OBJECTIVE: To analyze the clinical features and pathogenesis of familial Fahr’s disease in Chinese.
METHODS: To report one family line of Fahr disease and review the data of 49 cases in 14 families from previous domestic literature to explore its clinical and imaging features.
RESULTS: Familial Fahr disease is autosomal recessive or dominant, with clinical manifestations of hypo-intelligence, extrapyramidal impairment, seizure G and psychiatric abnormalities; neuroimaging showed bilateral symmetrical basal ganglia, dentate nucleus and cerebral cortical calcifications.
CONCLUSION: Familial Fahr disease has diverse clinical symptoms, and the diagnosis mainly relies on a positive family history and cranial CT/MRI examinations; the metabolism of trace elements iron, calcium and phosphorus plays an important role in the pathogenesis.
Familial Fahr disease is clinically rare, and since the first Chinese national lineage was described by Wang Guoxiang in 1991, few domestic family lines have been reported. We report a new family lineage of Fahr disease and review 14 family lines with complete previous domestic literature, with a total of 49 patients, with the following results.
Data and methods
1. Data: There were 49 patients, 21 males and 28 females, aged 3.5-69 years, with an age of onset of 2 months-68 years in 14 families; 2-6 patients in three generations in each family; 2 cases of cerebral hemorrhage, 1 case of cerebral infarction, 1 case of diabetes mellitus; and 1 case of postnatal asphyxia.
2. Diagnostic criteria: the definition of familial Fahr’s disease proposed by Moskowitz in 1971: symmetrical basal ganglia calcification; no clinical manifestations of pseudo- or pseudo-pseudo-hypoparathyroidism; normal serum calcium and phosphorus levels; normal renal tubular response to parathyroid hormone; genetic evidence; no infectious, toxic and metabolic causes.
3. Ancillary tests: blood calcium, phosphorus and parathyroid hormone, head CT or X-ray were performed in all patients, and head MRI, EEG or electromyography were performed in some patients.
4. Treatment: symptomatic management was the main focus.
A new family report: Pre-existing patient, female, 17 years old, first child, full-term cesarean section, good growth and development. 16 years old started to develop episodic limb convulsions, loss of consciousness, foaming at the mouth and urinary incontinence, each lasting several minutes. Examination: decreased calculation, left ear AC
Family investigation: no history of consanguineous marriage among 9 people in 3 generations. The patient had 3 cases, 1 male and 2 female. The cranial CT of both the patient’s maternal grandfather and mother showed bilateral symmetrical calcification of the nucleus accumbens; laboratory tests were unremarkable. Her maternal grandfather had episodic twitching of the limbs and head-eye turning to the left at the age of 68, with 1-2 episodes per year; it was accompanied by episodic frottage and a feeling of rising gas, which passed instantly; her mother was 46 years old and had no clinical symptoms.
Results
1. Clinical symptoms: 32 cases had neurological symptoms, and some patients had several symptoms at the same time, including decreased intelligence in 29 cases (59.2%), extrapyramidal symptoms in 11 cases (%), seizures in 10 cases (22.4%), speech disorders in 7 cases (14.3%), limb numbness and weakness in 6 cases (12.2%), mental abnormalities in 5 cases (10.2%), and hearing loss in 2 cases ( 4.08%).
2. Mode of inheritance: 4 families were definitely autosomal dominant, 4 families were probably autosomal dominant, and the remaining mode of inheritance was not clear.
3. Serological examination: blood calcium, phosphorus and parathyroid hormone metabolism were all within the normal range.
Neuroimaging: cranial CT showed that the calcification foci were located in the basal ganglia in 49 cases (100%), cerebellum and dentate nucleus in 17 cases (34.7%), cortical gray-white matter junction area in 15 cases (30.6%), and thalamus in 4 cases (8.16%); some patients had short T1 and short T2 signals on cranial MRI.
5. Electrophysiological examination: 5 cases had scattered slow waves on EEG and 3 cases had focal spike waves.
6.Efficacy: clinical symptoms and calcification foci were not significantly changed.
Discussion
Fahr’s disease, also known as familial idiopathic basal ganglia calcification, was reported by Fahr in 1930 and was characterized by massive calcium deposits in the walls of cerebral vessels, especially in the vessels of the nucleus accumbens and the dentate nucleus.Geschwind found that the gene for this disease was located on the long arm of chromosome 14. Regarding the mechanism of calcification in the basal ganglia, most studies suggest that vascular factors are predominant and that abnormalities in the metabolism of trace elements such as iron, calcium, phosphorus, and aluminum play a key role. Schmitt suggested that there is no difference in the distribution of trace elements between sites in the same brain tissue and that differences exist in different brain tissues. Histochemical examination confirmed that damage to extravascular membrane cells plays an important role in the development of the disease.
Ivanyi et al. performed 15,000 autopsies before finding 4 cases of primary symmetric basal ganglia calcification. 2318 cranial CT cases were examined by Gomille and the detection rate of basal ganglia calcification was 12.5%, with the highest incidence of pale bulb calcification at 96.4%, followed by cerebellum, white matter and brainstem. The common symptoms are mental retardation, seizures, movement disorders, dystonia, and psychiatric abnormalities; neurological examination shows signs of damage to the pyramidal system, extrapyramidal system, and cerebellum. Most foreign studies have concluded that the main symptom of FCBG is mental retardation or extrapyramidal damage, about 50%, while seizures account for only 4.5%, and about 45.5% of cases have no obvious clinical symptoms but only imaging changes.
The relationship between clinical symptoms and the location and extent of calcified foci in FCBG has been inconsistent in foreign studies. Avrahami believes that the size of calcified foci in the basal ganglia should be more than 800 mm2 to be diagnostic.
The sensitivity of CT for the diagnosis of basal ganglia calcification is better than that of MRI due to the poor signal discrimination of MRI for calcification, but the T2 phase of MRI often shows more areas of signal abnormality than CT for calcified foci, which can more accurately reflect the relationship with clinical symptoms because it shows the chronic progression of metabolic or inflammatory processes that precede the formation of calcified foci.
The EEG of FCBG has no specific manifestation, and some patients with concomitant G seizures can only find focal epileptic G-like discharges, the site of which does not match the distribution of calcified foci. The EEG can only be used as an auxiliary diagnostic tool.
The treatment of this disease has no specific drugs and is generally symptomatic and ineffective. Clinical attention must be paid to intracranial calcifications due to other causes, such as pseudohypoparathyroidism, tuberous sclerosis, Cokayne’s syndrome, mitochondrial encephalopathy, and Wilson’s disease.