Fragile X mental retardation 1 is the gene underlying fragile X syndrome (FXS). Its product, fragile X mental retardation protein, is closely involved with development of brain and neurons. PCR and Southern blotting have been the major methods for laboratory diagnosis of FXS. In this article, the progress in the molecular diagnosis of FXS is reviewed.
Fragile X Mental Retardation Protein ; genetics ; Fragile X Syndrome ; diagnosis ; genetics ; Humans ; Pathology, Molecular ; methods

Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked intellectual disability. The main features of the patients include intellectual disability/global developmental delay, characteristic face, anomalies of fingers and toes, hypogonadism, linear skin hyperpigmentation, and tooth abnormalities in female patients, and obesity in male patients. A case of BFLS caused by a novel mutation of PHF6 gene who was treated in the Department of Pediatrics, Xiangya Hospital, Central South University was reported. The 11 months old girl presented the following symptons: Global developmental delay, characteristic face, sparse hair, ocular hypertelorism, flat nasal bridge, hairy anterior to the tragus, thin upper lip, dental anomalies, ankyloglossia, simian line, tapering fingers, camptodactylia, and linear skin hyperpigmentation. The gene results of the second-generation sequencing technology showed that there was a novel heterozygous mutation site c.346C>T (p.Arg116*) of the PHF6 (NM032458.3), variation rating as pathogenic variation. During the follow-up, the patient developed astigmatism, strabismus, awake bruxism, and stereotyped behavior, and the linear skin hyperpigmentation became gradually more evident. The disease is lack of effective therapy so far.
Humans ; Male ; Female ; Child ; Infant ; Intellectual Disability/genetics* ; Mental Retardation, X-Linked/pathology* ; Obesity/complications* ; Hypogonadism/pathology*

Fragile X-associated tremor/ataxia syndrome(FXTAS) is a neurodegenerative disease caused by FMR1 gene permutation(PM). The main clinical manifestations are intention tremor and/or ataxia, and the pathogenesis was related to RNA toxicity. In this paper, the research progress of clinical manifestatios, pathological characteristics, epidemiology and molecular mechanisms will be reviewed.
Ataxia ; genetics ; Female ; Fragile X Mental Retardation Protein ; genetics ; Fragile X Syndrome ; complications ; diagnosis ; genetics ; pathology ; Humans ; Male ; Tremor ; genetics

OBJECTIVE: To explore the genetic basis for a pedigree affected with X-linked recessive mental retardation Claes-Jensen type. METHODS: Genomic DNA was extracted from peripheral blood samples of the patient, his parents (phenotypically normal) and two elder brothers with similar clinical manifestations. Whole exome sequencing was carried out for the proband, and the result was verified by Sanger sequencing. RESULTS: The proband was found to harbor a hemizygous c.1565C>T missense variant in exon 11 of the KDM5C gene. The transition has resulted in replacement of serine by phenylalanine at position 522 (p.Ser522Phe). Sanger sequencing showed that the patient's two elder brothers and mother carried the same variant, which was predicted to be probably damaging by SIFT, PolyPhen2 and Mutation_Taster. The three affected brothers presented with similar clinical phenotypes characterized by mental retardation, speech delay, behavioral problem, self-limited epilepsy responsible to medication, short stature and microcephaly. The mother only had mild cognitive impairment and learning disability. The same variant was not found in their father and was unreported previously. CONCLUSION The c.1565C>T (p.Ser522Phe) of the KDM5C gene probably underlay the X-linked recessive mental retardation Claes-Jensen type in this pedigree.
Aged ; Female ; Histone Demethylases/genetics* ; Humans ; Male ; Mental Retardation, X-Linked/pathology* ; Mutation, Missense/genetics* ; Pedigree ; Phenotype ; Whole Exome Sequencing

Congenital insensitivity to pain with anhidrosis (CIPA) is a very rare genetic disorder of the peripheral nervous system characterized by recurrent episodes of unexplained fever, generalized anhidrosis, insensitivity to pain and temperature, and accompanied by self-mutilating behavior and mental retardation. We report on a 16 month-old boy with CIPA who exhibited these characteristic clinical features. A sural nerve biopsy revealed markedly reduced numbers of unmyelinated and small myelinated fibers, consistent with the characteristic features of CIPA.
Atrophy ; Case Report ; Fingers ; Human ; Hypohidrosis/pathology* ; Hypohidrosis/complications ; Infant ; Korea ; Male ; Mental Retardation/pathology ; Mental Retardation/complications ; Microscopy, Electron ; Nerve Fibers/ultrastructure ; Nerve Fibers/pathology ; Pain Insensitivity, Congenital/pathology* ; Pain Insensitivity, Congenital/complications ; Self Mutilation/pathology ; Self Mutilation/etiology ; Sural Nerve/pathology ; Tongue

This report presents a rare example of a bilateral congenital anophthalmos and an agenesis of the optic pathways. The MR imaging studies revealed that the eyeballs, optic nerves, optic chiasm, optic tracts and optic radiation were absent. The chromosomal examination was normal. Mild mental retardation was also observed. Apart from the rarity of the anophthalmos and the total absence of the optic pathways, no etiologic reason for this pathology could be detected, which makes this case more significant.
Abnormalities, Multiple/diagnosis ; Adult ; Anophthalmos/*complications ; Female ; Humans ; Magnetic Resonance Imaging ; Mental Retardation/complications ; Optic Chiasm/abnormalities ; Optic Nerve/abnormalities ; Visual Pathways/*abnormalities/pathology

Fragile X syndrome (FXS) is one of the most prevalent mental retardations. It is mainly caused by the loss of fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein and can regulate the translation of its binding RNA, thus regulate several signaling pathways. Many FXS patients show high susceptibility to epilepsy. Epilepsy is a chronic neurological disorder which is characterized by the recurrent appearance of spontaneous seizures due to neuronal hyperactivity in the brain. Both the abnormal activation of several signaling pathway and morphological abnormality that are caused by the loss of FMRP can lead to a high susceptibility to epilepsy. Combining with the research progresses on both FXS and epilepsy, we outlined the possible mechanisms of high susceptibility to epilepsy in FXS and tried to give a prospect on the future research on the mechanism of epilepsy that happened in other mental retardations.
Brain ; physiopathology ; Epilepsy ; etiology ; genetics ; pathology ; Fragile X Mental Retardation Protein ; genetics ; metabolism ; Fragile X Syndrome ; complications ; genetics ; Humans ; RNA-Binding Proteins ; metabolism

OBJECTIVEThe aim of this study was to explore the genetic features of a family with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (MHBDD) which may provide the basis for the diagnosis and genetic counseling.

METHODClinical data of the proband was collected, total RNA and genomic DNA were extracted from the peripheral blood. The whole coding region of the ACAT1 gene was amplified by RT-PCR. 5' noncoding region of the ACAT1 gene and all 6 exons and flanking intron regions of the HADH2 gene were amplified by PCR. All amplification products were directly sequenced and compared with the reference sequence.

RESULT(1) The patient was a one-year-old boy who presented with psychomotor retardation and astasia when he was admitted to the hospital. Biochemical test revealed slight hyperlactatemia (3.19 mmol/L) and magnetic resonance imaging showed delayed myelination. 2-Methylacetoacetyl-CoA thiolase deficiency was suggested by gas chromatography-mass spectrometry. (2) There was no mutation in the ACAT1 gene and a hemizygous missense mutation c.388C > T was found in the 4 exon of the HADH2 gene which resulted in p. R130C. Proband's mother was the heterozygote and the father was normal.

CONCLUSIONThis is the first report on MHBDD patient and HADH2 mutation in China. p.R130C is responsible for the pathogenesis of the disease in the infant.

3-Hydroxyacyl CoA Dehydrogenases ; genetics ; Acetyl-CoA C-Acetyltransferase ; deficiency ; genetics ; Acyl Coenzyme A ; genetics ; metabolism ; Base Sequence ; DNA Mutational Analysis ; Dyskinesias ; Heterozygote ; Humans ; Infant ; Intellectual Disability ; enzymology ; genetics ; pathology ; Lipid Metabolism, Inborn Errors ; genetics ; pathology ; Male ; Mental Retardation, X-Linked ; Mutation, Missense ; Pedigree ; Reverse Transcriptase Polymerase Chain Reaction

ObjectiveTo investigate the clinical (including reproductive) manifestations and genetic characteristics of familial fragile X syndrome (FXS).

METHODSWe collected the clinical data about a case of familial FXS by inquiry, testicular ultrasonography, semen analysis, determination of sex hormone levels, and examinations of the peripheral blood karyotype and Y chromosome microdeletions. Using Southern blot hybridization, we measured the size of the CGG triple repeat sequence of the fragile X mental retardation-1 (FMR1) gene and determined its mutation type of the pedigree members with a genetic map of the FXS pedigree.

RESULTSAmong the 34 members of 4 generations in the pedigree, 3 males and 1 female (11.76%) carried full mutation and 9 females (26.47%) premutation of the FMR1 gene. Two of the males with full FMR1 mutation, including the proband showed a larger testis volume (>30 ml) and a higher sperm concentration (>250 ×10⁶/ml), with a mean sperm motility of 50.5%, a mean morphologically normal sperm rate of 17.5%, an average sperm nuclear DNA fragmentation index (DFI) of 18.5%, a low level of testosterone, normal karyotype in the peripheral blood, and integrity of the azoospermia factor (AZF) region in the Y chromosome. One of the second-generation females carrying FMR1 premutation was diagnosed with premature ovarian failure and another 3 with uterine myoma.

CONCLUSIONSSome of the FXS males in the pedigree may present macroorchidism and polyzoospermia but with normal semen parameters. In the intergenerational transmission, premutation might extend to full mutation, with even higher risks of transmission and extension of mutation in males, especially in those with >80 CGG triple repeat sequences. Therefore, it is recommended that the couples wishing for childbearing receive genetic testing, clinical guidance, and genetic counseling before pregnancy and, if necessary, prenatal diagnosis and preimplantation genetic diagnosis.

Chromosome Deletion ; Chromosomes, Human, Y ; genetics ; DNA Fragmentation ; Female ; Fragile X Mental Retardation Protein ; genetics ; Fragile X Syndrome ; genetics ; Genetic Testing ; Humans ; Infertility, Male ; genetics ; Karyotyping ; Male ; Mutation ; Organ Size ; Pedigree ; Pregnancy ; Preimplantation Diagnosis ; Risk ; Sex Chromosome Aberrations ; Sex Chromosome Disorders of Sex Development ; genetics ; Sperm Count ; Testis ; diagnostic imaging ; pathology