Striatonigral Degeneration, Childhood-Onset

A number sign (#) is used with this entry because of evidence that childhood-onset striatonigral degeneration (SNDC) is caused by compound heterozygous mutation in the VAC14 gene (604632) on chromosome 16q22.

Clinical Features

Lenk et al. (2016) reported 2 unrelated boys, aged 5 and 2 years, with abrupt onset of a neurodegenerative disorder after normal early development. The first patient was normal until age 3 years, when he developed an abnormal dystonic gait with frequent falls and subsequent dystonia of the upper limbs. Deterioration was observed during infection and after general anesthesia. Six months after onset, there was rapid escalation of the symptoms, with status dystonicus and increased serum creatine kinase. At age 5, he was nonverbal and had hypersalivation, increased muscle tone, and dystonic movements of the face, limbs, and trunk. Cognitive testing was not performed, but he could follow simple commands. The second patient showed normal development until age 18 months, when he developed a steppage gait, increased ankle plantar flexion, hypertonicity of the hips and ankles, and brisk tendon reflexes. He subsequently lost the ability to walk independently. In addition, speech became slowed and sparse, and he showed dysphagia with drooling. Brain imaging in both patients showed progressive abnormal T2-weighted hyperintensities in the striatum, with subtle hypointensities in the substantia nigra.

Inheritance

The transmission pattern of SNDC in the families reported by Lenk et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated boys with SNDC, Lenk et al. (2016) identified compound heterozygous mutations in the VAC14 gene (604632.0001-604632.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Cultured fibroblasts from both patients showed abnormal vacuolization, consistent with PI(3,5)P2 deficiency, and the abnormalities were rescued after transfection with wildtype VAC14.