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Understanding the inherited neurodegenerative diseases of childhood has evolved dramatically in the past 40 years. Fundamental discoveries in biochemistry uncovered the metabolic basis for many of these diseases. The subsequent identification of variant forms created additional challenges for the clinician. These variant forms share similar, if not identical, biochemical defects, but exhibit widely differing clinical expressions. Recent progress followed the rapid development and application of molecular-genetic strategies and the close linkage between clinical observations and basic science advances. The successes of molecular genetics have provided significant clarifications, but have also generated further examples of the marked heterogeneity within these disorders. These advances explain how disorders with clearly different phenotypic expression can result from different mutations within the same gene and, conversely, how disorders with similar clinical features result from mutations in different genes. Examples of the former include GM2-gangliosidosis variants and examples of the latter include the neuronal ceroid lipofuscinoses. Thus, at the clinical, biochemical, and molecular level, the clinician is faced with an increasingly complex knowledge base, the unraveling of which may present major diagnostic hurdles.

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Inherited neurodegenerative diseases represent a significant proportion of referrals to tertiary care centers, especially those specializing in the care of children. For all inherited neurometabolic diseases as a group, the overall incidence is about 1 in 3700 births, and for those neurodegenerative disorders considered here, incidence may approach 1 in 5000 births. Technological advancements have in no way diminished the need for careful characterization of the clinical phenotype. Rather, enhanced diagnostic capabilities raise important public health policy issues including development of the necessary infrastructure to monitor outcome of diagnosis and treatment and to analyze the overall impact on society.

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Regardless of the biochemical and molecular mechanisms, common patterns of disease expression emerge according to age at onset. Disorders presenting in infancy and early childhood are characterized by delayed development or loss of acquired developmental milestones that follows a period of delay or plateau in development. Onset in school-aged children or adolescents is characterized by declining school performance and behavioral or personality changes. In adulthood, faltering personal or work habits suggest declining cognitive abilities, movement disorder, or gait difficulties. As such, clinical assessment should include historical information regarding changes in development or behavior, evidence of cognitive difficulties, and altered motor control and a careful family history including consanguinity, previous deaths in childhood or adolescence, early-onset dementia, or a diagnosis of progressive cerebral palsy. Progressive neurological manifestations fall outside the established pathogenesis for cerebral palsy. A thorough clinical examination should incorporate assessment for dysmorphic features, hepatosplenomegaly, or skeletal deformities, and careful neurological and ophthalmologic evaluations, the latter for abnormalities of voluntary eye movement, corneal clouding, lens opacities, and retinal abnormalities such as retinitis pigmentosa, macular degeneration, cherry-red spot maculae, and optic atrophy.

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Neurodegenerative disease may be explained by a number of processes that should be excluded including other metabolic conditions such as diabetes mellitus or porphyria, toxic encephalopathies (heavy metal poisoning, antiepileptic or ...

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