Clinical, Pathological And Genetic Study Of Kennedy Disease In A Chinese Family

Objective:Kennedy's disease,also known as spinal and bulbar muscular atrophy,is a late-onset form of motor neuron disease which is slowly progressive in nature.First described by Kennedy et al.in 1968,the genetic basis was identified in 1991 when La Spada et al.mapped the gene to the proximal long arm of the X-chromosome(Xq11-12). Kennedy's disease is characterized by slowly progressive bulbar and proximal muscle weakness usually beginning in the shoulder and pelvic girdles with frequently occurring gynaecomastia,tremor,testicular atrophy,impotence and infertility.Distal muscle involvement may be later detectable in an advanced course of disease.The molecular basis of SBMA is the expansion of trinucleotide CAG repeat,which encodes the polyglutamine tract,in the first exon of the androgen receptor(AR) gene.The region is polymorphic within the normal population,numbering between10-36 repeats,whereas in Kennedy's disease this repeat region is expanded to number between 40 and 62.Expansion of this region to beyond 40 repeats places this protein in the pathogenic range.Individuals with higher numbers of repeats generally tend to develop symptoms at an earlier age.In recent ten years,research about Kennedy disease has been made much advance abroad,,however in China the research about Kennedy disease began much later.We report the genetically proven Kennedy disease pedigree in China mainland in order to explore its clinical presentation,pathological features and molecular mechanism.Method:The proband is a 38-year-old man.Since age of 16 year old,he found his breast was bigger than his peers in bathroom.Since age of 30 year old,he found he could not stand up immediately after squatting down.At age of 37,he began to feel myasthenia of limbs,and his weakness gradually worsen.So his daily life and farmwork has been affected unavoidably.At the age of 25,he married a healthy woman and had a boy later.He had visited sevsral local hospitals,but could not get a definite diagnosis.According to the proband's statement,we conduct a thorough survey of the family.Informed consent was obtained from all family members in this pedigree and genetic counseling provided as appropriate.Genomic DNA were extracted from peripheral blood according to standard procedures.The CAG repeated sequence in the exon 1 of AR geng was amplified by PCR and sequenced directly.Result:The sequencing results show that the proband has 54 CAG repeats and other affected individual has 55 CAG repeats,and one presymptomatic individual has 54 CAG repeats.3 famale carriers also have been diagnosed. Conclusion:These results demonstrate that SBMA is often misdiagnosed because of lack of knowledge about SBMA,so the report of this disease in our country is severely neglected.Gene determination is the most reliable method of diagnosis and presymptomatic individuals can also be found in advance.The progression of SBMA is usually much slower than that of bulbar atrophy or atrophic lateral sclerosis(ALS).Nerve biopsy revealed demylination change in peripheral nerve;and muscle biopsy revealed muscle atrophy origining from nerve.Because of lack of reported cases,we can not explore the correlation between CAG length and progression rate of the disease or age of onset.