The mucopolysaccharidoses: advances in medical care lead to challenges in orthopaedic surgical care.

The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders with clinical manifestations relevant to the orthopaedic surgeon. Our aim was to review the recent advances in their management and the implications for surgical practice. The current literature about MPSs is summarised, emphasising orthopaedic complications and their management. Recent advances in the diagnosis and management of MPSs include the recognition of slowly progressive, late presenting subtypes, developments in life-prolonging systemic treatment and potentially new indications for surgical treatment. The outcomes of surgery in these patients are not yet validated and some procedures have a high rate of complications which differ from those in patients who do not have a MPS. The diagnosis of a MPS should be considered in adolescents or young adults with a previously unrecognised dysplasia of the hip. Surgeons treating patients with a MPS should report their experience and studies should include the assessment of function and quality of life to guide treatment. Cite this article: Bone Joint J 2017;99-B:1132-9.

Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency.

Clinical finding of cutis laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic cutis laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)-congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade. Here, we further expand the list of inborn errors of metabolism associated with cutis laxa by describing the clinical presentation of a 17-month-old girl with Leigh-like syndrome due to enoyl coenzyme A hydratase, short chain, 1, mitochondria (ECHS1) deficiency, a mitochondrial matrix enzyme that catalyzes the second step of the beta-oxidation spiral of fatty acids and plays an important role in amino acid catabolism, particularly valine.

Enzyme replacement therapy for mucopolysaccharidosis VI: long-term cardiac effects of galsulfase (Naglazyme®) therapy.

Characteristic cardiac valve abnormalities and left ventricular hypertrophy are present in untreated patients with mucopolysaccharidosis type VI (MPS VI). Cardiac ultrasound was performed to investigate these findings in subjects during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB, rhN-acetylgalactosamine 4-sulfatase, galsulfase, Naglazyme®). Studies were conducted in 54 subjects before ERT was begun and at specific intervals for up to 96 weeks of weekly infusions of rhASB at 1 mg/kg during phase 1/2, phase 2, and phase 3 trials of rhASB. At baseline, mitral and aortic valve obstruction was present and was significantly greater in those ≥12 years of age. Mild mitral and trace aortic regurgitation were present, the former being significantly greater in those <12 years. Left ventricular hypertrophy, with averaged z-scores ranging from 1.6-1.9 SD greater than normal, was present for ages both <12 and ≥12 years. After 96 weeks of ERT, ventricular septal hypertrophy regressed in those <12 years. For those ≥12 years, septal hypertrophy was unchanged, and aortic regurgitation increased statistically but not physiologically. Obstructive gradients across mitral and aortic valves remained unchanged. The results suggest that long-term ERT is effective in reducing intraventricular septal hypertrophy and preventing progression of cardiac valve abnormalities when administered to those <12 years of age.

Expert recommendations for the laboratory diagnosis of MPS VI.

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). This enzyme is required for the degradation of dermatan sulfate. In its absence, dermatan sulfate accumulates in cells and is excreted in large quantities in urine. Specific therapeutic intervention is available; however, accurate and timely diagnosis is crucial for maximal benefit. To better understand the current practices for diagnosis and to establish diagnostic guidelines, an international MPS VI laboratory diagnostics scientific summit was held in February of 2011 in Miami, Florida. The various steps in the diagnosis of MPS VI were discussed including urinary glycosaminoglycan (uGAG) analysis, enzyme activity analysis, and molecular analysis. The following conclusions were reached. Dilute urine samples pose a significant problem for uGAG analysis and MPS VI patients can be missed by quantitative uGAG testing alone as dermatan sulfate may not always be excreted in large quantities. Enzyme activity analysis is universally acknowledged as a key component of diagnosis; however, several caveats must be considered and the appropriate use of reference enzymes is essential. Molecular analysis supports enzyme activity test results and is essential for carrier testing, subsequent genetic counseling, and prenatal testing. Overall the expert panel recommends caution in the use of uGAG screening alone to rule out or confirm the diagnosis of MPS VI and acknowledges enzyme activity analysis as a critical component of diagnosis. Measurement of another sulfatase enzyme to exclude multiple sulfatase deficiency was recommended prior to the initiation of therapy. When feasible, the use of molecular testing as part of the diagnosis is encouraged. A diagnostic algorithm for MPS VI is provided.

Clinical, enzymatic and molecular characterization of nine new patients with malonyl-coenzyme A decarboxylase deficiency.

We report nine new patients with malonic aciduria associated with enzyme-confirmed malonyl-CoA decarboxylase (MCD) deficiency in eight. Clinical details were available on eight, and molecular genetic characterization was obtained for nine. As for 15 previously described patients, cardinal clinical manifestations included developmental delay and cardiomyopathy; metabolic perturbations (e.g. acidosis) and seizures, however, were infrequent or not observed in our patients. For all, detection of elevated malonic acid in urine (+/- increased C3DC acylcarnitine by analysis employing tandem mass spectrometry) led to pursuit of enzyme studies. MCD activities (nmol/h PER mg protein) revealed: control (n = 22), 16.2 +/- 1.8 (SEM; range 5.7-46.2); patients (n = 8, assayed in duplicate), 1.7 +/- 0.3 (10% of parallel control; range 0.6-2.8). Molecular characterization by DNA sequence analysis and multiplex ligation-dependent probe amplification revealed nine novel mutations (c.796C>T; p.Gln266X, c.481delC; p.Leu161CysfsX18, c.1367A>C; p.Tyr456Ser, c.1319G>T; p.Ser440Ile, c.1430C>T; p.Ser477Phe, c.899G>T; p.Gly300Val, c.799-1683_949-1293del3128, and two other large genomic deletions comprising exons 1 or the complete gene) and two known mutations in the MLYCD gene. Our findings increase the number of enzyme-confirmed MCD-deficient patients by >50%, and expand our understanding of the phenotypic and molecular heterogeneity of this rare disorder.

Cannabis cookies: a cause of coma.

Despite the prevalence of cannabis use in the community, reports of adverse effects in young children are rare. Two cases of cannabis-induced coma are reported following accidental ingestion of cannabis cookies. The possibility of cannabis ingestion should be considered in cases of unexplained coma in a previously well young child if signs of conjunctival hyperaemia, pupillary dilatation and tachycardia are present and other causes such as CNS infection or trauma are unlikely. Specific screening for cannabinoids should be undertaken.

Chagas's disease in the Amazon Basin: Ii. The distribution of Trypanosoma cruzi zymodemes 1 and 3 in Pará State, north Brazil.

In Pará State, Brazil, 123 Trypanosoma cruzi stocks were isolated from 12 silvatic mammal species, five silvatic triatomine species and individuals with acute Chagas's disease. 100 T. cruzi stocks were identified as zymodeme (Z) 1, 17 as Z3 and 6 as Z3 with Z1 ASAT character, but none were T. cruzi Z2. Z1 was predominantly isolated from arboreal mammals, especially Didelphis marsupialis; Z3 was mainly found in terrestrial or burrowing mammals, particularly Dasypus novemcinctus and Monodelphis brevicaudata. It is not clear whether gene exchange occurs between the groups designated as zymodemes but the enzymic "distance" between T. cruzi Z1, Z2 and Z3, their different geographical distributions, host associations and local transmission cycles support the view that these zymodemes represent taxonomic units of fundamental epidemiological significance. T. cruzi (Z1) was isolated for the first time from the silky anteater (Cyclopes didactylus).

Differentiation of newly isolated strains of Trypanosoma (Schizotrypanum) cruzi by agglutination and precipitation reactions.

Serological relationships between new isolates of Trypanosoma cruzi from a single locality have been examined by direct agglutination and immunodiffusion, and compared with established strains. The strains were divided into three groups according to the absorption properties of their precipitinogens. The three groups were defined by the same characteristics as those in which strains of wide-ranging provenance and long laboratory history have been placed by previous workers. A lack of correspondence between the antigenic constitutions of the groups as described here and as described previously was demonstrated using reference strains. Relatedness values were calculated from agglutination titres, which indicated a complex heterogeneity of antigens, and from which a scheme of relationships was drawn.