidosis Type VI
Patients with a mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy) have many clinical signs similar to those of mucopolysaccharidosis type I such as disproportionate short stature, coarse facial features and hepatosplenomegaly, but intellectual disability is absent. Rapid and slow progressive forms are known. Stenosis of the cranio-cervical junction, leading to compression of the spinal cord, and vision impairment due to corneal clouding and glaucoma represent common complications.
The Dwarf Pony
Mucopolysaccharidosis Type VII
Only a few (about 100) patients with a mucopolysaccharidosis type VII (MPS VII, Sly disease, deficiency of Beta-glucuronidase) have been described. The phenotypic spectrum of this enzyme defect ranges form letal hydrops fetalis to a very mild form with only slight skeletal deformities. Symptoms of the severe form are comparable to those seen in other mucopolysaccharidoses.
The Dwarf Pony
Mucopolysaccharidosis Type IX
Mucopolysaccharidosis type IX (MPS IX) has been named a disease in which the enzyme hyaluronidase is deficient, and that is clinically characterized by mild short stature and notable periarticular soft tissue masses, but without neurological or visceral involvement. After the first description by Natowicz and co-authors in 1996 further cases of one family have been described who showed clinical signs of a juvenile arthritis.
The Fish
Cystinosis
Cystinosis is caused by mutations in the CTNS gene encoding for the carrier protein cystinosin that has the task to transport cystin out of the lysosomal compartment. A defect of the cystinosin function results in intra-lysosomal cystin accumulation in all cells. First of all the kidneys are affected, starting with proximal tubular damage during the first year of life, followed by end-stage renal failure during mid-childhood. Also the eyes, thyroid, pancreas and muscles are affected. In some older patients also the CNS can be involved.
The Tarantula
Sialidosis & Galactosialidosis
Due to clinical features, these two clinical pictures are hardly distinguishable. Sialidosis is caused by a lysosomal neuramidase deficiency. Galactosialidosis is characterized by a deficiency of lysosomal neuraminidase and b-galactosidase. This is caused by a lack of an activator and transport protein for these two enzymes. Initially, this enzyme was called protective protein. Later, the protective protein was also characterized as Cathepsin A. Initially the children with sialidosis type II or galactosialidosis resemble children with MPS 1 (Hurler phenotype). The course especially in late infantile and juvenile forms can be complicated by renal failure with proteinuria. Probably the Hydrops fetalis is the most frequent and most severe manifestation of the disease. Sialidosis type I, also called Cherry Red Spot Myoclonus Syndrome, is associated without the changes observed in MPS. In late childhood or adolescence, there is loss of visual acuity, polymyoclonus and seizures.
The Mole
GM2-Gangliosidosis
GM2-Gangliosidosis can be caused by a deficiency of hexosaminidase A (Tay-Sachs disease), or of hexosaminidases A and B (Sandhoff disease) or of GM2 activator protein (GM2 activator defect). Based on clinical features, the diseases cannot be distinguished. In the classic clinical picture, a pronounced sensitivity to noise is noticeable in the very first months of life. Loud noises such as closing doors or clapping hands lead to Moro-like motor manifestations. Already before the 6th month of life the motor development is limited. The diagnosis is often made because a cherry red spot is found during the ophthalmological examination. The infants are hypotonic, have poor head control. Verticalisation is delayed. A macrocephalus develops. At the beginning of the second year of life, the infants lose again their laboriously acquired abilities as well as vocalization and become blind. As a rule, the course is complicated by an epilepsy that is difficult to treat. Non-classical forms of the disease - described as juvenile or adult forms - are difficult to diagnose because the classic features are missing. The main findings in attenuated forms of epilepsy are motor developmental disorders and seizures with and without myoclonies in childhood, adolescence and young adulthood, a combination of early dementia, psychosis (often delusional), ataxia and distal paresis (motor neuron disease as in Friedreich's ataxia).
Lysosomal acid lipase deficiency
The lysosomal enzyme acid lipase (LAL) - or Wolman Disease and Cholesteryl Ester Storage Disease (CESD) - has the function to release cholesterol from cholesteryl esters and triglycerides; therefore a defect of this enzyme leads to the accumulation of these lipids in several tissues and organs, predominatly in the liver and vessels. Two main clinical phenotypes are caused by an acid lipase deficiency: Wolman disease and Cholesteryl Ester disease. Wolman disease is a rapidly progressive disorder, characterized by severe failure to thrive, diarrhoea, vomiting and hepatosplenomegaly, leading to death at the age of 6-8 months from cachexia. Cholesteryl ester storage disease (CESD) represents the more attenuated phenotype of LAL deficiency with a wide spectrum of clinical presentation. Clinical signs include liver enlargement, short stature, gastrointestinal bleeding and chronic abdominal pain. Some patients live to adulthood with unpredictable course, other die in their juvenile years due to failure of liver function or myocardial infarction.
