Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency.

BACKGROUND: Mucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I-IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described. METHODS: In this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis. RESULTS: The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS. CONCLUSION: Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X.

100 years of inherited metabolic disorders in Austria-A national registry of minimal birth prevalence, diagnosis, and clinical outcome of inborn errors of metabolism in Austria between 1921 and 2021.

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare disorders characterized by disruption of metabolic pathways. To date, data on incidence and prevalence of IMDs are limited. Taking advantage of a functioning network within the Austrian metabolic group, our registry research aimed to update the data of the "Registry for Inherited Metabolic Disorders" started between 1985 and 1995 with retrospectively retrieved data on patients with IMDs according to the Society for the Study of Inborn Errors of Metabolism International Classification of Diseases 11 (SSIEM ICD11) catalogue. Included in this retrospective register were 2631 patients with an IMD according to the SSIEM ICD11 Classification, who were treated in Austria. Thus, a prevalence of 1.8/10 000 for 2020 and a median minimal birth prevalence of 16.9/100 000 (range 0.7/100 000-113/100 000) were calculated for the period 1921 to February 2021. We detected a male predominance (m:f = 1.2:1) and a mean age of currently alive patients of 17.6 years (range 5.16 months-100 years). Most common diagnoses were phenylketonuria (17.7%), classical galactosaemia (6.6%), and biotinidase deficiency (4.2%). The most common diagnosis categories were disorders of amino acid and peptide metabolism (819/2631; 31.1%), disorders of energy metabolism (396/2631; 15.1%), and lysosomal disorders (395/2631; 15.0%). In addition to its epidemiological relevance, the "Registry for Inherited Metabolic Disorders" is an important tool for enhancing an exchange between care providers. Moreover, by pooling expertise it prospectively improves patient treatment, similar to pediatric oncology protocols. A substantial requirement for ful filling this goal is to regularly update the registry and provide nationwide coverage with inclusion of all medical specialties.

Clinical Phenotype and Bone Biopsy Characteristics in a Child with Proteus Syndrome.

Proteus syndrome is a rare genetic disorder, which is characterized by progressive, segmental, or patchy overgrowth of diverse tissues of all germ layers, including the skeleton. Here, we present a 9-year-old girl with a somatic-activating mutation (c.49G > A; p.Glu17Lys) in AKT1 gene in a mosaic status typical for Proteus syndrome. She presented with hemihypertrophy of the right lower limb and a "moccasin" lesion among others. A transiliac bone biopsy was analyzed for bone histology/histomorphometry as well as bone mineralization density distribution (BMDD) and osteocyte lacunae sections (OLS) characteristics based on quantitative backscattered electron imaging. Bone histomorphometry revealed highly increased mineralizing surface (Z-score + 2.3) and mineral apposition rate (Z-score + 19.3), no osteoclasts (Z-score - 2.1), and an increased amount of primary bone in the external cortex. BMDD abnormalities included a decreased mode calcium concentration in cancellous bone (Z-score - 1.7) and an increased percentage of highly mineralized cortical bone area (Z-score + 2.4) compared to reference. OLS characteristics showed several differences compared to reference data; among them, there were the highly increased OLS-porosity, OLS-area, and OLS-perimeter on the external cortex (Z-scores + 6.8, + 4.4 and 5.4, respectively). Our findings suggest that increased bone formation reduced matrix mineralization in cancellous bone while the enhanced amount of primary bone in the external cortex increased the portion of highly mineralized cortical bone and caused OLS-characteristics abnormalities. Our results indicate further that remodeling of primary bone might be disturbed or delayed in agreement with the decreased number of osteoclasts observed in this child with Proteus syndrome.

Arthrogryposis is a descriptive term, not a specific disease entity: escobar syndrome is an Example.

BACKGROUND: Children born with multiple congenital contractures have been almost always given the diagnosis of arthrogryposis multiplex congenita. Arthrogryposis is a descriptive term, not a specific disease entity. A heterogeneous group of conditions associated with multiple congenital joint contractures (mostly syndromic) should be considered. METHODS: The records of seven children (four boys and three girls with aged 6months- 11 years) of different ethnic origins have been included in this study. The constellation of specific craniofacial dysmorphic features, spine malformation complex, and appendicular skeletal abnormalities in addition to camptodactyly, talipes equinovarus and rocker- bottom feet were a cluster of malformation complex encountered in our patients. Via comprehensive clinical and imaging study (3D reconstruction CT scan), definite diagnosis of Escobar syndrome has been approached. RESULTS: The clinical and imaging phenotype was the key factor towards etiological understanding, treatment and genotype confirmation. We identified compound heterozygous mutations (c.459dupA [p.Val154Serfs*24] and c.794T>G [p.Leu265Serfs*24] of the CHRNG gene in four patients. Bilateral flexion contractures of the knees have been treated by using Iliazarov external fixator. Simultaneous corrections of scoliosis have been achieved by applying either dual traditional growing rods or single growing rods. CONCLUSIONS: The clinical and radiological phenotypic characterizations are the fundamental tool in differentiating Escobar from other forms of multiple contractures. The aim of this study are three folds, firstly to demonstrate the importance of detecting the etiological understanding in children presented with multiple contractures, secondly to refute the general conception among the vast majority of pediatricians and orthopedic surgeons that arthrogryposis multiplex is a diagnostic entity. And thirdly, we were able to detect severe spine deformity via 3D reconstruction CT scan, namely unsegmented posterior spinal bar.

Piepkorn type of osteochondrodysplasia: Defining the severe end of FLNB-related skeletal disorders in three fetuses and a 106-year-old exhibit.

The Piepkorn type of lethal osteochondrodysplasia (POCD) is a rare and lethal dwarfing condition. Four cases have been reported to date. The characteristic features are distinctly shortened "flipper-like" limbs, polysyndactyly, excessive underossification, especially of the limb bones and vertebrae, and large (giant) chondrocytes in the cartilaginous bone primordia. These characteristics allowed the diagnosis of Piepkorn type of osteochondrodysplasia in four new cases, three fetuses of 15 to 22 weeks and one 106-year-old museum exhibit. Piepkorn type of osteochondrodysplasia has been assigned to the giant cell chondrodysplasias such as atelosteogenesis type 1 (AO1) and boomerang dysplasia (BD). Analysis of the Filamin B gene in 3p14.3, which is associated with these disorders, allowed the identification of the first FLNB mutations in Piepkorn type of osteochondrodysplasia. The heterozygous missense mutations, found in the three fetuses, were located in exons 28 and 29, encoding the immunoglobulin-like repeat region R15, one of three mutational hot spots in dominant FLNB-related skeletal disorders. Direct preparations and alcian blue staining revealed single upper and lower arm and leg bone primordia, preaxial oligodactyly, and polysyndactyly with complete fusion and doubling of the middle and end phalanges II-V to produce eight distal finger rays. Considering the unique clinical features and the extent of underossification, Piepkorn type of osteochondrodysplasia can be regarded as a distinct entity within the AO1-BD-POCD continuum.

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. Proteoglycans (PGs) are major constituents of the extracellular matrix of the brain and were proposed to contribute to synaptic plasticity. This report addressed PGs in rat hippocampus and suggests that PGs brevican and versican are linked to spatial memory, and form a complex with the GluR1 subunit of the AMPA receptor, a key signaling molecule in memory mechanisms.

Comparative study of CO2- and Er:YAG laser ablation of multiple cutaneous neurofibromas in von Recklinghausen's disease.

With a prevalence of 1 in 3,000 births, neurofibromatosis type 1 (NF1) is one of the most common genetic disorders and is characterized by an uninhibited expansion of neural tissue. Occasionally, severe deformities occur, but frequently considerable cosmetic disfigurement is caused by the development of hundreds of benign cutaneous neurofibromas. The objective of this study was to evaluate the erbium:yttrium-aluminium-garnet (Er:YAG) laser as a therapeutic option for the removal of multiple cutaneous neurofibromas. In this prospective, comparative, in vivo study, 15,580 neurofibromas (44 operations on 21 patients) were removed via electrosurgery, CO2- or Er:YAG laser ablation. In 12 adjacent test areas, we compared the zone of thermal necrosis, the postoperative pain, the time to reepithelialization, the duration of postoperative erythema and the cosmetic outcome of these surgical methods. When compared to electrosurgery and CO2 laser ablation, the Er:YAG laser ablation outperformed the other methods of tumor removal. Rapid healing by second intention as well as the minimal discomfort and scar formation following Er:YAG laser ablation were noted. After 36 months of follow-up, permanent dyspigmentation was rare and hypertrophic scarring was not observed. Er:YAG laser vaporization of multiple cutaneous neurofibromas is a simple and rapid procedure that results in significantly better cosmetic results than CO2 laser treatment or electrosurgery.

Stone Babies: A Pictorial Essay With Insights From 25 Museal Lithopaedions.

BACKGROUND: Lithopaedion, or "stone baby," represents an exceptionally rare clinical phenomenon with fewer than 350 documented cases existing in the medical literature. This condition arises when an advanced extrauterine pregnancy ceases its developmental trajectory and undergoes a lithification process, potentially resulting in a calcified mass with fetal-like morphology. Typically, lithopaedions remain asymptomatic for decades, but may occasionally elicit acute symptoms necessitating medical intervention. However, predominantly, these entities are incidental findings discovered during radiological examinations or autopsies. RESULTS: In this article, we present a comprehensive overview of 25 lithopaedion cases, including unreported cases from several European medical museums. When feasible, additional radiological imaging was conducted to enhance diagnostic clarity. Furthermore, this article situates lithopaedions within a broader historical perspective and a detailed etiopathogenetic framework, elucidating the physiological and pathological mechanisms contributing to their formation. The phenomenon of lithopaedion is a testimony to the complex and often enigmatic nature of the human body. CONCLUSIONS: By compiling and scrutinizing a substantial number of cases, this review offers valuable insights into the clinical implications of lithopaedions. Furthermore, it highlights the necessity for ongoing research and meticulous documentation of rare medical conditions like this, in order to contribute to a deeper understanding of extraordinary phenomena.

The articular and the craniocervical abnormalities are of confusing age of onset in patients with Maroteaux-Lamy disease (MPS VI).

BACKGROUND: Maroteaux-Lamy disease (MPS Type VI) is an autosomal recessive lysosomal storage disorder. Skeletal abnormalities are vast. Early recognition may facilitate timely diagnosis and intervention, leading to improved patient outcomes. The most challenging is when patients manifest a constellation of craniocervical and articular deformities with variable age of onset. METHODS: We collected 15 patients with MPS VI (aged from 6 years-58 years). From within our practice in Pediatric Orthopedics, we present patients with MPS type VI who were found to manifest a diverse and confusing clinical presentation of hip deformities and cervical cord compression. Stem cell transplants were proposed as treatment tool and enzyme replacement therapy has been instituted in some patients. RESULTS: The spectrum of the clinical involvement in our group of patients was supported firstly via the clinical phenotype followed by assessment of the biochemical defect, which has been detected through the deficiency of N-acetylgalactosamine-4-sulfatase (arylsulphatase B) leading to increased excretion of dermatan sulphate. Secondly, through the molecular genetic results, which showed homozygous or compound heterozygous mutation in the ARSB gene on chromosome 5q14. Hip replacements and decompression operations have been performed to restore function and to alleviate pain in the former and life saving procedure in the latter. CONCLUSIONS: The efforts in searching for the etiological diagnosis in patients with skeletal dysplasia/MPSs has not been rewarding as many had anticipated. This emerged from several facts such as improper clinical documentation, missing diagnostic pointers in radiographic interpretations, limited knowledge in skeletal dysplasia and its variants, and the reliance on underpowered studies. Physicians and radiologists are required to appreciate and assess the diverse phenotypic and the radiographic variability of MPS VI. The importance of considering MPS in the differential diagnosis of other forms skeletal dysplasia is mandatory. Finally, we stress that the value of early diagnosis is to overcome dreadful complications.

Brain malformations in diprosopia observed in clinical cases, museum specimens and artistic representations.

BACKGROUND: Diprosopus is a rare malformation of still unclear aetiology. It describes a laterally double faced monocephalic and single-trunk individual and has to be distinguished from the variant Janus type diprosopus. RESULTS: We examined seven double-faced foetuses, five showing true diprosopus, and one each presenting as monocephalic Janiceps and parasitic conjoined twins. Four of the foetuses presented with (cranio)rachischisis, and two had secondary hydrocephaly. Three foetuses showed cerebral duplication with concordant holoprosencephaly, Dandy-Walker cyst and/or intracranial anterior encephalocele. In the Janiceps twins, cerebral duplication was accompanied by cerebral di-symmetry. In the parasitic twins the cyclopic facial aspects were suggestive of concordant holoprosencephaly. In one of the true diprosopus cases, pregnancy was achieved after intracytoplasmic sperm injection. Whole-exome sequencing, perfomed in one case, did not reveal any possible causative variants.The comparison of our double-faced foetuses to corresponding artistic representations from the Tlatilco culture allowed retrospective assignment of hairstyles to brain malformations. CONCLUSION: Brain malformations in patients with diprosopus may not be regarded as an independent event but rather as a sequel closely related to the duplication of the notochord and neural plate and as a consequence of the cerebral and associated craniospinal structural instabilities.

Smith-Lemli-Opitz syndrome - Fetal phenotypes with special reference to the syndrome-specific internal malformation pattern.

BACKGROUND: Autosomal-recessive SLOS is caused by mutations in the DHCR7 gene. It is defined as a highly variable complex of microcephaly with intellectual disability, characteristic facies, hypospadias, and polysyndactyly. Syndrome diagnosis is often missed at prenatal ultrasound and fetal autopsy METHODS: We performed autopsies and DHCR7 gene analyses in eight fetuses suspected of having SLOS and measured cholesterol values in long-term formalin-fixed tissues of an additional museum exhibit RESULTS: Five of the nine fetuses presented classical features of SLOS, including four cases with atrial/atrioventricular septal defects and renal anomalies, and one with additional bilateral renal agenesis and a Dandy-Walker cyst. These cases allowed for diagnosis at autopsy and subsequent SLOS diagnosis in two siblings. Two fetuses were mildly affected and two fetuses showed additional holoprosencephaly. These four cases and the exhibit had escaped diagnosis at autopsy. The case with bilateral renal agenesis presented a novel combination of a null allele and a putative C-terminus missense mutation in the DHCR7 gene CONCLUSIONS: In view of the discrepancy between the prevalence of SLOS among newborns and the carrier frequency of a heterozygous DHCR7 gene mutation, the syndrome-specific internal malformation pattern may be helpful not to miss SLOS diagnosis in fetuses at prenatal ultrasound and fetal autopsy.

Clinical and Genetic Heterogeneity in Six Tunisian Families With Horizontal Gaze Palsy With Progressive Scoliosis: A Retrospective Study of 13 Cases.

Background: Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) is a rare autosomal recessive congenital disorder characterized by the absence of conjugate horizontal eye movements, and progressive debilitating scoliosis during childhood and adolescence. HGPPS is associated with mutations of the ROBO3 gene. In this study, the objective is to identify pathogenic variants in a cohort of Tunisian patients with HGPPS and to further define ROBO3 genotype-phenotype correlations. Methods: Thirteen Tunisian patients from six unrelated consanguineous families all manifesting HGPPS were genetically investigated. We searched for the causative variants for HGPPS using classical Sanger and whole exome sequencing. Results: Four distinct homozygous mutations were identified in ROBO3 gene. Two of these were newly identified homozygous and non-synonymous mutations, causing effectively damage to the protein by in silico analysis. The other two mutations were previously reported in Tunisian patients with HGPPS. Mutations were validated by Sanger sequencing in parents and affected individuals. Conclusion: To the best of our knowledge, this is the largest ever reported cohort on families with HGPPS in whom ROBO3 mutations were identified. These molecular findings have expanded our knowledge of the ROBO3 mutational spectrum. The relevance of our current study is two-fold; first to assist proper management of the scoliosis and second to protect families at risk.

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

OBJECTIVES: 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. METHODS: Twelve children (seven girls and five boys) aged 7-10 years were enrolled in this study. Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities. A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara. Hemiepiphysiodesis was performed to re-align the genu varum in three children. RESULTS: Other forms of metaphyseal dysostosis were ruled based on full clinical and radiographic phenotypes, with confirmation through molecular pathology. Mutations in the COL10A1 gene located on chromosome 6q21-q22.3 were confirmed. Re-alignment was accomplished in our group of patients. CONCLUSION: The most striking clinical features of Schmid metaphyseal chondrodysplasia which appear within the first 2-3 years of life are: moderate short limbs and short stature, a waddling gait, and increasing shortness of stature with age. The Schmid type of metaphyseal chondrodysplasia is a disorder that arises from defective type X collagen, which is typically found in the hypertrophic zone of the physes. Moderate short stature and a waddling gait associated with pain are the most common clinical presentations. Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases.

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.

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.

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.

Expert Opinions on Managing Fertility and Pregnancy in Patients With Mucopolysaccharidosis

Abstract The mucopolysaccharidosis (MPS) disorders are rare genetic diseases caused by deficiencies in lysosomal enzymes involved in the degradation of glycosaminoglycans, leading to pulmonary, cardiac and neurological dysfunctions, skeletal anomalies, impaired vision, and/or hearing and shortened life spans. Whereas in the past, few individuals with MPS reached adulthood, better diagnosis, multidisciplinary care, and new therapies have led to an increasing number of adult patients with MPS. Therefore, fertility and pregnancy questions in this patient population are becoming more important. Management of fertility issues and pregnancy in patients with MPS is challenging due to the lack of documented cases and a dearth in the literature on this topic. This review presents multidisciplinary expert opinions on managing fertility and pregnancy based on case studies and clinical experience presented at a meeting of MPS specialists held in Berlin, Germany, in April 2015. An overview of the existing literature on this subject is also included.

Reduced levels of DEAD-box proteins DBP-RB and p72 in fetal Down syndrome brains.

Down syndrome (DS) is characterized by abnormal brain morphology and neurological and behavioral functions. The pivotal role of helicases in brain development, growth, and differentiation made us evaluate three DEAD BOX proteins, DEAD-box protein 1 (DBP-RB), DEAD-box protein 3 (HLP2), DEAD-box protein 72 (P72), and the RuvB-like DNA helicase (TIP49b), in fetal brain of controls and DS subjects, using two-dimensional electrophoresis with subsequent mass spectroscopic (MALDI-MS) identification. HLP2 and TIP49b brain levels were comparable between DS and controls, and protein levels of p72 and DBP-RB were significantly reduced in DS fetal cortex (p72: 2.04+/-1.90 vs. 5.57+/-2.56 in controls, p < 0.01; DBP-RB: 0.58+/-0.94 vs. 1.90+/-0.97 in controls, p < 0.01). Impairment of the helicases p72 and DBP-RB may reflect or lead to deficient growth and differentiation of brain development early in life and can be considered pathogenetic factors along with the reported deficits of transcription, splicing, and elongation factors already described in fetal DS brains.

Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA.

Mucopolysaccharidosis IVA (MPS IVA), a progressive lysosomal storage disease, causes skeletal dysplasia through excessive storage of keratan sulfate (KS). We developed an ELISA-sandwich assay that used a MAb specific to KS. Forty-five blood and 59 urine specimens from MPS IVA patients (ages 1-65 y) were analyzed to determine whether KS concentration is a suitable marker for early diagnosis and longitudinal assessment of disease severity. Blood specimens were obtained from patients categorized as phenotypically severe (n = 36) and milder (n = 9). Urine specimens were also analyzed from patients categorized as severe (n = 56) and milder (n = 12), respectively. Blood KS levels (101-1525 ng/mL) in MPS IVA patients were two to eight times higher than those in age-matched controls (15-323 ng/mL). It was found that blood KS level varied with age and clinical severity. Blood KS levels in both MPS IVA and controls peaked between 5 and 10 y of age (mean, 776 versus 234 ng/mL, respectively). Blood levels in severe MPS IVA were 1.5 times higher than in the milder form. In contrast to blood, urine KS levels in both MPS IVA and controls peaked between 1 and 5 y (15.3 versus 0.26 mg/g creatinine), and thereafter declined with age. Urine KS level also varied with age and clinical severity, and the severe MPS IVA phenotype was associated with 6.7 times greater urine KS excretion than the milder one. These findings indicate that the new assay for blood or urine KS may be suitable for early diagnosis and longitudinal assessment of disease severity in MPS IVA.