Fazio-Londe Disease

A number sign (#) is used with this entry because Fazio-Londe disease is caused by homozygous mutation in the C20ORF54 gene (SLC52A3; 613350) on chromosome 20p13. One such family has been reported.

Mutations in the SLC52A3 gene also cause Brown-Vialetto-Van Laere syndrome (BVVLS; 211530), a similar disorder with the additional feature of sensorineural hearing loss.

Description

Fazio-Londe disease is a progressive bulbar palsy with onset in childhood that presents with hypotonia and respiratory insufficiency (summary by Bosch et al., 2011).

Clinical Features

Londe (1894) reported affected 5- and 6-year-old brothers whose parents were first cousins. Marinesco (1915) described it in a 12-year-old girl and her 8-year-old brother. Pyramidal tracts were not involved. Fazio's cases are said (Gomez et al., 1962) to have been a mother and her 4.5-year-old son.

Benjamins (1980) described an identically affected sib of the child reported by Gomez et al. (1962). The boy had been seen at age 29 months because of progressive inspiratory stridor. He showed mild bilateral ptosis and almost immobile vocal cords. At 32 months he had difficulty swallowing, ptosis, bilateral facial weakness, absent gag reflex, generalized hyperreflexia and diminished diaphragmatic motion. He died at 36 months of age; the sib had died at 44 months. The disorder showed phenotypic overlap with amyotrophic lateral sclerosis (ALS; 105400).

Bosch et al. (2011) reported 2 sibs from a consanguineous family. The first child, a boy, presented at 6 months of age with a short history of progressive muscle weakness followed by life-threatening apneic spells requiring ventilation. He had generalized muscle weakness, severe head lag, and diaphragmatic paralysis. His sister presented at 3 months of age with failure to thrive and generalized axial muscle weakness. Sensorineural hearing loss was excluded by brainstem-evoked response audiometry.

Biochemical Features

The proband of the consanguineous family with Fazio-Londe disease reported by Bosch et al. (2011) had an acylcarnitine profile suggestive of multiple acyl-CoA dehydrogenase deficiency (MADD; 231680), with an abnormal concentration of short- and medium-chain moieties.

Clinical Management

Because of the possibility of riboflavin responsiveness, the first patient of Bosch et al. (2011) was treated with high-dose riboflavin (vitamin B2, 10 mg/kg per day). The MADD-associated metabolic abnormalities disappeared within days and the patient's muscle tone slowly improved over the next month. He was able to walk independently at age 22 months. The diaphragmatic paralysis persisted and he required nightly ventilation until 41 months of age. At 46 months of age his cognitive development was normal, and he demonstrated no further cranial nerve palsy. Based on these results, the patient's sister was also treated with riboflavin. She experienced normalization of muscle tone within 7 days and rapid catch-up growth. After 3 months of riboflavin supplementation, her growth and development were normal.

Molecular Genetics

Bosch et al. (2011) identified a consanguineous family with 2 affected children who were found to be homozygous for a splice site mutation in the C20ORF54 gene (613350.0008). Spinal muscular atrophy (SMA; 253300) had been excluded by genetic testing.