Identification of 17 novel mutations in 40 Argentinean unrelated families with mucopolysaccharidosis type II (Hunter syndrome).

Mucopolysaccharidosis type II (MPSII) is an X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase (IDS). The human IDS gene is located in chromosome Xq28. This is the first report of genotype and phenotype characterization of 49 Hunter patients from 40 families of Argentina. Thirty different alleles have been identified, and 57% were novel. The frequency of de novo mutations was 10%. Overall, the percentage of private mutations in our series was 75%.

Fabry disease in latin america: data from the fabry registry.

The purpose of these analyses was to characterize demographic and baseline clinical characteristics of Latin American patients with Fabry disease compared to that of patients in the rest of the world. Observational data reported to the Fabry Registry were obtained from untreated patients or prior to treatment with enzyme replacement therapy. As of October 1, 2010, 3,752 patients were enrolled in the Fabry Registry worldwide, including 333 patients within Latin America. Latin American patients tended to be younger than Fabry Registry patients enrolled in the rest of the world: mean current age 35.5 years versus 39.2 years for men (p < 0.05 by t-test), mean age 37.8 years versus 43.6 years for women (p < 0.05 by t-test). A smaller percentage of Latin American patients have received enzyme replacement therapy, compared to patients in the rest of the world: 67% versus 80% for men, and 19% versus 39% of women, respectively. Thirty-one percent of men and 22% of women in Latin America reported experiencing a significant cardiovascular, renal, or cerebrovascular event, at a mean age of 35 ± 12.6 years in men and 44 ± 12.3 years in women. Cardiovascular events were the most common type of initial clinical event among men and women in Latin America. The medical community in Latin America should be aware of Fabry disease as a possible cause of renal or cardiac dysfunction. Increased awareness will facilitate prompt diagnosis and initiation of treatment.

Fabry disease in Argentina: an evaluation of patients enrolled in the Fabry Registry.

AIMS: Fabry disease (FD) is an X-linked inborn error of metabolism caused by alpha-galactosidase A deficiency. The Fabry Registry is an ongoing, global observational database that compiles clinical data from patients with FD. METHODS: Demographic and baseline clinical characteristics of Fabry Registry patients enrolled in Argentina were analysed and compared with patients enrolled in the rest of the world (ROW). Baseline clinical parameters included chronic kidney disease (CKD) stage, urine protein-to-creatinine ratio and left ventricular posterior wall thickness. Only data from untreated patients were included. RESULTS: As of 1 October 2010, 3752 patients were enrolled in the Registry, 70 patients from Argentina and 3682 from the ROW. Argentinean male subjects were younger than Fabry Registry male subjects enrolled in ROW: mean current age 32.5 years vs. 39.0 years for men (p = 0.0257 by t-test). The current age (mean ± standard deviation) of female subjects enrolled in Argentina was not significantly different from that of female subjects enrolled in the ROW: 40.1 ± 17.28 vs. 43.2 ±17.95 years respectively (p = 0.2967). Overall, a smaller percentage of patients from Argentina received ERT compared with patients in the ROW (54% vs. 58% respectively). When evaluated by gender, more men and fewer women in Argentina received ERT compared with ROW (85% vs. 79% for men and 27% vs. 38% for women). A larger proportion of patients in ROW had severe CKD (stage 4 or 5) compared with Argentina (9.8% vs. 0%), most likely because of the older age of the ROW population. CONCLUSIONS: The enrolment of Argentinean patients into the Fabry Registry has steadily increased, as has the inclusion of female and paediatric patients with FD. The medical community in Argentina should be aware of FD in these populations, as awareness will facilitate prompt diagnosis and initiation of treatment, thus leading to improved outcomes.

GFAP mutations, age at onset, and clinical subtypes in Alexander disease.

OBJECTIVE: To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations. METHODS: We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and χ(2) tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes. RESULTS: LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course. CONCLUSIONS: AAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups.

Enfermedad de orina a jarabe de arce / Maple syrup urine disease

Las enfermedades metabólicas pueden presentarse con síntomas, signos y laboratorios inespecíficos, que si no se consideran entre los diagnósticos diferenciales pueden retrasar el diagnóstico de estos pacientes, lo que lleva a un alto grado de secuelas neurológicas o muerte en etapas tempranas. La enfermedad de Orina a Jarabe de Arce es una enfermedad metabólica de baja incidencia caracterizada por la acumulación de niveles tóxicos de valina, isoleucina y principalmente leucina. Se presenta un paciente sin antecedentes que a los 11 días de vida comienza con mala actitud alimentaria, letargia y fontanela tensa. Descartadas las causas infectológicas se realizó un screening para enfermedades metabólicas. Se diagnosticó Leucinosis (Enfermedad de orina con olor a Jarabe de Arce) y se inició el tratamiento con restricción de leucina, valina e isoleucina en la dieta. A los pocos días del tratamiento el paciente mostró evidencias de mejoría clínica y en los parámetros de laboratorio.

Clinical signs, symptoms and lab tests of neonatal metabolic diseases may be unspecific and a high grade of suspicion is necessary to include them among the differential diagnosis avoiding a significant delay in recognizing this condition and consequent risk of neurologic handicap or early dead. Maple syrup urine disease is a congenital metabolic disorder with a low rate of prevalence and characterized by a toxic accumulation of the amino acids valine, isoleucine and mainly leucine. In this report we describe the history of a patient apparently healthy that on the 11th day after birth initiates symptoms like poor feeding, lethargy and tense fontanel. Excluded sepsis a work up for metabolic disease was performed, being diagnosed a leucinosis (Maple syrup urine disease). A dietary treatment with leucine, valine and isoleucine restriction was immediately initiated and a few days after the patient showed significant clinical and lab improvement. A short description and discussion of this disease is presented.

[Restless legs syndrome in Fabry disease: clinical feature associated to neuropathic pain is overlooked]. / Sindrome de piernas inquietas en la enfermedad de Fabry: asociación con dolor neuropatico.

INTRODUCTION: Neuropathic pain (NP) is a main feature of Fabry disease (FD) as consequence of small fiber neuropathy. Restless legs syndrome (RLS) in FD was not described, but it is an important feature in other small fiber neuropathies, i.e., diabetes. The aim of this study was to assess the prevalence of RLS in patients with FD, and its association with neuropathy. PATIENTS AND METHODS: We investigated the occurrence of RLS in four families of classical FD, diagnosed in accordance with the criteria of the International RLS Study Group. Eleven patients, 6 hemicigote and 5 heterocigote, ages among 19 to 32 years old for males and 45 to 56 years old for females, were studied. The 6 hemizigote and 2 heterozigote patients were on enzyme therapy with agalsidase beta. RESULTS: One heterocigote patient had not clinical NP and the other 10 patients had small fiber sensory neuropathy with symptoms: burning and painful feet. RLS was present in 3/6 hemicigote and 1/5 heterocigote patients (36%). In these four patients, RLS was associated with dysesthesias or pain crisis and it was characterized to be a desire to move the low extremities as crisis of motor restlessness. RLS was characterized for worsening of symptoms with rest without diurnal changes. Patients have to uncover the feet for improving burning or sometimes they have to get out of bed in the night looking for relief. Both NP and RLS improved after 3 years of enzyme replacement therapy. CONCLUSIONS: Our data shows that RLS is associated to NP as a treatable manifestation of small fiber involvement in the course of FD.

Síndrome de piernas inquietas en la enfermedad de Fabry: asociación con dolor neuropático / Restless legs syndrome in fabry disease: clinical feature associated to neuropathic pain is overlooked

El dolor neuropático (DN) es una manifestación muy frecuente en la enfermedad de Fabry (EF) porafectación de la fibra fina. El síndrome de piernas inquietas (SPI) se caracteriza por disestesias en las piernas e impulso a moverlas. El SPI suele estar asociado a neuropatía de fibra fina, por ejemplo, diabetes. Nuestra hipótesis se basó en que la intensidaddel DN en la EF podría hacer pasar por alto el SPI. Pacientes y métodos. Se evaluaron 11 pacientes de cuatro familias con EF clásica, seis hemicigotos y cinco heterocigotas, diagnosticados por análisis enzimático y molecular. Rango de edad: en varones, de 19 a 32 años, y en mujeres, de 45 a 56 años. Todos tuvieron un exhaustivo interrogatorio a la búsquedadel SPI y del DN. Los seis hemicigotos recibieron cinco años de tratamiento de reemplazo enzimático (TRE) con agalsidasa beta, y dos mujeres tuvieron igual TRE en los últimos tres años. Resultados. Tres hemicigotos y sólo una heterocigota manifestaron SPI (36%). El SPI apareció después de comenzar el DN. Características del SPI: siempre ligado al DN, presencia de día y de noche, necesidad de mover las piernas en sacudidas o bien frotarse una con otra y descubrirse los pies para aliviarla quemazón, dos pacientes se levantaban a caminar como estrategia de alivio. Después de tres años de TRE, se mejoró el DN y el SPI. Conclusiones. El SPI no está descrito en la EF, pero en nuestra serie se presentó junto con DN, el cual, por su magnitudy emotividad asociadas, podría contribuir a no diagnosticar el SPI; ambas manifestaciones mejoraron con el TRE con agalsidasa beta

Neuropathic pain (NP) is a main feature of Fabry disease (FD) as consequence of small fiber neuropathy.Restless legs syndrome (RLS) in FD was not described, but it is an important feature in other small fiber neuropathies, i.e., diabetes. The aim of this study was to assess the prevalence of RLS in patients with FD, and its association with neuropathy.Patients and methods.We investigated the occurrence of RLS in four families of classical FD, diagnosed in accordance with the criteria of the International RLS Study Group. Eleven patients, 6 hemicigote and 5 heterocigote, ages among 19 to 32 years old for males and 45 to 56 years old for females, were studied. The 6 hemizigote and 2 heterozigote patients were onenzyme therapy with agalsidase beta. Results. One heterocigote patient had not clinical NP and the other 10 patients had small fiber sensory neuropathy with symptoms: burning and painful feet. RLS was present in 3/6 hemicigote and 1/5 heterocigote patients (36%). In these four patients, RLS was associated with dysesthesias or pain crisis and it was characterized tobe a desire to move the low extremities as crisis of motor restlessness. RLS was characterized for worsening of symptoms with rest without diurnal changes. Patients have to uncover the feet for improving burning or sometimes they have to get out of bedin the night looking for relief. Both NP and RLS improved after 3 years of enzyme replacement therapy. Conclusions. Our data shows that RLS is associated to NP as a treatable manifestation of small fiber involvement in the course of FD

[Neuropathic pain in Fabry's disease: heterogeneous remission in three years of enzyme replacement therapy]. / Dolor neuropático en la enfermedad de Fabry: remisión heterogénea en tres años de tratamiento de reemplazo enzimático.

INTRODUCTION: Fabry's disease is associated with acute neuropathic pain (NP). When six males with classic Fabry's disease ended three years of enzyme replacement therapy (ERT), studies were conducted to analyse the progression of the NP. PATIENTS AND METHODS: All of them received 1 mg/kg of agalsidase beta every 14 days. NP in hands and feet was evaluated at 0, 6, 12, 24 and 36 months, two modalities being considered: a) very intense pain or Fabry crises (FC), which forced the patient to rest, take analgesics and apply cold locally; b) acroparesthesias (AP), lower intensity itching, tingling and burning sensations that did not prevent them from continuing with their activities of daily living. The intensity of the FC (IFC) and the AP (IAP) were recorded using the Visual Analogue Scale, and the frequency with which both (FrFC and FrAP, respectively) appeared was measured in days. The one-tailed Wilcoxon test, binomial distribution and bootstrap method were used to carry out the analysis. RESULTS: After six months of ERT the IFC, IAP and FrCF remained the same, although the FrAP had become worse. As shown by the NP indexes that relate IFC/FrFC and IAP/FrAP, progress was therefore favourable. At one year, IFC continued, but FrFC and IAP were lower. At two years, the four NP measurements improved in five patients, although the FC and AP indexes did not vary in one patient. At three years, all the NP variables improved in the six patients. The slope representing NP as a function of time in all the bootstrap analyses was found to be p < 0.001. CONCLUSIONS: NP responded in a favourable, significant and heterogeneous manner and therefore justifies the early indication of ERT.

Dolor neuropático en la enfermedad de Fabry: remisión heterogénea en tres años de tratamiento de reemplazo enzimático / Neuropathic pain in Fabry’s disease: heterogeneous remission in three years of enzyme replacement therapy

Introdución. La enfermedad de Fabry se asocia con undolor neuropático agudo (DN). Cuando seis varones con enfermedadde Fabry clásica finalizaron tres años de tratamiento de reemplazoenzimático (TRE), se analizó la evolución del DN. Pacientesy métodos. Todos recibieron 1 mg/kg de agalsidase beta cada 14días. El DN en manos y pies se evaluó a 0, 6, 12, 24 y 36 meses, condos modalidades: a) dolores muy intensos o crisis Fabry (CF), queobligaban al reposo, analgésicos y aplicación local de frío; b) acroparestesias(AP), sensaciones de hormigueos, pinchazos y quemazónde menor intensidad, que permitían continuar las tareas de lavida diaria. Se registró la intensidad de las CF (ICF) y de las AP(IAP) con la escala analógica visual, y la frecuencia de apariciónen días de ambas (FrCF y FrAP, respectivamente). En el análisis seusó la prueba de Wilcoxon de una cola, distribución binomial y elmétodo bootstrap. Resultados. En seis meses de TRE permanecióigual la ICF, la IAP y la FrCF, y empeoró la FrAP. Luego hubo unaevolución favorable, observada por los índices de DN que relacionanICF/FrCF y IAP/FrAP. Al año, la ICF persistía, pero habíamenores FrCF e IAP. A los dos años mejoraron las cuatro medicionesdel DN en cinco enfermos, aunque un paciente no varió los índicesde CF y AP. A los tres años, los seis pacientes mejorarontodas las variables del DN. La pendiente representativa del DN enfunción del tiempo en el total de remuestreos resultó p < 0,001. Conclusiones.El DN tuvo una respuesta favorable, significativa y heterogénea,y justifica la indicación temprana del TRE

Introduction. Fabry’s disease is associated with acute neuropathic pain (NP). When six males with classic Fabry’sdisease ended three years of enzyme replacement therapy (ERT), studies were conducted to analyse the progression of the NP.Patients and methods. All of them received 1 mg/kg of agalsidase beta every 14 days. NP in hands and feet was evaluated at 0,6, 12, 24 and 36 months, two modalities being considered: a) very intense pain or Fabry crises (FC), which forced the patient torest, take analgesics and apply cold locally; b) acroparesthesias (AP), lower intensity itching, tingling and burning sensationsthat did not prevent them from continuing with their activities of daily living. The intensity of the FC (IFC) and the AP (IAP)were recorded using the Visual Analogue Scale, and the frequency with which both (FrFC and FrAP, respectively) appeared wasmeasured in days. The one-tailed Wilcoxon test, binomial distribution and bootstrap method were used to carry out the analysis.Results. After six months of ERT the IFC, IAP and FrCF remained the same, although the FrAP had become worse. As shownby the NP indexes that relate IFC/FrFC and IAP/FrAP, progress was therefore favourable. At one year, IFC continued, but FrFCand IAP were lower. At two years, the four NP measurements improved in five patients, although the FC and AP indexes didnot vary in one patient. At three years, all the NP variables improved in the six patients. The slope representing NP as a functionof time in all the bootstrap analyses was found to be p < 0.001. Conclusions. NP responded in a favourable, significant andheterogeneous manner and therefore justifies the early indication of ERT

[Congenital mirror movements. Three new cases of a rare condition]. / Movimientos en espejo congénitos. Tres nuevos casos de una rara entidad.

INTRODUCTION: Mirror movements (MM) are involuntary shudders which occur at the same time as voluntary movements of the homologous contralateral muscles. They may occur alone or associated with other pathology. CLINICAL CASES: We present three new cases of congenital MM (CMM) and discuss their clinical, physiopathological and genetic aspects. Case 1. A four year old boy was brought to the clinic because he dropped things held in one hand when he tried to take things with the other. On examination it was seen that when he made a voluntary movement with one hand, the other hand made a similar movement simultaneously and involuntarily. This phenomenon had been observed since he was a few months old. Apart from this, the rest of the neurological examination was normal. Cerebral MR was also normal. Neuropsychological assessment showed borderline intellectual function. Case 2. The first patient's father, who was 26 years old, knew no details of his own family history. Since childhood he had noticed that he himself had made similar movements to those of his son. However, with time, he had managed to partially control and even inhibit these movements. His cerebral MR scan was normal. Case 3. An 11 year old boy consulted for MM, non-fluctuating congenital palpebral ptosis and nocturnal enuresis. The neurological examination and his intelligence were found to be normal. One of his sisters had palpebral ptosis and nocturnal enuresis without MM. His cerebral MR, X-ray of his spine, EMG, electroretinogram, CPK, blood lactate, glucemia, urine and urological examination were normal. CONCLUSIONS: MM may be another manifestation within the clinical spectrum of diverse encephalopathies; may be associated with different syndromes (Kallman, Klippel-Feil and Usher amongst others) or may present alone. Both familial and sporadic cases have been described. We consider our cases 1 and 2 to be of the familial CMM condition, with autosomal dominant inheritance, in which MM was the only finding. The association observed in case 3 has not previously been described. It may possibly be a condition transmitted by autosomal recessive inheritance.