Genetic, Radiologic, and Clinical Variability in Brown-Vialetto-van Laere Syndrome.

Brown-Vialetto-van Laere syndrome is characterized by a progressive sensorimotor neuropathy, optic atrophy, hearing loss, bulbar dysfunction, and respiratory insufficiency. Mutations in SLC52A2 and SLC52A3, encoding riboflavin transporters RFVT2 and RFVT3, respectively, are the genetic basis of this disorder, often referred to as riboflavin transporter deficiency types 2 and 3, respectively. We present cases of both types of riboflavin transporter deficiency, highlighting the distinguishing clinical features of a rapidly progressive motor or sensorimotor axonal neuropathy, optic atrophy, sensorineural hearing loss, and bulbar dysfunction. One child presented with isolated central apnea and hypoventilation, not previously described in genetically confirmed Brown-Vialetto-van Laere, later complicated by diaphragmatic paralysis secondary to phrenic nerve palsy. Magnetic resonance imaging showed T2 hyperintensity in the dorsal spinal cord in 2 children, as well as previously unreported cervical nerve root enlargement and cauda equina ventral nerve root enhancement in 1 child. Novel homozygous mutations were identified in each gene-a NM_024531.4(SLC52A2):c.505C > T, NP_078807.1(SLC52A2):p.(Arg169Cys) variant in SLC52A2 and NM_033409.3(SLC52A3):c.1316G > A, NP_212134.3(SLC52A3):p.(Gly439Asp) variant in SLC52A3. Both treated children showed improvement on high-dose riboflavin supplementation, highlighting the importance of early recognition of this treatable clinical entity.

MR imaging and spectroscopic study of epileptogenic hypothalamic hamartomas: analysis of 72 cases.

BACKGROUND AND PURPOSE: Reports of MR imaging in hypothalamic hamartomas associated with epilepsy are few, and the number of patients studied is small. We aimed to detail the relationship of hypothalamic hamartomas to surrounding structures, to determine the frequency and nature of associated abnormalities, and to gain insight into mechanisms of epileptogenesis. METHODS: We systematically examined MR imaging studies of 72 patients with hypothalamic hamartoma and refractory epilepsy (patient age, 22 months to 31 years). A dedicated imaging protocol was used in 38 cases. Proton MR spectroscopy of the hypothalamic hamartoma was performed for 19 patients and compared with the metabolite profile of the thalamus in 10 normal children and the frontal lobe in 10 normal adults. RESULTS: Compared with normal gray matter, hypothalamic hamartomas were hyperintense on T2-weighted images (93%), hypointense on T1-weighted images (74%), and had reduced N-acetylaspartate and increased myoinositol content shown by MR spectroscopy. Hypothalamic hamartomas always involved the mammillary region of the hypothalamus, with attachment to one or both mammillary bodies. Intrahypothalamic extension (noted in 97%) tended to displace the postcommissural fornix and hypothalamic gray matter anterolaterally, such that the hypothalamic hamartomas nestled between the fornix, the mammillary body, and the mammillothalamic tract. Larger hamartoma size was associated with central precocious puberty. Associated findings of questionable epileptic significance included anterior temporal white matter signal intensity abnormalities (16%) and arachnoid cysts (6%). Malformations of cortical development were observed in only two patients, and hippocampal sclerosis was not observed. CONCLUSIONS: Hypothalamic hamartomas can be readily distinguished from normal hypothalamic gray and adjacent myelinated fiber tracts, best appreciated on thin T2-weighted images. MR imaging and spectroscopy suggest reduced neuronal density and relative gliosis compared with normal gray matter. Associated epileptogenic lesions are rare, supporting the view that the hypothalamic hamartoma alone is responsible for the typical clinical features of the syndrome. The intimate relationship to the mammillary body, fornix, and mammillothalamic tract suggests a role for these structures in epileptogenesis associated with hypothalamic hamartomas.