Inherited Metabolic Disorders Presenting with Ataxia

Abstract

Ataxia is a common clinical feature in inherited metabolic disorders. There are more than 150 inherited metabolic disorders in patients presenting with ataxia in addition to global developmental delay, encephalopathy episodes, a history of developmental regression, coarse facial features, seizures, and other types of movement disorders. Seizures and a history of developmental regression especially are important clinical denominators to consider an underlying inherited metabolic disorder in a patient with ataxia. Some of the inherited metabolic disorders have disease specific treatments to improve outcomes or prevent early death. Early diagnosis and treatment affect positive neurodevelopmental outcomes, so it is important to think of inherited metabolic disorders in the differential diagnosis of ataxia.

Developmental neurobiology of cerebellar and Basal Ganglia connections

“…The underlying biological pathways linked to EOA-dystonia including cellular energy production and signal transduction are thus associated with metabolic processes including Krebs (TCA) cycle and fatty acid-lipid-metabolic processes 7 . Clinically, inherited metabolic disorders are frequently linked with cerebellar pathology and/or ataxia 47 . The TCA cycle is crucial for mitochondrial ATP production, fulfilling the high-energy demands of the cerebellum, cortical areas and basal ganglia.…”

“…If we consider EOA from a metabolic perspective, there are about 150 inherited metabolic disorders that are listed with mixed EOA phenotypes 52 , including dystonia, chorea and/or athetosis, hypokinetic-rigid syndrome, tremor, and myoclonus 8,53 . Despite the heterogeneity in underlying metabolic gene defects 47 , the vast majority (>95%) of these genotypes are described as a mixed EOA phenotypes including comorbid dystonia. Although we have identified Krebs-cycle and fatty acid/lipidmetabolic processes as the most statistically significant common metabolic pathways underling EOAdystonia, other metabolic processes may thus cause a variety of mixed EOA phenotypes including comorbid dystonia, as well.…”

Clinical Reasoning: A 28-Year-Old Woman With Vision Loss and an Unusual Gait

“…67 Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by brain iron accumulation (with an "eye of the tiger" sign on imaging), leading to movement disorders and a pigmentary retinopathy. 7 Refsum disease is a disorder of peroxisomal function that results in retinitis pigmentosa, cerebellar ataxia, and polyneuropathy. Importantly, unlike other peroxisomal disorders, this is a treatable disorder that is responsive to restriction of phytanic acid intake.…”

“…[15][16][17] Other, less common neurogenetic ataxias manifesting with retinal degeneration include infantile cerebellar-retinal degeneration but in contrast to our patient, tends to be present from birth. 7 Optic atrophy is also a core feature of the cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome, which is caused by ATP1A3 mutations and can overlap with other ATP1A3-related disorders. 18 Our patient demonstrated decreased cone and rod photoreceptor function on ERG, consistent with a cone-rod dystrophy.…”

Neuroimaging in cerebellar ataxia in childhood: A review

“…In this review, we will focus on the most common form of ataxia in childhood, cerebellar ataxia (CA), and its neuroimaging findings on MRI. CA in childhood may be caused by a wide number of acquired or hereditary diseases 1–10 . The goal of this review is to discuss and summarize the neuroimaging findings of the most common or most important causes of CA in childhood and present causes of pediatric CA with specific findings on MRI.…”