Clinical characteristics and genetic analysis of a case with adult neuronal ceroid lipofuscinosis type 7 due to variant of MFSD8 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic variants in a patient with adult ceroid lipofuscinosis neuronal type 7 (ACLN7).@*METHODS@#A female patient diagnosed with ACLN7 in Henan Provincial People's Hospital in June 2021 was selected as the study subject. Clinical data, auxiliary examination and result of genetic testing were retrospectively analyzed.@*RESULTS@#The patient, a 39-year-old female, has mainly presented progressive visual loss, epilepsy, cerebellar ataxia and mild cognitive decline. Neuroimaging analysis has revealed generalized brain atrophy, prominently cerebellum. Fundus photography has revealed retinitis pigmentosa. Ultrastructural skin examination has revealed granular lipofuscin deposits in the periglandular interstitial cells. Whole exome sequencing revealed that she has harbored compound heterozygous variants of the MSFD8 gene, namely c.1444C>T (p.R482*) and c.104G>A (p.R35Q). Among these, c.1444C>T (p.R482*) was a well established pathogenic variant, while c.104G>A (p.R35Q) was a missense variant unreported previously. Sanger sequencing confirmed that the daughter, son and elder brother of the proband have respectively carried heterozygous c.1444C>T (p.R482*), c.104G>A (p.R35Q), and c.104G>A (p.R35Q) variants of the same gene. The family has therefore fit with the autosomal recessive inheritance pattern of the CLN7.@*CONCLUSION@#Compared with previously reported cases, this patient has the latest onset of the disease with a non-lethal phenotype. Her clinical features have involved multiple systems. Cerebellar atrophy and fundus photography may be indicative of the diagnosis. The c.1444C>T (p.R482*) and c.104G>A (p.R35Q) compound heterozygous variants of the MFSD8 gene probably underlay the pathogenesis in this patient.

Retinal function in patients with the neuronal ceroid lipofuscinosis phenotype / Estudo da função retiniana em pacientes com o fenótipo da lipofuscinose ceróide neuronal

ABSTRACT Purpose: To analyze the clinical features, visual acuity, and full-field electroretinogram (ERG) findings of 15 patients with the neuronal ceroid lipofuscinosis (NCL) phenotype and to establish the role of ERG testing in NCL diagnosis. Methods: The medical records of five patients with infantile NCL, five with Jansky-Bielschowsky disease, and five with juvenile NCL who underwent full-field ERG testing were retrospectively analyzed. Results: Progressive vision loss was the initial symptom in 66.7% of patients and was isolated or associated with ataxia, epilepsy, and neurodevelopmental involution. Epilepsy was present in 93.3% of patients, of whom 86.6% presented with neurodevelopmental involution. Fundus findings ranged from normal to pigmentary/atrophic abnormalities. Cone-rod, rod-cone, and both types of dysfunction were observed in six, one, and eight patients, respectively. Conclusion: In our study, all patients with the NCL phenotype had abnormal ERG findings, and the majority exhibited both cone-rod and rod-cone dysfunction. We conclude that ERG is a valuable tool for the characterization of visual dysfunction in patients with the NCL phenotype and is useful for diagnosis.

RESUMO Objetivo: Analisar o quadro clínico, a acuidade visual e o eletrorretinograma de campo total (ERG) de 15 pacientes com o fenótipo da lipofuscinose ceróide neuronal (LCN), estabelecendo o papel do eletrorretinograma no seu diagnóstico. Métodos: Eletrorretinograma foi realizado em 5 pacientes com lipofuscinose ceróide neuronal infantil, 5 com doença de Jansky-Bielschowsky e 5 com lipofuscinose ceróide neuronal juvenil sendo feita uma análise retrospectiva dos registros médicos. Resultados: A perda progressiva da acuidade visual foi o sintoma inicial em 66,7%; isolada ou associada à ataxia, epilepsia e involução do desenvolvimento neuropsico motor. Epilepsia foi o sintoma inicial em 93,3% e 86,6% apresentaram involução do desenvolvimento neuropsicomotor. Achados fundoscópicos variaram de normal a alterações pigmentares/atróficas. Disfunção de cone-bastonete foi constatada em 6 pacientes, bastonete-cone em 1 e em 8 pacientes observou-se disfunção proporcional de ambos os sistemas. Conclusão: O eletrorretinograma foi alterado em todos os pacientes, e o achado mais frequente foi o comprometimento de cones e bastonetes. O eletrorretinograma constitui, portanto, uma ferramenta valiosa para caracterizar a disfunção visual em pacientes com o fenótipo da lipofuscinose ceróide neuronal, contribuindo para seu diagnóstico.

Perioperative care of a patient with neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses [NCL] are a group of inherited, autosomal recessive, and progressive neurodegenerative diseases, which result from an enzymatic defect or the deficiency of a transmembrane protein, leading to the accumulation of lipopigments [lipofuscin] in various tissues. NCL results in the impairment of function in several end-organs including the central nervous system with loss of cognitive and motor function, myoclonus, and intractable seizures. Additional involvement includes the cardiovascular system with arrhythmias and bradycardia as well as impairment of thermoregulation leading to perioperative hypothermia. Given the complexity of the end-organ involvement and the progressive nature of the disorder, the anesthetic care of such patients can be challenging. Till date, there are a limited number of reports regarding the anesthetic management of patients with NCL. We present an 18-year-old patient with NCL who required anesthetic care during replacement of a vagal nerve stimulator. Previous reports of anesthetic care for these patients are reviewed, the end-organ involvement of NCL discussed, and options for anesthetic care presented

Dificuldades no diagnóstico clínico e eletrencefalográfico de lipofuscinose ceróide neuronal / Pitfalls in the clinical and electroencephalographic diagnosis of ceroid lipofuscinosis

Tradicionalmente, as lipofuscinoses ceróides neuronais (LCN) eram classificadas de acordo com a idade de início e características clínicas em quatro grandes grupos. Recentemente, os estudos genéticos possibilitaram uma classificação mais pormenorizada dessa entidade em oito formas, permitindo o diagnóstico mais preciso de casos previamente considerados atípicos. Por outro lado, foi demonstrado que mutações de um mesmo gene poderiam ser responsáveis por grande variedade de fenótipos clínicos. O objetivo deste estudo é apresentar dois irmãos com achados clínicos e eletrencefalográficos compatíveis com a forma juvenil de LCN mas com alterações ultra-estruturais características da forma infantil tardia dessa doença. Os achados eletrencefalográficos auxiliam no diagnóstico da LCN, mas pouco contribuem na sua classificação.

A Case of Late Infantile Neuronal Ceroid Lipofuscinosis

Neuronal ceroid lipofuscinosis, which is also known as Batten-Bielschowsky disease, is a group of neuro degenerative disorders, associated with various progressive symptoms including seizures, dementia, visual loss and cerebral atrophy. We experienced a case of late infantile neuronal ceroid lipofuscinosis in a 6-year-old boy who had progressive myoclonic seizures, ataxia, rapid psychomotor deterioration and visual loss. Photic stimulation at 2 to 5 Hz elicited a discrete spike and wave discharges in the occipital region on an electroencephalogram. Magnetic resonance imaging of the brain showed generalized cerebral and cerebellar atrophy. An electron microscopic examination of the skin revealed characteristic curvilinear inclusion bodies. An optic fundoscopy revealed a devastated retina and severe optic atrophy. We report this case with the brief review of related literature.

Juvenile neuronal ceroid lipofuscinosis.

A case of juvenile neuronal ceroid lipofuscinosis (JNCL) diagnosed on the basis of clinical features, electrophysiologic studies and skin electron microscopy is reported. JNCL was suspected on the basis of characteristic symptoms including progressive loss of vision, seizures, mental retardation and motor disabilities. Diagnosis was confirmed by neurophysiological and biopsy studies. The disease is caused by 23 different mutations in a gene recently isolated on chromosome 16 p11.2-12.1. Although universally fatal, characterisation of mutations can help in prenatal diagnosis in future pregnancies.

Lysosomal storage disorders in Thailand: the Siriraj experience.

Lysosomal storage disorders are a heterogeneous group of biochemical genetic disorders; currently 40-50 are known. The clinical phenotype is determined by the tissue distribution of the storage material and degree of enzyme deficiency. The genetic transmission is mostly autosomal recessive. Lysosomal storage disorders can be divided into three groups according to the major organ system pathology: (1) Primary involvement of the central nervous system without significant somatic or skeletal pathology. Disorders of grey matter, eg gangliosidosis and disorders of white matter eg the leucodystrophy are the most common; (2) Primary involvement of the reticuloendothelial system with or without associated neuropathology, eg Niemann-Pick disease and Gaucher disease; (3) Multisystem involvement in which skeletal manifestations are prominent features. The mucopolysaccharidosis and mucolipidoses are the two major forms with this clinical phenotype. Lysosomal storage disorders identified at Siriraj Hospital are neuronal ceroid lipofuscinosis, GMI gangliosidosis, mucolipidosis II, Maroteaux-Lamy, sialidosis, Sly syndrome, Hunter syndrome, Morquio syndrome, Gaucher disease, Niemann-Pick, Sandhoff disease, Pompe's disease and many more. Most patients came from the provinces where consanguinity is common. Confirmation usually is done by enzyme assays using skin fibroblast culture or leucocytes. Genetic counseling is extremely important and prenatal diagnosis is recommended to high-risk couple.

Lipofuscinose ceróide neuronal: relato de quatro casos com estudo por histoquímica retal, microscopia eletrônica de conjuntiva e necrópsia / Neuronal ceroid-lipofuscinosis: report of 4 cases with study by rectal histochemistry, conjunctiva electron mycroscopy and necropsy

Os autores relatam os achados neuropatológicos e clínicos de quatro casos de lipofuscinose ceróide ou doença de Batten. Dois casos foram estudados por necrópsia: o encéfalo mostrou atrofia e neurônios contendo pigmento citoplasmático com características tintoriais de lipofuscina. Um caso foi diagnosticado por estudo histoquímico citoplasmático com características tintoriais de lipofuscina. Um caso foi diagnosticado por estudo histoquímico de biópsia retal, em material congelado em nitrogênio líquido demonstrando-se células ganglionares mioentéricas contendo acúmulo citoplasmático de material granular fosfatase ácida positivo, bem como em grande número de macrófagos do córion. O quarto caso foi diagnosticado por microscopia eletrônica e biópsia de conjuntiva, com identificaçäo de inclusöes curvelíneas membranáceas e tipo impressäo digital

Ceroidolipofuscionosis neural: presentación de 4 pacientes / Neural ceroid-lipofuscionosis: discussion of four cases

Se describen por primera vez en nuestro medio 4 pacientes del sexo femenino, provenientes de 3 familias no emparentadas entre sí, que presentan una enfermedad degenerativa del sistema nervioso central del tipo ceroidolipofuscinosis neuronal forma juvenil o enfermedad de Spielmeyer-Vogt. En una de las familias el cuadro fue de aparición esporádica y en las 3 restantes el modo de herencia fue compatible con el autosómico recesivo. En todos los casos el diagnóstico definitivo se basó en los hallazgos clínicos, electrofisiológicos y ultraestructurales. Se hace énfasis en el estudio morfológico ultraestructural como criterio confirmatorio y para la clasificación de estas entidades