Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Fe de errores de «Enfermedad de Fabry: espectro clínico de los angioqueratomas» / rratum of «Fabry Disease and the Clinical Spectrum of Angiokeratomas»

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Fabry disease in children and response to enzyme replacement therapy: results from the Fabry Outcome Survey.

The Fabry Outcome Survey (FOS) was established to extend the knowledge of the natural history of Fabry disease and to assess the effects of enzyme replacement therapy (ERT) with agalsidase alfa. As of March 2009, 64 boys and 34 girls with Fabry disease had enrolled in the FOS and been treated with agalsidase alfa for at least 6 months. The prevalence of symptoms tended to be reduced after 12 and 24 months of ERT in patients who experienced symptoms at baseline. In the entire population, non-significant decreases in the prevalence of gastrointestinal problems in boys and pain crises in girls were observed after 12-24 months. Kidney function and left ventricular mass indexed to height remained stable. Fifty-eight treatment-related adverse events were reported in 23 patients (21 boys and 2 girls), including 55 infusion reactions. Anti-agalsidase alfa IgG antibodies were found in two boys. No IgE antibodies were reported. This study represents the largest observational study of paediatric Fabry disease patients treated with ERT and indicates continued safety of long-term ERT in children. Continued long-term follow-up is recommended to determine early initiation of ERT, which could potentially slow or prevent the progression of serious morbidities of Fabry disease.

Síndrome de Sotos: nueva mutación «sin sentido» del gen NSD1 que presenta cutis laxa neonatal / Sotos syndrome: a novel nonsense mutation in nsd1 gene, presenting with neonatal cutis laxa

El síndrome de Sotos se caracteriza por sobrecrecimiento con facies peculiar, macrocefalia, talla alta y alteraciones del desarrollo psicomotor. Presentamos a un paciente de 20 meses de edad con diagnóstico confirmado por genética molecular con detección de mutación nonsense en el gen NSD1 no descrita previamente, exhibiendo cutis laxa como la característica fenotípica más llamativa en el periodo neonatal. Esta asociación se había descrito previamente en 3 pacientes con diagnóstico clínico de síndrome de Sotos sin diagnóstico molecular confirmatorio. En nuestro paciente, la presencia de cutis laxa llevó al diagnóstico diferencial con los defectos congénitos de glucosilación. En el seguimiento posnatal presentó una somatometría con perímetro cefálico y talla mayores de p97 (cercano a p50 al nacimiento), junto con el desarrollo de rasgos fenotípicos característicos del síndrome de Sotos durante los primeros meses de vida, los que proporcionaron la clave para el diagnóstico clínico y la investigación molecular (AU)

Sotos syndrome is an overgrowth condition characterized by facial gestalt, macrocephaly, excessive height, and different degrees of developmental delay. We report the case of a 20-month-old boy with a confirmatory molecular study, showing a novel nonsense mutation in NSD1 gene, presenting cutis laxa as the main phenotypic trait in the neonatal period. This association has been previously described in 3 patients with a clinical diagnosis of Sotos syndrome, without confirmatory molecular analysis. Our patient was tested for congenital disorders of glycosilation as part of the cutis laxa differential diagnosis. During the postnatal follow-up period the head circumference and height became greater than 97th percentile (having been close to the 50th in the newborn period). These facts and the progressive development of characteristic phenotypic features of Sotos syndrome during the first months of life gave us the clue for the clinical diagnosis and the molecular investigation (AU)

Fabry disease in Spain: description of Spanish patients and a comparison with other European countries using data from the Fabry Outcome Survey (FOS).

AIMS: Fabry disease (FD) is an X-chromosome-linked transmitted lysosomal storage disorder as a result of the deficient activity of enzyme α-galactosidase A. This leads to accumulation of neutral glycosphingolipids associated with organ involvement and premature death. We report the clinical characteristics of Spanish patients enrolled on the Fabry Outcome Survey (FOS; an international multicentre registry for the disease) and also compare these data with those from the rest of Europe. METHODS: Baseline clinical data of 92 patients (41 males and 51 females) are described and analysed globally and according to gender. We compare the data of Spanish patients with those previously published from the rest of Europe patients in FOS. RESULTS: Mean age of onset of symptoms in men was 20, and 24 years in women, with a mean delay of 11 years to the diagnosis in both genders. The predominant clinical involvement in male patients was renal (69%), cardiac (66%) and neurological (60%), and for female patients, it was neurological (42%), cardiac (33%), keratopathy (30%) and nephropathy (28%). Disease severity was significantly higher in male patients. Compared to the rest of European FOS-patients, Spanish patients were diagnosed at an earlier age with a smaller proportion of disease-related involvement for most organ irrespective of gender, though not its global severity in male patients. CONCLUSIONS: We present the largest cohort of Spanish patients diagnosed with FD. The pattern of involvement (though not its global severity) could be different in Spanish patients in comparison with others from Europe. Expanding the knowledge of FD will permit early diagnosis as well as the possibility of starting the specific treatment.

[Sotos syndrome: a novel nonsense mutation in NSD1 gene, presenting with neonatal cutis laxa]. / Síndrome de Sotos: nueva mutación «sin sentido¼ del gen NSD1 que presenta cutis laxa neonatal.

Sotos syndrome is an overgrowth condition characterized by facial gestalt, macrocephaly, excessive height, and different degrees of developmental delay. We report the case of a 20-month-old boy with a confirmatory molecular study, showing a novel nonsense mutation in NSD1 gene, presenting cutis laxa as the main phenotypic trait in the neonatal period. This association has been previously described in 3 patients with a clinical diagnosis of Sotos syndrome, without confirmatory molecular analysis. Our patient was tested for congenital disorders of glycosilation as part of the cutis laxa differential diagnosis. During the postnatal follow-up period the head circumference and height became greater than 97(th) percentile (having been close to the 50(th) in the newborn period). These facts and the progressive development of characteristic phenotypic features of Sotos syndrome during the first months of life gave us the clue for the clinical diagnosis and the molecular investigation.

First experience of enzyme replacement therapy with idursulfase in Spanish patients with Hunter syndrome under 5 years of age: case observations from the Hunter Outcome Survey (HOS).

Hunter syndrome (mucopolysaccharidosis type II [MPS II], OMIM309900) is a rare X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulphatase, resulting in accumulation of glycosaminoglycans (GAGs), multisystem organ failure and early death. Enzyme replacement therapy (ERT) with idursulfase is commercially available since 2007. Early access programs were established since 2005. However, limited information on the effects of ERT in young children is available to date. The aim of this analysis was therefore to determine the effects of ERT on patients younger than 5 years of age. We report data from six Spanish patients with confirmed Hunter syndrome who were younger than 5 years at the start of ERT, and had been treated with weekly intravenous infusions of idursulfase between 6 and 14 months. Baseline and treatment data were obtained from the Hunter Outcome Survey (HOS). HOS is an international database of MPS II patients on ERT or candidates to be treated, that collects data in a registry manner. HOS is supported by Shire Human Genetic Therapies, Inc. (Cambridge, MA, USA). At baseline, all patients showed neurological abnormalities, including ventriculomegaly, hydrocephaly, cerebral atrophy, perivascular changes and white matter lesions. Other signs and symptoms included thoracic deformity, otitis media, joint stiffness and hepatosplenomegaly, demonstrating that children under 5 years old can also be severely affected. ERT reduced urinary GAG levels, and reduced spleen (n = 2) and liver size (n = 1) after only 8 months. Height growth was maintained within the normal range during ERT. Joint mobility either stabilized or improved during ERT. In conclusion, this case series confirms the early onset of signs and symptoms of Hunter syndrome and provides the first evidence of ERT beneficial effects in patients less than 5 years of age. Similar efficacy and safety profiles to those seen in older children can be suggested, although further studies including a direct comparison with older patients would still be required.

Severe cardiac phenotype of Berardinelli-Seip congenital lipodystrophy in an infant with homozygous E189X BSCL2 mutation.

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive condition associating insulin resistance, absence of subcutaneous fat and muscular hypertrophy. Disease-causing mutations have been described in AGPAT2 and BSCL2 genes. Hypertrophic cardiomyopathy is a classical late (third decade) complication which has only been occasionally described in childhood. We report on a 4-month-old Chinese male infant who presented with a severe BSCL "cardiac" phenotype comprising heart failure, hypertension and hypertrophic cardiomyopathy.

Fabry disease and the skin: data from FOS, the Fabry outcome survey.

BACKGROUND: Fabry disease (also known as Anderson-Fabry disease) is a rare, X-linked lysosomal storage disorder that is characterized by accumulation of globotriaosylceramide throughout a range of tissues in the body. OBJECTIVES: To ascertain the prevalence and nature of cutaneous manifestations in patients with Fabry disease and to relate these to the severity of systemic manifestations of the disease. METHODS: We have documented the dermatological features of this disease with reference to data from 714 patients (345 males, 369 females) registered on the Fabry Outcome Survey (FOS), a multicentre European database. RESULTS: We confirm that the commonest disease manifestation is angiokeratoma. Overall, 78% of males and 50% of females had one or more dermatological abnormality, the commonest being angiokeratoma (66% males, 36% females), hypohidrosis (53% males, 28% females), telangiectasia (23% males, 9% females) and lymphoedema (16% males, 6% females). We demonstrate for the first time that the presence of cutaneous vascular lesions correlates with the severity of the systemic manifestations of the disease (pain, renal failure, cardiac disease, premature cerebrovascular disease) as assessed by a severity scoring system. Although the condition is X linked, there is a surprisingly high prevalence of abnormalities in females. CONCLUSIONS: The FOS database is a useful epidemiological tool in establishing the variety and relevance of cutaneous manifestations in Fabry disease. The present study confirms that the presence of dermatological manifestations appears to be a marker of greater severity of systemic disease, which emphasizes the importance of the dermatological assessment of these patients.

Enzyme replacement therapy with agalsidase alfa in children with Fabry disease.

AIM: To assess the effects of enzyme replacement therapy (ERT) in children with Fabry disease. METHODS: Safety and efficacy of ERT with agalsidase alfa, 0.2 mg/kg infused over 40 minutes every 2 weeks for 23 weeks, were studied in a multicentre open-label trial in nine boys and four girls. Median age at the start of the study was 11.0 years (range 3.5-18 years). RESULTS: Fifty-four adverse events were reported in 11 patients. No serious adverse events related to ERT were reported. Twelve of the 54 adverse events were considered possibly or probably related to ERT. Infusion reactions (8 mild, 3 moderate) occurred in four boys, in seven infusions. One boy developed IgG antibodies, although he continued to make good clinical progress. At the end of the study, two of the four boys and the one girl on regular pain medication at baseline had stopped taking analgesics. Brief Pain Inventory (BPI) scores decreased in most patients by week 12 and were sustained until the end of the study. This change was greater in the boys, who had higher (worse) BPI scores at baseline. Pain-related quality of life (QoL) scores also decreased during the study. Plasma globotriaosylceramide concentrations and urinary globotriaosylceramide:sphingomyelin ratios decreased after 12 and 23 weeks of therapy, particularly in the boys. Increases in sweat volume were recorded in three out of five of the boys and in one of two girls tested after 23 weeks of treatment. CONCLUSION: ERT with agalsidase alfa in children with Fabry disease is well tolerated and, in the short term, appears to decrease pain and to improve pain-related QoL.

Cistinosis: desde los cristales de cistina a la cistinosina / No disponible

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[Fabry's disease: diagnosis in the pediatric age group]. / Enfermedad de Fabry: reconocimiento en la edad pediátrica.

OBJECTIVE: Fabry's disease is the second most frequent alteration of glycosphingolipid lysosomal storage diseases (after Gaucher's disease). Typical symptomatology starts in the first decade of life. Neuropathic pain, gastrointestinal involvement with abdominal pain, vomiting and diarrhea and cutaneous manifestations (angiokeratoma) significantly impair quality of life. However, diagnosis is usually made late, in adults aged 20-30 years old. Thus, the aim of this review is to draw pediatricians' attention to the manifestations of Fabry's disease in infancy and childhood, especially now that enzymatic replacement therapy with proven efficacy is available. METHOD: We performed an extensive literature review to present the maximum available information on the pediatric manifestations of Fabry's disease. RESULTS: The most frequent symptomatology before the age 16 years includes neuropathic pain, angiokeratoma, abdominal pain, vomiting, diarrhea, hypoacousia, proteinuria, ophthalmologic alterations, hypohidrosis, fever, and characteristic facial phenotype. The onset of Fabry's disease may occur in infancy but the mean delay in diagnosis is 10 years after the first symptoms. CONCLUSIONS: Increased awareness of Fabry's disease in infancy and childhood could lead to early diagnosis and treatment thus avoiding disease progression.

Enfermedad de Fabry: reconocimiento en la edad pediátrica / Fabry's disease: diagnosis in the pediatric age group

Objetivo: La enfermedad de Fabry es la segunda alteración más frecuente por acumulación lisosómica de glucoesfingolípidos (después de la enfermedad de Gaucher). La sintomatología típica de la enfermedad suele empezar a manifestarse a partir de la primera década de la vida. Los síntomas del proceso, como dolor neuropático, afectación gastrointestinal con dolor abdominal, vómitos y diarreas, y manifestaciones cutáneas (angioqueratoma), son motivo de una importante afectación de la calidad de vida. Sin embargo, el diagnóstico de la enfermedad suele hacerse de manera muy diferida, por lo general en el adulto de 20-30 años. Así pues, la finalidad de esta revisión es llamar la atención a la comunidad pediátrica sobre las manifestaciones de la enfermedad de Fabry en el niño, especialmente en este momento en que un tratamiento de sustitución enzimática ha demostrado su efectividad para conseguir la regresión de la enfermedad. Método: Revisión de la bibliografía dirigida a ofrecer el máximo de información sobre las manifestaciones pediátricas de la enfermedad de Fabry. Resultados: La sintomatología más frecuente en menores de 16 años consiste en dolor neuropático, angioqueratoma, dolores abdominales, vómitos y diarreas, hipoacusia, proteinuria, alteraciones oftalmológicas, hipohidrosis, fiebre y fenotipo facial característico. La enfermedad de Fabry de inicio en la infancia suele diagnosticarse, en promedio, unos 10 años después del inicio de la sintomatología. Conclusiones: Un reconocimiento progresivo de la enfermedad de Fabry en la infancia puede permitir el diagnóstico rápido y la instauración de un tratamiento eficaz, evitando la progresión de ésta (AU)

[Diagnostic strategy for mitochondrial diseases]. / Estrategia diagnóstica de las enfermedades mitocondriales.

OBJECTIVE: The variability of both phenotypic and genotypic expression in mitochondrial diseases makes clinical diagnosis difficult, which is essential to establish therapy, aid in genetic counselling or for performing prenatal diagnosis. We have therefore proposed a strategy to help determine correct diagnosis of these alterations, in an attempt to rationalize the number of tests and, whenever possible, avoid tissue biopsy and minimize the size of the biopsy when indicated. DEVELOPMENT: Based on mitochondrial metabolism and molecular bases, as well as their alterations, a preliminary metabolic examination is carried out including at least one study of cytoplasmatic (lactate/pyruvate) and mitochondrial oxide reduction (hydroxibutirate/acetoacetate) in basal conditions or, if required, following glucose overload or an effort test. Metabolic study, in addition to clinical exploration, are the screening tests used to determine the need for tissue biopsy in which biochemical (pyruvate dehydrogenase, free and total carnitine, beta oxidation enzymes and respiratory chain complexes), genetic (mitochondrial DNA or nuclear alterations) and histologic tests are carried out to confirm diagnosis. CONCLUSIONS: a) Metabolic exploration may discard mitochondrial disease and many cases, avoid the use of an invasive procedure such as tissue biopsy. b) Biochemical study of tissue biopsy is the only useful key in the confirming of the diagnosis when no mitochondrial and/or nuclear DNA are observed.