Inherited Metabolic Diseases in Neurodevelopmental and Neurobehavioral Disorders

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In the past few years, there has been a veritable explosion in the discovery of “new” inborn errors of metabolism. These new conditions are involved in complex pathways of intermediary metabolism affecting processes heretofore unknown. The phenotypes of these new conditions are in many ways milder than the classically described metabolic disorders. Several of these conditions present as nonsyndromic neurodevelopmental and/or neurobehavioral disorders. As such, these conditions should be considered in the differential diagnosis of conditions such as mental retardation, autism spectrum disorders, movement disorders, and cerebral palsy. This article reviews several of these recently described conditions including the clinical presentation, the biochemical profile, the diagnostic approach, and therapeutic options.

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Guanidinoacetate Methyltransferase Deficiency

Guanidinoacetate methyltransferase (GAMT) deficiency (Online Mendelian Inheritance in Man [OMIM] + 601240) is an autosomal recessive inborn error of creatine biosynthesis. GAMT deficiency is characterized by developmental arrest or delay in the first few months of life with epilepsy and extrapyramidal movements as common features.1 Neurologic signs and symptoms are variable, and autistic spectrum disorders are sometimes seen in older affected individuals. The diagnosis of GAMT deficiency is

Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency (OMIM #271980), also known as 4-hydroxybutyric aciduria (4-HBA), is an autosomal recessive inborn error of metabolism first described by Jakobs et al in 1981.14 Since then, over 150 cases have been identified. Clinical features include mild to severe impairment of motor skills, language, speech, and intellect. Many affected individuals also presented with hypotonia and a nonprogressive form of truncal and appendicular ataxia. The causative

Adenylosuccinate Lyase Deficiency

Adenylosuccinate lyase (ADSL) deficiency (OMIM #103050) is an autosomal recessive disorder of purine metabolism. Characteristic neurologic features include psychomotor delay, autism, and seizures.19 The associated gene is adenylosuccinate lyase (ADSL). This enzyme deficiency is characterized by increased amounts of succinyl adenosine (S-Ado) and succinyl aminoimidazole carboxamide ribotide (SAICAR) in CSF, urine, and to a lesser extent plasma. Treatment has been aimed at replenishing purine

Phosphoribosylpyrophosphate Synthetase Superactivity

Phosphoribosylpyrophosphate synthetase (PRPS1) superactivity (OMIM #300661) is an X-linked inborn error of purine metabolism with features of gout and hyperuricemia. Some individuals affected with PRPS1 superactivity also have neurodevelopmental abnormalities, including sensorineural deafness. The associated gene is phosphoribosylpyrophosphate synthetase (PRPS1). PRPS1 superactivity should be suspected in individuals with hyperuricemia, gout, mental retardation, and sensorineural deafness.

PRPS1

Dihydropyrimidine Dehydrogenase Deficiency

Dihydropyrimidine dehydrogenase (DPYS) deficiency (OMIM + 274270) is an autosomal recessive disorder of pyrimidine catabolism known also as uraciluria thyminuria. DPYS deficiency is also known as an inborn error of β-amino acid metabolism. Excess amounts of uracil, thymine, and 5-hydroxymethyluracil accumulate in the urine of affected individuals. The causative gene is dihydropyrimidine dehydrogenase (DPYS) located on chromosome 1 at 1p22. There is much phenotypic variation with DPYS

Glucose Transport Defect, Blood-Brain Barrier

Glucose transport defect of the blood-brain barrier (GLUT1 deficiency syndrome, OMIM #606777) is an autosomal dominant inborn error of glucose transport across the blood-brain barrier. Affected individuals present with mental retardation and learning disabilities; also common are ataxia, dystonia, seizures, and acquired microcephaly. The responsible gene is solute carrier member 2, family 1 (SLC2A1) located on chromosome 1 at 1p35 to 31.3. SLC2A1 encodes a facilitated glucose transporter

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