ABSTRACT
Purpose@#Progressive familial intrahepatic cholestasis (PFIC) is a rare genetic autosomal recessive disease caused by mutations in ATP8B1, ABCB11 or ABCB4. Mutational analysis of these genes is a reliable approach to identify the disorder. @*Methods@#We collected and analyzed relevant data related to clinical diagnosis, biological investigation, and molecular determination in nine children carrying these gene mutations, who were from unrelated families in South China. @*Results@#Of the nine patients (five males, four females) with PFIC, one case of PFIC1, four cases of PFIC2, and four cases of PFIC3 were diagnosed. Except in patient no. 8, jaundice and severe pruritus were the major clinical signs in all forms. γ-glutamyl transpeptidase was low in patients with PFIC1/PFIC2, and remained mildly elevated in patients with PFIC3. We identified 15 different mutations, including nine novel mutations (p.R470HfsX8, p.Q794X and p.I1170T of ABCB11 gene mutations, p.G319R, p.A1047P, p.G1074R, p.T830NfsX11, p.A1047PfsX8 and p.N1048TfsX of ABCB4 gene mutations) and six known mutations (p.G446R and p.F529del of ATP8B1 gene mutations, p.A588V, p.G1004D and p.R1057X of ABCB11 gene mutations, p.P479L of ABCB4 gene mutations). The results showed that compared with other regions, these three types of PFIC genes had different mutational spectrum in China. @*Conclusion@#The study expands the genotypic spectrum of PFIC. We identified nine novel mutations of PFIC and our findings could help in the diagnosis and treatment of this disease.
ABSTRACT
Objective Multiple carboxylase deficiency(MCD) is an autosomal recessively inherited defect of organic acid metabolism.The underlying mechanism is biotinidase(BT) or holocarboxylase synthetase(HLCS) deficiency.The authors reported 15 cases of MCD(clinical characteristics,diagnosis and treatment) and outcomes of long-term follow-up.Methods The clinical data of 15 patients with MCD admitted to Guangzhou Women and Children's Medical Center between Aug.2001 and Feb.2013 were analyzed.The diagnosis was confirmed by urinary organic acid analysis with gas chromatography/mass spectrometry (GC/MS),blood enzymatic determination and gene analysis.The patients consisted of 12 male and 3 female.The onset age ranged from newborn infants to 16 months.Results 1.Remarkable elevations of urinary lactate,3-oxy-butyric acid,3-OH-isovalerate,methylcitrate,3-methylcrontonylglycine,3-OH-propionate were detected in all of 15 cases.Fourteen cases with HLCS deficiency and 1 case with BT deficiency were confirmed by gene analysis.2.Most of patients with HLCS deficiency presented in the neonatal period or early infancy.The main clinical manifestations were skin rash (14 cases),tachypnea (9 cases),developmental retardation (8 cases),vomiting(5 cases),poor feeding (3 cases),developmental regradation (1 case),convulsion (1 case).Laboratory evaluation showed persistent metabolic acidosis and varied degree of ketosis,lactic acidosis,hyperuricacidemia,ammoniemia and hypoglycemia.Biotin was given to 13 patients in 10 mg/d and their metabolic disorders were corrected within 48 h,except one who gave up treatment and died.Treatment with Biotin in 5 mg/d provided clinical stability and normal neurodevelopmental outcome on follow-up for 3-11 (6.47 ± 2.70) years.3.One patient with BT deficiency presented with severe neurological symptoms(impaired consciousness,limbs trembling,tachypnea with irregular respiratory rhythm) at 16 months old.Demyelination of corpus callosum was evident on magnetic resonance imaging.Biotin treatment was given to him on the second of onset,and 1-year follow-up indicated significant improvement of his clinical symptoms,but the right limb weakness did not completely recover.Conclusions The main clinical features of HLCS deficiency include frequent skin rash,tachypnea,and metabolic disorders.BT deficiency may produce variable neurologic manifestations including demyelination of corpus callosum.Urinary organic acid analysis with GC/MS is critical to the early diagnosis of MCD.Prompt biotin treatment is recommended to correct metabolic derangements and continued therapy is essential to the improvement of long-term prognosis.Delayed commencement of therapy in BT deficiency can result in irreversible neurological damage.
ABSTRACT
<p><b>OBJECTIVE</b>To analyze the clinical characteristics and genetype of one children who had been diagnosed with pyruvate dehydrogenase complex deficiency.</p><p><b>METHOD</b>Comprehensive analyses of this case were performed, including clinical symptoms, signs, biochemical examinations and therapeutic effects. The eleven exons and splicing areas of PDHA1 were amplified with genomic DNA from whole blood. And variations were investigated by sequencing the PCR product. The patient was diagnosed with pyruvate dehydrogenase complex deficiency by sequence analysis of PDHA1 gene.</p><p><b>RESULT</b>The patient was a 2 years and 4 monthes old boy. He presented with muscle hypotonia and weakness for one year, and experienced recurrent episodes of unstable head control, unable to sit by himself or stand without support, with persistently hyperlactacidemia. Metabolic testing revealed blood lactate 5.37 mmol/L, pyruvate 0.44 mmol/L, and lactate/pyruvate ratio was 12.23. MRI of the brain showed hyperintense signals on the T2 and T2 Flair weighted images in the basal ganglia bilaterally. Sequence analysis of PDHA1 gene showed a G>A point mutation at nucleotide 778, resulting in a substitution of glutarnine for arginine at position 263 (R263Q). And the diagnosis of pyruvate dehydrogenase complex deficiency was identified. By giving the therapy with ketogenic diet, vitamin B(1), coenzyme Q(10) and L-carnitine , the boy was in a stable condition.</p><p><b>CONCLUSION</b>The severity and the clinical phenotypes of pyruvate dehydrogenase complex deficiency varied. Sequence analysis of PDHA1 gene revealed a 788G>A (R263Q) mutation. Patients who presented with unexplained muscle hypotonia, weakness and hyperlactacidemia could be diveded by gene analysis. And appropriate treatment can improve the quality of life.</p>