Clinical And Genetic Study In Chinese Patients With Infantile Neuroaxonal Dystrophy

Background: Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder involving axons in both central and peripheral nervous system. The clinical picture is characterized by progressive psychomotor regression with onset within 3 years of age, symmetric pyramidal tract signs, vision impairment, failure in the early stage, electromyography (EMG) showed denervation and the cranial MRI showed cerebellar atrophy. It always progress to spastic tetraplegia, blind and dementia, and leading to death before the age of 10 years. Mutations in PLA2G6 (22q13.1) encoding iPLA2-VIA (cytosolic Ca²⁺-independent phospholipids A₂, group VIA) were identified in most of INAD patients in 2006. The definitive diagnosis required both clinical and neuropathological data before 2006. Three genetic studies in INAD patients has been published up to date, with 44 different PLA2G6 mutations identified. There are only 3 INAD patients clinical diagnosed by typical clinical and neuropathological features. However, until now, no PLA2G6 mutation analysis has been reported in China.Objective: To delineate clinical and genetic characteristics of Chinese patients with INAD. To detect PLA2G6 gene mutation in 11 patients which were collected in the Peking University First Hospital. To delineated genotype-phenotype correlation,and make a definite diagnosis in order to set up the basis of genetic counseling and prenatal diagnosis.Methods: Physical examinations, laboratory examinations, electrophysiological and neuroimaging study were analyzed in 11 patients with clinical diagnosis of INAD. Informed consent was obtained from all the families tested before the study. PCR assays and followed by DNA sequence analysis were used to find PLA2G6 gene mutations. These data collected and all works have been done in Peking University First Hospital .Results:1.Clinical featuresAll cases showed the typical clinical features of INAD like reported. The clinical picture is characterized by progressive psychomotor regression with onset within 3 years of age., symmetric pyramidal tract signs, electromyography (EMG) showed denervation and the cranial MRI showed cerebellar atrophy. Urinary organic and amino acids analysis, serum lactic acid and pyruvate were unrevealing in all cases. The presence of axonal swelling was found in skin biopsy specimens from 3 cases.2.Genetic analysisPLA2G6 gene mutation were found in ten out of 11 patients (except patient 11). There were 10 kinds of mutations (17 mutations) totally,including 8 novel mutations and 2 previously reported mutations. Five patients had heterozygous compound mutations, Two patients had homozygoous mutation , 3 patient had only 1 heterozygous mutation up to now . Eight kinds of novel mutations including c.1 A>G, c.208C>T (p.R70X), c.1111G>A (p.V371M), c.1117G>A (p.G373R), c.1633A>G (p.K545E), c.1771C>T (p.R591W), c.1970C>T (p.A657V) and IVS10+1 G>A. Two kinds of reported mutations, including c.109 C>T (p.R37X) and c.238G>A (p.A80T). In the later analyze of family constellation. All these mutations were inherited from their parents who were heterozygous carrier with normal phenotype.Conclusions: This is the first report to analyze the PLA2G6 gene in 11 clinically diagnosed INAD patients in China. We set up the molecular genetic diagnostic method, and 10 patients have been found the PLA2G6 gene mutations and confirmed diagnosis. The clinical features of Chinese patients with INAD are consistent with those described in previous reports of patients from other ethnics, but the genotypes of our patient are different from previoursly reported. Totally, 10 kinds (17 times) mutations were found, and among them eight are novel mutations. All mutations located in exons 2, 8, 12 , 13, 14 and splicing site in intron 10. Exon 2 was probably the"hot"exon, 4/10 patients with mutations and 3/10 kinds mutations in this exon. Mutations, c.1 A>G starting code change(3/10 patients,3/17 times mutations), c.1771C>T(p.R591W)(2/10 patients, 3/17 times mutations),IVS10+1 G>A(2/10 patients, 3/17 times mutations), c.1970C>T(p. A657V)(2/10 patients, 2/17 times mutations)are probably"hot"mutations in Chinese INAD patients.There is no distinctive genotype-phenotype correlation. This study can offer precise genetic counseling and prenatal diagnosis for the related families.