Susanne Gerit Kircher

Hippocampal proteoglycans brevican and versican are linked to spatial memory of Sprague-Dawley rats in the morris water maze.

Proteoglycans (PGs) are major constituents of the extracellular matrix and have recently been proposed to contribute to synaptic plasticity. Hippocampal PGs have not yet been studied or linked to memory. The aim of the study, therefore, was to isolate and characterize rat hippocampal PGs and determine their possible role in spatial memory. PGs were extracted from rat hippocampi by anion‐exchange chromatography and analyzed by nano LC‐MS/MS. Twenty male Sprague–Dawley rats were tested in the morris water maze. PGs agrin, amyloid beta A4 protein, brevican, glypican‐1, neurocan, phosphacan, syndecan‐4, and versican were identified in the hippocampi. Brevican and versican levels in the membrane fraction were higher in the trained group, correlating with the time spent in the target quadrant. α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor GluR1 was co‐precipitated with brevican and versican. Levels for a receptor complex containing GluR1 was higher in trained while GluR2 and GluR3‐containing complex levels were higher in yoked rats. The findings provide information about the PGs present in the rat hippocampus, demonstrating that versican and brevican are linked to memory retrieval in the morris water maze and that PGs interact with α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor GluR1, which is linked to memory retrieval.

The Diversity of the Clinical Phenotypes in Patients With Fibrodysplasia Ossificans Progressiva

Background The clinical presentation, phenotypic characterization and natural history of fibrodysplasia ossificans progressiva (FOP) are diverse and the natural history of the disease is, to a certain extent, different from one patient to another. Methods In a series of 11 patients (eight girls and three boys, aged 0 - 16 years), variable clinical presentations were the landmarks of these patients. At birth, all of our patients manifested short great toes in a valgus position. Marfan syndrome was the suggested diagnosis in three children aged 3 - 8 years and in two pre-adult patients. Clinical symptoms were torticollis, painful spine, and painful and marked limitation of the pelvic movements. Monophalangia associated with Marfanoid habitus was also a prevailing clinical presentation. Results Our results were based upon the appearance of the earliest pathologic feature of FOP in correlation with the clinical presentation. In infants (0 - 1 year), three infants showed congenital hallux valgus and stiff spine. In the pediatric group (3 - 8 years), all children showed no mutation in the fibrillin-1 (FBN1) gene. Their prime presentation was a progressive torticollis with simultaneous development of erythematous subfascial nodules, most commonly located on the posterior neck and back. In pre-adult group (10 - 16 years), four patients presented with monophalangia associated with painful movements because of the progressive heterotopic ossification of the spine and the weight bearing zones and marked elevation of alkaline phosphatase. Genetic confirmation has been performed in six patients who manifested the classical mutation of the ACVR1 gene. The rest of the patients were assessed via clinical and radiographic phenotypes. Conclusion The early recognition of FOP can be performed by noticing the short halluces and thumbs at early infancy and later on the high alkaline phosphatase activity in areas of heterotopic ossification. Misconception of FOP is of common practice and eventually unnecessary diagnostic biopsies might deteriorate the progression of the condition. The detection of ACVR1 gene mutation was a confirmatory procedure. Interestingly, the timing of the onset and the location of progressive heterotopic ossifications were extremely variable and confusing among our group of patients.

Unique medical issues in adult patients with mucopolysaccharidoses.

The mucopolysaccharidoses are a group of inherited metabolic diseases caused by deficiencies in enzymes involved in the sequential degradation of glycosaminoglycans (GAGs) leading to substrate accumulation in various tissues and organs. GAG accumulation can cause growth retardation and progressive damage to respiratory, cardiovascular, musculoskeletal, nervous, gastrointestinal, auditory, and visual systems. In the past, few people with severe phenotypic mucopolysaccharidosis (MPS) reached adulthood. However, better methods for diagnosis, multi-disciplinary care, and new therapies have extended lifespan, leading to an increasing number of patients surviving beyond childhood. The growing number of adult MPS patients poses significant challenges for clinicians who may not be familiar with the clinical manifestations of MPS. In addition, as new interventions have changed the natural history of these disorders, it is difficult to anticipate both the impact on life expectancy and other complications that may occur as these patients age. Because the MPS disorders are multi-organ diseases, their management requires a coordinated multi-disciplinary approach. Here we discuss the unique pattern of medical issues and multi-organ involvement in adult patients with MPS and identify the challenges that are associated with management of MPS. This review is based on information from an expert investigator meeting with MPS specialists held October 2-4, 2014 in Dublin, Ireland, as well as on current literature searches focusing on MPS and adults.

Health-related quality of life in mucopolysaccharidosis: looking beyond biomedical issues

The mucopolysaccharidoses (MPS) comprise a heterogeneous family of rare, genetic lysosomal storage disorders that result in severe morbidity and reduced life expectancy. Emerging treatments for several of these disorders have triggered the search for clinically relevant biomarkers and clinical markers associated with treatment efficacy in populations and individuals. However, biomedical measures do not tell the whole story when characterizing a complex chronic disorder such as MPS. Health-related quality of life (HRQoL) tools that utilize patient reported outcomes to address patient parameters such as symptoms (pain, fatigue, psychological health), functioning (activity and limitations), or quality of life, have been used to supplement traditional biomedical endpoints. Many of these HRQoL tools have demonstrated that quality of life is negatively impacted in patients with MPS. There is both the opportunity and need to formally standardize and validate HRQoL tools for the different MPS disorders.

Noninvasive diagnosis of tubular damage by the use of urinary chondroitin-4-sulfate/heparan sulfate ratio.

20 healthy children, 20 children with tubulointerstitial nephritis (TIN) and 20 children with glomerulonephritis in the active state were examined. Polyacrylamide gel electrophoresis of urinary proteins, beta-2-microglobulin excretion and acid glycosaminoglycan electrophoresis were performed. Polyacrylamide-gel electrophoresis showed in all the cases with TIN low molecular weight proteinuria, no bands were observed in healthy children and in all the cases of glomerulonephritis high molecular weight proteinuria. Beta-2-microglobulin determination showed no differences between healthy children and children with glomerulonephritis, but showed high levels in the group of children with TIN. Acid glycosaminoglycan electrophoresis showed in the group of children with healthy children a mean chondroitin-4-sulfate-/heparan sulfate ratio (CS/HS) of 3.8 +/- 0.4. Children with TIN presented a low ratio of 1.5 +/- 0.5. Patients with glomerulonephritis showed a mean ratio of 3.7 +/- 0.3. Our results clearly show that tubular damage can be revealed by a low quotient of chondroitin-4-sulfate to heparan sulfate.

Muscle Weakness: A Misleading Presentation in Children With Distinctive Syndromic Entities (Clinical Case Reports)

Marked ligamentous hyperlaxity and muscle weakness/wasting associated with awkward gait are the main deficits confused with the diagnosis of myopathy. Seven children (6 boys and 1 girl with an average age of 8 years) were referred to our department because of diverse forms of skeletal abnormalities. No definitive diagnosis was made, and all underwent a series of sophisticated investigations in other institutes in favor of myopathy. We applied our methodology through the clinical and radiographic phenotypes followed by targeted genotypic confirmation. Three children (2 boys and 1 girl) were compatible with the diagnosis of progressive pseudorheumatoid chondrodysplasia. The genetic mutation was correlated with the WISP 3 gene actively expressed by articular chondrocytes and located on chromosome 6. Klinefelter syndrome was the diagnosis in 2 boys. Karyotyping confirmed 47,XXY (aneuploidy of Klinefelter syndrome). And 2 boys were finally diagnosed with Morquio syndrome (MPS type IV A) as both showed missense mutations in the N-acetylgalactosamine-sulfate sulfatase gene. Misdiagnosis can lead to the initiation of a long list of sophisticated investigations.

Pregnancy in patients with mucopolysaccharidosis: a case series

The mucopolysaccharidoses (MPS disorders) are rare inherited diseases associated with multi-organ accumulation of glycosaminoglycans, leading to musculoskeletal, respiratory, cardiac, neurological, ophthalmological, otolaryngological, and gastrointestinal abnormalities. As a result of improvements in diagnosis, multi-disciplinary care, and therapies such as enzyme replacement therapy and hematopoietic stem cell transplantation, an increasing number of patients with MPS are reaching adulthood and are involved in family planning. Data on fertility and pregnancy outcome in MPS is sparse and comprises primarily isolated case reports. To address this evidence gap, we present a case series on fertility and pregnancy in eight mothers and five fathers with MPS. This case series demonstrates that women with MPS have high-risk pregnancies and deliveries secondary to their underlying disease. However, with appropriate pre-conceptual multi-disciplinary evaluation, optimization and discussion regarding potential risks, combined with regular multi-disciplinary maternal and fetal surveillance in a tertiary center, the outcome of most pregnancies in this case series seems to be favorable with all babies developing normally. Partners of fathers with MPS had uncomplicated pregnancies and deliveries. All children were healthy, with normal growth and development.

Spine malformation complex in 3 diverse syndromic entities: Case reports.

Rationale:Clinical and radiographic phenotypic characterizations were the base line tool of diagnosis in 3 syndromic disorders in which congenital cervico-thoracic kyphosis was the major deformity. Patients concerns:Directing maximal care toward the radiographic analysis is not only the axial malformation but also toward the appendicular abnormalities was our main concern. We fully documented the diversity of the spine phenotypic malformation complex via the clinical and radiographic phenotypes. Diagnoses:We established the diagnosis via phenotypic/genotypic confirmation in 3 diverse syndromic entities namely acampomelic campomelic dysplasia, Larsen syndrome and Morquio syndrome type A (mucopolysaccharidosis type IV A). Interventions:Surgical interventions have been carried out in the Larsen syndrome and Morquio syndrome type A, resepectively. Outcomes:The earliest the diagnosis is, the better the results are. The necessity to diagnose children in their first year of life has many folds, firstly the management would be in favor of the childs growth and development and secondly, the prognosis could be clearer to the family and the medical staff as well. Our current paper is to sensitize paediatricians, physicians and orthopedic surgeons regarding the necessity to detect the aetiological understanding in every child who manifests a constellation of malformation complex. Lesons:Scoliosis and kyphosis/kyphoscoliosis are not a diagnosis in themselves. Such deformities are mostly a symptom complex correlated to dozens of types of syndromic associations. The rate curve progression and the final severity of congenital spine tilting are related to 3 factors: (a) the type of vertebral malformation present, (b) the patients phenotype, and (c) the diagnosis.

The constellation of skeletal deformities in a family with mixed types of mucopolysaccharidoses: Case report

Introduction:A 13-year-old child was clinically diagnosed with mucopolysaccharidosis type VI—Maroteaux–Lamy syndrome (MPS VI) at the age of 5 years, and the diagnosis was confirmed biochemically and genetically (homozygous mutation in ARSB gene). At that time, his older brother manifested with increasing severe mental retardation. His urinary glycosaminoglycan excretion in urine was elevated, but there was only 1 mutation in the ARSB gene defining him as a healthy carrier of MPS VI. The 15-year-old boy was born with dysmorphic facial features, cleft lip and palate, and multiple contractures associated with profound skeletal deformities manifested, severe mental retardation, and seizures, leading to the diagnosis of cerebral palsy from birth on.Clinical and radiographic phenotypic characterization was the baseline tool to document the older sibling, parents, and relatives, all of them examined at the Orthopaedic Hospital of Speising, Vienna, Austria. The family history (from maternal and paternal sides) showed >10 subjects with variable clinical histories of hyperactivity and attention deficit disorder, depression, and a diversity of skeletal abnormalities, such as dysplastic spondylolisthesis, discovertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age). Methods:Eleven patients in a family with interrelated marriages (two male siblings of 15 and 13-year-old), parents and relatives over three generations were enrolled. One of the siblings was diagnosed with Maroteaux-Lamy syndrome at the age of five-years and mutation of the ARBS gene has been encountered. The older sibling manifested at birth craniofacial abnormalities associated with multiple contracture and seizures. Cerebral palsy was the suggested diagnosis. Clinical and radiographic phenotypes were the baseline tool to document the older sibling, parents and relatives at the orthopaedic Hospital of Speising, Vienna, Austria. These were followed by whole Exome sequencing in three family subjects. Results:A series of genetic studies in the older sibling showed homozygous mutation in GNS gene compatible with MPS IIID. Both parents are first related and were found to be heterozygous for N-acetylglucosamine-6-sulfatase GNS gene. Family history showed more than 10 subjects with variable clinical presentations such as dysplastic spondylolisthesis, disco-vertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age). Conclusion:Owing to the multiple systemic involvements, a genetic cause was suspected and a molecular genetic investigation by using whole-exome-sequencing method in 3 family subjects (trios) was performed: the 15-year-old boy and his parents. A homozygous splice-site-mutation in the GNS gene could be found, compatible with mucopolysaccharidosis–Sanfillipo syndrome (type IIID). Both parents are first related and were now found also to be heterozygous for the GNS gene mutation found in their older son. Therefore, both parents are heterozygous carriers for the ARSB gene mutation but also the GNS gene mutation. In the son with MPS VI, no mutation in the GNS gene was found, but the brother with MPS IIID was heterozygous for the ARSB gene mutation.We presume that the intrafamilial variability of clinical signs in different family members could be the result of various mutations in the ARSB/GNS genes in the carriers or potential modulating effects of other genes or differences in genetic backgrounds.

Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management: Schmid's Type of Metaphyseal Chondrodysplasia

There are several types of metaphyseal chondrodysplasia and various clinical types have been differentiated. The Schmid type of metaphyseal chondrodysplasia is the most common. Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. The Schmid type of metaphyseal dysostosis is characterized by failure of normal mineralization of the zone of provisional calcification, leading to widened physes and enlarged knobby metaphyses, effectively causing shortening of the tubular bones, splaying of the metaphyses, coxa vara, and bow legs. Orthopaedic interventions were primarily performed on the lower extremities.