Hereditary Ferritinopathy: A Novel Mutation, Its Cellular Pathology, and Pathogenetic Insights

Abstract

We report a family of French Canadian and Dutch ancestry with hereditary ferritinopathy (neuroferritinopathy) and a novel mutation (C insertion at nt646-647 in exon 4) in the ferritin light chain gene, resulting in a longer than normal protein. Our failure to immunostain most of the abnormal ferritin deposits in the proband with a conformation-dependent monoclonal antibody to ferritin light chain supported a previously postulated conformational change of ferritin light chain in this disease. The posterior putamen and cerebellum were the primary pathologic loci in our proband, but asymptomatic hepatocytic intranuclear accumulations of iron and ferritin also were present. Both neurons and glia displayed highly distinctive, if not pathognomonic, swollen to vacuolated nuclei containing ferritin and iron. Hyaline deposits, again staining for both ferritin and iron, were additional morphologic features that may be unique to the ferritinopathies. The iron, at least in putamen where there was a nearly 40-fold increase, appeared to be both in the ferrous (Fe2+) and ferric (Fe3+) form; it was the most likely cause of the observed neuronal and glial apoptosis. We found morphologic evidence of both lipid peroxidation and abnormal nitration of proteins in putaminal neurons and glia, confirming the expected oxidative stress due to this excessive iron. Biochemical and immunohistochemical abnormalities in mitochondria also were demonstrated, probably due to an imbalance in iron homeostasis that had a deleterious effect on the respiratory chain.

Neuroferritinopathy: a new inborn error of iron metabolism

“…Seven pathogenic mutations in FTL1 have since been described [1][2][3][4][5][6][7]. Six are frameshift mutations which alter the reading frame and are predicted to extend the ferritin light chain peptide at the site of the pore in the ferritin molecule.…”

“…The mutations result in the accumulation of ferritin and iron within central neurons, in particular within the basal ganglia [1][2][3][4], leading to oxidative stress and ultimately resulting in neurodegeneration [2,8].…”

Mutant Ferritin L-chains That Cause Neurodegeneration Act in a Dominant-negative Manner to Reduce Ferritin Iron Incorporation

“…This disorder, named hereditary hyperferritinopathy with cataract syndrome (OMIM code 600886) is characterized by high levels of serum and tissue L-ferritins and by early onset bilateral cataract, caused by the formation of L-ferritin microcrystallines in the lens (8). More severe and rare is the group of diseases named neuroferritinopathies (9) or hereditary ferritinopathies (10) (OMIM code 606159). Clinically these disorders are characterized by abnormal involuntary movements and cognitive decline that often appear in the 3rd to 6th decade of life.…”

“…Six pathogenic mutations have been identified so far (9,10,(12)(13)(14)(15)(16). They are all private mutations found in single families, except the 460InsA found in several patients of North Anglia.…”

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

“…Conversely, brain accumulation of ferritin and iron has been demonstrated. 122 Iron accumulation likely directly causes clinical symptoms and neurodegeneration by free radical toxicity as previously discussed. Affected individuals have MRI evidence of iron deposition in the basal ganglia.…”