Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common ...Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common late life neurodegenerative disease,Alzheimer’s disease,and the most common early life neurodegenerative diseases,neuronal ceroid lipofuscinoses.Genetic studies reported an overlap of clinically diagnosed Alzheimer’s disease and mutations in genes known to cause neuronal ceroid lipofuscinoses.Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders.This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases.A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts,the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations.Here,we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer’s disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.展开更多
BACKGROUND Adult neuronal ceroid lipofuscinosis(ANCL)can be caused by compound heterozygous recessive mutations in CLN6.The main clinical features of the disease are neurodegeneration,progressive motor dysfunction,sei...BACKGROUND Adult neuronal ceroid lipofuscinosis(ANCL)can be caused by compound heterozygous recessive mutations in CLN6.The main clinical features of the disease are neurodegeneration,progressive motor dysfunction,seizures,cognitive decline,ataxia,vision loss and premature death.CASE SUMMARY A 37-year-old female presented to our clinic with a 3-year history of limb weakness and gradually experiencing unstable walking.The patient was diagnosed with CLN6 type ANCL after the identification of mutations in the CLN6 gene.The patient was treated with antiepileptic drugs.The patient is under ongoing followup.Unfortunately,the patient’s condition has deteriorated,and she is currently unable to care for herself.CONCLUSION There is presently no effective treatment for ANCL.However,early diagnosis and symptomatic treatment are possible.展开更多
BACKGROUND Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this conditi...BACKGROUND Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this condition, and the clinical course consisted of delayed developmental skills initially and later regression of previously acquired skills. The cases were initially considered as childhood disintegrative disorder(CDD); however, when whole exome sequencing(WES) genetic testing was done, they proved to be variant late infantile ceroid lipofuscinosis. This is the first report from Jordan.CASE SUMMARY Clinical presentation included developmental delay and initially speech delay,followed by lose of sphincter control. Motor development was normal until 4 years of age, then they developed ataxia(fear of going downstairs) and weakness while walking. Atonic and myoclonic seizures become intractable, and this was followed by inability to stand or sit and loss of expressive language. In addition to complete blood count test, liver function test, kidney function test, serum electrolyte test, and blood sugar test, serum amino acid profile, B12 level test,thyroid function test, and a brain computed tomography scan were also normal.An electroencephalogram showed a generalized spike and wave pattern, and magnetic resonance imaging showed little to no abnormalities. After dealing with the cases as CDD, WES testing proved a final diagnosis of variant late infantile ceroid lipofuscinosis. Current treatment is anti-epileptic drugs and supportive care at home, and they are now in vegetative state.CONCLUSION This report highlights the importance of WES for the identification of genetic diseases, especially neurodegenerative disorders.展开更多
TPP-Ⅰ(tripeptidyl peptidase-Ⅰ) protein turnover was studied by observing the role of rat TPP-Ⅰ in neuromedin B(NMB) and other neuropeptides degradations in some physiological situations. The mixtures of rat TPP-Ⅰ ...TPP-Ⅰ(tripeptidyl peptidase-Ⅰ) protein turnover was studied by observing the role of rat TPP-Ⅰ in neuromedin B(NMB) and other neuropeptides degradations in some physiological situations. The mixtures of rat TPP-Ⅰ with each of NMB, other neuropeptides and Ala-Ala-Phe-MCA were made respectively under the same conditions. The reaction was observed at different timeand monitored by means of high performance liquid chromatography(HPLC) and time-of-flight mass spectrometry(TOF-MS) in vitro. NMB was broken down at the same degree as Ala-Ala-Phe-MCA by rat TPP-Ⅰ and Gly-Asn-Leu was released within 16 h, but other neuropeptides were not digested within 24 h. TPP-Ⅰ is the predominant proteolytic enzyme responsible for the intracellular degradation of neuromedin B. NMB has recently been found to be a good natural substrate for rat lysosomal TPP-Ⅰ.展开更多
基金supported by the Deutsche Forschungsgemeinschaft(DFG,425373668,HE 3220/4-1)(to GH).
文摘Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common late life neurodegenerative disease,Alzheimer’s disease,and the most common early life neurodegenerative diseases,neuronal ceroid lipofuscinoses.Genetic studies reported an overlap of clinically diagnosed Alzheimer’s disease and mutations in genes known to cause neuronal ceroid lipofuscinoses.Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders.This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases.A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts,the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations.Here,we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer’s disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.
文摘BACKGROUND Adult neuronal ceroid lipofuscinosis(ANCL)can be caused by compound heterozygous recessive mutations in CLN6.The main clinical features of the disease are neurodegeneration,progressive motor dysfunction,seizures,cognitive decline,ataxia,vision loss and premature death.CASE SUMMARY A 37-year-old female presented to our clinic with a 3-year history of limb weakness and gradually experiencing unstable walking.The patient was diagnosed with CLN6 type ANCL after the identification of mutations in the CLN6 gene.The patient was treated with antiepileptic drugs.The patient is under ongoing followup.Unfortunately,the patient’s condition has deteriorated,and she is currently unable to care for herself.CONCLUSION There is presently no effective treatment for ANCL.However,early diagnosis and symptomatic treatment are possible.
文摘BACKGROUND Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this condition, and the clinical course consisted of delayed developmental skills initially and later regression of previously acquired skills. The cases were initially considered as childhood disintegrative disorder(CDD); however, when whole exome sequencing(WES) genetic testing was done, they proved to be variant late infantile ceroid lipofuscinosis. This is the first report from Jordan.CASE SUMMARY Clinical presentation included developmental delay and initially speech delay,followed by lose of sphincter control. Motor development was normal until 4 years of age, then they developed ataxia(fear of going downstairs) and weakness while walking. Atonic and myoclonic seizures become intractable, and this was followed by inability to stand or sit and loss of expressive language. In addition to complete blood count test, liver function test, kidney function test, serum electrolyte test, and blood sugar test, serum amino acid profile, B12 level test,thyroid function test, and a brain computed tomography scan were also normal.An electroencephalogram showed a generalized spike and wave pattern, and magnetic resonance imaging showed little to no abnormalities. After dealing with the cases as CDD, WES testing proved a final diagnosis of variant late infantile ceroid lipofuscinosis. Current treatment is anti-epileptic drugs and supportive care at home, and they are now in vegetative state.CONCLUSION This report highlights the importance of WES for the identification of genetic diseases, especially neurodegenerative disorders.
文摘TPP-Ⅰ(tripeptidyl peptidase-Ⅰ) protein turnover was studied by observing the role of rat TPP-Ⅰ in neuromedin B(NMB) and other neuropeptides degradations in some physiological situations. The mixtures of rat TPP-Ⅰ with each of NMB, other neuropeptides and Ala-Ala-Phe-MCA were made respectively under the same conditions. The reaction was observed at different timeand monitored by means of high performance liquid chromatography(HPLC) and time-of-flight mass spectrometry(TOF-MS) in vitro. NMB was broken down at the same degree as Ala-Ala-Phe-MCA by rat TPP-Ⅰ and Gly-Asn-Leu was released within 16 h, but other neuropeptides were not digested within 24 h. TPP-Ⅰ is the predominant proteolytic enzyme responsible for the intracellular degradation of neuromedin B. NMB has recently been found to be a good natural substrate for rat lysosomal TPP-Ⅰ.
