Clinico-radiological phenotyping and diagnostic pathways in childhood neurometabolic disorders—a practical introductory guide

Abstract

Inborn errors of metabolism (IEM) although individually rare, together constitute a significant proportion of childhood neurological disorders. Majority of these disorders occur due to deficiency of an enzyme in a specific metabolic pathway, leading to damage by accumulation of a toxic substrate or deficiency of an essential metabolite. Early diagnosis is crucial in many of these conditions to prevent or minimise brain damage. Whilst many of the neuroimaging features are nonspecific, certain disorders demonstrate specific patterns due to selective vulnerability of different structures to different insults. Along with clinical and biochemical profile, neuroimaging thus plays a pivotal role in differentiating metabolic disorders from other causes, in providing a differential diagnosis or suggesting a metabolic pathway derangement, and on occasion also helps make a specific diagnosis. This allows initiation of targeted metabolic and genetic work up and treatment. Familiarity with the clinical features, relevant biochemical features and neuroimaging findings of common metabolic disorders to facilitate a prompt diagnosis cannot thus be overemphasized. In this article, we describe the latest classification scheme, the clinical and biochemical clues and common radiological patterns. The diagnostic algorithm followed in daily practice after clinico-radiological phenotyping is alluded to and illustrated by clinical vignettes. Focused sections on neonatal metabolic disorders and mitochondrial disorders are also provided. The purpose of this article is to provide a brief overview and serve as a practical primer to clinical and radiological phenotypes and diagnostic aspects of IEM.

Clinicoradiologic Correlation in 22 Egyptian Children With Megalencephalic Leukoencephalopathy With Subcortical Cysts

“…Moreover, cystic cavitation may occur in methylmalonic acidemia and Leigh syndrome, and temporal cysts have been described in galactosemia, but these disorders usually show characteristic biochemical abnormalities. 36,40 However, genetic analysis would be important in future studies to determine whether the genotype affects clinicoradiologic association in patients with MLC.…”

“…These disorders depart from MLC by their distinctive clinical, biochemical, and neuroimaging features, such as more rapid and severe course (eg, Canavan and infantile Alexander diseases), prominent weakness and hypotonia (eg, merosin-deficient congenital muscular atrophy), diagnostic biochemical abnormalities (eg, GA-1), specific distribution of cerebral white matter changes (eg, frontal predominance in Alexander disease and periventricular in GA-1), basal ganglia/brain stem affection (thalamus and globus pallidus in Canavan disease; thalamus and basal ganglia in Alexander and gangliosidosis; striatum and dentate in GA-1 and L2-hydroxyglutaric aciduria), contrast enhancement of certain brain structures (eg, periventricular area, basal ganglia, and brain stem in Alexander disease), characteristic findings in magnetic resonance spectroscopy (eg, a high peak of N-acetyl aspartate in Canavan diseases), but no typical subcortical cysts of MLC. 4,5,[32][33][34][35][36][37][38][39] Anterior temporal subcortical cysts are found in other leukodystrophies, such as Aicardi-Goutieres syndrome and cystic leukoencephalopathy without megalocephaly, but both disorders had no macrocephaly. 22,36 Cysts are seen at different distributions in other leukodystrophies, such as periventricular and deep white matter cysts in Lowe syndrome; corpus callosal "cysts" in mucopolysaccharidosis; subependymal cysts in peroxisomal disorders, D-2 hydroxyglutaric aciduria, and pyruvate dehydrogenase E 1-alpha deficiency; and supra-and infratentorial cysts in leukoencephalopathy with calcifications and cysts and Coats-plus syndrome.…”

“…4,5,[32][33][34][35][36][37][38][39] Anterior temporal subcortical cysts are found in other leukodystrophies, such as Aicardi-Goutieres syndrome and cystic leukoencephalopathy without megalocephaly, but both disorders had no macrocephaly. 22,36 Cysts are seen at different distributions in other leukodystrophies, such as periventricular and deep white matter cysts in Lowe syndrome; corpus callosal "cysts" in mucopolysaccharidosis; subependymal cysts in peroxisomal disorders, D-2 hydroxyglutaric aciduria, and pyruvate dehydrogenase E 1-alpha deficiency; and supra-and infratentorial cysts in leukoencephalopathy with calcifications and cysts and Coats-plus syndrome. Moreover, cystic cavitation may occur in methylmalonic acidemia and Leigh syndrome, and temporal cysts have been described in galactosemia, but these disorders usually show characteristic biochemical abnormalities.…”

Doenças neurometabólicas hereditárias e a importância das classificações baseadas em achados de imagem

“…As doenças neurometabólicas hereditárias (DNMHs) representam um heterogêneo grupo de doenças que englobam os chamados erros inatos do metabolismo, as leucodistrofias, as mitocondriopatias, as doenças de depósito, entre outras (1) . São doenças individualmente raras, mas que em seu conjunto representam uma proporção significativa das doenças neurológicas em crianças (1,2) . Os achados clínicos e de imagem podem ser inespecíficos e se sobreporem, tornando o diagnóstico ainda mais desafiador.…”

“…Os achados clínicos e de imagem podem ser inespecíficos e se sobreporem, tornando o diagnóstico ainda mais desafiador. Todavia, como algumas DNMHs apresentam possibilidades terapêuticas, o diagnóstico precoce é imprescindível, a fim de prevenir ou minimizar o dano neurológico (1) . Portanto, o reconhecimento de alguns achados de imagem que possam estreitar o diferencial é essencial na prática da neurorradiologia.…”