RESUMEN
BACKGROUND: Brown-Vialetto-Van Laere (BVVL) syndrome is a rare disorder characterised by progressive pontobulbar palsy and sensorineural deafness. Causative mutations in genes encoding human riboflavin transporter 2 (hRFT2) and 3 (hRFT3) have been identified in BVVL patients. METHODS AND RESULTS: We report the clinical and molecular features of a severe BVVL patient in whom screening of SLC52A3/hRFT2 was negative. Sequence analysis identified two novel compound heterozygous mutations in SLC52A2/hRFT3, namely c.155C>T and c.1255G>A, leading to the amino acid changes p.S52F and p.G419S, respectively. Functional studies show that these defects impair the gene expression of the corresponding transporter, resulting in a significant reduction of riboflavin transport. CONCLUSIONS: These findings support the pathogenetic role of SLC52A2/hRFT3 in BVVL with important clinical and therapeutic implications.
Asunto(s)
Parálisis Bulbar Progresiva/genética , Pérdida Auditiva Sensorineural/genética , Proteínas de Transporte de Membrana/genética , Receptores Acoplados a Proteínas G/genética , Secuencia de Aminoácidos , Preescolar , Análisis Mutacional de ADN , Resultado Fatal , Humanos , Masculino , Datos de Secuencia Molecular , Alineación de SecuenciaRESUMEN
Hereditary spastic paraplegias (HSPs) are relatively frequent disorders presenting great genetic heterogeneity. The recent identification of mutations in SPG5/CYP7B1 in six autosomal recessive kindred linked to the SPG5 locus on chromosome 8q prompted us to test the relative frequency of SPG5/CYP7B1 variants in 12 families and in sporadic HSP patients by high-resolution melting screening combined with direct sequencing. We present two patients who harbored three mutations (including two novel variants) in SPG5/CYP7B1 and white matter involvement evidenced at brain MRI. In HSP patients in whom no other genes were mutated, screening of SPG5/CYP7B1 seems to have a low diagnostic yield in autosomal recessive (8%) and sporadic (<1%) cases, even in those with complicated clinical features.
Asunto(s)
Encéfalo/patología , Mutación/genética , Fibras Nerviosas Mielínicas/patología , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , Esteroide Hidroxilasas/genética , Adolescente , Adulto , Encéfalo/metabolismo , Encéfalo/fisiopatología , Niño , Preescolar , Cromosomas Humanos Par 8/genética , Familia 7 del Citocromo P450 , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Humanos , Imagen por Resonancia Magnética , Masculino , Fibras Nerviosas Mielínicas/metabolismo , Linaje , Valor Predictivo de las Pruebas , Paraplejía Espástica Hereditaria/fisiopatología , Adulto JovenAsunto(s)
Cuerpo Calloso/patología , Paraplejía/complicaciones , Paraplejía/genética , Mutación Puntual/genética , Proteínas/genética , Adolescente , Atrofia/complicaciones , Niño , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Y/genética , Análisis Mutacional de ADN , Exones/genética , Femenino , Humanos , Masculino , Linaje , Adulto JovenRESUMEN
Brown-Vialetto-van Laere (BVVL) and Fazio-Londe (FL) are rare and clinically overlapping motor neurons syndromes. Recently BVVL has been associated with mutations in C20orf54/hRFT2 and defective riboflavin transport. We compared clinical and laboratory features of 6 patients (age range 11-17 years), with features of BVVL and FL overlap syndromes. Patients were assessed as following: blood levels of riboflavin and redox status, electrophysiological, neuroradiological and pulmonary studies, ALS functional rating scale and molecular genetic analysis. Two patients manifested deafness at ages of 3 and 10 years, and developed later subacute progressive ponto-bulbar palsy. A third patient markedly improved after intravenous immunoglobulins (IVIG), but then relapsed remaining unresponsive to treatment; he was not deaf although had abnormal auditory evoked responses (BAERs). The remaining 3 patients had no deafness, although likewise manifested subacute progressive ponto-bulbar palsy. We found hRFT2 mutations in 3/6 patients manifesting deafness or abnormal BAERs. No patient had reduced riboflavin blood levels. However, on riboflavin supplementation (10mg/kg/day) the most severely affected BVVL patient stopped progression of symptoms following 8 months of treatment. BVVL and FL are severe progressive diseases with overlapping symptoms although only hRFT2 mutated patients manifest deafness. Riboflavin supplementation seems to stabilize and improve progression of the disease.