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1.
Genet Med ; 26(5): 101086, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38288684

RESUMEN

PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder. Biallelic pathogenic variants in CYP27A1, encoding for sterol 27-hydroxylase, impair cholic acid (CA) and chenodeoxycholic acid (CDCA) synthesis and lead to accumulation of cholestanol and C27 bile alcohols. Treatment with CDCA decreases the accumulation of these harmful metabolites and slows disease progression. Currently, CDCA is contraindicated for use during pregnancy based on animal studies that showed that high-dose CDCA may cause fetal harm when administered to pregnant animals. Data regarding the safety of CDCA treatment in humans are lacking. METHODS: We present a case series of 19 pregnancies in 9 women with CTX who either received CDCA treatment throughout pregnancy or did not. RESULTS: In 11 pregnancies where mothers continued CDCA treatment, no complications were reported, and newborns were born at or near full term, with normal birth weight and Apgar scores. In 8 pregnancies where mothers did not receive CDCA, 2 newborns experienced elevated bilirubin soon after birth. One woman who stopped treatment during her pregnancy deteriorated neurologically while off treatment. CONCLUSION: The data we present support the benefit of continued CDCA treatment in pregnant women with CTX for both the affected women and their offspring.


Asunto(s)
Ácido Quenodesoxicólico , Xantomatosis Cerebrotendinosa , Humanos , Femenino , Ácido Quenodesoxicólico/uso terapéutico , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Xantomatosis Cerebrotendinosa/genética , Embarazo , Adulto , Colestanotriol 26-Monooxigenasa/genética , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/genética , Recién Nacido
2.
J Inherit Metab Dis ; 45(5): 981-995, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35758105

RESUMEN

Inborn errors of metabolism are genetic disorders that need to be recognized as early as possible because treatment may be available. In late-onset forms, core symptoms are movement disorders, psychiatric symptoms, and cognitive impairment. Eye movement disorders are considered to be frequent too, although specific knowledge is lacking. We describe and analyze eye movements in patients with an inborn error of metabolism, and see whether they can serve as an additional clue in the diagnosis of particularly late-onset inborn errors of metabolism. Demographics, disease characteristics, and treatment data were collected. All patients underwent a standardized videotaped neurological examination and a video-oculography. Videos are included. We included 37 patients with 15 different inborn errors of metabolism, including 18 patients with a late-onset form. With the exception of vertical supranuclear gaze palsy in Niemann-Pick type C and external ophthalmolplegia in Kearns-Sayre syndrome, no relation was found between the type of eye movement disorder and the underlying metabolic disorder. Movement disorders were present in 29 patients (78%), psychiatric symptoms in 14 (38%), and cognitive deficits in 26 patients (70%). In 87% of the patients with late-onset disease, eye movement disorders were combined with one or more of these core symptoms. To conclude, eye movement disorders are present in different types of inborn errors of metabolism, but are often not specific to the underlying disorder. However, the combination of eye movement disorders with movement disorders, psychiatric symptoms, or cognitive deficits can serve as a diagnostic clue for an underlying late-onset inborn error of metabolism.


Asunto(s)
Trastornos Mentales , Enfermedades Metabólicas , Errores Innatos del Metabolismo , Trastornos del Movimiento , Trastornos de la Motilidad Ocular , Humanos , Enfermedades Metabólicas/diagnóstico , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/genética , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/etiología , Trastornos de la Motilidad Ocular/etiología
3.
Neurol Sci ; 41(4): 943-949, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31863326

RESUMEN

OBJECTIVE: To evaluate the safety and effectiveness of chenodeoxycholic acid (CDCA) treatment in patients with cerebrotendinous xanthomatosis (CTX). METHODS: Two retrospective cohort studies were conducted in CTX patients who underwent CDCA treatment: one in the Netherlands (NL; CDCA-STUK-15-001) and one in Italy (IT; CDCA-STRCH-CR-14-001). Eligible patients were aged 2-75 years, had been diagnosed with CTX, and were treated with CDCA orally for ≥1 year. The impact of CDCA treatment on biochemical markers (including serum cholestanol levels) and disease signs and symptoms were assessed, in addition to the safety and tolerability of CDCA treatment. RESULTS: A total of 35 patients were screened in the NL study and were diagnosed with CTX at 25.6 (± 13.7 SD) years on average. These patients were treated with CDCA and followed up for a median of 9.00 (range: 0.4-26.3) years. In addition, 28 patients were enrolled in the IT study and were diagnosed at 35.0 (± 11.4 SD) years on average (median duration of CDCA treatment: 5.75 [range: 0.0-25.0] years). Signs and symptoms of disease resolved, improved, or remained stable in many patients, with concomitant improvements in biochemical marker levels (serum cholestanol, p < 0.001; 7α-hydroxy-4-cholesten-3-one, p < 0.001 [IT study]). CONCLUSIONS: The outcomes of these retrospective cohort studies indicate that CDCA is effective in the long-term treatment of CTX, with an acceptable safety profile.


Asunto(s)
Ácido Quenodesoxicólico/farmacología , Colestanol/sangre , Fármacos Gastrointestinales/farmacología , Xantomatosis Cerebrotendinosa/sangre , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Adulto , Biomarcadores/sangre , Ácido Quenodesoxicólico/administración & dosificación , Ácido Quenodesoxicólico/efectos adversos , Estudios de Seguimiento , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Humanos , Italia , Persona de Mediana Edad , Países Bajos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
4.
Clin Genet ; 96(2): 126-133, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30919934

RESUMEN

In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3-5/LGMD2C-E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR-LGMD and MMD in the Netherlands amounted to 14.4 × 10-6 . Thirty-three novel mutations were identified. A wide range in age of onset (0-72 years) and loss of ambulation (5-74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non-invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.


Asunto(s)
Predisposición Genética a la Enfermedad , Distrofia Muscular de Cinturas/epidemiología , Distrofia Muscular de Cinturas/genética , Alelos , Biomarcadores , Biopsia , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Distrofia Muscular de Cinturas/diagnóstico , Países Bajos/epidemiología , Fenotipo , Vigilancia de la Población , Estudios Retrospectivos
5.
Neuropediatrics ; 50(1): 54-56, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30477031

RESUMEN

We report the case of a 9 year-old boy, presenting with an acute encephalitis with cerebrospinal fluid pleiocytosis. MRI showed T2/FLAIR (fluid attenuated inversion recovery) hyperintense signals of basal ganglia and cortex, EEG (electro encephalogram) showed diffuse slowing with epileptic discharges. A repetitively elevated IgM/IgG serologic response against Mycoplasma pneumoniae was observed with polymerase chain reaction in serum and cerebrospinal fluid remaining negative. No other pathogen or antigen could be identified. High IgG and IgM levels against the glycolipid galactocerebroside were detected in serum but not in CSF. After treatment with corticosteroids, the patient fully recovered. Brain MRI and EEG investigation returned completely normal. Besides a primary infection of the central nervous system, M. pneumoniae is associated with a parainfectious encephalitis in children which may be mediated by antibodies to galactocerebroside.


Asunto(s)
Autoanticuerpos/sangre , Encefalitis/sangre , Galactosilceramidas/sangre , Mycoplasma pneumoniae , Neumonía por Mycoplasma/sangre , Niño , Encefalitis/diagnóstico por imagen , Humanos , Masculino , Neumonía por Mycoplasma/diagnóstico por imagen
6.
J Inherit Metab Dis ; 41(4): 641-646, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-28894950

RESUMEN

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism (IEM) due to mutations in the CYP27A1 gene. The clinical picture ranges from being nearly asymptomatic in early childhood, up to severe disability at adult age. Infantile-onset diarrhea and juvenile-onset cataract are the earliest symptoms in childhood. In the current study, we evaluated the presence of autism spectrum disorder (ASD) in a large cohort of CTX patients. METHODS: We performed a retrospective patient file study in 77 genetically confirmed Dutch CTX patients to determine the frequency of ASD. In addition, we compared plasma cholestanol levels in CTX patients with and without a diagnosis of ASD and tried to establish a relation between CYP27A1 genotype and ASD. RESULTS: In our CTX cohort, 10 patients (13%; nine pediatric and one adult) with ASD were identified. At the time of diagnosis of ASD, most patients only exhibited symptoms of diarrhea and/or intellectual disability without signs of cataract or neurological symptoms. No correlation was found between the presence of ASD and the level of cholestanol or CYP27A1 genotype. The behavioral problems stabilized or improved after treatment initiation with chenodeoxycholic acid (CDCA) in all pediatric patients. CONCLUSIONS: We conclude that ASD is an early and probably underestimated frequent feature in CTX. Metabolic screening for CTX should be performed in patients with ASD when accompanied by diarrhea, intellectual disability, juvenile cataract, and/or neurological involvement. Early recognition allows for earlier initiation of specific treatment and will improve clinical outcome. Our results add CTX to the list of treatable IEMs associated with ASD.


Asunto(s)
Trastorno del Espectro Autista/diagnóstico , Xantomatosis Cerebrotendinosa/diagnóstico , Adolescente , Adulto , Trastorno del Espectro Autista/sangre , Catarata/etiología , Ácido Quenodesoxicólico/uso terapéutico , Niño , Preescolar , Colestanol/sangre , Diarrea/etiología , Femenino , Humanos , Discapacidad Intelectual/etiología , Masculino , Estudios Retrospectivos , Xantomatosis Cerebrotendinosa/sangre , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Adulto Joven
7.
J Ultrasound Med ; 37(6): 1565-1574, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29159899

RESUMEN

The differential diagnosis of upper extremity mononeuritis multiplex includes neuralgic amyotrophy, vasculitic neuropathy, and Lewis-Sumner syndrome. We describe 3 patients initially suspected of neuralgic amyotrophy, who had an extremely painful, protracted, progressive disease course, not fitting one of these established diagnoses. Nerve ultrasonography showed focal caliber changes of the roots, plexus, and limb nerves. Electromyography showed predominant multifocal axonopathy. Ongoing autoimmune neuropathy was suspected. Steroid treatment provided temporary relief, and intravenous immunoglobulin A sustained pain decrease and functional improvement. These patients appear to have extremely painful axonal inflammatory neuropathy, with a good response to immune-modulating treatment.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Neuritis del Plexo Braquial/diagnóstico , Dolor/etiología , Ultrasonografía/métodos , Extremidad Superior/diagnóstico por imagen , Extremidad Superior/inervación , Anciano , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Neuritis del Plexo Braquial/complicaciones , Neuritis del Plexo Braquial/tratamiento farmacológico , Diagnóstico Diferencial , Electromiografía/métodos , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulinas , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico
8.
J Lipid Res ; 58(5): 1002-1007, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28314860

RESUMEN

Cerebrotendinous xanthomatosis (CTX) is a treatable neurodegenerative metabolic disorder of bile acid synthesis in which symptoms can be prevented if treatment with chenodeoxycholic acid supplementation is initiated early in life, making CTX an excellent candidate for newborn screening. We developed a new dried blood spot (DBS) screening assay for this disorder on the basis of different ratios between the accumulating cholestanetetrol glucuronide (tetrol) and specific bile acids/bile acid intermediates, without the need for derivatization. A quarter-inch DBS punch was extracted with methanol, internal standards were added, and after concentration the extract was injected into the tandem mass spectrometer using a 2 min flow injection analysis for which specific transitions were measured for cholestanetetrol glucuronide, taurochenodeoxycholic acid (t-CDCA), and taurotrihydroxycholestanoic acid (t-THCA). A proof-of-principle experiment was performed using 217 Guthrie cards from healthy term/preterm newborns, CTX patients, and Zellweger patients. Using two calculated biomarkers, tetrol:t-CDCA and t-THCA:tetrol, this straightforward method achieved an excellent separation between DBSs of CTX patients and those of controls, Zellweger patients, and newborns with cholestasis. The results of this small pilot study indicate that the tetrol:t-CDCA ratio is an excellent derived biomarker for CTX that has the potential to be used in neonatal screening programs.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Pruebas con Sangre Seca/métodos , Glucurónidos/metabolismo , Tamizaje Neonatal/métodos , Xantomatosis Cerebrotendinosa/sangre , Xantomatosis Cerebrotendinosa/diagnóstico , Adolescente , Niño , Preescolar , Colestasis/complicaciones , Femenino , Humanos , Recién Nacido , Masculino , Xantomatosis Cerebrotendinosa/complicaciones , Xantomatosis Cerebrotendinosa/metabolismo
9.
Am J Hum Genet ; 92(6): 946-54, 2013 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-23664116

RESUMEN

Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.


Asunto(s)
Proteínas Portadoras/genética , Atrofia Muscular Espinal/genética , Mutación Missense , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Proteínas Portadoras/metabolismo , Preescolar , Secuencia Conservada , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Genes Dominantes , Estudios de Asociación Genética , Ligamiento Genético , Aparato de Golgi/metabolismo , Aparato de Golgi/patología , Células HeLa , Humanos , Masculino , Proteínas Asociadas a Microtúbulos , Atrofia Muscular Espinal/congénito , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Linaje , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN
10.
Rheumatology (Oxford) ; 55(7): 1273-6, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27032423

RESUMEN

OBJECTIVE: The aim was to examine the prevalence of abnormal creatine kinase (CK) and thyroid stimulating hormone (TSH) values and previously unknown myopathy or thyroid disease in patients with suspected FM syndrome (FMS). METHODS: All adult patients with suspected FMS referred to the study hospital between November 2011 and April 2014 could participate. Patients with a history of myopathy or a previous diagnosis of thyroid disorder were excluded. Outcome measures were the percentages of abnormal CK and TSH values and the final diagnosis in those patients. RESULTS: Three hundred and seventy-three patients were included in this study (94% female, mean age 42 years). Of these patients, 7.5% (95% CI: 5.2, 10.6%) had an abnormal CK according to the local reference values. Applying the European Federation of the Neurological Societies guideline, this changed to 0.5% (95% CI: 0.2, 1.9%). In none of these patients was hyperCKaemia-related myopathy diagnosed, and the final diagnosis was FMS in 89% of the patients. Of the total number of patients, 3.5% (95% CI: 2.1, 5.9%) had an elevated TSH and 1.4% (95 CI: 0.6, 3.1%) a lowered TSH, with one patient having a somewhat lowered free thyroid hormone level. The final diagnosis was FMS in all these patients. CONCLUSION: Abnormal CK and TSH values are rare in patients with suspected FMS and do not result in an alternative diagnosis. Therefore, it seems that routine testing of CK and TSH levels in patients with suspected FMS referred to secondary care does not contribute to the diagnostic process.


Asunto(s)
Creatina Quinasa/sangre , Fibromialgia/diagnóstico , Tirotropina/sangre , Adulto , Biomarcadores/sangre , Estudios Transversales , Femenino , Fibromialgia/sangre , Humanos , Masculino , Valor Predictivo de las Pruebas , Valores de Referencia
12.
Eur J Pediatr ; 175(1): 143-6, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26156051

RESUMEN

UNLABELLED: We present a two-week old girl who was diagnosed with cerebrotendinous xanthomatosis (CTX), an inborn error of bile acid synthesis, after a diagnostic workup for convulsions which were shown to be caused by a parechovirus encephalitis. The diagnosis of CTX was confirmed with CYP27A1 mutation analysis. She was started on chenodeoxycholic acid (CDCA) supplementation, which inhibits cholestanol production through a feedback mechanism, at the advised dosage of 15 mg/kg/day. Within 6 weeks, she developed jaundice with hepatomegaly. CDCA supplementation was stopped after which liver size and function rapidly normalised. CDCA supplementation was then restarted and maintained at 5 mg/kg/day. Cholestanol, liver enzymes and total bilirubin were frequently monitored in the patient, who is now 2.8 years of age, and have remained within normal range. Her psychomotor development has been normal. CONCLUSION: adequate metabolic control was achieved in an infant with CTX with CDCA supplementation at a dosage of 5 mg/kg/day and was well tolerated. CDCA supplementation at 15 mg/kg/day seems hepatotoxic in infants and should not be used. This is relevant in view of the possible inclusion of CTX in newborn screening programs in the near future. WHAT IS KNOWN: Cerebrotendinous xanthomatosis (CTX), an inborn error of bile acid synthesis, is a progressive neurological disorder. Symptoms of CTX can be halted, and likely prevented, with chenodeoxycholic acid (CDCA) supplementation, making CTX a good candidate for newborn screening. What is New: CDCA supplementation at the advised dosage of 15 mg/kg/day in children seems hepatoxic in infants with CTX. Adequate metabolic control in an infant with CTX was achieved with CDCA supplementation at 5 mg/kg/day and well tolerated.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Ácido Quenodesoxicólico/efectos adversos , Xantomatosis Cerebrotendinosa/complicaciones , Ácido Quenodesoxicólico/administración & dosificación , Preescolar , Encefalitis Viral , Femenino , Humanos , Recién Nacido , Tamizaje Neonatal , Parechovirus , Infecciones por Picornaviridae/complicaciones , Xantomatosis Cerebrotendinosa/etiología , Xantomatosis Cerebrotendinosa/metabolismo
13.
Muscle Nerve ; 51(1): 35-41, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24817269

RESUMEN

INTRODUCTION: In this exploratory study we investigated whether ultrasound can visualize the neonatal cervical roots and brachial plexus. METHODS: In 12 healthy neonates <2 days old, the neck region was studied unilaterally with ultrasound using a small-footprint 15-7-MHz transducer. RESULTS: The C5-C8 nerve roots and brachial plexus could be imaged with sufficient delineation of the root exits to assess their integrity. The brachial plexus was more difficult to discern from the surrounding area in neonates compared with adults, especially in the interscalene region because of the smaller amount of connective tissue in and surrounding muscles and nerves. In addition, the large deposits of brown fat make for a different ultrasound appearance of the neonatal neck compared with adults. CONCLUSIONS: Ultrasound of the neonatal cervical nerve roots is feasible and may be used as a non-invasive screening technique to assess nerve root integrity in obstetric brachial plexus injury.


Asunto(s)
Plexo Braquial/diagnóstico por imagen , Vértebras Cervicales/diagnóstico por imagen , Raíces Nerviosas Espinales/ultraestructura , Ultrasonografía , Plexo Braquial/anatomía & histología , Vértebras Cervicales/anatomía & histología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Raíces Nerviosas Espinales/anatomía & histología , Tomografía Computarizada por Rayos X
14.
J Inherit Metab Dis ; 38(2): 359-61, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25488625

RESUMEN

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder. Male patients develop adrenocortical insufficiency (80 % before 18 years), a chronic myelopathy (adrenomyeloneuropathy (AMN); all in adulthood), or progressive cerebral demyelination (cerebral ALD; 40 % before 18 years). Cerebral ALD is treated with haematopoetic cell transplantation (HCT). It is unknown if AMN still develops in patients with X-ALD that underwent HCT for cerebral ALD in childhood. PATIENTS AND METHODS: A retrospective observational study was performed by selecting all adult patients with X-ALD in our cohort that underwent HCT in childhood. RESULTS: This retrospective study found that three out of five patients in our cohort who underwent HCT in childhood developed signs of myelopathy in adulthood. CONCLUSION: These data suggest that HCT for cerebral ALD in childhood does not prevent the onset of AMN in X-ALD in adulthood.


Asunto(s)
Adrenoleucodistrofia/cirugía , Trasplante de Células Madre Hematopoyéticas , Enfermedades de la Médula Espinal/etiología , Adolescente , Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/diagnóstico , Adulto , Factores de Edad , Niño , Preescolar , Progresión de la Enfermedad , Humanos , Masculino , Estudios Retrospectivos , Enfermedades de la Médula Espinal/diagnóstico , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
16.
Brain ; 135(Pt 4): 1081-101, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22396395

RESUMEN

Myasthenia gravis is a paralytic disorder with autoantibodies against acetylcholine receptors at the neuromuscular junction. A proportion of patients instead has antibodies against muscle-specific kinase, a protein essential for acetylcholine receptor clustering. These are generally of the immunoglobulin-G4 subclass and correlate with disease severity, suggesting specific myasthenogenic activity. However, immunoglobulin-G4 subclass antibodies are generally considered to be 'benign' and direct proof for their pathogenicity in muscle-specific kinase myasthenia gravis (or other immunoglobulin-G4-associated disorders) is lacking. Furthermore, the exact electrophysiological synaptic defects caused at neuromuscular junctions by human anti-muscle-specific kinase autoantibodies are hitherto unknown. We show that purified immunoglobulin-G4, but not immunoglobulin-G1-3, from patients with muscle-specific kinase myasthenia gravis binds to mouse neuromuscular junctions in vitro, and that injection into immunodeficient mice causes paralysis. Injected immunoglobulin-G4 caused reduced density and fragmented area of neuromuscular junction acetylcholine receptors. Detailed electrophysiological synaptic analyses revealed severe reduction of postsynaptic acetylcholine sensitivity, and exaggerated depression of presynaptic acetylcholine release during high-rate activity, together causing the (fatigable) muscle weakness. Intriguingly, compensatory transmitter release upregulation, which is the normal homeostatic response in acetylcholine receptor myasthenia gravis, was absent. This conveys extra vulnerability to neurotransmission at muscle-specific kinase myasthenia gravis neuromuscular junctions. Thus, we demonstrate that patient anti-muscle-specific kinase immunoglobulin-G4 is myasthenogenic, independent of additional immune system components, and have elucidated the underlying electrophysiological neuromuscular junction abnormalities.


Asunto(s)
Inmunoglobulina G/efectos adversos , Inmunoglobulina G/sangre , Miastenia Gravis/sangre , Enfermedades de la Unión Neuromuscular/complicaciones , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores Colinérgicos/inmunología , Potenciales de Acción/efectos de los fármacos , Adulto , Animales , Autoanticuerpos/sangre , Modelos Animales de Enfermedad , Electromiografía , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Placa Motora/efectos de los fármacos , Placa Motora/fisiopatología , Contracción Muscular/efectos de los fármacos , Fuerza Muscular/efectos de los fármacos , Fuerza Muscular/fisiología , Miastenia Gravis/complicaciones , Miastenia Gravis/inmunología , Miastenia Gravis/terapia , Conducción Nerviosa/efectos de los fármacos , Conducción Nerviosa/fisiología , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/patología , Unión Neuromuscular/fisiopatología , Unión Neuromuscular/ultraestructura , Enfermedades de la Unión Neuromuscular/patología , Plasmaféresis/métodos , Adulto Joven
17.
BMJ Neurol Open ; 5(2): e000426, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37609505

RESUMEN

Background: Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction disorder and the clinical triad consists of proximal muscle weakness, autonomic symptoms and reduced tendon reflexes. Sluggish pupillary reflexes are common but dilated fixed pupils are rare. Case presentation: We report a patient with a rare clinical course of LEMS. The patient was hospitalised due to progressive dyspnoea. She was ambulant and independent of oxygen at hospitalisation. The following day she suffered an in-hospital cardiac arrest based on hypoxia due to sputum stasis. The neurology department was consulted since the patient did not trigger on the ventilator after cessation of sedation. On neurological examination, the patient had dilated and fixed pupils, severe muscle weakness and areflexia, but a normal consciousness. Finally, she was diagnosed with LEMS. In this case report, the clinical course and diagnostic workup including anti-VGCC antibody testing, imaging and the results of electrophysiological studies are discussed. We also emphasise the importance of malignancy screening since the conventional chest CT was negative for lung carcinoma, but PET-CT raised a high suspicion for small-cell lung carcinoma. Conclusions: A rare course of LEMS, with early respiratory failure and wide, fixed pupils. Regarding repetitive nerve stimulation, it is important to stimulate long enough to see the incremental response. Furthermore, this study illustrated the importance of malignancy screening with PET-CT when there is a high suspicion of small-cell lung carcinoma with negative conventional CT.

18.
Nutrients ; 15(21)2023 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-37960277

RESUMEN

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disease characterized by sterol 27-hydroxylase (CYP27A1) deficiency and, thus, a lack of bile acid synthesis with a marked accumulation of 7α-hydroxylated bile acid precursors. In addition to their renowned lipid-emulgating role, bile acids have been shown to stimulate secretion of the glucose-lowering and satiety-promoting gut hormone glucagon-like peptide 1 (GLP-1). In this paper, we examined postprandial bile acid, glucose, insulin, GLP-1 and fibroblast growth factor 19 (FGF19) plasma profiles in patients with CTX and matched healthy controls. Seven patients and seven age, gender and body mass index matched controls were included and subjected to a 4 h mixed meal test with regular blood sampling. CTX patients withdrew from chenodeoxycholic acid (CDCA) and statin therapy three weeks prior to the test. Postprandial levels of total bile acids were significantly lower in CTX patients and consisted of residual CDCA with low amounts of ursodeoxycholic acid (UDCA). The postprandial plasma glucose peak concentration occurred later in CTX patients compared to controls, and patients' insulin levels remained elevated for a longer time. Postprandial GLP-1 levels were slightly higher in CTX subjects whereas postprandial FGF19 levels were lower in CTX subjects. This novel characterization of CTX patients reveals very low circulating bile acid levels and FGF19 levels, aberrant postprandial glucose and insulin profiles, and elevated postprandial GLP-1 responses.


Asunto(s)
Xantomatosis Cerebrotendinosa , Humanos , Xantomatosis Cerebrotendinosa/metabolismo , Ácidos y Sales Biliares , Ácido Quenodesoxicólico , Insulina , Péptido 1 Similar al Glucagón , Sistema Enzimático del Citocromo P-450 , Glucosa
19.
Clin Chim Acta ; 539: 170-174, 2023 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-36529270

RESUMEN

BACKGROUND AND AIMS: Cerebrotendinous Xanthomatosis (CTX) is a treatable disorder of bile acid synthesis caused by deficiency of 27-sterol hydroxylase -encoded by CYP27A1- leading to gastrointestinal and progressive neuropsychiatric symptoms. Biochemically, CTX is characterized by accumulation of the bile alcohol cholestanetetrol glucuronide (GlcA-tetrol) and the deficiency of tauro-chenodeoxycholic acid (t-CDCA) and tauro-trihydroxycholestanoic acid (t-THCA). MATERIALS AND METHODS: To ascertain the feasibility of CTX newborn screening (NBS) we performed a study with deidentified Dutch dried blood spots using reagents and equipment that is frequently used in NBS laboratories. 20,076 deidentified newborn blood spots were subjected to flow-injection (FIA)-MS/MS and UPLC-MS/MS analysis to determine the concentration of GlcA-tetrol and calculate the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios. RESULTS: Using UPLC-MS/MS analysis both GlcA-tetrol concentration and/or metabolite ratios GlcA-tetrol/t-CDCA proved to be informative biomarkers; newborn DBS results did not overlap with those of the CTX patients. For FIA-MS/MS, GlcA-tetrol also was an excellent marker but when using the combination of the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios also did not yield any screen positives. CONCLUSION: Newborn screening for CTX using only metabolite ratios following the measurement of three CTX biomarkers is possible using either FIA-MS/MS or UPLC-MS/MS, which paves the way for introduction of CTX NBS.


Asunto(s)
Xantomatosis Cerebrotendinosa , Humanos , Recién Nacido , Xantomatosis Cerebrotendinosa/diagnóstico , Xantomatosis Cerebrotendinosa/metabolismo , Espectrometría de Masas en Tándem , Estudios Retrospectivos , Tamizaje Neonatal/métodos , Cromatografía Liquida , Ácido Quenodesoxicólico
20.
Neurology ; 99(13): 559-566, 2022 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-35918173

RESUMEN

OBJECTIVES: To describe long-term follow-up brain MRI findings in patients with cerebrotendinous xanthomatosis (CTX) treated with chenodeoxycholic acid (CDCA). METHODS: Of a cohort of 79 Dutch patients with CTX, we retrospectively reviewed brain MRI findings of patients at diagnosis (before the start of treatment) and after long-term follow-up (7-27 years) in 12 patients. In addition, we report on 2 families with remarkable brain MRI findings. RESULTS: MRI abnormalities showed progression in all 7 patients diagnosed at 24 years or older and only in 1 of 5 patients diagnosed younger than 24 years. MRI findings in the other patients diagnosed younger than 24 years were normal at baseline and remained normal even after follow-up of more than 25 years. The total MRI scores at baseline were 2 and 19 and at follow-up 4 and 37, respectively, for patients diagnosed before or after the age of 24 years, despite a comparable number of treatment years. DISCUSSION: MRI findings are fully in line with our long-term treatment effect article, emphasizing the importance of early diagnosis and treatment in CTX. Expanding the spectrum of brain MRI findings (including the finding of a posterior leukoencephalopathy) leads to a better understanding of the heterogeneity of this treatable disease.


Asunto(s)
Xantomatosis Cerebrotendinosa , Adulto , Ácido Quenodesoxicólico/uso terapéutico , Estudios de Cohortes , Humanos , Imagen por Resonancia Magnética , Estudios Retrospectivos , Xantomatosis Cerebrotendinosa/diagnóstico por imagen , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Adulto Joven
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