Brown-Vialetto-Van Laere syndrome-2 is an autosomal recessive progressive neurologic disorder characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting resulting in respiratory insufficiency and loss of independent ambulation. Because it ... Brown-Vialetto-Van Laere syndrome-2 is an autosomal recessive progressive neurologic disorder characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting resulting in respiratory insufficiency and loss of independent ambulation. Because it results from a defect in riboflavin metabolism, some patients may benefit from high-dose riboflavin supplementation (summary by Johnson et al., 2012). See also BVVLS1 (211530), caused by mutation in the SLC52A3 gene (613350).
Megarbane et al. (2000) reported a large inbred Lebanese family with 4 patients, including 3 males and 1 female, with severe features of Brown-Vialetto-Van Laere syndrome. The proband showed normal early childhood development until about age 2.5 years, ... Megarbane et al. (2000) reported a large inbred Lebanese family with 4 patients, including 3 males and 1 female, with severe features of Brown-Vialetto-Van Laere syndrome. The proband showed normal early childhood development until about age 2.5 years, when he developed progressively abnormal hearing and walking. Physical examination at age 8 years showed profound deafness with absent brainstem auditory-evoked potentials, tongue fasciculations, bulbar dysfunction, scoliosis, and axial and limb hypotonia with little spontaneous movements. He had severe neck weakness with an inability to hold up his head, proximal and distal limb weakness and atrophy, and clawed hands. Deep tendon reflexes and plantar responses were absent. Intelligence appeared to be normal. He died of respiratory failure at age 11 years. His younger brother was similarly affected, and also had facial paresis, inability to close the eyes tightly, absent pupillary reflexes, and poor gag reflex, which indicated multiple cranial nerve abnormalities. EMG was neurogenic with fibrillation activity. He died suddenly at age 7 years. The boys' sister was reportedly affected, but died at age 4 years. A male first cousin had slightly less severe muscle weakness and slightly later onset at age 3.5 years, but also showed deafness and diffuse muscle weakness and atrophy. Johnson et al. (2012) reported an 11-year-old Scottish girl with BVVLS2. She presented with ataxic gait at age 18 months. At age 6 years, she showed weakness of the fingers, which rapidly progressed to severe upper limb weakness over the course of a few weeks. She also developed bilateral sensorineural hearing loss. By 7 years of age, she was wheelchair-bound due to axial hypotonia and weakness, but could walk with support as her lower limbs retained strength. Other features included optic atrophy, sleep hypoventilation, and severe axonal sensorimotor neuropathy. Metabolic testing showed evidence of carnitine deficiency and a urinary organic acid profile suggestive of MADD (231680). Treatment with high-dose riboflavin resulted in the normalization of her acylcarnitine and urinary organic acid profiles. She also showed quantitative improvements in her pulmonary function, brainstem auditory evoked potentials, and visual evoked potentials, and some improvement in upper limb strength. Haack et al. (2012) reported a girl with BVVLS2. After normal psychomotor development, she presented at age 3 years with impaired hearing, clumsiness, impaired walking due to ataxia, and vertical nystagmus. She also developed progressive optic atrophy with visual impairment and aggressive behavior. Neurologic studies showed absent reflexes in the lower extremities and an axonal sensory neuropathy. She was confined to a wheelchair from the age of 5 years. At age 5.5 years, she showed right-sided facial nerve palsy and tongue wasting with fasciculations. Laboratory analysis showed increased levels of several acylcarnitine and hydroxy-acylcarnitine species; however, plasma riboflavin was normal. Treatment with oral riboflavin supplementation resulted in improvement in fine motor skills and assisted gait, as well as normalization of laboratory findings. Ciccolella et al. (2013) reported a boy with severe, early-onset BVVLS2. He had normal early psychomotor development and began to walk at age 12 months. At age 2 years, he presented with progressive dysphonia and exercise intolerance with dyspnea and cyanosis. He later developed sensorineural hearing loss, decreased visual acuity, shoulder and axial muscle weakness, kyphosis, wasting and weakness of the hand muscles, and walking difficulties with foot drop. The disorder was rapidly progressive; at age 3 years, he was hospitalized for acute respiratory failure and died.
In affected members of a large consanguineous Lebanese family with severe Brown-Vialetto-Van Laere syndrome-2, Johnson et al. (2012) identified a homozygous mutation in the SLC52A2 gene (G306R; 607882.0001). A Scottish girl with the disorder was also found to ... In affected members of a large consanguineous Lebanese family with severe Brown-Vialetto-Van Laere syndrome-2, Johnson et al. (2012) identified a homozygous mutation in the SLC52A2 gene (G306R; 607882.0001). A Scottish girl with the disorder was also found to be homozygous for the G306R mutation. In a girl with BVVLS2, Haack et al. (2012) identified compound heterozygous mutations in the SLC52A2 gene (607882.0002 and 607882.0003). Transfection of the mutations in HEK293 cells showed that both caused a significant decrease in SLC52A2 transporter activity compared to wildtype. In a boy with severe early-onset BVVLS2 resulting in death at age 3, Ciccolella et al. (2013) identified compound heterozygous mutations in the SLC52A2 gene (607882.0004-607882.0005). Each of the unaffected parents was heterozygous for 1 of the mutations. Patient cells showed significantly decreased riboflavin transport (about 29%) compared to controls.