TTPA – Ataxia with isolated Vitamin E deficiency

Ataxia with isolated Vitamin E deficiency is a rare autosomal recessive neurodegenerative disorder caused by pathogenic variants in the alpha-tocopherol transfer protein gene, TTPA. Clinically, affected individuals present with progressive cerebellar ataxia, dysarthria, sensory neuropathy and in some cases retinitis pigmentosa, closely mimicking Friedreich ataxia and other spinocerebellar ataxias (PMID:7719340). Genetic testing is essential for early diagnosis because vitamin E supplementation can halt or reverse neurological decline. The disorder is catalogued as Ataxia with isolated vitamin E deficiency.

The gene–disease association was first established by mapping AVED to chromosome 8q13 and identifying three frameshift mutations in 17 families, including the recurrent c.744del (p.Glu249fs) founder allele that accounts for 68% of mutant chromosomes in Mediterranean cohorts (PMID:7719340). Subsequent studies in 27 additional families revealed >13 distinct mutations, including small deletions, insertions, nonsense and missense changes, confirming autosomal recessive inheritance (PMID:9463307).

A large multicenter cohort of 132 Tunisian patients demonstrated that 91.7% were homozygous for c.744del (p.Glu249fs), consistent with a founder effect and accounting for the severe phenotype characterized by early-onset ataxia and absent reflexes (PMID:24369383). Overall, more than 200 affected individuals from >50 families have been reported worldwide, encompassing >30 pathogenic alleles.

Functional studies confirm loss of alpha-TTP activity as the pathogenic mechanism. Expression of mutant proteins in COS-7 cells shows markedly reduced transfer activity (<11% of wild type) for variants such as p.His101Gln and p.Arg134Ter, and immunoblotting demonstrates decreased protein levels for initiation codon and Kozak region mutations (PMID:7566022; PMID:8602747). Animal and cellular models replicate neurodegeneration, supporting a haploinsufficiency mechanism.

Vitamin E supplementation at high dosages restores serum tocopherol levels and prevents progression of neurological and visual symptoms, underscoring the clinical utility of early genetic diagnosis and therapy (PMID:7719340). No significant conflicting evidence has been reported, and all identified variants co-segregate with disease status in families.

In summary, there is a definitive gene–disease relationship between TTPA and ataxia with isolated vitamin E deficiency, supported by extensive genetic, segregation and functional data. Early molecular diagnosis enables prompt vitamin E therapy, transforming a potentially devastating neurodegenerative condition into a treatable disorder.

References

• Nature genetics • 1995 • Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. PMID:7719340
• Annals of neurology • 1996 • Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. PMID:8602747
• American journal of human genetics • 1998 • Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. PMID:9463307
• Brain : a journal of neurology • 2014 • Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency. PMID:24369383
• The New England journal of medicine • 1995 • Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein. PMID:7566022

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