A 19-year-old man of gypsy ancestry with mild non-progressive mental retardation (IQ = 60), showed no evidence of anoxia at birth and developed gait disturbances by age 13. He was admitted at the ages of 14 and 18 to different institutions, with episodes of acute psychosis responsive to neuroleptics. In the latest admission he was diagnosed with Wilson disease and received treatment with d-penicillamine, valproic acid, and trazodone. Eleven months later, he was admitted to our hospital in a state of confusion with apathy. Neurologic examination showed severe ataxia, bradykinetic-rigid syndrome, and plantar extensor responses. Laboratory findings included normal liver function, plasma ceruloplasmin of 26 ng/mL, copper of 76 ng/mL, and urine copper of 8.1 ng/mL. Kayser–Fleischer rings were not present. Abdominal ultrasound was normal. Serum ferritin was 16 ng/mL (N = 20 to 300), serum iron was 174 μg/mL (N = 65 to 175,) and IBC was 376 μg/mL (N = 250 to 450). MRI showed slightly asymmetric pallidal hyperintensity in T2 and fluid-attenuated inversion recovery images and hypointensity in T1. A diffuse atrophy was also evident, predominating in the frontoparietal and vermian regions (). Upon withdrawal of all medication the patient experienced a dramatic improvement, resuming his daily routine. After 1 year, neurologic examination revealed mild bradykinesia, symmetric cog-wheel rigidity, slight ataxia, and bilateral Babinski sign. No behavioral or cognitive deterioration were observed during this follow-up period.
Figure 1 MRI study of the patient (a through e) and his mother (f). A bilateral pallidal hyperintensity can be observed in axial T2-weighted (a), fluid-attenuated inversion recovery (b), and coronal T2 images; no significant surrounding hypointensities were noted (more ...)
We observed nine family members () and performed biochemical and genetic studies in all and MRI studies in the patient, his mother, and younger brother.
Figure 2 Pedigree of the family in study (a): black square = individual with clinical signs, low ferritin levels, MRI findings and FTL mutation; half-filled circle = low ferritin levels, MRI findings and FTL mutation; low ferritin levels and FTL mutation; circle (more ...)
None of the other relatives observed had signs of neurologic or psychiatric disease, other than an uncle who had been previously diagnosed with schizophrenia. The patient and his mother displayed a similar pattern of pallidal necrosis in MRI (see ).
We extracted DNA from 50 randomly selected and anonymous Guthrie cards obtained from the national neonatal phenylketonuria screening program. This study was authorized by the ethics committee of the Medical Genetics Institute where samples were obtained.
After informed consent was obtained, genomic DNA was extracted from blood samples using the Puregene system (Gentra Systems, Minneapolis, MN) according to the manufacturer’s protocol and from Guthrie cards using Chelex. For analysis of the FTL
gene (OMIM 134790), DNA was amplified by PCR and sequenced, using primers FTLgIF, FTL1bF, FTL2R, FTL3F, FTL4R1
and primers FTLp1 (5′TGAGCCACTTCTTCCGCGAAT3′) and FTLp2 (5′TGAGCCACTTCTTCCGCGAAC3′). For confirmation of the G474A mutation, a PCR-RFLP assay was developed, using primers FTL3F/FTL4R for PCR amplification, followed by digestion with BsaHI.
Serum ferritin levels were evaluated using chemiluminescence immunoassay, serum iron by colorimetric analysis without precipitation, and serum transferrin by nephelometry.