A number sign (#) is used with this entry because Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is caused by homozygous or compound heterozygous mutation in the SLC52A2 gene (607882) on chromosome 8q24.

Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is an autosomal recessive progressive neurologic disorder characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency. Some patients may lose 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; Foley et al., 2014).

For discussion of genetic heterogeneity of Brown-Vialetto-Van Laere syndrome, see BVVLS1 (211530).

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 claw 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.

Foley et al. (2014) reported 18 patients from 13 families with BVVLS2 confirmed by genetic analysis. One of the patients had previously been reported by Johnson et al. (2012). The most common presenting symptom was an ataxic gait, reported in 9 (50%) of 18 patients, secondary to a progressive sensory neuropathy. Symptom onset occurred in childhood, but varied between ages 7 months (nystagmus) and 8 years (ataxic gait). Most (93%) patients had optic atrophy, and all had sensorineural hearing loss. Other features included tongue fasciculations, respiratory distress, rapidly progressive upper limb weakness, weakness of the neck muscles, and areflexia. All had normal cognition despite significant visual and hearing impairment. Ten (59%) of 17 patients tested had abnormal acylcarnitine profiles. Neurophysiologic studies were consistent with an axonal sensorimotor neuropathy, and sural nerve biopsy showed loss of large diameter myelinated axons without regenerative features.

Gorcenco et al. (2019) reported a 35-year-old Swedish man with BVVLS2 who had sensory ataxia, severe hearing and vision loss, polyneuropathy with proprioception difficulties, dysarthria, and decreased deep tendon reflexes. He had normal development until age 3 years when he developed hearing loss. Progressive vision loss with bilateral optic atrophy began at age 4 years. His balance and gate abnormalities presented in childhood and progressed. Neurography studies showed reduced amplitude in sensory fibers.

Foley et al. (2014) found that high-dose riboflavin resulted in significant and sustained clinical and biochemical improvement in patients with BVVLS2 confirmed by genetic analysis. Two patients were reported in detail: a child who presented at age 22 months and was started on riboflavin immediately with favorable response within a month, and a patient (Johnson et al., 2012) who was started on riboflavin therapy at age 10 years with a favorable response within 3 months.

Gorcenco et al. (2019) reported plasma riboflavin levels in response to interval oral dosing in a 35-year-old man with BVVLS2. Initially, oral riboflavin was administered at a dose of 500 mg 3 times daily. On this dosing regimen, plasma riboflavin levels were low first thing in the morning, rose up to 4 hours after intake, and then gradually decreased. Riboflavin administration was then changed to 250 mg 6 times per day, which resulted in a more constant plasma level and led to a calculated 27% higher plasma riboflavin level over a 24-hour period. One year after the 6 times per day dosing was initiated, the patient had a slight improvement in gait, sitting stability, and alternating hand movements. The patient also experienced a slight improvement in visual acuity, had almost normal color vision, and had improved peripheral vision with central scotomas. Gorcenco et al. (2019) concluded that their approach does not demonstrate an improved clinical effect of 6 times per day dosing of riboflavin compared to other riboflavin dosing regimens in BVVLS2, but does support the use of more frequent dosing based on plasma concentrations.

The transmission pattern of BVVLS2 in the family reported by Megarbane et al. (2000) was consistent with autosomal recessive inheritance.

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.

By Sanger sequencing of the SLC52A2 gene in 78 patients of various origins with a phenotype of cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency from 21 medical centers, Foley et al. (2014) identified 8 different biallelic mutations (see, e.g., 607882.0001; 607882.0003; 607882.0006-607882.0007) in 13 probands (including the Scottish patient previously reported by Johnson et al., 2012) and 5 affected family members. The most common mutation was G306R, which was found in homozygous state in 3 Lebanese families and in compound heterozygous state in 2 families and 3 singleton patients. In vitro functional expression studies showed that the mutations caused reduced or absent riboflavin uptake and reduced riboflavin transporter protein expression.