Primary carnitine transporter deficiency
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Infantile neuroaxonal dystrophy, also as known as Seitelbelger disease, is a rare autosomal recessive neurodegenerative disorder that usually presents before 3 years of age with psychomotor regression. Clinical features include early truncal hypotonia followed by spastic quadriparesis, strabismus, nystagmus, and cerebellar ataxia. Severe muscle weakness can lead to bulbar dysfunction and difficulties in breathing and feeding. Seizures may occur in a minority. Genetic testing is the key element for the diagnosis and disease classification. Nearly 80% of affected children have mutations in the PLA2G6 gene on chromosome 22q13.1. The disease has a rapid progressive course leading to severe spasticity, cognitive decline, and visual impairment. Many affected children do not survive beyond their first decade.
(1) Infantile neuroaxonal dystrophy is a rare autosomal recessive neurodegenerative disorder with disease onset in the first 3 years of life. Atypical neuroaxonal dystrophy may start in early childhood.
(2) Clinical features include early psychomotor regression or delay, truncal hypotonia, progressive cognitive decline, and severe quadriparesis. Strabismus, optic neuritis, and nystagmus are also common.
(3) The disease has a rapid progression, culminating in death by 10 years of age. Progression is slower in atypical neuroaxonal dystrophy.
(4) Mutations in the PLA2G6 gene have been identified in most individuals with infantile neuroaxonal dystrophy. Demonstration of the PLA2G6 mutation may confirm the diagnosis in the setting of appropriate clinical features.
(5) Treatment is symptomatic and supportive. A multidisciplinary approach is recommended to increase quality of life.
(6) Physicians should be aware of this condition while evaluating a patient with neurodevelopmental regression.
Neuroaxonal dystrophy refers to a group of degenerative disorders that share the same pathologic axonal spheroids throughout the central nervous system. Infantile neuroaxonal dystrophy is a subgroup of neuroaxonal dystrophy that include axonal swellings in CNS and peripheral nerves. Spheroids can also be found in pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome), idiopathic neurodegeneration with brain iron accumulation and Schindler type (08).
The discovery of PLA2G6 gene mutations have expanded the classification, and it was found that 78% of patients with infantile neuroaxonal dystrophy have mutations in the PLA2G6 gene with a locus on chromosome 22q13.1 (17). Mutations in the PLA2G6 gene have also been detected in patients with idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. Now it appears that “PLA2G6-associated neurodegeneration (PLAN)” stands for a functional classification of mutation-positive patients to reflect the shared molecular etiology of the diseases, and it comprises a continuum of the phenotypes with overlapping clinical and radiological features: infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and PLA2G6-related dystonia-parkinsonism. Infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation have very similar clinical phenotypes with widespread neurodegeneration that begins within the first 2 years of life. Brain iron accumulation can be seen in patients with infantile neuroaxonal dystrophy. Some individuals develop high levels of iron accumulation in the globus pallidus. PLA2G6-related dystonia-parkinsonism can present with bradykinetic movement disorder beginning at 15 to 30 years of age (05) and have a different phenotype than infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation (07). Enhanced molecular diagnostic methodologies such as whole exome sequencing, and targeted gene panel testing lead to continued identification of PLA2G6 mutations expanding the clinical spectrum. Wang and colleagues described a neuroaxonal dystrophy case with hearing impairment in 2018 (24). Tan and colleagues and Li and colleagues described new pathogenic heterozygous variations of PLA2G6 gene (09; 18).
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