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Familial Fahr Disease in a Turkish Family

Abstract and Introduction

Fahr syndrome refers to a rare syndrome characterized by symmetrical and bilateral intracranial calcification. We present a 42year-old woman with Fahr disease, but lacking extrapyramidal symptoms or a metabolic disorder. Her neurological examination was normal. Computed tomographic scans demonstrated symmetrical calcification over the basal ganglia, thalamus and cerebellum. No underlying cause for the bilateral calcification was found. When screening other family members, we detected Fahr syndrome in her two daughters and three brothers, revealing that the disease was an autosomal dominant trait. Fahr disease may be clinically asymptomatic, but have pronounced positive brain imaging findings. Computed tomographic scanning remains the most effective screening tool for adult relatives.

Fahr disease is a rare syndrome characterized by bilateral, symmetrical intracranial calcifications and neuropsychological impairment. Within the basal ganglia, the globus pallidus is the most frequent site of calcification, but deposits may be present in the putamen, caudate nucleus, internal capsule, dentate nucleus, thalamus, cerebellum and cerebral white matter.[1,2] Histologically, the deposits, which can contain proteins and polysaccharides, are found in the perivascular space and in the media layer of small vessels. The pathogenesis is not known, but may be secondary to impairment of the blood brain barrier or to a neuronal calciumphosphorus metabolism disorder.[1,3] Most cases present with extrapyramidal symptoms.[4] The onset is frequently seen in the fourth and sixth decades of life, though occasional cases have been reported in children.[5,6]

We report six asymptomatic patients, three men and three women, with familial Fahr disease with intracranial calcifications as a common feature.[7,8] Computed tomography (CT) scans of all patients demonstrated extensive symmetrical calcifications over the basal ganglia and dentate nuclei. No underlying cause was found.

Case Reports
The subjects were 7 siblings: 4 men (ages 52, 50, 36, and 32 years old) and 3 women (ages 46, 44, and 42 years old). Their parents were cousins. The index case was a 42-year-old woman admitted with severe headaches for 18 months. Her physical and neurological examinations were normal. Laboratory investigations were within normal limits, as were the serum levels of parathyroid hormone (PTH), calcium, phosphorous, alkaline phosphatase (ALP), and vitamin D. Compatible with Fahr syndrome, massive symmetrical calcifications in the cerebellum, cranial segment of the dentate nucleus, lentiform nucleus, and thalamus were seen on magnetic resonance imaging (MRI) (Figure 1 and Figure 2).

This patient's older brother had been previously diagnosed with idiopathic Fahr syndrome. CT evaluation was performed and massive intracranial calcifications compatible with Fahr syndrome were also noted in the 44- and 46-year-old sisters, as well as in the 50- and 36year-old brothers. A CT of the 32-year-old brother was normal. These family members had normal laboratory evaluations and were regarded as having familial Fahr syndrome.

The etiology of Fahr syndrome is not fully understood. It accompanies various pathologies; familial cases have been reported. Genetic transmission is autosomal dominant in most cases (e.g. the familial); autosomal recessive is present in a few.[9] Genetic heterogeneity and

an anticipatory effect have been observed. One multigenerational family with linkage to the idiopathic basal ganglia calcification, 1 (IBGC1) of chromosome 14 has been identified, but the causal gene is still unknown.[10] Although MRI is a more sensitive technique for neurological pathologies, CT is more sensitive for imaging calcified regions[6] and remains the most effective screening tool for adult relatives, though false negative results may still occur. The minimum age at which a negative CT scan can exclude the disease has not been established.[11] Symptoms usually develop after 30 years of age, although symptomatic cases during childhood have been described. There is a report of two Fahr syndrome cases that were initially asymptomatic but became symptomatic on long-term follow up.[12] Patients diagnosed with idiopathic Fahr syndrome should be monitored, and regular neuropsychiatric evaluation performed.