L-Ferritin Deficiency

A number sign (#) is used with this entry because of evidence that L-ferritin deficiency (LFTD) is caused by homozygous or heterozygous mutation in the FTL gene (134790) on chromosome 19q13. Two unrelated individuals, 1 homozygous and 1 heterozygous for mutations, have been reported.

Clinical Features

Cremonesi et al. (2004) found decreased L-ferritin levels in a healthy 52-year-old woman who was a control subject in a genetic study of hyperferritinemia-cataract syndrome (HHCS; 600886). She had no history of iron deficiency anemia or neurologic dysfunction, and hematologic examination was normal except for decreased serum L-ferritin.

Cozzi et al. (2013) reported a 23-year-old woman, born of parents from the same region of Calabria, Italy, with complete absence of serum L-ferritin, but otherwise normal hematologic parameters. She developed idiopathic generalized seizures at age 7 years, but the seizures were well-controlled; anticonvulsive therapy was stopped at age 22 years without recurrence. She had mild neuropsychologic impairment, as well as restless legs syndrome demonstrated by polysomnography. The only other notable feature was progressive hair loss. Serum hemoglobin, mean corpuscular volume, haptoglobin, total red blood cells, iron levels, transferrin, and transferrin saturation were all normal. Brain and liver imaging showed no evidence of iron deposition.

Molecular Genetics

In a healthy 52-year-old woman with low serum L-ferritin, Cremonesi et al. (2004) identified a heterozygous mutation in the ATG start codon of the FTL gene (M1V; 134790.0018), predicted to disable protein translation and expression. The findings suggested that L-ferritin has no effect on systemic iron metabolism and that haploinsufficiency of L-ferritin does not cause neurologic or hematologic clinical effects.

In a 23-year-old woman with complete absence of serum L-ferritin, Cozzi et al.(2013) identified a homozygous truncating mutation in the FTL gene (E104X; 134790.0019). The FTL gene was chosen for sequencing because the patient had undetectable serum levels of L-ferritin. There was no FTL protein in patient fibroblasts, although mRNA levels were similar to controls. FTH (134770) expression was normal, and patient cells showed increased iron incorporation into H homopolymer ferritin compared to controls. This was associated with a 4-fold decrease of the labile iron pool in patient cells. Expression of wildtype FTL ameliorated these cellular defects. E104X fibroblasts showed additional abnormalities, including increased turnover of H homopolymer ferritin and increased production of reactive oxygen species and increased cellular toxicity compared to controls. Reprogrammed neurons from patient fibroblasts also showed increased reactive oxygen species as well as iron deficiency. Cozzi et al. (2013) stated that this was the first patient reported with complete loss of FTL, but noted that the phenotype could result either from a loss of FTL function or a gain of function via altered activity of the FTH homopolymer.