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1.
JIMD Rep ; 65(4): 233-238, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38974615

RESUMEN

Riboflavin transporter deficiency (RTD) is a genetic disorder of reduced riboflavin (vitamin B2) uptake that causes progressive, multifocal neurological dysfunction. Most patients present in early childhood; if patients present later in life, symptoms usually develop more gradually. We report three previously healthy young adults, who developed rapidly progressive neurological symptoms after decreasing dietary intake of meat and dairy. After a diagnostic odyssey, the diagnosis of a riboflavin transporter deficiency was made. Treatment with high dose oral riboflavin (20-40 mg/kg/day) partially reversed symptoms. This case series highlights that reduced riboflavin intake as a result of dietary changes can unmask RTD at a later age. We emphasize the importance of early recognition of this progressive and potentially lethal disease and show that timely treatment with high dose riboflavin is highly effective.

2.
Eur J Paediatr Neurol ; 41: 91-98, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36410285

RESUMEN

Vici syndrome (OMIM 242840) is a very rare autosomal recessive multisystem disorder first described in 1988. In 2013, bi-allelic loss-of-function mutations in EPG5 were reported to cause Vici syndrome. Five principal diagnostic features of Vici syndrome have been proposed: agenesis of the corpus callosum, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. We identified 15 patients carrying a homozygous founder missense variant in EPG5 who all exhibit a less severe clinical phenotype than classic Vici syndrome. All 15 show typical brain abnormalities on MRI. The homozygous founder variant in EPG5 they carry results in a shorter in-frame transcript and truncated, but likely still residual, EPG5 protein. We speculate that the residual EPG5 protein explains their attenuated phenotype, which is consistent with two previous observations that low expression of EPG5 can lead to an attenuated Vici syndrome phenotype. We propose renaming this condition EPG5-related neurodevelopmental disorder to emphasize the clinical variability of patients with bi-allelic mutations in EPG5.


Asunto(s)
Catarata , Humanos , Catarata/genética , Fenotipo , Homocigoto , Cuerpo Calloso , Proteínas Relacionadas con la Autofagia , Proteínas de Transporte Vesicular/genética
3.
Neonatology ; 119(6): 777-780, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36122554

RESUMEN

An increasing number of women of reproductive age follow vegan diets. Because vegan diets are deficient in a number of essential nutrients, guidelines address the necessity of supplementations such as iron, zinc, and vitamin B12. However, the risk of riboflavin (vitamin B2) deficiency is not properly addressed. We report a case of a male neonate with a life-threatening hypoglycaemia and lactic acidosis due to severe riboflavin deficiency. The mother followed a strict vegan diet with intermittent use of supplements (folic acid, vitamin B12, vitamin D, omega 3). This case highlights the importance of adequate counselling of all pregnant women adhering to vegan diets to ensure sufficient intake of essential nutrients and vitamins, including riboflavin.


Asunto(s)
Dieta Vegana , Embarazo , Recién Nacido , Femenino , Humanos , Masculino , Dieta Vegana/efectos adversos
4.
Clin Genet ; 100(6): 692-702, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34463354

RESUMEN

Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Miopatías Estructurales Congénitas/diagnóstico , Miopatías Estructurales Congénitas/genética , Fenotipo , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Sustitución de Aminoácidos , Biomarcadores , Biopsia , Niño , Preescolar , Estudios Transversales , Femenino , Genes Ligados a X , Estudios de Asociación Genética/métodos , Genotipo , Histocitoquímica , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación , Miopatías Estructurales Congénitas/epidemiología , Países Bajos , Adulto Joven
5.
Life (Basel) ; 11(8)2021 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-34440515

RESUMEN

INTRODUCTION: Lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems are common in Duchenne muscular dystrophy (DMD), but not systematically assessed in regular care. We aimed to determine the prevalence of bladder and bowel dysfunction (BBD) in DMD patients compared with healthy controls (HC). METHODS: The Childhood Bladder and Bowel Dysfunction Questionnaire (CBBDQ) based on the International Rome III criteria and the International Children's Continence Society was filled out by 57 DMD patients and 56 HC. Additionally, possible associations of BBD with, for example, medication use or quality of life were evaluated in an additional questionnaire developed by experts. RESULTS: In 74% of patients versus 56% of HC ≥ 1 LUTS (n.s.) were reported, 68% of patients versus 39% of HC reported ≥1 bowel symptom (p = 0.002) and 53% of patients versus 30% of HC reported combined LUTS and bowel symptoms (p = 0.019). A negative impact of BBD on daily life functioning was reported by 42% of patients. CONCLUSIONS: These data underscore that standard screening for BBD is needed and that the CBBDQ could be of added value to optimize DMD care.

6.
Pediatr Neurol ; 102: 62-66, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31371121

RESUMEN

BACKGROUND: Hereditary folate malabsorption is a multisystem disease owing to biallelic variants in the gene encoding the proton-coupled folate transporter. Hereditary folate malabsorption is treated with folinic acid, aimed to restore blood and cerebrospinal fluid folate levels. Little is known as to whether oral or intramuscular supplementation of folinic acid is most effective. METHODS: Here we describe a one-year-old boy with hereditary folate malabsorption presenting with the typical features including failure to thrive, aphthous stomatitis, macrocytic anemia along with severe developmental impairment and epilepsy, as well as a magnetic resonance imaging of the brain showing bilateral occipital, cortical calcifications characteristic of hereditary folate malabsorption. We compared the effect of treatment with oral folinic acid versus intramuscular folinic acid supplementation by measuring plasma and cerebrospinal fluid folate levels. RESULTS: Compared with oral administration, intramuscular treatment resulted in higher folate levels in blood and, most importantly, normalization of folate levels in cerebrospinal fluid. Clinically, nearly all systemic and neurological symptoms resolved. CONCLUSION: Normal cerebrospinal fluid folate levels can be achieved in individuals with hereditary folate malabsorption with intramuscular (but not with oral) administration of folinic acid.


Asunto(s)
Deficiencia de Ácido Fólico/tratamiento farmacológico , Leucovorina/farmacología , Síndromes de Malabsorción/tratamiento farmacológico , Complejo Vitamínico B/farmacología , Humanos , Lactante , Inyecciones Intramusculares , Leucovorina/administración & dosificación , Masculino , Complejo Vitamínico B/administración & dosificación
7.
Nat Commun ; 10(1): 3094, 2019 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-31300657

RESUMEN

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.


Asunto(s)
Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Receptores AMPA/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Estudios de Cohortes , Femenino , Heterocigoto , Humanos , Lactante , Mutación con Pérdida de Función , Imagen por Resonancia Magnética , Masculino , Trastornos del Neurodesarrollo/diagnóstico por imagen , Adulto Joven
8.
JIMD Rep ; 33: 87-92, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27683254

RESUMEN

Mutations in the mitochondrial arginyl tRNA synthetase (RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). Here we report two patients, compound heterozygous for RARS2 mutations, presenting with early onset epileptic encephalopathy and (progressive) atrophy of both supra- and infratentorial structures. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. Both patients carried a novel missense mutation c.1544A>G (p.(Asp515Gly)) in combination with either a splice site (c.297+2T>G) or a frameshift (c.452_454insC) mutation. The splice site mutation induced skipping of exon 4.These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. We propose to classify RARS2-associated phenotypes as an early onset mitochondrial encephalopathy, since this is more in agreement with both clinical presentation and underlying genetic cause.

9.
Lancet Infect Dis ; 16(11): e261-e266, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27641775

RESUMEN

Mycoplasma hominis is a commensal organism in the genitourinary tract that can cause life-threatening CNS infections in neonates after intrauterine infection or through vertical transmission during birth. We present a case of an 11-day-old neonate presenting with fever and supporting laboratory evidence of a CNS infection. No systemic maternal infection or maternal genitourinary tract infection occurred at the time of delivery. Empirical treatment was initiated, consisting of amoxicillin, cefotaxime, and aciclovir. After clinical deterioration, 16S ribosomal DNA PCR in cerebrospinal fluid detected M hominis, antibiotic treatment was switched to moxifloxacin, and pharmacokinetic data were obtained. This Grand Round illustrates the challenges that exist in the diagnosis and treatment of M hominis meningoencephalitis: bacterial cultures are often negative and recommended empirical antimicrobials do not provide adequate antimicrobial coverage. Optimal antimicrobial treatment regimens for M hominis meningoencephalitis are unknown. Although we describe successful treatment of a neonate with a complicated M hominis meningoencephalitis with moxifloxacin, caution with fluoroquinolone monotherapy (including moxifloxacin) has to be taken into account because resistance to fluoroquinolones has previously been described.


Asunto(s)
Antibacterianos/uso terapéutico , Fluoroquinolonas/uso terapéutico , Meningoencefalitis/diagnóstico , Meningoencefalitis/tratamiento farmacológico , Aciclovir/uso terapéutico , Amoxicilina/uso terapéutico , Antivirales/uso terapéutico , Cefotaxima/uso terapéutico , Líquido Cefalorraquídeo/microbiología , Femenino , Fiebre/etiología , Fluoroquinolonas/farmacocinética , Humanos , Recién Nacido , Meningoencefalitis/microbiología , Moxifloxacino , Mycoplasma hominis/aislamiento & purificación , Reacción en Cadena de la Polimerasa
10.
J Inherit Metab Dis ; 39(4): 559-64, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26973221

RESUMEN

INTRODUCTION: Riboflavin (vitamin B2) is absorbed in the small intestine by the human riboflavin transporters RFVT1 and RFVT3. A third riboflavin transporter (RFVT2) is expressed in the brain. In 2010 it was demonstrated that mutations in the riboflavin transporter genes SLC52A2 (coding for RFVT2) and SLC52A3 (coding for RFVT3) cause a neurodegenerative disorder formerly known as Brown-Vialetto-Van Laere (BVVL) syndrome, now renamed to riboflavin transporter deficiency. Five years after the diagnosis of the first patient we performed a review of the literature to study the presentation, treatment and outcome of patients with a molecularly confirmed diagnosis of a riboflavin transporter deficiency. METHOD: A search was performed in Medline, Pubmed using the search terms 'Brown-Vialetto-Van Laere syndrome' and 'riboflavin transporter' and articles were screened for case reports of patients with a molecular diagnosis of a riboflavin transporter deficiency. RESULTS: Reports on a total of 70 patients with a molecular diagnosis of a RFVT2 or RTVT3 deficiency were retrieved. The riboflavin transporter deficiencies present with weakness, cranial nerve deficits including hearing loss, sensory symptoms including sensory ataxia, feeding difficulties and respiratory difficulties which are caused by a sensorimotor axonal neuropathy and cranial neuropathy. Biochemical abnormalities may be absent and the diagnosis can only be made or rejected by molecular analysis of all genes. Treatment with oral supplementation of riboflavin is lifesaving. Therefore, if a riboflavin transporter deficiency is suspected, treatment must be started immediately without first awaiting the results of molecular diagnostics.


Asunto(s)
Parálisis Bulbar Progresiva/diagnóstico , Pérdida Auditiva Sensorineural/diagnóstico , Deficiencia de Riboflavina/diagnóstico , Parálisis Bulbar Progresiva/genética , Parálisis Bulbar Progresiva/terapia , Diagnóstico Diferencial , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/terapia , Humanos , Proteínas de Transporte de Membrana/genética , Técnicas de Diagnóstico Molecular , Mutación , Pronóstico , Deficiencia de Riboflavina/genética , Deficiencia de Riboflavina/terapia
11.
Neuromuscul Disord ; 25(6): 457-60, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25891278

RESUMEN

Necrotizing autoimmune myopathy (NAM) is a rare variant of idiopathic inflammatory myopathies associated with various underlying conditions. We describe a 48-year-old woman with a history of breast cancer who presented with acute respiratory failure and progressive loss of strength in her limb muscles over a period of two months. Muscle biopsy was consistent with necrotizing myopathy. No signs of active tumour were found. Immunoblot was positive for anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. Based on the subacute onset and muscle biopsy a diagnosis of NAM was made. Treatment with immunosuppressive and immunomodulating therapy led to almost complete recovery. Respiratory insufficiency as a presenting symptom of NAM is unusual. Recognition of this manifestation is crucial as early and aggressive treatment can lead to substantial recovery.


Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Miositis/diagnóstico , Insuficiencia Respiratoria/complicaciones , Anticuerpos , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , ARN Helicasas DEAD-box/inmunología , Femenino , Humanos , Helicasa Inducida por Interferón IFIH1 , Persona de Mediana Edad , Músculo Esquelético/patología , Miositis/complicaciones , Miositis/tratamiento farmacológico , Miositis/inmunología , Necrosis
12.
Artículo en Inglés | MEDLINE | ID: mdl-24862654

RESUMEN

OBJECTIVE: Executive dysfunction occurs in 30-50% of amyotrophic lateral sclerosis (ALS) patients and is most frequently assessed with the verbal fluency test. The verbal fluency index (VFI) has been developed to correct for slowness of speech in ALS, and reflects the average thinking time per word. However, its use as a marker of cognitive impairment is hindered by the absence of valid norm scores. Therefore, we provide normative data for the VFI. METHODS: Dutch volunteers were demographically matched to the Dutch ALS population and completed the verbal fluency index (one-minute and three-minute spoken letter fluency). Multiple stepwise linear regression was performed to assess the influence of demographic variables, past medical history and medication use. RESULTS: 273 volunteers participated in this study. Educational level was negatively correlated to one-minute and three-minute VFI performance (r = -0.3 and r = -0.4, p < 0.001, respectively). No correlations for age, gender, medication and past medical history were found. A formula for standardized z-scores, corrected for educational level, for the one-minute and three-minute VFI was calculated. CONCLUSIONS: We provide Dutch normative data for the spoken verbal fluency index, which can be used internationally, but validation in other languages is recommended. The findings illustrate the importance of valid disease-specific norm scores for time-dependent cognitive tests in ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/complicaciones , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Pruebas Neuropsicológicas , Conducta Verbal/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Valores de Referencia , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas
13.
Artículo en Inglés | MEDLINE | ID: mdl-22889176

RESUMEN

The assessment of frontal functions in ALS patients is important because of the overlap with the behavioural variant of frontotemporal dementia (bvFTD). We investigated the applicability and reliability of the Frontal Assessment Battery (FAB) within a cohort of predominantly prevalent ALS patients. The FAB was administered to 85 ALS patients and eight ALS-bvFTD patients. Original scores and the percentage of items that could be performed were recorded. Item-adjusted scores of the FAB were calculated. The ALS Functional Rating Scale-Revised version (ALSFRS-R) was used to assess disease severity. Eighty-seven patients (94%) had ALS symptoms of more than one year. Twenty patients (21.5%) were not able to perform one or more FAB items. The original FAB score correlated with the ALSFRS-R score (r = 0.30; p < 0.01), while the item-adjusted FAB score did not. In contrast to the original FAB scores, the item-adjusted FAB score was lower in ALS-bvFTD patients (66.7, range 33.3-100) compared to ALS patients without bvFTD (94.4, range 38.9-100; p < 0.01). In summary, 20% of prevalent ALS patients could not complete the FAB, which limits its use in ALS and emphasizes the importance of disease specific instruments and adjusting for motor impairment in cognitive and behavioural examinations of ALS patients.


Asunto(s)
Esclerosis Amiotrófica Lateral/diagnóstico , Autoevaluación Diagnóstica , Pruebas Neuropsicológicas , Psicometría/métodos , Encuestas y Cuestionarios , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
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