RESUMEN
BACKGROUND: Pompe disease is a rare autosomal recessive disorder caused by a deficiency of the lysosomal enzyme alpha-glucosidase responsible for degrading glycogen. Late-onset Pompe disease has a complex multisystem phenotype characterized by a range of symptoms. METHODS: An expert panel from the Middle East and North Africa (MENA) region met to create consensus-based guidelines for the diagnosis and treatment of late-onset Pompe disease for the MENA region, where the relative prevalence of Pompe disease is thought to be high but there is a lack of awareness and diagnostic facilities. RESULTS: These guidelines set out practical recommendations and include algorithms for the diagnosis and treatment of late-onset Pompe disease. They detail the ideal diagnostic workup, indicate the patients in whom enzyme replacement therapy should be initiated, and provide guidance on appropriate patient monitoring. CONCLUSIONS: These guidelines will serve to increase awareness of the condition, optimize patient diagnosis and treatment, reduce disease burden, and improve patient outcomes.
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Consenso , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/terapia , Guías de Práctica Clínica como Asunto , África del Norte/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Humanos , Medio Oriente/epidemiologíaRESUMEN
BACKGROUND: Mucopolysaccharidosis type IVa (Morquio A syndrome) and mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) are rare inherited lysosomal storage diseases associated with significant functional impairment and a wide spectrum of debilitating clinical manifestations. These conditions are thought to have higher-than-average prevalence rates in Saudi Arabia due to high rates of consanguineous marriage in the country. There are several unmet needs associated with the management of these diseases in Saudi Arabia. MAIN BODY: The aim of this manuscript is to contextualize unmet management needs and provide recommendations to optimize diagnosis, multidisciplinary care delivery, and local data generation in this disease area. An expert panel was assembled comprising seven consultant geneticists from across Saudi Arabia. The Delphi methodology was used to obtain a consensus on statements relating to several aspects of mucopolysaccharidosis types IVa and VI. A consensus was reached for all statements by means of an online, anonymized voting system. The consensus statements pertain to screening and diagnosis, management approaches, including recommendations pertaining to enzyme replacement therapy, and local data generation. CONCLUSION: The consensus statements presented provide specific recommendations to improve diagnostic and treatment approaches, promote multidisciplinary care and data sharing, and optimize the overall management of these rare inherited diseases in Saudi Arabia.
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Mucopolisacaridosis IV , Humanos , Arabia Saudita , Mucopolisacaridosis IV/terapia , Mucopolisacaridosis IV/diagnóstico , Mucopolisacaridosis IV/epidemiología , Consenso , Mucopolisacaridosis VI/terapia , Mucopolisacaridosis VI/diagnóstico , Terapia de Reemplazo EnzimáticoRESUMEN
Holoprosencephaly (HPE) is a defect of embryonic forebrain resulting from failure of growth and segmentation of the anterior end of the neural tube. It has been classified into 4 types based on the severity of associated brain and facial malformations. The most severe variety called alobar HPE is generally associated with major cranio-facial anomalies such as cyclopia, ethmocephaly, cebocephaly, or cleft-lip/palate. Significant etiological heterogeneity exists in HPE and includes both genetic and environmental causes. Maternal diabetes is a well-established environmental factor with a significant increased risk for HPE. We report on a Saudi Arab girl born to a diabetic mother, with the alobar type of holoprosencephaly, associated with very minimal cranio-facial defects. However, she displayed several other congenital malformations. In addition, she was diagnosed with cystic fibrosis. Simultaneous occurrence of cystic fibrosis and congenital anomalies has been rare.
RESUMEN
AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function.
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Encéfalo/fisiopatología , Discapacidad Intelectual/genética , Receptores AMPA/fisiología , Transmisión Sináptica/fisiología , Alelos , Animales , Carnitina O-Palmitoiltransferasa/metabolismo , Membrana Celular/metabolismo , Cromatografía de Afinidad , Retículo Endoplásmico/metabolismo , Femenino , Humanos , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/fisiopatología , Masculino , Espectrometría de Masas , Proteínas de la Membrana/genética , Ratones , Microscopía Inmunoelectrónica , Mutación , Proteínas del Tejido Nervioso/genética , Linaje , Proteómica , RatasRESUMEN
Bardet-Biedl syndrome is an autosomal recessive disorder characterized by rod-cone dystrophy, postaxial polydactyly, obesity, hypogenitalism, mental retardation, and renal dysfunction. It has both interfamilial and intrafamilial clinical variation. We have studied the clinical spectrum of 11 Saudi Arabian patients from four consanguineous families. Postaxial polydactyly was seen in eight individuals and rod-cone dystrophy in almost all patients. Night blindness and diminished visual acuity manifested at varying ages, beginning as early as 36 months. Obesity was found to be common. Renal anomalies were detected in eight patients (72%) and two of them developed end-stage renal failure at 14 and 15 years of age. We also found an increased prevalence of Hirschsprung's disease among these patients. Hypogenitalism was manifested as micropenis in males and delayed sexual maturation in females. Heart defects were uncommon in our series. In contrast, there was increased susceptibility to develop diabetes mellitus and two of our patients developed diabetes at 15 and 22 years of age.
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Síndrome de Bardet-Biedl/patología , Anomalías Múltiples/patología , Adolescente , Adulto , Pueblo Asiatico , Síndrome de Bardet-Biedl/complicaciones , Niño , Preescolar , Familia , Femenino , Humanos , Recién Nacido , Masculino , Arabia Saudita/etnología , Adulto JovenRESUMEN
The presence of hydrometrocolpos and postaxial polydactyly in a neonate can be caused by two genetic conditions; namely, McKusick-Kaufman syndrome and Bardet-Biedl syndrome. There are no distinct clinical features that allow discrimination between the two syndromes, as the cardinal features of rod-cone dystrophy, obesity, learning disability and renal dysfunction in Bardet-Biedl syndrome are age dependent. McKusick-Kaufman syndrome is characterized by vaginal atresia with hydrometrocolpos, postaxial polydactyly and congenital heart defect. Here we report an unusual presentation of Bardet-Biedl syndrome: a neonate born in a consanguineous family having an older sibling diagnosed with Bardet-Biedl syndrome presenting with postaxial polydactyly and vaginal atresia; the latter causing hydrometrocolpos, hydronephrosis and renal failure. Relief of urinary obstruction by exploratory laparotomy and aspiration of fluid, and vaginal reconstruction gradually reversed the hydronephrosis and renal failure. The patient developed end-stage renal failure towards the end of her first decade, possibly due to underlying renal pathology associated with Bardet-Biedl syndrome.
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Lesión Renal Aguda/diagnóstico por imagen , Lesión Renal Aguda/etiología , Síndrome de Bardet-Biedl/complicaciones , Síndrome de Bardet-Biedl/diagnóstico por imagen , Hidrocolpos/diagnóstico por imagen , Hidrocolpos/etiología , Femenino , Humanos , Hidronefrosis/diagnóstico por imagen , Hidronefrosis/etiología , Recién Nacido , Urografía , Vagina/anomalías , Vagina/diagnóstico por imagenRESUMEN
Hirschsprung's disease (HSCR) is a developmental disorder characterized by the absence of enteric neurons in distal segments of the gut. Though HSCR is isolated (nonsyndromic) in most cases, its association with chromosomal aberrations, some congenital anomalies, and a few syndromes has been documented. We report the association of HSCR with Bardet-Biedl syndrome in 2 siblings born to consanguineous Saudi Arabian parents. Both cases were diagnosed during the neonatal period. The first patient had the severe variety of the disease with aganglionosis involving the entire colon and terminal ileum. He died of postoperative complications. The second child had a limited short segment variety of HSCR. For social reasons, the surgical intervention was done only at 5 years of age with no documented complications.
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Síndrome de Bardet-Biedl/diagnóstico , Síndrome de Bardet-Biedl/genética , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/cirugía , Sulfato de Bario , Enema/métodos , Resultado Fatal , Femenino , Enfermedad de Hirschsprung/cirugía , Humanos , Recién Nacido , Laparotomía/métodos , Masculino , Radiografía Abdominal/métodos , Medición de Riesgo , Arabia Saudita , Hermanos , Resultado del Tratamiento , Ultrasonografía DopplerRESUMEN
Adams-Oliver syndrome (AOS) consists of congenital scalp defects with variable limb defects of unknown pathogenesis. We report on two children with AOS plus additional features including intrauterine growth retardation (IUGR), cutis marmorata telangiectatica congenita (CMTC), pulmonary hypertension (PH), intracranial densities shown in one case to be sites of active bleeding and osteopenia. Autopsy in one case revealed defective vascular smooth muscle cell/pericyte coverage of the vasculature associated with two blood vessel abnormalities. Pericyte absence correlated with vessel dilatation while hyperproliferation of pericytes correlated with vessel stenosis. These findings suggest a unifying pathogenic mechanism for the abnormalities seen in AOS. These and previously reported cases establish that a subset of AOS patients is at high risk for PH.