Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene.

Mutations in the TUBB4A gene have been identified so far in two neurodegenerative disorders with extremely different clinical features and course: whispering dysphonia, also known as dystonia type 4 (DYT4), and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). We describe a patient with slowly progressive spastic paraparesis, segmental dystonia, intellectual disability, behavioral problems, and evidence of permanent, incomplete myelination associated with progressive cerebellar atrophy. Whole exome sequencing revealed a novel E410K de novo heterozygous mutation in the TUBB4A gene. The clinical and radiological picture of our patient is different from the classic phenotype; thus, it expands the phenotypic variation of TUBB4A-gene-related disorders.

Molecular and functional studies of retinal degeneration as a clinical presentation of SACS-related disorder.

BACKGROUND: ARSACS (autosomal-recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorder caused by SACS gene mutations and characterized by a triad of symptoms: early-onset cerebellar ataxia, spasticity and peripheral neuropathy. A characteristic retinal nerve fiber hypertrophy has been reported in several individuals with ARSACS. METHODS: We describe a patient with a unique clinical presentation of ataxia, nystagmus, dysarthria, hearing impairment, and retinal degeneration. Whole-exome-sequencing was performed as well as morphological studies in the patient's fibroblasts. RESULTS: A compound heterozygosity for a novel D3269N and N2380K mutations in the SACS gene was found. The parents are carriers. Morphological studies revealed a dramatic decrease in the number of cell mitochondria as well as a difference in mitochondrial network morphology. CONCLUSIONS: Retinal degeneration has never been reported in ARSACS. Since sacsin is involved in the mitochondrial fusion-fission process, we speculate that defected fission process may be responsible for an impaired mitochondrial function and retinal degeneration. Our patient has a unique clinical presentation of SACS mutations inconsistent with the classic ARSACS triad but also different from the "atypical" presentations described in the literature. Further studies are necessary to clarify the factors that modify the SACS related phenotype.