Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation

Abstract

Neuroferritinopathy is a progressive potentially treatable adult-onset movement disorder caused by mutations in the ferritin light chain gene (FTL1). Features overlap with common extrapyramidal disorders: idiopathic torsion dystonia, idiopathic Parkinson's disease and Huntington's disease, but the phenotype and natural history have not been defined. We studied a genetically homogeneous group of 41 subjects with the 460InsA mutation in FTL1, documenting the presentation, clinical course, biochemistry and neuroimaging. The mean age of onset was 39.4 years (SD = 13.3, range 13-63), beginning with chorea in 50%, focal lower limb dystonia in 42.5% and parkinsonism in 7.5%. The majority reported a family history of a movement disorder often misdiagnosed as Huntington's disease. The disease progressed relentlessly, becoming generalized over a 5-10 year period, eventually leading to aphonia, dysphagia and severe motor disability with subcortical/frontal cognitive dysfunction as a late feature. A characteristic action-specific facial dystonia was common (65%), and in 63% there was asymmetry throughout the disease course. Serum ferritin levels were low in the majority of males and post-menopausal females, but within normal limits for pre-menopausal females. MR brain imaging was abnormal on all affected individuals and one presymptomatic carrier. In conclusion, isolated parkinsonism is unusual in neuroferritinopathy, and unlike Huntington's disease, cognitive changes are absent or subtle in the early stages. Depressed serum ferritin is common and provides a useful screening test in routine practice, and gradient echo brain MRI will identify all symptomatic cases.

Neuroferritinopathy: a new inborn error of iron metabolism

“…Since the discovery of NBIA disorders, therapeutic targets that may be able to slow the progression of disease have remained limited. In our institute, we have attempted iron chelation in a handful of symptomatic patients with little benefit [12], though a recent case report of a patient with an idiopathic NBIA syndrome has suggested some ability to improve clinical and radiological features [20].…”

“…Uniquely, however, neuroferritinopathy is the only autosomal dominant NBIA syndrome, and in contrast to many of the other NBIA disorders, patients present late in adulthood with a variety of extrapyramidal movement disorders such as asymmetric focal onset chorea or focal dystonia [12].…”

Xeroderma pigmentosum is a definite cause of Huntington's disease‐like syndrome

“…Conditions such as DRPLA, neuroferritinopathy or chorea‐acanthocytosis can also present as HD‐like disorders. The main characteristics of these conditions are summarized in Table 1 11, 13, 14, 15, 16, 17, 18, 19, 20…”

Iron chelation in the treatment of neurodegenerative diseases

“…Brain iron deposition can be documented long before neurological symptoms appear [78]. In symptomatic patients with neuroferritinopathy, 4000 mg deferoxamine weekly over a period of 14 months, 2000 mg deferiprone for two months or regular monthly venesections for six months did not result in clinical improvement [79]. Monthly venesections also showed no effect in another case study [80].…”