Cases Of Infantile Neuroaxonal Dystrophy Research Articles

Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients

BackgroundPhospholipase-associated neurodegeneration (PLAN) caused by mutations in the PLA2G6 gene is a rare neurodegenerative disorder that presents with four sub-groups. Infantile neuroaxonal dystrophy (INAD) and PLA2G6-related dystonia-parkinsonism are the main two subtypes. In this cohort, we reviewed clinical, imaging, and genetic features of 25 adult and pediatric patients harboring variants in the PLA2G6.MethodsAn extensive review of the patients’ data was carried out. Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS) was used for evaluating the severity and progression of INAD patients. Whole-exome sequencing was used to determine the disease's underlying etiology followed by co-segregation analysis using Sanger sequencing. In silico prediction analysis based on the ACMG recommendation was used to assess the pathogenicity of genetic variants. We aimed to survey a genotype-genotype correlation in PLA2G6 considering all reported disease-causing variants in addition to our patients using the HGMD database and the chi-square statistical approach.ResultsEighteen cases of INAD and 7 cases of late-onset PLAN were enrolled. Among 18 patients with INAD, gross motor regression was the most common presenting symptom. Considering the INAD-RS total score, the mean rate of progression was 0.58 points per month of symptoms (Standard error 0.22, lower 95% − 1.10, and upper 95% − 0.15). Sixty percent of the maximum potential loss in the INAD-RS had occurred within 60 months of symptom onset in INAD patients. Among seven adult cases of PLAN, hypokinesia, tremor, ataxic gate, and cognitive impairment were the most frequent clinical features. Various brain imaging abnormalities were also observed in 26 imaging series of these patients with cerebellar atrophy being the most common finding in more than 50%. Twenty unique variants in 25 patients with PLAN were detected including nine novel variants. Altogether, 107 distinct disease-causing variants from 87 patient were analyzed to establish a genotype–phenotype correlation. The P value of the chi-square test did not indicate a significant relationship between age of disease onset and the distribution of reported variants on PLA2G6.ConclusionPLAN presents with a wide spectrum of clinical symptoms from infancy to adulthood. PLAN should be considered in adult patients with parkinsonism or cognition decline. Based on the current knowledge, it is not possible to foresee the age of disease onset based on the identified genotype.

Infantile neuroaxonal dystrophy caused by PLA2G6 gene mutation in a Chinese patient: A case report.

Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disorder. Phospholipase A2 group VI (PLA2G6) gene mutations have been identified in the majority of individuals with INAD. The present case report is on a Chinese female pediatric patient (age, 18 months) diagnosed with INAD with deafness. To date, only four cases of INAD with hearing loss have been reported, PLA2G6-association has not been investigated. Next-generation DNA sequencing technology was used to identify disease-associated genes and Sanger sequencing was applied to verify the mutation in the patient's pedigree. Two mutations were identified in the PLA2G6 gene: c.1T>C (E2) and c.497 (E4) to c.496 (E4): Insert C. The distribution frequency of those mutations in the Single Nucleotide Polymorphism, HapMap, 1000 Genomes and Exome Aggregation Consortium databases was 0. However, cases of INAD appear to be underreported, particularly those from China. The identification of two mutations in the present study suggests unique PLA2G6 mutations in Chinese patients, and greatly expands on the spectrum of known mutations in INAD patients.

Two unusual cases of PLA2G6-associated neurodegeneration from India.

Phospholipase A2-associated neurodegeneration (PLAN) comprises of three disorders with overlapping presentations. The most common of these is classical or infantile-onset phospholipase A2-associated neurodegeneration, also known as infantile neuroaxonal dystrophy (INAD). Only 1 case of INAD has been reported from India till now. We report two genetically confirmed patients seen at a tertiary care pediatric hospital. Both these patients presented with infantile onset of neuroregression. We believe that INAD is underrecognized and underreported from India.

Conjunctival Biopsy in Infantile Neuroaxonal Dystrophy

To describe a case of infantile neuroaxonal dystrophy with optic nerve atrophy and to discuss the diagnostic role of conjunctival biopsy. We performed a complete ophthalmologic examination and a diagnostic conjunctival biopsy on a girl with a neurodegenerative disease. On the basis of "spheroid" inclusions in the unmyelinated axons, we diagnosed infantile neuoroaxonal dystrophy. Optic atrophy is an important finding in infantile neuroaxonal dystrophy, and conjunctival biopsy is a reliable and very convenient diagnostic test.

Intermitochondrial septate structures in dystrophic axons.

Intermitochondrial septate structures were found in the dystrophic axons of two cases of infantile neuroaxonal dystrophy. Septate structures were previously seen in some tumors (glioblastomas and Schwannomas) and several organs of vertebrates and invertebrates, but never in human central nervous system (CNS). The structures were studied by transmission and transmission tilt electron microscopy. A proposed model was constructed and X-rayed. Artist's depictions are shown and described. The intermitochondrial septate structures have a periodicity of 120 A which puts them within the range of those structures previously reported. It was found that our structures are not true junctions, but a complex interdigitation of the outer membranes of the involved mitochondria.

Morphological investigations on axonal swellings and spheroids in various human diseases.

Axonal swellings and spheroids in various human diseases were studied by light and electron microscopy. 4 cases of infantile neuroaxonal dystrophy, 2 of degenerative diseases, 2 brain tumors and 3 of cerebrovascular disease were examined. Ultrastructurally most spheroids in infantile neuroaxonal dystrophy consisted of interconnected tubules, stacked membranotubular profiles, alternating layered membranes and accumulations of neurofilaments. Combinations of these four constituents were seen only in infantile neuroaxonal dystrophy. "Torpedos" (fusiform swelling of the axon of a Purkinje cell) consisted exclusively of neurofilaments. Spheroids in case 6 (mental retardation) and 7 (atypical teratoma) consisted of interwoven skeins of neurofilaments and grouped mitochondria. Spheroids in case 8 (demyelination) and 9 (cerebrovascular disease) consisted of packed complex bodies and mitochondria. Spheroids in cases 10 and 11 (cerebrovascular disease) consisted of degenerating organelles only. The morphological differences between cases 9, 10 and 11 probably depends on the severity and timing of the cerebral injury. Most spheroids show similar histological and histochemical properties, but ultrastructural study may give some clue to the origin of the bodies.

Infantile neuroaxonal dystrophy. An electron microscopic study of a case clinically resembling neuronal ceroid-lipofuscinosis.

An unusual case of infantile neuroaxonal dystrophy (INAD) in which seizures were the presenting and predominant clinical feature is described. Although the clinical manifestations were indistinguishable from neuronal ceroid-lipofuscinosis, the diagnosis was readily established by electron microscopic examination of the brain biopsy specimen. Even after the ultrastructural features were known, the dystrophic axons were not evident by light microscopy. This case broadens the clinical picture of INAD to include seizures as the presenting complaint and suggests that some patients with childhood epilepsy who "deteriorate" may have this genetically determined disease.

Infantile neuroaxonal dystrophy. Histological and electron microscopical study of two cases.

Two cases of infantile neuroaxonal dystrophy in female siblings are reported. The clinical features, with a fatal outcome within 7 years and 3 years respectively, were characterized by progressive psycho-motor retardation. The first manifestation of the disease appeared at the age of one and half years and at the age of 4 months, respectively. Light microscopy shows spheroids with a selective distribution in medulla, posterior horn of spinal cord and cerebral cortex, diffuse cerebellar cortical atrophy with sclerosis, sudanophilic fatty deposits and status dysmyelinisatus in the striatum. Electron microscopy shows tubulomembranous structures composed of usually compactly arranged smooth membranes, aggregations of mitochondria in the spheroids, filamentous inclusions simulating Hirano bodies in the spheroid and axon. Spheroids were present in nerve cell perikarya, axons, dendrites, and presynaptic terminals.

Evolution clinique de la dystrophie neuro-axonale infantile à la lumière de la chronologie des atrophies systématisées sous-jacentes

The anatomo-clinical study of 4 cases of infantile neuroaxonal dystrophy enables us: 1. (1) to describe its clinical features: the disease starts usually at the end of the first year of life after a normal early psychomotor development; severe hypotonia, arrest of mental development followed by a rapidly progressive dementia, optic atrophy, progressive appearance of hypertonia with a pyramidal syndrome, bulbar signs, sphincter disturbances, death between the ages of 4 and 10 years; 2. (2) to stress the main histological features of the disorder: presence of spheroid bodies in the grey matter with a clear-cut predominance in the sensory bulbo-spinal relay nuclei, multiple system atrophies (optic and pyramidal pathways, cerebellar cortex, posterior columns), diffuse sclerosis of the white matter, accumulation of neutral fats in the striatum and the pallidum, histiocytic proliferation in the splenic Malpighian follicles; 3. (3) to confirm, through electron microscopy, the localization of the spheroids in the axon terminals and the presynaptic endings; 4. (4) to attempt a correlation between the clinical features and the evolution of the lesions in the central nervous system.

Neuro-muscular biopsy in the diagnosis of infantile neuroaxonal dystrophy. Ultrastructural study of 3 cases 2 of them familial

The authors report the ultrastructure of neuromuscular biopsies in three cases of infantile neuro-axonal dystrophy. The presence of spheroids in peripheral and intramuscular nerves, but also in the motor end plates allows the diagnostic of this disease, without doing cerebral biopsy.

Infantile neuroaxonal dystrophy.

Four cases of infantile neuroaxonal dystrophy (a familial progressive disorder of the central nervous system) are presented with clinical and pathological findings. The clinical picture is characterized by a fairly normal development of the children up to about one year of age when a standstill and regression of motor and psychic development became apparent. Some children develop a marked generalized hypotonia, others a spasticity. Optic nerve atrophy is usually another early clinical sign. Pathologically a marked cerebellar atrophy and the occurrence of so-called ''speroid bodies'' are characteristic; the latter are signs of neuroaxonal degeneration. One of the patients presented here showed extrapyramidal signs which so far have not been seen in infantile neuroaxonal dystrophy.